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

welcome to the huberman Lab podcast where we discuss science and science-based tools for everyday [Music] life I'm Andrew huberman and I'm a professor of neurobiology and Opthalmology at Stanford school of medicine today my guest is Dr Robert malenka Dr Robert malenka is a professor of Psychiatry and Behavioral Sciences at Stanford University School of Medicine he is both a medical doctor in MD and a researcher a PhD his laboratory is famous for having discovered some of the key components allowing neuroplasticity that is the nervous system's ability to change in response to experience in addition Dr malena's research is considered Central to the textbook knowledge about how reward systems in the brain are organized and function indeed Dr malena's research over the last 10 or 15 years has merged what was once two disparate Fields the first being the study of neuroplasticity again the nervous system's ability to change in response to experience and the other field being the field of dopamine as it relates to pleasure and addiction his laboratory has shown for instance that when we seek out particular forms of pleasure regardless of whether or not they are healthy for us that changes the way that our reward circuitry works and actually changes the way that dopamine is released and how it impacts the brain and his work has also informed how we seek out healthy Pleasures including healthy food and social connection today's discussion explores all of these topics and by the end of today's disc discussion you will have a rich understanding of how neurochemicals like dopamine and serotonin work in parallel to reinforce that is to increase the probability that we will engage in certain types of thinking and behaviors so if you are somebody interested in neuroplasticity that is how the nervous system can change in response to experience Andor you are interested in reward systems what motivates us and what we are likely to pursue in the future given our choices of past and if you are interested in things like social connection and empathy or lack thereof today's discussion encompasses all of those topics it is worth mentioning that Dr Melena is a true luminary in all of the fields I just mentioned as well as several other fields in fact when you look out on the landscape of modern Neuroscience what you'll discover is that a very large percentage of the top Laboratories studying neuroplasticity and reward systems and so on all stemmed from having trained in Dr mra's laboratory so it's a real honor and pleasure to be able to host him today and I'm sure that our discussion is going to greatly enrich the way that you think about brain function neuroplasticity and reward before we begin I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford it is however part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme I'd like to thank the sponsors of today's podcast our first sponsor is Roka Roka makes eyeglasses and sunglasses that are of the absolute highest quality the company was founded by two All-American swimmers from Stanford and everything about Roa eyeglasses and sunglasses were designed with performance in mind I've spent a lifetime working on the biology of the visual system and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly Roa understands those challenges and the biology the visual system such that they've designed sunglasses and Eyeglasses that always allow you to see with Crystal clarity now initially Roa eyeglasses and sunglasses were designed for sports performance and as a consequence all of their glasses are designed to be very lightweight and to not slip off your face if you get sweaty however the design of the glasses includes some that are specifically for sport and others whose aesthetic really allows you to use them for sport as well as out to dinner or to work etc and that's how I use them if you'd like to try Roa eyeglasses and sunglasses you can go to roka.com that's r.com and enter the code huberman to save 20% off your first order again that's Roa r.com and enter the code huberman at checkout today's episode is also brought To Us by levels levels is a program that lets you see how different foods and behaviors affect your health by giving you realtime feedback on your diet using a continuous glucose monitor one of the most important factors impacting your immediate and long-term health is the way that your body manages its blood glucose or sometimes referred to as blood sugar levels to maintain energy and focus throughout the day you want to keep your blood glucose steady without big spikes or dips using levels you can monitor how different types of foods and different food combinations as well as food timing and things like exercise combined to impact your blood glucose levels I started using levels a little over a year ago and it gave me a lot of insight into how specific Foods were spiking my blood sugar and then leaving me feeling tired for several hours afterwards as well as how the spacing of exercise and my meals was impacting my overall energy and in doing so it really allowed me to optimize how I eat what I eat when I exercise and so on such that my blood glucose levels and energy levels are stable throughout the day if you're interested in learning more about levels and trying a continuous glucose monitor yourself go to levels. link huberman right now levels is offering an additional two free months of membership again that's levels. link l nk/ huberman to get two free months of membership and now for my discussion with Dr Robert malanka Dr malanka Rob welcome yeah thanks for having me delighted to have you here both for sake of your medical knowledge training as a psychiatrist and of course as a luminary in the field of neuroplasticity dopamine and reward systems social systems your knowledge of autism and social interactions a newer interest in or perhaps old interest in psychedelics and what they're doing and potential for mental health there are just so many things that you've done in this field I've been a long long time fan of your work since your days as an assistant professor I've tracked your career I've learned a tremendous amount from you by observing you and from being your colleague so really delighted to have you here you're making me blush and I don't blush easily well it's it's it's all true and I and I will say as well you've also trained an enormous number of incredible scientists um Carl daiser off the Carl daer off um an a lmy always speaks incredibly highly of you as a mentor and I'm somebody she's learned a tremendous amount from and pretty much anyone that's worked on neuroplasticity on dopamine and reward systems addiction and now in the fields of autism and soon psychedelics as well references as you often and you've been mentioned many times before on this podcast if not by name by work so again thank you for being here I'd love to kick off the conversation 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 you know we hear so much about dopamine people talk about dopamine hits people think about dopamine as pleasure dopamine reward for the novice how how would you frame the dopamine system I mean it does a bunch of different things in different areas of the brain and body but to you what what does dopamine represent as its major function in the brain and could you give us a kind of General Contour of the neural circuits that allow this chemical to more or less um put value on our experiences yeah that's very well put um as you point out dopamine is one of the major what we term neuromodulators in the brain a chemical signaling messenger that the brain uses to mediate a complex array of actions um it's 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 communicat with another part of the brain because the brain is this very complex you know it's the most complex organism organ in the universe um with lots of different nerve cells talking to each other simultaneously and as neuroscientists we try to parse what different brain areas are doing and what different neuromodulators might be doing and dopamine was discovered oh I should know this many decades ago um and it's it's as I said the major chemical messenger molecule in the so-called brains reward circuitry and when you're talking about so what is the brains reward circuitry this is a part of the brain that tells us something is reinforcing in our environment some stimuli or in quotes is rewarding makes us feel better or good although that's a gross oversimplification and and before getting into the details of dopamine and its function in the reward circuitry I think it's useful to talk about wh why do we need a reward circuitry why do we need something in our brain that tells us this feels good or this feels bad and it goes back to Evolution I I am a biological scientist that means I believe in evolution um and if you think about the evolution of our species um everything is driven by developing mechanisms that increase our survival and it's really useful you need something in your nervous system that tells you some stimuli in your environment is important for your survival or some stimulus in your environment is dangerous so it's not magic that um sugary high-fat Laden foods are highly reinforcing and rewarding rewarding it's not an accident there has to be a mechanism in the brain that tells us that it's not an accident that most of the time for most of us a sexual experience is pretty reinforcing is pretty rewarding it's not an accident that warmth feels really good when you're cold that water tastes much better when you're really thirsty there have 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 Lon was and we can get into that so this was a long rued way of saying what the reward circuitry tells us is this event this stimulus it could be an external stimulus like I said you know a crispy cream doughnut which I happen to love and I have to be very disciplined so I don't eat too many of them um it um it could be a drug of abuse and maybe we'll talk about that a little bit all of these stimuli seem to activate and cause the release of dopamine in this brains reward circuitry so now we need to get into a little bit of detail um neuroscientists 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 um are in a part of the brain sort of what we call the lower midbrain um the dopamine neurons sort are part of the reward circuitry are 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 I think uh the roof of the midbrain is the tectum it means roof and the base of the midbrain it means floor which is tegmentum 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 are absolutely correct and I always forget that so thank you for pointing that out it's a it's a it's a side effect of teaching neuro anatomy and then uh which I once did back in the early 80s but I've forgotten everything I taught okay um anyhow so these dopamine neurons and we can talk about other types of dopamine neurons they send messages what we call projections um using Telegraph wires that we call axons they send projections to many different brain regions the key one in the brains reward circuitry being an area again with a very complicated name called the nucleus succumbent and maybe Andrew you know I actually don't know how that name evolved the nucleus accumbent and I'm sure I should know because I've been studying it for 30 years but I have never looked up the uh Genesis of that name well the fortunate thing about this podcast is it's both on audio platforms like Spotify and apple but also on YouTube and so now we can be absolutely sure that somebody has put it into the YouTube comments underneath this episode and therefore everyone will learn including us so I don't know the origins of the word nucleus and it it's it's a gross oversimplification but it's the activity of these dopamine neurons in the ventral tegmental area um that then cause the release of this powerful neuromodulated neuromodulator dopamine in the nucleus succumbent which has a is part of another brain structure with a tough to remember name called the ventral striatum um and then magic happens and when I say magic happens even though we've been studying how dopamine modifies the properties of cells in this nucleus cumbent 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 here the simple way would be to say as highly rewarding but it's a little more complicated than that what what it tells us is that there's something really important happening in our environment um so did could we say that it cues the arousal system it it it it gets the arousal system going there's close ties to our memory systems which hopefully intuitively makes some sense if something really important is happening in your environment because again we 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 CR I I I like all doughnuts so I don't want to emphasize any one manufacturer of one doughnut versus the other I I like sugar Laden fat Laden Foods that's why I never eat them because I like them so much and I use that as an example but because that was an important event for my survival this reward circuitry yes it stimulates my arousal system it gets me to pay attention um it also has very close ties to memory systems um and to to go off on a little bit of a tangent I think the one um I don't want to say it's a mistake I think perhaps somewhat oversimplification of how people conceptualize dopamine's role in the brain is even though it's a major important role is for it to be active and released during highly reinforcing experiences like sex like really good food like drugs of abuse it also can get activated subdivisions of the system during painful stimuli and during aversive stimuli um which again are really important for you to be aware of to say oh my God that's really bad for me um and so the dopamine system this reward circuitry and its subcomponents that maybe perhaps signal more salience or a aversion in the environment are closely tied to arousal systems and memory systems um again hopefully for somewhat obvious reasons you want to remember powerfully reinforcing events in your life as well as powerfully emotionally or physically painful events in your life so I hope I answered um your question to a modest degree no um far better than a modest agree that that's an excellent description of the dopamine system from a true expert um and the question I have is about some of the context and Nuance of the system but in in sort of real world terms how 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 they can be active over long periods of time or short periods of time but let's use the example of the donut I'm I'm I like a glazed oldfashioned donut I actually don't have a craving for sweet things but Donuts is is is an exception I like the glaze old fashioned donut but if I were to see just a little piece of a glazed oldfashioned donnut versus a full glazed oldfashioned doughnut could I expect that more dopamine is released to the anticipation of the complete doughnut and then the other question is how does context influence the dopamine system for instance if I'm very full yep a glazed oldfashioned doughnut might be aversive to me yeah um whereas if I'm just a little bit hungry um or if I'm actually more uh on a schedule of rewarding myself for abstaining from sweet fatty foods then abstaining from the food might be its own form of reward yeah 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 contingen gencies we want to um you know have good health metrics and maybe have a certain aesthetic qualities to our body but we also want the donut and so how does a simp a system as simple as a one neuromodulator system and the VTA to nucleus accumbent 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 um I I think you beautifully put be very very eloquent description um you just said it it's staggeringly simple simultaneously staggeringly complex and you you ask several different questions so context makes an enormous importance and that's one of the reasons I became interested in the dopamine reward circuitry is as you know as a colleague in the academic Neuroscience world but your listeners probably don't I started out my career studying very basic me mechanisms of plasticity how does the brain modify itself and what makes the brain different than compu the comp computer hardware is are the physical Connections in the brain are constantly changing the strength of the communication similarly for the dopamine reward circuitry it's highly plastic and it's highly contextually dependent um and so you gave the example of donuts and feeding and I'll answer your question about the cues um yes it's I I used to give the example of Thanksgiving so let me give that example you know in the morning of Thanksgiving all for most of us in in the United States um the morning of Thanksgiving if you're at home visiting your parents the smells of the apple pie the smells of the turkey cooking are highly repetitive highly reinforcing you're anticipating that fun event you're anticipating Uncle Joe coming to visit you for Thanksgiving and that's all because these cues the smells the anticipation of Uncle Joe's your previous experiences are part are part of your memory system sort of talking to in a simple way your reward circuitry so you're building up this anticipation one can almost say this craving which maybe we'll talk about in the context of addiction and then make a long story short think about that evening at the end of Thanksgiving those exact same cues the exact same smell of the apple pie turkey and Uncle Joe himself at the very least they're no longer repetitive meaning they might actually be aversive the last thing you want is a piece of apple pie you can't wait for Uncle Joe to leave your Thanksgiving dinner and I always argue that does not happen magically that happens because your brain has been modified by the context in which it sits and this very important modulatory system this reward circuitry is responding to the exact same stimuli with a very different response so that I'm just telling you I'm repeating what you said the phenomenology and and again my other favorite example is any of us who have been in an intimate relationship knows that the the love of your life can turn to the vein of your existence in 20 seconds um and again that doesn't happen magically this person who you crave who you love does something and two minutes later your brain is saying oh my God I you know I may have to break up with this person or this is an incredibly painful exper emotional experience and what fascinates me about the brain is how does the brain mediate that rapid change so now back to so yes context makes is everything about how this powerful neuromodulatory system that uses dopamine works and the truth is we don't know it's because the inputs onto these dopamine neurons the other nerve cells that are driving the activity of the dopamine neurons and I I've actually studied this in my lab at Stanford University with a colleague you know well leean Lao who's a you know a worldclass neuroscientist um we've 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 visual areas from somata sensory areas um and I'm not giving you a really good answer because that's one of the goals of my research to try to understand how cont text how the history that you've had with these cues which we're going to get back to of the donut or of a drug how has that modified how this neuromodulatory system responds um similarly the the nucleus accumbent the the target of this powerful modulator dopamine is receiving Communications what we call inputs from all sorts of brain regions that you know about Andrew your audience may not they it receives inputs from an area called the hippocampus which you may have covered in previous podcasts which is very powerfully very important for memories both establishing new memories and again remember that makes sense you want this system this dopamine reward circuitry to be very connected to memory systems so the the nucleus succumbent the activity in the nucleus succumb is modulated by dopamine while it is receiving information from the hippocampus which helps incode new memories while it's receiving information from a brain area called the amydala which tells is a part of the brain involved in our emotional experiences the accumbens also receives inputs from the prefrontal cortex which is this brain area as you know know better than me Andrew um is important for decision making for planning our activity and I could go on and on well could we talk about prefrontal cortex for a moment um because um it always was surprising to me that prefrontal cortex is talked about as this higher executive function area but then when you look at the neuroanatomy it's as we say monos synaptically as and I know one connection um away from structures like the amydala one connection away from structures like the the nucleus secum in other words prefrontal cortex to me is every bit as ancient um as some of these other structures that we think of as more ancient and really the whole ancient evolv 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 it seems to know um okay we're recording a podcast now and there are certain rules there are certain things we're going to do and not do um but what's fascinating about the and I'm so glad you gave a bunch of different examples because what's fascinating for instance about the uh the relationship example is that yes at one moment um we can adore somebody and another moment later if they do something or don't do something we can be incredibly frustrated with them they can even become aversive to us um hopefully that doesn't happen too frequently hopefully but um 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 um the prefrontal cortex is uniquely positioned to really say okay right now we are in a mode of for lack of a better word love and loving like be in the in the verb tense of loving be in the verb tense of arguing we're now arguing you know we're in the verb tense of of of reconciliation you know kind of somewhere in between or something of that sort and how a structure in a circuit as simple as the dopamine system right one molecule could suddenly say oh you know what now getting over my anger is rewarding whereas 5 minutes ago being right and being the most angry was rewarding and then 5 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 saying whatever you do I'm just delighted by it incredible like to me I can't think of a more interesting system in Neuroscience well I mean that was eloquently put um 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 on the one hand you have done a mar you know fantastic job over the last few years in your podcast of making complex um subjects accessible to a lay audience um 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 academic neuroscientists ourselves we 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 um it's Modified by these prefrontal um inputs which are simultaneously telling our memory systems you know pay attention here um I'm repeating what you just said the context makes a big difference the history you have with the person or stimuli with whom you're interacting like to bring this back to your you know which I never the initial question is a small piece of a donut activate the queue that that small piece of a donut activate the reward circuitry and cause release of dopamine to the same extent as the full doughnut depends on your experience with duts I mean I think for you and me because we seem to both have you know like donuts they're highly repetitive for us um probably doesn't matter because we have learned even a little piece of a doughnut activates all of our memory system saying man that's an oldfashioned glazed doughnut I want to eat that I want to get one or I want to have the discipline not to eat it um so I hope I'm answering your question and I'm 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 a ton of important work in this area of addiction I mean one of the basic questions I have about addiction is you know we hear that certain drugs are more addicting than other drugs or certain behaviors we also hear that we can become addicted to anything when Anna lmy was on this podcast um I said what's the most um unusual addiction you've ever seen and she talked about a patient um who sadly um committed suicide at some point later that uh she told us had been addicted to water to drinking of any kind first alcohol but then water eventually um and so so my question about addiction in the dopamine system is you know for let's pick a drug um Like Cocaine mhm um I've never done cocaine um but people who have done cocaine tell me that it feels very good um and one of the more Salient features of the cocaine high is that it comes on very fast and it ends pretty quickly too is the rate of dopamine increase related to The Addictive property uh of a drug or behavior um as much as how much dopamine is released and that's a very sophisticated question and the answer is yes and that's usually the uh the lecture I give the way I think about addiction um and obviously my friend and colleague Anna lmy 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 neuroscientists trying to understand how addictive substances modify reward circuitry modify the connections in the reward circuitry modify how dopamine neurons Act and the way I you like any what appears to be a simple term it's layered with complexity um addiction is somewhat of a Continuum and I like to think about whether you're talking about substances like cocaine and I will explicitly answer your question soon or opioids as we as you know we're going in this country there is an opioid epidemic um I I I do like to think about addictive liability and it is in my view it is pretty clear that when we're talking about drugs they have different degrees of addictive liability I mean I had a cup of coffee this morning and I and many of us listening to this podcast it's really hard to start our day without getting that hit of C 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 um so I would say caffeine causes tolerance but I would not say it has a particularly High addictive liability um whereas drugs like psychos stimulants Like Cocaine um have a very or opioids have a very high addictive liability so to answer your mechanistic question there have been some famous studies done um by the director of the National Institute on drug abuse nor vof um 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 dopam doine how much dopamine is released in the cumbin and the kinetics of the dopamine release as you said how rapidly it's released to get a little technical even with a drug like cocaine or opioids it's not only the drug itself it's the root of administration because the root 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 free based cocaine and cocaine does have like methampetamine a very high addictive liability I teach the neurobi I I give lectures to students at Stanford about neurobiology of addiction as part of a team course team taught course I have kids um who I had to deal with and what you know what I always say is you know you it's not that if you use this drug you're automatically going to become an addict um but you're taking that risk and it is impossible to become addicted to a substance if you've never used it by definition but back to the root of administration so I I went off that's actually interesting statement um you know because I think we may have heard that in high school although I um to be honest wasn't the most attentive high school student and I regret that high school students pay attention Okay for eventually I came around but but there was an uphill battle there um but you that you can't become addicted to something that you've never done which um I just want to earmark that because I think it's a profound statement because it points to the importance of the memory system but also plasticity and so I I want to make sure that eventually we get around to talking about how um the amount of dopamine released in the kinetics how that might influ inuence plasticity basically what I'm asking here 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 behavior or when we are under the influence of a drug or whether or not it actually modifies neural circuitry in a way that um makes a broader range of uh drugs or experiences attractive to us it's probably the latter but so let me get back and I will answer that in a second to the point I was making so it's not only the substance it's the root of administration so and you know as I said you can't develop a problem with a substance and develop 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 um epidemic was so powerful is it it gets into when you're smoking it or injecting it it gets in and and people do this now with methampetamine 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 methampetamine 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 gives you this overwhelming compulsion and urge I want to do it again even though it may not actually feel all that good it's it's it's real and and again this gets into you know we didn't have an addiction problem for any substance other than alcohol um you know for most of Humanity's existence because these substances Like Cocaine methampetamine synthetic opioids like fent they didn't exist and our brain you know the truth is our brains are were not are not designed to handle those kinds of very powerful substances as many of you know I've been taking ag1 daily since 2012 so I'm delighted that they're sponsoring the podcast ag1 is a vitamin mineral probiotic drink that's designed to meet all of your foundational nutrition needs now of course I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits every day but often times I simply can't get enough servings but with ag1 I'm sure to get enough vitamins and minerals and the probiotics that I need and it also contains adaptogens to help buffer stress simply put I always feel better when I take ag1 I have more focus and energy and I sleep better and it also happens to taste great for all these reasons whenever I'm asked if you could take Just One supplement what would it be I answer ag1 if you'd like to try ag1 go to drink a1.com huberman to claim a special offer they'll give you five free travel packs plus a year supply of vitamin D3 K2 again that's drink a1.com huberman so where do you want to go from here you asked a question about you know the the neuromechanisms of the of what we call addiction yeah I'd like to know about the role of neuroplasticity and addiction I I do want to highlight something you said and I apologize for um interrupting a moment ago and and then ref it was an interruption based on real excitement because a um uh a person I know quite well who is a recovered cocaine addict told me and then by the way folks this isn't I have a friend and I'm actually you know I truly have never tried cocaine um and this person said that the first time they did cocaine his thought was I hate this and I can't wait to do it again ex and and that's exactly how you described it and I think that is a fairly common experience with people suffering from an addiction disorder we're not supposed to use the word addicts anymore because that's a little bit judgmental that's new nomencl something along those lines got it calling someone an addict as opposed to being addicted yeah being um and um that is a beautiful description I hate it but I want to do it again um and again it just shows the P the power of this system which remember evolved for our survival so very simple way of thinking about it is these drugs are tricking the reward circuitry to say this stimulus this experience is really important for my survival I have to go do it again and again and again a side question is the huge question is why does some people develop an addiction problem and others who have used the substance just don't um and as again as a worldclass neuroscientist yourself you know the answer it's always a complex combination of underlying genetics the environment in which they find themselves the environment in which they grew up and how that modified their reward circuitry so to get it your question um 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 methampetamine opioids like morphine heroin change the what the synapses the synapses are the connections from other nerve cells onto dopamine neurons onto the nerve cells and the accumbens and these connections these synapses can change and drugs of abuse cause powerful changes in those connections and therefore powerful changes in the activity of the dopamine neurons and the neurons in the in the vental in the in the nucleus succumb and in fact the types of changes that occur appear to be similar to the types of changes that have evolved for good uses for adaptive forms of learning and memory um so again this is an example that this superficially simple dopamine reward circuitry is changing all the time it 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 and the dopamine system um you said before and I love this statement even so 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 um taken or partaken 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 what the answer is I mean in in the work my lab and other labs have done in preclinical rodent models I want to um the answer is yes a single administration of a drug of abuse Like Cocaine like morphine can cause relatively several days several weeks of changes in the connections onto dopamine neurons and onto um the neurons in the nucleus succumbent those changes that does not mean these changes are permanent or um or irreversible but the changes last a long time um 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 quotes addictive you know again why in certain individuals to be honest it's it's not a big deal yeah I did cocaine at this party it was nice but I don't feel any craving or urge to do it again um whereas other individuals it sets them down you know a a very bad path and really badly affects their life and that's a huge question in the research field because obviously if we could make predictions on which individuals are more susceptible um and you know not to get too political here um but it's also you know whether you become 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 Health you know healthy ways like you know as you have articulated I think in in your podcast getting exercise you know you and I both like to get exercise I feel really good sometimes it's painful during the exercise but afterwards I feel great um very almost the inverse of the cocaine response the desire and then the I hate this but I can't wait to do it again it seems like exercise is often the opposite 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 because that gets me off thinking about this hurts but um so anyhow back to addiction um so yes these drugs can cause yeah I don't want to definitely not permanent changes from a single exposure um 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 in human subjects brains is is not completely clear but I think there are parallels so the changes might last you know a few days a week or two um 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 get stronger and they last longer which is kind of intuitively obvious um but again the big question is why um in human subjects there are people who can use these substances and not develop a serious problem and there are others where they're they're very very damaging um 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 um to have that experience and that's an individual decision um we've we've done some podcast episodes about alcohol cannabis Etc and there does seem to be a pretty wide variation in people's response to the information I think because there are people out there who well I've I've got friends who are recovered alcoholics who will tell me the first drink they took y they use language like you know it combined with the um chemistry of my body in a way that nothing before ever had and they felt like it was like this magic Elixir right that has not been my experience and I I've heard the same stories and it's it's hard for me to relate because like you alcohol does not have that effect on me and that's where that'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 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 um and obviously if it runs in family you have to worry about how the environment of that family influences there's a lot of studies saying there is a genetic component um maybe like you if I have a drinker two in the afternoon I just fall asleep and it does not have that effect on me and um and and one can imagine similar things for other drugs of abuse there are people who have used cocaine have used methampetamine who you know who find it modestly enjoyable but it's not you know the be all or end all it isn't this incredibly powerful experience and you just talked about I think a friend or a colleague who said I hate it I hate that but I want to do it again and that's fascinating yeah 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 um you I can relate I mean can I tell you a little vignette about me which I love to tell sure um sure and it gets into how the reward circuitry is so closely associated with memory systems and how cu's associate it with powerful experiences develop their own reinforcing or aversive quality so long story short when I was a young kid in I can't remember in my 20s maybe 20 I spent a few weeks in Paris I started smoking cigarettes I mean this is a long time ago and I got it's cigarettes are very interesting nicotine is highly addictive as are as the tobacco companies were fully aware of high addictive liability very high addictive liability people will rob people for the money to buy cigarettes um they may not Rob because although they my understanding is they become quite expensive but I guess devote signic counterfeit cigarettes are a huge market for organized crime there are third parts of our of our in the world third world countries where organized crime produce counterfeit cigarettes and are making hundreds of millions or billions of dollars um and so I think nicotine as it is delivered in cigarettes as you know I mean tobacco companies put in a lot of work to figure out the exact dose of nicotine that will make you get that kind of feeling that only lasts for a few minutes so you want to do it again and again um so we can talk about the and nicotine you know what becomes a a problem in a specific Society with addiction is not only based on the neurobiological actions if we're talking still about drugs or substances of that substance it's heavily influenced by the availability of the substance to but my my little story is I smoke some cigarettes in Paris I I I I I learned why people like to smoke it was very satisfying to have a cigarette in a Parisian Cafe it just you know and it's very interesting because the first few times you inhale tobacco you get dizzy it's kind of aversive and it's exactly what you articulate it despite that you want to do it again so I I it was just a lot of fun for me I enjoyed it and I was disciplined you know at some point whenever this was I came back to the United States I didn't smoke um because I knew it was bad for you but to this day 40 years later every time I go back to Paris I get Cravings I actually just want to get a pack of cigarettes I want to um Fe have that feeling again of inhaling the smoke but the point is of how you know powerful these reward 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 behaviorally defined way something is reinforcing is if it the behavior that led to that stimuli it makes you want to do that behavior again rewarding means it actually felt in quotes good um it's an important actually can be different again as you defined by your friend who his I forget I think it was cocaine cocaine was highly reinforcing but it was not necessarily enjoyable or rewarding and isn't that fascinating I have a some colleagues in the addiction field um I one of them is retired now Kent barage and Terry Robinson they they coin they distinguish between the terms wanting and liking and think about that liking something means it's something you like you enjoy um wanting means you want it but you don't necessarily like it or enjoy it and that's a description of your friend's experience with cocaine some of us have been in destructive relationships where you want that individual but you're not sure you necessarily like that individual sometimes people will be in relationships where they actively dislike the other person which 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 um one of the things that's very prominent in 12-step programs is to create rewards around abstaining from the drug or behavior and I should mention that programs like 12ep when followed seem to have very high success rates at least that's what Ana lmy tells me um that in some ways they are modifying the wanting and liking they're splitting the wanting and liking of you know alcohol for instance creating a a liking of sobriety more than the wanting of alcohol for instance that's beautifully put um and I think that's right um how that plays out in the neurom mechanisms that as a neuroscientist I'm interest in it man that's a tough one um but I think that's why those programs are pretty successful it's helping the person make those dissociations um and I I don't know that much about those programs because I have not seen patience 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 um getting some satisfa 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 um the way you described it is exactly right those those programs are highly reinforcing for abstinence behaviors everything from the social connection which we we're going to get to social connection as we know um to the way that people start to conceptualize their addict self versus other self it's actually involves a splitting of the self in in interesting ways um as long as we're talking about Donuts cigarettes alcohol cocaine um I'm curious uh before we move to um a bit more on neuroplasticity is there anything that people ought to know about how different substances and behaviors that are addicting might impact the dopamine reward circuitry differently so for instance um we talked about cocaine as having this very rapid onset big increase in dopamine then a crash as we know um a certain pattern of kinetics as you describe it um the opioid crisis is is you you know incredibly serious problem right now uh as is methamphetamine but it sounds like methamphetamine functions a bit like cocaine and in terms of its kinetics yes so an opioid is a very different chemical than Co cocaine um but it sounds like it impacts the dopamine system um is the dopaminergic activity caused by opioids responsible for the addictive properties of opioids or do people also like the feeling of being under opioids I personally hate it coming out of surgery like they gave me they gave me vicadin once um and I I hated it I'd rather have the pain post-operative pain than take something like um you know vicadin or or a valium or fentanyl or anything like that to me is just completely aversive um but I realize that there are many millions of people that feel quite differently um it's a great question so I think all the studies both in human beings and preclinical animal models yes would suggest that the The Addictive liability of opioids and psychos stimulants 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 succumbent they do it if we want to get a little scientifically technical here via very different mechanisms so cocaine and methampetamine what the drugs known as psychos stimulant um actually bind to a protein in the brain or a molecule in the brain that is responsible for sucking up it's a vacuum cleaner sucking up the dopamine after it's been released and cocaine prevents that dopamine from being vacuumed up so the cocaine hangs around longer meth not only prevents the dopamine from being vacuumed up it actually causes the reverse it actually causes the direct release of dopamine from what we call nerve terminals from the site where dopamine's released opioids work very differently 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 in increase the activity within the dopamine neurons themselves causing a big massive bigger than normal release of dopamine so that's one commonality um but anybody who has used these drugs or read about these drugs the subjective experience of the drugs are dramatically different and that's because of the actions they're having not only in the reward circuitry but throughout the brain so and it's interesting you talked about vicadin 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 um and that's a different question that even when you're talking about opioids all drugs are not cre they're not identical fenel has a much big larger um addictive liability because of its molecular properties and how it's interacting with the opioid system in our brains and The receptors the actual proteins in the brain that it interacts with but the subjective experience of opioids I mean it's interesting uh some people love it that's you know if we go back history as you know there were the um opium dens throughout um Asia um there were Wars about opioids the the the famous opioid Wars between China and the United Kingdom I mean showing you how powerful um the availability of a substance like an opioid can be so I'm I'm going off in a tangent apologize but commonality is dopamine release in the acumin but it's a if remember what a ven 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 methampetamine it's a stimulator you're you know people are grinding their teeth they're hyped up for most people opioids are the exact opposite you I mean in opium dens from the movies I watched and watching narcos and all those TV shows you're often you're lying down you're you're kind of in almost a dreamlike state so very different subjective experiences I'd like to just take a brief break and thank one of our sponsors which is element element is an electrolyte drink that has everything you need and nothing you don't that means plenty of salt sodium magnesium and potassium the so-called electrolytes and no sugar now salt magnesium and potassium are critical to the function of all the cells in your body in particular to the function of your nerve cells also called neurons and we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance element contains a science back electrolyte ratio of 1,000 milligrams that's 1 gram of sodium 200 milligrams of potassium and 60 milligrams of magnesium I typically drink element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes and while I do any kind of physical training and after physical training as well especially if I've been sweating a lot and certainly I drink element in my water when I'm in the sauna and after going in the sauna because that causes quite a lot of sweating if you'd like to try element you can go to drink element that's LM nt.com huberman to claim a free element sample pack with your purchase again that's drink element lnt.com huberman yeah I had an experience with h opioid recently uh not voluntarily over the Christmas holiday we went to visit friends and before um going to sleep I wanted some tea and I asked if they had any non-caffeinated tea so they gave me this tea and um and that night I had the most bizarre dreams I've ever had and I slept for 14 hours the next morning I was like what was that tea uh and I felt off in the morning and I went it was actually a blue lotus flour tea that is actually illegal in the United States but it is sold and it has morphine like um compounds in it um and I am one of those people that's very susceptible to even low doses of any kind of Novel drug you know so so I'm interesting have you ever taken cough syrup with dextr methorphan no I avoid that stuff uh well I you know I have I have a tendency when I get a cold I it gets into my lungs I cough a lot and I think this has been reported this is my anecdotal experience I'm I'm confirming what you said Dexter mooran is a different sort of opioid and actually some people develop a problem with it for me it gives me really bizarre dreams really similar to what you were describing very unusual and that's a whole different conversation about what makes us dream and what the what are the meaning of dreams fascinating and I hope you covered maybe you've covered that we have not yet but we are intending to do a whole series on sleep and dreaming definitely get into it I started out in sleep research so I have a fondness for it well drug research and sleep research have a long history overlap with Alan Hobson's work on L I worked with Alan Hopson okay by the way folks if you're interested in the the relationship between hallucinations and dreaming Alan Hobson is a good name to start your uh your rabbit rabbit hole 19 oh my God I'm dating myself 19 oh 70 I can't remember if it was 76 or 77 I worked with Alan Hopson as an undergraduate at Harvard Medical School no as an undergraduate at Harvard he was at Harvard Medical School yeah right amazing I love his writing and I learned a lot from it he was really ahead of his time yes he was we'll get 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 kid who oh I and even in medical school I I literally was not confident of my opinions at all I was very shy was thought all of the ideas I had must be obvious and I should never say them out loud do you mind if I ask um since since you ra this I I think it's really important I mean you you have this incredible uh career track record um I you know you're adored by your colleagues you're highly respected You've Won just about every reward award there is to win in Neuroscience so was there something in particular that um like was in an overnight thing where one day you woke up and thought you know I actually believe in myself but if you wouldn't mind sharing that because I think before we T get back into some of the the science I you know this is science is a human endeavor and and most people listening are probably not science but I think everybody deals with these issues of of of self-doubt and people appear to have varying levels of confidence but uh what what happened uh it's thank you for asking um it no for me it was a very gradual process and I'm I'm not as a as an undergraduate as a medical student even as a postto 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 it's a very gradual process I think it the increase in my confidence I think began when I was a postto 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 nickol at UCSF and Roger 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 scientists are these geeky individuals wearing white coats with no passion or emotion and nothing could be further from the truth the most successful scientists I know are pretty passionate and pretty intense about what they're working on and driven um I mean then this is a gross generalization so anyhow during my postto 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 um 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 um so I have been um 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 G I gained more and more confidence I so for me it it was this very gradual um buildup of many different experiences where I developed some confidence that you know 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 uh you know people struggle with the that very issue and um clearly showing up again and again over a long period of time is helpful but as you said you know TR learning to trust one's ideas just a brief anecdote when I was um coming up in Neuroscience a few years behind you um not 20 years behind me not too not too many I meanes um but I recall the incredible number of high-profile papers on neuroplasticity and long-term potentiation long-term depression these are terms related to the modification of synapses um that Rob malanka 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 sorry Roger I love I'd love to hear that I love I was under the impression he worked for you and only later did I learn that you were uh his postto so and then and then we collaborated as equs you became peers very quickly very quickly so you had and Roger you know I Roger's wonderful I I did have the confidence even as a postto and actually even as a grad student even though I was a little insecure about my ideas I wanted to be treated as an equal that's the one thing I did have I never felt that I was working for somebody else I always felt that I was working for myself and that we were colleagues um even though my mentors or my had more experience and I could learn from them but I like that that you're working for yourself even though you have mentors I think there's some there's some real gems in what you just described so thank you for 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 fairly straightforward nowadays I I like to think more people know what dopamine is and understand it thanks to your work and Anna's work and some discussions have taken place on our podcast other podcasts but you know it's 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 it's um 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 um clearly we are a social species and a lot of your work in the last um decade and a half or so has focused on the relationship between the reward circuitry which you beautifully described for us and social interaction and connection and where I'm going with this is ultimately this has huge implications for autism and autism spectrum disorders I don't know if nowadays is it okay I 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 um I don't know many parents who would 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 how are we supposed to talk about autism nowadays I I I I am very interested in the pathophysiology of what the iCal profession terms autism spectrum disorder as you pointed out there 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 in sensory processing impairments and lots of different aspects of our behaviors that are important and I think nobody would say would argue those individuals on the severe Spectrum do not have some sort of in quotes disorder the issue we have to be sensitive to is it's it's a heterogeneous disorder like many brain issues that psychiatrists deal with like depression we all um like obsessive compulsive disorder like various anxiety disorders it's always on a Continuum and a spectrum so for autism spectrum disorder there are individuals who are high functioning who one could argue have a different style of interacting socially may have a different way of processing sensory information but who have who would prefer not to be viewed as having an illness but rather would be viewed as having a different style of living and interaction and I think we need to respect that so the challenge is again not oversimplifying a complex heterogeneous disorder um and both being respectful of the people who don't want to be defined as having a neur psychiatric or brain disorder while equally being respectful of people like your friends with severely impaired children who deserve help who deserve research and it's a tough one because my understanding from to be honest just reading articles in the lay press and going to websites from organizations that philanthropically support research related to autism within that community of individuals who are not researchers but who are have family members or are themselves dealing with some degree of autism spectrum disorder there's disagreements about how to what terminology to use how to deal with them and it's complicated I think we just have to respect everybody and if you're interacting with individuals you you know I think it's appropriate what do you prefer um I do know as a medical professional there and especially when you're dealing with children there are children who need help and I I 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 beautifully I think it beautifully answers it and encompasses all sides um so that we can move forward and I think we so as we use the term uh autism or children or people with Autism um that's what we're referring to I think people are very sensitive especially those individuals who are neuroatypical who previously might be diagnosed as autism spectrum disorder but would prefer to not be labeled as having a brain illness that that's fine um it's kind of once you are an adult you can make that decision for yourself we certainly have colleagues at Stanford and elsewhere who at least by my non-clinical assessment seem to fall somewhere on that spectrum and again it's a Continuum just like you know the experience of depression is in a Continuum but all right and as with depression you wouldn't love a child or an adult any less because they have depression nor would you love a child or adult any less uh because of uh expression of some autism I know the point people don't you know and so we we have been we are being trained in the medical profession to be very for you know and our society is going this way too very careful with the terms we use and the labeling of individuals um so you know I've been taught you can say individuals living with an Autism Spectrum Disorder um some people don't like using the term oh 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 too as we both know well for sake of fluid conversation we will do our best but um we will acknowledge from the outset that we are well meaning but far from perfect and how we'll handle this well put well put so and thinking about social interactions and leaving aside anything related to autism for the moment it appears that the circuits in the brain that mediate the desire to spend time with others of the same species maybe even with other species like a dog um are fairly hardwired but modifiable they we were born with the capacity to build them up mhm um and that social behavior is highly rewarded is it rewarded through the dopamine system and what if any involvement is there of the serotonergic system and we haven't talked about serotonin yet but I'd love to bring up serotonin at this point maybe you could educate us a little bit about serotonin because um gosh if dopamine is fascinating serotonin is at least as incredible um yeah great question so I I think for me the easiest way for me to answer it is actually just tell you my research history and how a lab like mine at Stanford that at one point was studying what I what you and I would call fairly hardcore molecular mechanisms of neuroplasticity how do connections between nerve cells change and what molecules are changing and pretty hardcore molecular stuff how did I end up studying social behaviors in mice and what I hope hope we'll end up talking about even developing behavioral models of what I will Define as empathy in mice the answer is very simple my lab was working on roles of classic dopamine reward circuitry and how it changes in models of addiction we haven't talked about depression models of depression because just intuitively hopefully your listeners can understand if one component of depression is what we call anhedonia the inability to experience reward you know eating a doughnut is no longer satisfying having sex is no longer that much fun which is a component of depression if there's a mechanism in the brain that tells you something is rewarding by definition that's not functioning normally in severe depression so we were doing models of depression to figure out how the dopamine reward circuitry was changing as were many other labs we were studying addiction those with the obvious ones and I mean it might be entertaining to to your audience to learn how academic scientists think I was thinking those are fascinating topics they're pretty competitive um lots of other labs were working on it and I started thinking what other experiences might be modifying the reward circuitry I actually made some attempts to look at feeding Behavior but I don't want to I mean we actually never pursued that for a variety of reasons and that's obviously important because of there is an obesity epidemic in this country uh and we can talk about how the reward circuitry and some of the things we've learned from our studies of addiction may be helpful to understanding obesity but back to social interaction I started thinking well for most of us uh what I call a pro-social nonsexual experience is highly re enforcing um Andrew you're a pretty social guy I'm a pretty social guy most of the time I'd rather go to a movie a sporting event a dinner with friends um it's you know actually for me the most meaningful component of my life other than spending time with my children is spending time with my close friends um and I started thinking well why is that why do I have such a good time going to a ball game with my best friend or going out to dinner with another couple um and interacting it's because well it's highly reinforcing and if it's highly reinforcing it must involve the reward circuitry and then I started thinking evolutionarily it makes a lot of sense because if you are part of a social species there's a lot of evolutionarily a lot of advantages for your survival to be hanging out with other members of your species in a non-aggressive way it can increase your likelihood to find a mate and reproduce it can protect you from predators I mean that's why any of your listeners who ever watch um you know Wildlife shows or National Geographic shows there's a reason all these animals hang out together it's for protection from predators so there are all these reasons so about whenever it was 13 or 14 years ago my lab decided to start looking at how the reward circuitry may play a role in what I am going to call positive pro-social nonaggressive interactions um another word we use is just sociability um and for a variety of reasons back then this is God this is at least 13 years ago maybe 15 years ago a postto joined my lab named ghoul Dolan she's now a professor at John's Hopkins um and she had an interest in oxytocin um and as your listeners know um oxytocin is this evolutionarily conserved neuropeptide that's very important for parition 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 a well-known researcher in social behavior and bonding research called Larry young and he did some very important now somewhat classic work studying a species called the v in particular the Prairie V and Prairie VES are a species where they mate for life it's called pair bonding so One V will find another vult they basically get married they have kids and they're they hang out together for the rest of their life no divorce no 50% divorce r no 50% divorce rate and what Larry elegantly showed um in part in the early days in collaboration with a guy named Tom Insel who is a famous academic psychiatrist um they showed that oxytocin action within the nucleus succumbent within this reward circuitry was required and 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 I'm glad you brought that up because we'll keep this contemporary and the the the reality is that that recent paper got a lot of attention you know the paper I'm talking maybe oxytocin isn't playing as prominent role in pair bonding as people had thought and yet folks uh 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 yeah exactly and again the investigators who presented the work saying oxytocin may not be as important there are limitations to the manipulations they did which they would agree with so I'm just telling you so G Doan was a posto in my lab and we decid we formulated a project to look at the actions of oxytocin in the nucleus accumbens in mice and the reason we study mice is you they're what are known as a gen genetically tractable organism we have all sorts of really cool and sophisticated tricks we can do to probe brain circuitry the actions of neuromodulators like dopamine and serotonin and oxytocin in ways that we can't do in other species um and I'm going to get back to dopamine in a second and what we found was that oxytocin action in the nucleus accumbent was indeed important for promoting sociability probably for promoting the reinforcing component of a social interaction and that surprised us you know it was like wow it's it's oxytocin seems to be causing enhancing the release of serotonin in the nucleus accumbent and that will will I perhaps we'll get to this that led me off on a whole series of experiments trying to figure out how serotonin Works studying this drug we may talk about called MDMA which is ecstasy or Molly which actually causes release of Serotonin so we did that work and that got us working in serotonin simultaneously there were some other papers reporting that dop do amine release in the accumbens that dopamine is released in the accumbens during a social interaction a positive non-aggressive social interaction truth be told it may also be released during an aggressive interaction 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 happen during a non-aggressive social interaction it turns out that oxytocin is not only released in the nucleus accumbens it's released in the home of the dopamine neurons in the VTA so my lab and another lab from Northwestern showed that oxytocin can actually modulate dopamine neuron activity in the ventral tegmental area so I hope I'm making sense here I don't want to get too technical but it just shows how the you know we discuss these neuromodulators like dopamine I just brought in oxytocin we're going to talk about serotonin in a second unfortunately for your listeners they don't work in isolation they commun they influence each other in ways that I think it's important for us to understand and elucidate um that is not too much technical detail um and I think it's wonderfully rich with areas for us to discuss and I'm so very glad that you brought up that neither dopamine nor serotonin nor oxytocin work in isolation 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 way you know for instance turning on dopamine and turning off serotonin it's a waiting 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 too for that matter as this kind of warm feel good everything's mellow um you know not really associated with a reward and reinforcement and uh of course it's not that simple so when it comes to social interactions it sounds like oxytocin and serotonin are playing a prominent role also in the accumbens um and that dopamine is is activated too do I have that right okay so um I don't want to take us too far down the rabbit hole of neural circuit function but that to me um makes at least a brief discussion about the nucleus accumbent itself interesting like okay so I'm thinking nucleus I know that means a pile neurons an aggregation of neurons it's talking to this ventral striatum so we got a bunch of neur part of the ventral striatum it's a subdivision excuse me I misspoke um yeah it's part of the vental striatum and it's um and and the neurons there can be active and communicate with other brain areas but we're talking about a lot of nuance of function man so I'm not I'm smiling I don't know if your audiences can see me smiling because it's so I I sometimes go to bed feeling it's so complicated oh my God it is and and yet could we say that within the nucleus succumbent there are neurons that are acting as um accelerators and breaks um I mean is there a simple analogy that perhaps while not exhaustive can still be true because that's always the goal on this podcast there's no way we 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 really it's a really important role um but as you know it's always more complicated than we wanted to be a scientists especially when you're dealing with brain activity issues and how the brain mediates all its amazing functions um so historically we have thought about the nucleus succumbent and other components of this ventral strial brain area as primarily being composed of two different cell types and as you pointed out one being sort of an accelerator something that promotes certain behaviors um and the other cell type somewhat being a break saying don't do that behavior don't perform that motor action and the it it is true that there are these different cell types it is true that they are modulated by these modulators like dopamine and serotonin in different ways um and that simplistic hypothesis or urtic we call it has been very useful in making models about how the accumbent does all its wonderful things what I'm leading up to is it's it unfortunately it's a little more complicated but yes it's there are two different soul types and at least for your audience we can think about dopamine driving the activity of one promoting certain behaviors and inhibiting the activity of the other cell type and being a sort of break on certain behaviors as long as you and I as scientists appreciate it's not quite that simple 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 MH nonsexual interactions involve the choice of a lot of behaviors but also the suppression of a lot of behaviors and um and so maybe you you're starting to sense to what I'm doing here I I think for people to understand how a single structure like the accumbens could mediate social interaction and reward it what it sounds like it's doing is rewarding a certain category and catalog of Behavioral options and punishing or at least reducing the probability of the occurrence of other behavioral actions cuz when I go to dinner with friends if I know them really well I might hug them I might even say something mildly inappropriate and if I know the context to be safe right but at a dinner interview or a discussion with somebody you know I barely know I might watch my words a little bit more y um for instance and I think the incumbents and its Associated Circ I love the way you just put that probabilities it's my probability of having this behavior in the certain context is increased my Pro the probabilities of not doing certain behaviors and I think there's little doubt that this brain area called the nucleus succumbent 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 nonsexual interactions I actually also think it plays a role in empathy and I'm leading you there I want to have a discussion about that please um again the as a mechanistically driven neuroscientist what is frustrating for me is I 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 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 dev you know perhap you know if we bring it back to aism that are allowing the development of no 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 fun 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 drugable targets or even behavioral interventions that might actually help people for for example suffering from autism spectrum disorder of the sort that they actually want and need interact need therapeutic help I think looking at the social nection circuitry uh through the lens of autism is going to be very interesting for us to do I do have a question about what is being selected for in rewarding social interactions because obviously um we are living in a time where you know we don't have to aggregating groups necessarily to protect ourselves physically um it helps in certain ways um in certain circumstances but certainly to support ourselves and each other emotionally you know having people that we can call on when we're we not feeling so well M that we can look to uh for resources and that they can look to us um 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 like spend four days Alone um with a bunch of papers and lectures preparing for a podcast which I also really enjoy um but when I do that when I go out to dinner with friends or see friends I'm not thinking about buffering myself against loneliness when I do it I just like the interaction so um what sorts of um evolutionary hypothesis can we come up with as to why the human brain is so tuned for these social interactions why it's rewarded by not just one dopamine but also serotonin serotonin and oxytocin three prominent neuromodulatory uh chemicals in the brain are devoted at one sight 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 I think the answer I'm going to be able to give I hope it's not Tri and it may be a little bit obvious is and in some ways it's it's it's analogous to why drugs of abuse and addiction are also a problem is that the circuitry that is telling us a pro-social positive interaction is so highly reinforcing evolved over you know millions of years or hundreds of thousands of years whatever that that is and I the only hypothesis I can come up with and Andrew you may be able to come up with better ones is what I alluded to earlier is it it was very adaptive when we were more primitive organisms never mind non-human primates but when we were whatever we were to be a social species um for basically primarily two reasons for Reproductive purposes it increased your likelihood of reproducing if you were hanging out with other members of your species in a non-aggressive way um and for protection against predators um and there may be other reasons um probably child rearing too in in your absence you want trusted friends that can watch offspring thank you that very good point so the circuits the modulators we used that evolved over Millennia and as you pointed out um you know eventually I mean depending on the society in which you live you didn't need those social interactions for protection against predators um although you know if we look at our world now one can make arguments both ways if you're in a war zone is it better to be off by yourself is it better to be with a group of people um but so they the mechanisms evolved for one purpose and they don't just disappear because there's no disadvantage to having this mechanism that tells us that 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 this I think it's impossible at least currently and you can't find a partner with whom to have kids if you're socially isolated or it makes it much harder so I hope I'm answering your question I think um and then and then as you pointed out the 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 connected this notion feeling connected I'm uh and later we'll talk about psychedelics but this notion of feeling connected um 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 um that we feel in recalling Social experiences and anticipating social experiences is really powerful you you mentioned um 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 more power to you but this is actually a prominent discussion on social media you know there's an entire culture of young people in particular young men these days who at least from what I understand in the the research literature about this are socially isolated spending all 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 um and concern about mental health issues there uh Etc uh concern about porn overuse and addiction there Etc but social media itself is an incredible phenomenon to consider in light of everything we're talking about um I can't say even though I am on social all social media platforms um and I you know quite active there I can't say that I've ever been on social media and experienced the kind of delight and thrill and persistent energy uh increase that I experienced with inperson interaction and yet social media I have to assume is capitalizing on some of these same reward mechanisms in presumably the nucleus succumbent y so um are there any data I realize this a hard experiment to do in mice maybe impossible but are there any data that you're aware of that um that 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 um I agree with the point you're making although your your podcast audience probably doesn't know who I am I am in my late 60s I grew up well they know who you are now I grew up before computers before cell phones um 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 I mean for for all sorts of reasons there's a lot of positive and good from that back to your question can we get addicted I I can't speak to social media I can speak and anal limpy you know I think can is much more able to eloquently describe the issues around you I can just talk from my own experience that my cell phone is um and check you know this is in social media but checking my email messages checking my texting my text messages has a for me has a compulsive addictive quality a lever press it's like a lever press for a mouse and it it I and 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 um um so I don't know what else to say about it I uh I I think as a Society we we have to be aware of these issues and it's really comp 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 is planning to have children and adults on social media I mean 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 on social media it just seems to me that um Instagram Facebook LinkedIn Twitter have capitalized on this hardwired circuitry the release of O I mean to make it 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 a a negative thing but as you said they're thinking of us there's something about being recognized by others and maybe this is a good SE we're heading towards empathy here discuss about empathy I I think that's very well put that you 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 uh 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 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 the dangers of it we read about these kids who are socially isolated who make bad decisions based on what they're seeing with social media um but anyhow back to the neur Neuroscience you're absolutely correct um it's capitalizing on these mechanisms um that evolved for physical interpersonal Rea interactions because the our Evolution didn't anticipate right just as pornography is is capitalizing on the sexual arousal reward Circ Associated reward question about it just as the gambling industry does I mean as you know that 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 pricious someone uh you could tell I've been spending a lot of time around addicts and former addicts I've been researching some some things for the podcast um and a gambling addict uh told me something interesting they said you know the the real Stinger with being a gambling addict is that the next time really could change everything whereas no alcoholic says that 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 infantis small and yet um real potential that the next time really could wipe out their debt and per perhaps wipe out and yet we know they would lose that too right whatever winnings they and casinos are fully aware of this I've have been told by friends who know they they they employ you know full-time quantitative you know for lack of a better term well I I was GNA say computer geek I don't mean to that be um and neur I would be amazed if they don't have neuroscientists who have expertise in what's called neuroeconomics or behavioral economics um I'm 95% sure that has to be the case I occasionally sit down to the rette table because I just it's so passive and easy and not long ago actually I had the experience of winning a fairly not a large sum but but a meaningful sum of money and I'll tell you my sole 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 at another table played one hand and then and lost it and then just got back to my room as quickly as possible and then left Las Vegas as quickly as possible yeah gambling is but they'll probably get me the next time yeah gambling is a you know again it all gets back to this reward circuitry and the um intermittent re 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 roulet or craps table or poker table um by getting up and leaving right and 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 uh Fair degrees and I like to think my prefrontal cortex is working and yet it was still challenging in that moment gambling is really I mean yeah another human activity that's quite complicated it can be enjoyable or it can be incredibly damaging yeah and now people are going to think I was that gambling addict that I was referring to but I swear I'm not fortunately I feel very blessed that that's not my addiction um I'd like to talk about empathy and use that as a framework for eventually turning to our discussion of autism but um you have this perhaps long-standing interest but Recent research interest in empathy tell me about this work I'm not familiar with it yet okay so I am gonna I'm gonna I hope it's okay drag in the some work I've done on this drug called MDMA because it is related um so we were working on in my lab social behaviors positive pro-social behaviors um that stimulated me to start thinking about what are components of a positive pro-social non-aggressive interaction um a a a a common key component of that is having some empathy and compassion for the individuals you're hanging out with and it is a topic I've been interested in for many many decades I was once a psychiatrist um and to get on my whatever the word is hobby horse um I look at the world today I try to be optimistic uh 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 what always enters my mind and I've 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 is very similar you know 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 um and having compassion for somebody so I 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 to efforts that might help the human species enhance empathy and compassion is by studying the neurobiological underpinnings of it and I didn't realize I might be able to do that until I started studying sociability or pro-social behaviors in mice and then I was um able to H have a young woman scientist and I want to give her credit Mo'Nique Smith um you might want to have Mo'Nique on your padc she's a she's a Dynamo she's now an assistant professor at UCSD and Monique introduced me to a series of Behavioral assays that I like to use the I like to use the phrase they are measurements they are behavioral antecedants 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 man 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 um in in for human interactions I just think of you know any of we were talking about friendships any of us who have 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'm defining empathy so it's my belief that like any complex human behavior there are evolutionary reasons why that has been adaptive and important and maintained and if it's 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 I get a kick out of this um because it's it's pretty new for me so one assay and we we published a paper in a journal called science about this um 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 experienced no physical injury whatsoever will manifest behaviors indicating it is now in pain and it lasts maybe 4 to 20 hours but think about that a mouse just hang a mouse that is normal hanging out with another mouse in pain starts feeling and Ma pain itself and the and the mice are able to see one another and hear one another good point so you're getting to how is that communication happening and a lot more work needs to be done on it um Mo'Nique and her previous colleagues and others one component of it is probably an Al Factory Q or what we call a pheromone so the m and pan is secreting an odor 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 two others and then I'll tell you how it connects to reward circuitry um we developed a novel assay which is the social transfer of Pain Relief pain relief is called analgesia and I thought this was pretty cool so you take and this is in this paper that was published in science a year ago you take two mice and they're both in pain modest pain I don't want your listeners to get upset we are not hurting these mice too badly um 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 um so you have two mice in 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 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 I think it's not only that I'm not paying as much attention to the pain but I think there's actually some relief from what's known as the social buffering of pain so well I'm no hippie but I actually think that um all species including humans are secreting molecules mainly odorants that are perhaps even acting directly as as analgesics um and I can make that statement with without woring too much that people think I'm completely crazy because we had gnome soble on the podcast from the WIS men 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 phasal presson levels their immune molecules you know and and of course Nome works on Old faction 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 that makes us feel good on a normal day well 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 early neuroscientist and and I would probably at that point of um you know not been the type to just walk up and say hello to you because I wasn't in your field and you're this luminary and stuff but but I remember as I started good guy by you are very very good um I always say hi to everyone I I know you are and that that statement was a reflection on me not a ref on you but as I Advanced 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 respected would give a nod or something those nods meant a lot abut those nods could carry you a long distance I mean obviously we want to be intrinsically driven to do the work we do but but this social communication sociales I think there's a whole landscape of things so what you're describing um is incredible but I think makes a ton of sense yeah so we have the social transfer pain of analges here we're working on and there's a little bit of evidence in the literature suggesting this might work and then I'll talk about reward circuitry and maybe MDMA and is it an empathogen or not and how that might influence therapeutic efforts for autism we're working on behavioral models where we're asking the question will one Mouse behave to give another mouse a reward so it's the mouse that's behaving that has to press a bar or nose pooke or even experience a 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 it's what we call it generosity a generosity assay and early days it looks like it might be working we have I don't um and that's a generosity assay 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 antecedence 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 experienc pain just because it's 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 singulate cortex which human brain Imaging studies suggest are is active at it during empathic human responses and the projections of that area into the nucleus succumbent that's the connection um and we're interested in whether neuromodulators like dopamine and serotonin May influence these circuitry these connections that are involved in these in quotes empathic behaviors um etc etc um and we think drugs can be used as probes of those kinds of neuromodulatory mechanisms I hope this is all making sense it makes a excellent sense and is fascinating um I'm not one to suggest experiments to uh colleagues in areas where I don't work but I I I'm going to anyway yeah please um One You're a really smart guy so I will value your suggestions well you know I love the the motivational backbone to what you're describing here because I agree the world has a lot of issues and what it could be more important than to increase the amount of empathy and compassion in the world um 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 right like if I'm very hungry I mean we're all taught to put our own oxygen mask on first in some way too so that we don't all die uh so to speak but you know I grew up for instance with a one parent my mother was the kind of person who would see at that time there were far fewer homeless people on the street maybe they were all institutionalized I don't know um 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 in it was crazy I mean we couldn't get anywhere that was the problem is we we never arrive anywhere on time and that's my excuse for always being late I positively reinforced for being late I always run late and I always run incredible right just a very strong sense of of social connection that kind of thing but in any case you know some people are like that like she could not experience any um even modicum of inconvenience for helping others whereas I think most of us feel like if I'm rushing to catch a flight and I see someone who's struggling I'm probably going to help them if they're in acute pain or it seems like a dire circumstance but let's be honest most people are probably going to prioritize their own stress and and priorities for lack of a better word when the situation often calls for us to set those aside and and tend to people that are suffering so if there was a way to introduce the um the inter probe of the interplay of circuitries that involve how convenient or inconvenient it is like if we're wellfed 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 I we so first um you know 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 laid for a plane I'm not sure I would stop and help somebody and I'm not I guess it depends on on what sort of suffering I mean if they're hemorrhaging on the side of the road we all would but a flat tire right you might think oh goodness like do I have time for this 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 certain circumstances if if it's hungry itself will it work as hard to give another animal I mean it's a good question because I'm not sure what the outcome will be one could predict it might work harder because it understands the hunger in quotes more or it could 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 our mice grow up in academic environments and if it's a stranger how will you behave how will you behave if you had a fight with that Mouse previously and what if you had and and it also matters did you win the fight or did you lose the fight right you're Pro you know intuitively as we probably would all guess I'm more likely to help somebody I defeated in a fight previously because I'm the S you know I'm the hierarchy I'm the dominant one I'm probably less likely if that person beat me up so all these are great questions I think we can study them um I also think there are ways we can study these kinds of interactions in human subjects um not that I am going to do that myself someone at Stanford will yeah 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 and 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 um maybe considering the second question first I could imagine for instance that there are variations in brain wiring that would make it such that um a kid who then becomes an adult gets a tremendous amount of reward from um I don't know math U designing mugs um any number of activities but that through some variation and 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 um is there any evidence that that's the case in children who are classified as Autistic or having autism um I 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 ju so your audience certain members of your audience don't get mad we're remember our earlier conversation we we we made the 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 suggest that the reinforcing component of a social interaction is much less or lacking in our models of autism spectr spectrum disorder and certain individuals an important point is is that just genetically wired was that because in their early experiences they weren't able to get the century stimuli that tell them this is a reinforcing social experience unknown um at least those are topics that I think are worthy of Investigation um 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 um and it's very likely for some individuals answer is yes meaning they they they do lack some of the neuromechanisms that allow them but that probably doesn't apply to everybody I would I can say in our Mouse models of social interactions and our Mouse models of in quotes empathy in these um are my might show deficits um and those deficits 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 dma or ecstasy um so I hope I'm answering your question I 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 and the nucleus succumbent um 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 which one the mtma paper that par the borisy one yeah that D that that parsed the relative roles of dopamine in the nucleus accum versus serotonin in the nucleus comment by the way um folks uh by time this episode comes out an episode all about MDMA itself and it's modes of action will already um aired and you can find that but even if you haven't heard that um you know MDMA is an amazing molecule because it profoundly increases um dopamine uh and that's why the word methamphetamine is actually in y MDMA um still a surprise to many people to hear that but it also robustly increases serotonin transmission and what I love about the paper from your lab that explored this is that it at least by my read of the data it showed very convincingly that it's serotonin released in the nucleus acumin 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 there's a study in humans and in the mouse work that you've done doesn't seem to play as prominent a role in the social uh 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 um 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 social connections I'm not aware of any I don't think the I think it it is a it is a worthwhile it has been studied I I don't think we can close the door on the potential therapeutic uses of oxytocin from the 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 um and she's finding some potential benefit from that and vasopressin and 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 is not there yet in terms of MDMA um again complicated story um as you pointed out mgma it's it's major molecular targets don't want to get too technical here are the serotonin vacuum cleaner the the molecule that's vacuums up serotonin and the dopamine vacuum cleaner the molecule that um vacuums up and excuse my language sucks up dopamine when it's released um and because it's an amphetamine derivative um 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 do I don't want to use the term the the terminals to vomit outan serotonin that's what I say on the uh is that am I when talk about syntic release I'm known for when I my solo episodes for when I talk about synaptic release I'll um I'll say that they they vomit out what amphetamine derivative you work on synaptic transm that's almost an insult to a biologist what MDMA does is that it actually caus what's known as a reverse transport it actually causes it not only prevents the vacuum cleaners from sucking up the dopamine and serotonin it causes it to spew out dopamine and seratus 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 MDMA 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 human subjects a different experience than cocaine or methan or especially methampetamine presumably it's the fact that there's so much serotonin exactly and so if you actually get into and this is why for your audiences 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 propose and others in the field it's not just you know science is not done in isolation so I want to give credit where creditors do 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 5050 maybe it's 7030 8020 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 it 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 5050 it's more whatever 70 Ser 70% serotonin 30% dopamine um and then it does influence oxytocin in very complex ways um which is a further technical discussion um there was just a nice paper that came out that reported that serotone in release in a hypothalamic structure which again the hypothalamus you can explain to your listeners marish size structure above the roof of your mouth responsible for a sex temperature control uh feeding and satiety and a bunch of other things critical um and uh yeah and it's the home of oxy neurons that produce oxytosis 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 you know we like exract 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 dopamine release and dopamine the dopamine system and some of my colleagues in the MDMA field who I ECT 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 doesn't mean that substance is 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 feels good and so there are individuals that especially a you know as your listeners may know MDMA has gotten a lot of attention because it's in a therapeutic trial that's looks very promising for as an adjunct to psychotherapy for post-traumatic stress disorder and the the FDA the part of our government that approves or disapproves the legal distribution of therapeutic drugs may end up approving MDMA for certain uses um the point being is that once it if it gets approved my personal feeling is it will have some addictive liability it also has this very powerful what you and I might term Andrew a pro-social effect um some people even call it an empathogen that's a little controversial meaning it enhances your capacity for empathy to to experience the the emotional state of another individual to want to understand that person's experiences in emotional state um and our 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 its empathogenic effects are more likely to be mediated by its interactions with the serotonin system in in in this reward circuitry and we're actually doing a lot of work to test that hypothesis we're actually testing MDMA in these behavioral models of empathy in mice um and it looks like our hypothesis is being supported the other thing to to drive your your listeners crazy about sorry listeners how complex the brain is if you think it listen neither you nor I were Consulting the design phase and so we don't have to apologize for the brain's complexity because I don't 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 in another part of the brain with this wonderful name called the dorsal raap nucleus and it turns out the serotonin neurons talk to the dopamine neurons and influence the dopamine neurons and um so it's again the point we made earlier in your podcast even though it's fun and useful both for your listeners and as scientists to think about these powerful chemical Messengers in isolation because that's how we can make progress scientifically it's how your audience can understand some of the concepts that have been 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 acumin 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 via being mediated via the dopamine system and some of its social effects alth 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 that's what I'm most interested in really in the context of MDMA and we should just mention because we we do um uh like to mention these cave uh yes the and I can say this cuz I participated in a trial with MDMA it it is a very pleasant experience it's certainly not for everybody it's still is a schedule one drug at this moment absolutely um so you can go to jail for possessing and or selling in fact there was a big bust recently in Canada and another one in Brussels um large amounts of MDMA collected those people are probably going to go to prison for a long period of time so you you do you don't want to take it or possess it it's illegal um we're talking about clinical trials here but also um the fenel issue there's a lot of fent to mention to your list 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 so we are not encouraging the use of these but I will say that the um subjective experience of MDMA provided it's done in the appropriate clinical setting it's actually MDMA doesn't contain other things um dosed correctly Etc um is a pleasant one for sure and my my sense is that um the dopamine release uh is reinforcing the experience that the context that serotonin is providing with a social context right and and the word context there becomes important when we think about back to the 90s when there were a lot of raves and people were also you know getting um I guess positive feedback from the interactions they were having dancing all night partying with friends Etc I mean I think that um returning to the issue of autism and the role of Serotonin so in autism there seems to be less of a a reinforcement pathway for certain kinds of social interactions um in some individuals with autism um and I'm aware that there are some prescription treatments for autism that capitalize on the serotonergic system and dopamine system so um is it fentam to my knowledge the only FDA approved pharmacologic therapeutic for individuals with autism spectrum disorder is actually oh God I'm just blinking it it's it's not a serotonergic drug uh I'm I have to look it up I I want to say resperidone for agitation um 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 psychiatrists and individuals with G with good in 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 wellone clinical trials which in my view as an academic are 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 maplight Therapeutics and I'm not advertising from Mite I'm just doing a full disclosure it was found it with Carl daero who you've had on your podcast um and an entrepreneur in San Francisco named Caroline nicolich um and we have a phas two trial phase two trial means it's a safe drug we've done all the safety work um and it's a drug that targets a subtype of receptor for serotonin um serotonin works on many different I I don't know what word can I use other than receptor no U listeners of this podcast probably be familiar with recept sort of parking spots for for molecules um yes that the paper you I was referencing earlier from your lab it talked about serotonin 1B receptors being particularly importantly and so and the point being is you know I do have an interest in this on can you use the type of discoveries were' made in mice might it actually have any relevance to human sub human beings in particular those who some of which have some sort of sociability deficits um other companies are pursuing this too so MDMA itself there has been I don't know if it's ongoing there's a well-known organization I don't know if you've ever had anybody from maps on this the multidisiplinary association for psychedelic studies um Maps deserves a lot of credit for being a Pioneer in saying in particular with MDMA promoting the idea that you know this drug deserves rigorous and ethical study um that that's at least my view um and Maps which was founded by uh 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 I know maps and perhaps others have done some small trials studying MDMA in individuals high functioning individuals with some form of social anxiety um I'm saying this because this is public there's another company called mindmed which is one of the publicly traded psychedelic companies and this is on their website full disclosure I am on their scientific Advisory Board um they are gearing up to do a trial of a I don't want to get too technical of a certain form of MDMA there are two different types of MDMA that they have these horrible names called enantiomers um so the MDMA that is used for clinical trials that Maps it MDMA is a molecule and it has mirror images of itself and one one has the name r MDMA and one has the name s MDMA and they're they're called the s in Nan mirors 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 r an antier has a higher interaction with the serotonin system interesting um if if you look at the the literature on autism spectrum disorder in human subjects there's a bunch of papers suggesting serotonergic system 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 Etc that it's not also playing at least a similar role in right and I I fully agree with that and as we were discussing there's a there's a modestly extensive clinical literature meaning 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 order So based on that based on my lab's work on the role of serotonin in modifying reward circuitry its Ro role 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 drugie myself I am a child of the 60s and 70s so I did which means I'm 20 years older than you Andrew 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 the 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 and now I'm talking scientist to scientist with you Andrew they have molecular targets that we can manipulate in rigorous ways we can figure out where in the brain they act using the modern tools of Neuroscience 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'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 neurom modulatory system have such a powerful effect which is relatively specific on social interactions it doesn't make you want to go eat more Donuts it doesn't um I don't know for me there's a clue there there's something really important from that phenomenological observation in the human experiences that we can learn from I I completely agree about MDMA and um you know we've done a couple podcasts about psilocybin and by extension LSD because even though there are differences there cyon LSD as far as we understand largely work through um you know activation of the serotonin 2A receptor broadening a brain network connectivity so again it's serotonin serotonin serotonin but different receptors very different subjective experience um and I guess perhaps the best way to describe it is that LSD and psilocybin are almost always considered mystical in the in their subjective effects whereas um MDMA can be an empathogen and aogen um 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 um perhaps also because at least to my knowledge there is no substance in nature no plant no mushroom no Urgot no um any no mold um 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 um that folks like maps have are now doing such fantastic work on so I'm I'm very excited about what happening with the research on MDMA and I'm so glad that your laboratory has parsed the some of the relative roles of Serotonin The receptors involved um 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 note captions by the way folks um that uh Rob Malena here's labit focused on the serotonin 1B receptor so even just differences in receptor subtypes leading to profoundly different subjective outcomes I find that to be uh just one of the most important areas that one could even think about let alone work on uh thank you I appreciate the compliment I will also say un like everything we're we're finding it's not all about only serotonin and 1B but that's as you know there are again pointing to the the amazing and Powerful complexity of the human brain or the Mamon brain There are 16 different serotonin parking 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 in complex ways you 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 are now being probed as potential Therapeutics for various uh 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 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 I 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 um it tickles me and excites me with the appropriate caution um 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 re um understanding their therapeutic potential their mechanism of action it's more useful to divide them up into different categories the classic hallucinogens which are LSD and psilocybin the intor Imp pathogens which is MDMA which is really a qualitatively different drug there are other substances which we we don't have time to talk about like ibigan and iasa which are very complex and peyote but nevertheless I am tickled and excited as a child of the 60s and 70s um but I am also not Evangelical about their UT use and their therapeutic potential so as you can imagine what I'm going to say I think they should be the subject of rich ous sophisticated and most importantly ethical research um I I think we could learn a lot about how the brain works and its amazing capabilities I think we could I think they may notice I say may have therapeutic potential but I do not think they're going to be miracle cures and I do worry as somebody who lived through the 60s and 70s and watched because of the ly um the history with Timothy ly and his colleagues and the political landscape of how they were being used and promoted I am cautious that these substances need to be studied scientifically and rigorously um and I hope that's the case and I want to caution your audience that not everybody should take these substances they are not miracle cures and while they certainly may be be of benefit to certain individuals who are suffering and they certainly may provide unusual and in quotes mystical experiences for certain individuals I am very concerned that there are individuals out there that will gain access to these substances and have very bad experiences because 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 is a bad trip on LSD and I do have concerns that if you look at the clinical trials that have been done the well good 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 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 preclinical researchers to study these substances in the way they deserve to be studied um so I hope that um articulates my viewpoint I think so it 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 from the OPI oid uh lawsuit settlement with Purdue Pharmaceuticals to the study of ibigan um so there's a lot happening here no and I I just to be clear I think there's no problem with that and I actually would support that as long as the studies of ibigan are done thoughtfully carefully and ethically uh I see no problem with testing its efficacy in certain um mental illnesses and addiction and it's a it's actually a topic I know a little bit about but we'll save that for another time great 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 you're by no means uh retiring knows who knows I I certainly hope not but um I'm sure the listeners have now in a clear picture of the enormous number of contributions and areas he've worked everywhere from as I mentioned earlier neuroplasticity at the cellar level molecular level addiction um work relating to social cognition and social interactions rather um as it pertains to autism models and now psychedelics and empathy and on and on and again 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 mentioned raise still more questions that need to be resolved uh 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 convers 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 you that was a blast what I just did with you and I'd be happy to continue this conversation anytime uh so thank you for your very sophisticated and thoughtful questions to be continued yeah to be continued thank you for joining me for today's discussion all about neuroplasticity reward systems social connection and empathy with Dr Robert malanka if you're learning from and are enjoying this podcast please subscribe to our YouTube channel that's a terrific zeroc cost way to support us in addition please subscribe to the podcast on Spotify and apple and on both Spotify 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