 It's time to get started. So take a seat. It's the Science Café brought to you by... Without funding sources, without them, we wouldn't be able to produce. For those who might be new to the Science Café, we are a group of graduate students from the Organismic and Opportunity Biology and Neuroscience and Behavior Graduate Programs. Our goal is to bring amazing science being done at UMass out into the community and share it with you guys. So before we begin again, we have people taking photographs and videos. So if you guys don't want to be in those, we post those online. So please talk to our media people. Also, I think, there's a sign-up sheet again with... Please give us your email so we can contact you and tell you about future cafes. And lastly, the next cafe will be in October 11, and it will be our former president, Dina and Ivan, who will be talking about how nature and nurture interact to shape bodies of animals. So let's get started. Our guest today is David Mormon. He is a professor in the Neuroscience and Behavior program at UMass. Can you start by telling us how you got into neuroscience and more specifically, how did you come to a place where you are studying the pathologies of the brain? So thanks everybody for coming out and thank you very much for inviting me before I get to the question. I'm looking forward to hopefully an interactive conversation tonight. So I have been interested in neuroscience for a significant part of all my adult life. I started working in a lab when I was in high school. It was a lobster research lab at New York, Atlanta. So it was at Georgia State University, Chuck Durby, who studied olfaction in lobsters. And so they would drive down to Florida and go scuba diving and collect the lobsters. Best job ever by the way. And collect the lobsters and then bring them back to the lab and we would pluck off their antennas and we'd study olfaction receptors in their antennas. And we would actually do learning studies in them and study how if you paired an odor with a scary looming object to a lobster, how they would react and how they would learn to have fear. And then at the end of the year we'd have a big party and we'd put all the lobsters in. So it was a pretty great experience. That was my high school introduction to neuroscience research. And for me it was kind of tough. I've been working in labs ever since in college and during the summer I went to graduate school and did a couple of post-doc positions. And so yeah, I've been sort of obsessed with neuroscience the whole time. When I was in graduate school I studied cognitive neuroscience. So this question of how we pay attention and learn and remember is these very high level functions that make us sophisticated animals. And at the end of that period of time I was really interested in sort of applying that background to something clinical. You know, so that we could actually bring out of the world and try to help people. And so addiction was something that I was very interested in because maybe as we'll talk about, drug abuse, motivation, addiction, all these things have a lot to do with sort of these high level functions in us. How we learn and how we remember and how we are motivated for things. And so that was sort of what pulled me in that direction towards studying the neuroscience of addiction. And so I've been doing that since probably for about 13, over 13 years. Awesome. So let's talk about neuroscience now. But I feel like before we go deep into it, sometimes conversations between trained scientists and the public, the conversation gets lost because there's the technical way scientists talk and then there's the way most people talk in everyday life. So I wanted to kind of, how do you define some of the terms that are going to come up over and over that might or might not translate into how we use them in everyday conversations. So some of the ones I have are rewards, motivation, addiction, and drugs that we use. So it's actually interesting that you bring this up because these terms are not super well agreed upon. It's not like we can put a quantitative metric on what a reward is or what it is. And these terms have a long history in psychological and some degree neuroscience background. Reward actually is a funny term. I've actually gotten in trouble before using that term because it's a really loose term. So we think about rewards like, oh, you completed an exam and now you get a reward. That's not really what we're studying. When we talk about rewards in sort of scientific perspective, we're talking about something that can be a little bit more operationally defined. And a different term that's often used is the term reinforcer. And so when we use the term like reinforcer, then we can actually use a more precise definition that would be something like an outcome that if given to you will cause you to repeat a behavior that produced it. And so the nice thing about the term like that is that it's applicable to something like addiction or neuroscience, but it's also very applicable to evolutionary biology as you think. So if you're a squirrel and you're looking for nuts and you're going to go find a tree that has the most calorie dense nuts in it and in order to survive, you're going to maybe go repeat that behavior to go get the nuts from that tree. And so that's sort of how we define reinforcer. And this actually comes back to old school psychology form that I could do like that from the early 1900s and late 1800s where they really tried to operationalize these terms. And so that was contrasted with like a term like a punisher, which is sort of the opposite. So you imagine a reinforcer, if something that happens to you, you repeat the behavior. A punisher would be if it happens to you, you would stop doing that behavior. And it's really nice because between those two different dimensions, you can really categorize a very wide range of behaviors. And so that's sort of what we tend to use. And what happens ultimately when behavioral neuroscientists are talking to each other, they use the term reward by and large as opposed to reinforcer. It's just sort of a short end when you're talking about it. So if I say I'm going to give you some cake, that's a reward. If I'm going to give you a drug of abuse, that might be a reward. If I'm going to give you $20, that might be a reward. That's kind of loosely defined, but it's efficient. How about addiction and drugs of abuse? So again, big. These are big, loosely defined terms. So let's always start with drugs of abuse because addiction, I want to unpack a little bit more. So drugs of abuse, again, it's a funny question because a lot of these terms are human and society defined terms. It's not like a chemical. Not all drugs are drugs of abuse. So the question is a drug of abuse from a behavioral perspective would be a drug that ultimately has reinforcing properties. So if you take this drug, it causes you to want to take it again. So that would actually be a reinforcer. Now, there are lots of drugs that are psychoactive that are not reinforced. So for example, anti-schizophrenia drugs are medications that don't necessarily have reinforcing properties. So that's interesting because not every drug that targets the brain is rewarding or produces reinforcing and therefore will not necessarily become a drug of abuse. And so from a behavioral perspective, that's how we would define drugs of abuse. It's something that produces a rewarding property or a reinforcing property and then has the potential to kind of spiral out of control. There's more precise definitions when we dig into the neuroscience of it. And one thing, I've got some slides which I can show later, where what we see is that by and large, all most drugs of abuse target particular systems in the brain. In particular, there's one pathway that you've probably all heard a lot about, the dopamine pathway in the brain. And it turns out that you can kind of predict whether or not a drug is going to be a drug of abuse based on whether or not it produces an increase in the activation of this dopamine pathway. Not exclusively and I have a lot of opinions on dopamine and what it is and maybe we'll talk about that later. But if you want to skip the side of the behavioral perspective and jump into the neuroscience, there are particular brain pathways that these drugs engage which cause them to be drugs of abuse. Now if I want to talk about addiction, that's a more complicated issue. Because again, remember, the term addiction is a disease. It's a term that describes a disease. The scientific community has very much come to the consensus that addiction is a biological disease in the same way that cancer is a biological disease in the same way that diabetes is a biological disease. And it actually has many overlapping sort of disease-like components as things like diabetes or heart disease in that it is chronic, so it's persistent, it can last your whole life. It is relapsing, there's another term that's used, which means that it can come and go. You might get treatment for it, but if untreated, it can come back. And so in a lot of ways, we tend to think of addiction as sort of a psychiatric version of some of these other chronic relapsing diseases that can be treated, maybe hopefully one day cured, but has the potential to stick around and sort of flare up periodically. It's important to note that because there is obviously a very long history of conceptualizing addiction that has failure of willpower or inability to control yourself and a moral failing or a weakness. And for the most part, scientists don't think about it like that anymore. We have good science, we have genetics, we have physiology, we have brain structures. They really show us that addiction is something that changes in the brain. And so because of that, we can now say this is a biological phenomenon, it's a disease phenomenon. It's something that we can actually go after with modern medicine. But given that, it's still a complicated term because, again, it's a human-defined term. Addiction is defined by psychiatrists. The way that we get a formal definition of addiction or dependence is actually how it's described in the medical literature, is there are these diagnostic manuals, the DSM-5 is the version that we're currently on, diagnostic statistical manual, that says here is a list of behaviors that a patient might present with. And if the patient presents with, I can't remember the exact number, five of these, but ten behaviors, then they are probably exhibiting substance dependence. Note that that's not like cancer, where we can find a biomarker and say, oh look, these cells are cancerous, or diabetes, where we can actually take blood glucose levels or whatever. One of the things that we would really like to have, and do not yet have a really good example of, is biomarkers. So this is true of psychiatric diseases in general, depression maybe, and schizophrenia. We know it's sort of like psychiatrists can diagnose it by seeing it, but it's hard to actually say, addiction is defined by the dysregulation of this particular cell, or this particular brain structure. We still know, and it's a product of this and other psychiatric diseases is sort of being in their infancy. So that's a long-winded version. By the way, how does it work with questions here? Should people interrupt me if they have questions? If I'm being vague or if I'm not explaining this, so we'll have a five minute question section after a few questions, and then we'll open it to them. So hold your questions. If I'm not explaining something well, remind me and I'll try and unpack it more later. So I guess right now we're having kind of a societal conversation around several topics related to abuse, and also just drugs in general. First of all we have opioid epidemic, and then at the same time we have something like the push for legalization of marijuana. Have human societies always had this complex of a relationship with drugs, or is this something that we just invented recently? Sorry for that. I love this question. So let me first of all say I am interested in the question of sort of the societal and historical components of drug use. I'm not an expert. There are scholars who are sort of experts in the history and the moral widespread. I dabble in this a little bit, and so I shouldn't be, I'm not going to be able to give you authoritative answers. But I will tell you based on some of the reading that I've done based on being interested in this is yes, humans have been interested in drugs for a very, very, very long time. And it's an interesting question as to whether it's just humans that are interested in drugs. There are always stories that you will hear about elephants that will partake in overripe fruit that has fermented. There are certainly examples of, there's a colony of monkeys in St. Martins or St. Kids that has actually learned to go and get cocktails from the resort. And so they will actually sneak up and steal the leftover cocktails and drink them. So consuming drugs and alcohol and other drugs is not necessarily a purely human phenomenon, but it's much more amplified in humans. And I think there are interesting evolutionary reasons for that which we can get into. But I actually have a couple of slides, just fun pictures, not graphics or anything. So this is actually an article from yesterday in the New York Times. I don't know if you saw this article, there's some stuff in the news about how vaping now is an epidemic. So we have these perpetual epidemics of drugs. I mean vaping is the new form of nicotine delivery. Now that people aren't smoking cigarettes as much, they're inhaling vaporized nicotine flavors and things. So I brought that up because this is a time room topic, right? There's always something in the news. But one of the things that I, in looking through this, is that there's a lot of drugs that have been used over the course of history. This was one that I was not really that familiar with until looking into this. This is called fly agaric or amelida muscaria. It's a wild mushroom. It has psychoactive properties. And this is one of the oldest recorded known uses of drugs. So this is, you know, thousands of years BC. And it has mild psychoactive properties. And so the thought is, basically, there are stories of, who is it, the Iceman? So apparently there were markers of, in his pouch, there were certain fungi that were found. And there's one thought that actually some of these fungi had psychoactive properties. So it is very historic. So we've always had this problem. But it's an interesting question. We've always liked drugs. It's always important, and actually from an addiction perspective, it's important to note the difference between using drugs and having a problem with drugs. And that's important from a clinical perspective. And it's, again, something that we can unpack significantly. And one of the things that we know is that historically a lot of drug use has been medicinal, or it has been religious. And so one of the things that I found really interesting is that in cultures where there's been use of certain drugs historically from shamanic purposes or ritualistic purposes, there's not necessarily a problematic use of those drugs in the culture because it was banned to use them outside of whatever rituals. So they might be taking these mind altering substances, but they're not binging on the weekends. So there's a lot of interesting societal dynamics that are involved in this. But I think, here's another example of something that I found. This is from the USA. So there's a description of this drug called the Nepenthes pharmacone. And it was a drug that was put into the wine and it removed all pain and forgot all evil. And actually Nepenthes pharmacone means the drug that removes sadness. Now does anybody have an idea of what this might have been? That's a good guess. It actually was not. It probably would have the same effect. But we don't actually know exactly what it was, but current scholars think it was probably opium. And so interestingly, opium has been used historically as a pain reliever. So for medicinal purposes, but at least as far back as ancient Greece, it was also used for some of its psychoactive properties. And so we as humans have a very long history of drug use. There's other examples of... Here's another example. This is from the 1700s. It's kind of hard to see. This is a painting from Hogarth where it's actually a duplicate set of paintings. One is called Beer Street and the other is called Gin Lane. And the thought at the time was that on Beer Street, everything was fine because everyone was drinking beer and beer is a healthy drink. But when we started diving into distilled spirits, that's where you get into trouble. And you can see this degeneracy on the right and Gin Lane, whereas Beer Street is a very healthy and happy place. So we have a very mixed historical relationship with drugs. And so there's a question of how we've used it. We've always used it. When did it become a problem, necessarily? How different cultures and societies work? So I think this is a good point to pause and have the public ask questions that you guys have. Yeah. My name is Michael Healy. Thank you for doing the vocabulary to start off. Do you know the origin of the expression gold? Yeah, that's a really good question. Let me just be honest and say no. I don't officially know what it is. There's a temptation to say that it might have something to do with dopamine, which is, yeah, I'm not up on my lingo as well as I should be. And when you get into the drug world, you can dive deep into the lingo. Some of which is used and some of which I've never heard before in my entire life. But yeah, it's a great question. Sorry I don't know the answer. Thank you. Yeah. I'm going to look this up though and I'll try and see if I can find out. Yeah. Do we know if our microbiome has any interest in drugs, basically? So the big answer to your question is, is our microbiome influential in our interest in drugs? And the answer is almost certainly. We don't know how yet. This is an incredibly cutting-edge question. You are about current year cutting-edge research. The whole role of our microbiome, so for people who don't know, who don't study the microbiome, so this is sort of your gut bacteria. And so as you've probably seen, this is a very hot topic right now in biosciences, is that we are made up of millions of sub-organisms, little bacteria that are within our gut and elsewhere. And they historically have been related to things like our digestion and other things like that. But increasingly, more and more we've been finding that the gut bacteria have influences over our mental health and our mental states. So there's a huge line of research with respect to gut bacteria and depression, gut bacteria and other psychiatric diseases. There is the very beginnings of research into this. And so, I mean, the answer is we don't know yet. But given just the strength of what we've been finding as far as the relationship between gut bacteria and other psychiatric ills, I would not at all be surprised to see some sort of relationship. Unfortunately, we don't know what that linkage is. The other thing is what your question underscores, which I think is a really important question, is when we talk about something like addiction, we're talking about a confluence of many, many different components. So one might be our gut microbiome. Another might be our genetic background. Another might be the environment, whether or not we're raised in a stressful environment. And it's this combination of things. And that's one of the reasons that makes addiction such a hard thing to pin down. Well, we can't just pull up a drug that would fix the gut microbiome because it might not fix the genetics or it might not fix the fact that you're living in a very stressful situation. And so I think that each of these different targets are very... People are very excited to study these. I don't know if we're going to find one silver bullet necessarily, but I think that there's a lot of interest in this for sure. Yeah, it's a great, interesting line of research. Okay, so let's continue. Can you tell us a little bit about how the brain perceives a reward and why is the reward system so fine? We always feel like we need something like ice cream. Or why is it? So, again, there's a lot... I teach a class on this. So I teach a class on rewards and motivation and addiction. So it's going to be hard to unpack it into a short hour. So I apologize if I kind of script over things. They might want to sign up for my class. So let's start with, I think, the relatively easy question, which is why do we have this reward system? And it's simply because that's how we survive. I mean, basically, you imagine you want to create an organism that is able to maintain a certain caloric state so that it can go and reproduce and continue on. Again, from an evolutionary organismal perspective. And so the goal of one of our main motivating goals in life is to acquire things that give us calories to keep us alive. And so if you have a system that can very precisely detect what you're going to get something that is calorie-rich and maybe learn about it, kind of like the example I gave before, if you're a squirrel and you want to go find a tree that has the highest quality nuts, well, you should maybe learn what that tree looks like or you should learn where those trees are located and keep going back to that tree. And so from an evolutionary perspective, it's not surprising that we have a system. And I should note, humans are not particularly special. Humans are, you know, have a reward system that can allow them to go find rewards and capitalize off them. You know, basically all of these, definitely all vertebrates, probably most invertebrates, have this system that allows this to happen. And so, again, it kind of, from a general principle, it kind of makes sense. Okay, so that's sort of why do we have this system. How does it work? Again, it's a huge question. And one of the things that's really interesting is, okay, so you might imagine, I mentioned the dopamine molecule, right? So there's, you will see different levels of analysis when you talk about the reward system. The most simple level of analysis is people say, oh, when I see a reward, my dopamine levels go up, or when I get a reward, my dopamine levels go up and it makes me feel good, and so I keep doing that over and over again so that I can feel good. And that, you know, that's sort of a very superficial way of analyzing it. The reality is that our whole brain participates in rewards. And there's actually a really wonderful scientific review that was written by some colleagues who are not Michigan. Basically, going through the literature and just saying, you know, it used to be thought, oh, well, there's a reward pathway. There's the dopamine neurons, and they project to this part of the brain, and this part of the brain, and if you follow that pathway, you get a reward. But it turns out that basically, I don't want to say every part of your brain, but a lot, a lot, a lot of your brain is involved in processing reward. And again, it kind of makes sense. This is one of the most important things you can do is go out and find the appropriate nutrients that you need, right? And so it makes sense that you're a significant part of your brain if you dedicate it to it. There was a study just a year or two ago showing that your cerebellum, okay, which is in the back of your brain, your little mini brain in the back of your brain, and historically, everyone thought that the cerebellum was involved in controlling movement, right? It's just there to keep you upright and maybe make sure your arms stay in the right direction. Well, it turns out that if you study the neurons in the cerebellum, they're exquisitely tuned towards rewards. People have just found that your visual system, the visual cortex, part of your visual system, that should just be detecting whether the lights are on or off, or if there's a line or a circle in front of you, it's sensitive to rewards. And so your whole brain really is processing reward-related information. So there's not one single part of the brain where you can point out and be certain that that's... There's not so much. I mean, here I'll show you. Again, I've got a slide. These are some drugs. Yeah. There's another topic which we might want to talk about is non-drug things that could potentially be addictive, so non-chemicals, which I think is an interesting question. Here's my thing about dopamine. Here we go. So this is a figure from one of the textbooks that we use. And so you can kind of see, it's kind of hard to see, but essentially this here is where your dopamine neurons are located. And they project to all over your brain. And typically there's been what's considered a reward pathway. So these domains project dopamine, they're projected to this area called the nucleus of convents and the amygdala and the frontal cortex, the frontal lobe. And typically when people talk about the reward system, this is kind of what they're talking about. And you'll hear a lot about this. And this is sort of the... You can see it's from the behavioral neuroscience textbook. So this is kind of what we teach our first year undergraduates, right? This is sort of you're dipping your toes into reward neuroscience. But the reality of it is, as I mentioned, it's really just widespread throughout your whole brain. And so do all types of rewards show up in the brain the same way? They all have the same pathway? No. Basically. Again, this gets back to sort of the question that I was getting at before, or the issue that I mentioned before, about how all the drugs of abuse at least activate the dopamine system. And that's one thing. One reason why people are so focused on dopamine is that, in fact, when we learn about rewards, when we do behaviors that produce rewards, the dopamine system does seem to be engaged. So there are certain commonalities. And there's a reason... It seems like I'm kind of poo-pooing this system a little bit. But in fact, this dopamine nucleus of convents system does seem to show up a lot when we are taking drugs, when we're eating food, when we're thinking about sex, when we are bungee-tumping. So there's definitely some commonalities. And then what the details come into is different parts of the brain that come activated depending on whether it's a positive click or thumbs up on Facebook, or a drug of abuse that we snort, or a piece of cake that we eat. Then we start getting into subtle differences across brain structures. So it seems that this has been a whirlwind for a very long time. So it kind of leads us to the questions, are we slaves to the reward circuitry, or even maybe a little bit more metaphysical, is willpower real? Or are we just... Yes and no. There's never an easy question. So in some degree, yes, we are slaves to this system because we have to eat. If we don't eat, we die. And so to some degree, we need our reward system to survive. Now theoretically, I guess you know of a situation where somebody gives you unpalatable food or IV nutrients or something for the rest of your life and you don't really need it. But at least from an evolutionary perspective and for the most part humans in the world, we need this reward system to function. However, are we total robots that are slaves to it? So as soon as you see a piece of chocolate cake you're going to go for it, of course not. We can control it. And so there's a dynamic interplay between the parts of the brain, at least this is my conceptualization, between the parts of the brain that are pushing us to go and get rewards, that are more evaluative and that are saying, well, if you have that chocolate cake, then you need to go to the gym tomorrow or whatever. Or if you pick up that cigarette, there's a high likelihood that you might develop a cancer. And so there's always this sort of evaluative process. And there are parts of the brain that seem to be more involved in this evaluation. So you can imagine that there's sort of this inhibition or response inhibition that is sort of putting the brakes on our reward system. That's one way that people think about it. It's obviously a lot more sophisticated than that. So we do have willpower. We do have willpower. And sometimes it's stronger and sometimes it's weaker. There's a really neat finding that at the end of a long day of work people tend to sort of have less ability to control themselves. That's when we have happy hour. And that's when maybe you want to go out for a burger or a pizza. We have great ideals in the morning when we have lots of energy and we have this sort of energy to control ourselves. But as that gets weaker and weaker, if you've had a longer and longer or more stressful day, you actually have less ability to control, to resist that. One of the other things I think is really interesting, I'm going to jump around again, I apologize. I just want to put this up here. Oh, here we go. So this is a slide from National Institute on Drug Abuse, which is the National Institute of Health that's involved in this. It has a lot of really information-rich slides. And one of the things that they show is this figure of when, I'm sorry, this is data, I was told not to present data, but this is kind of interesting, generic data. This is when people start taking drugs, right? And I can really easily say people start taking drugs around when they're in their teenage years. That's not surprising, that kind of makes sense. You're not going to start smoking pot when you're in your 80s. You're not going to start drinking gin when you're in your 70s. And maybe some people might. But for the most part, you hear about teenagers and stuff that are doing this. Interestingly, when we start seeing a decrease, is about when the brain's frontal cortex finishes developing. So our brains are developing a lot longer throughout our lives than we realize. So the frontal cortex, which is that frontal part of the brain that I talked about, that's one of the last parts of the brain to develop. And it actually finishes developing in your 20s. So, you know, some people hear you're still working on, right? And it turns out that this part of the brain is really important for this willpower, right? And so it kind of all lines up if that makes sense. You know, our prefrontal cortex, our frontal cortex is not fully developed. Other parts of our brain that are driving us to go and get drugs or chocolate cake, whatever, bungee jump, you'll see, right? They're fully developed by the time we're teenagers. So those are ready to go. They're pushing us, right? But we actually don't have as much of an ability to put the brakes on it until we're in our later 20s. And so that's one of the sort of the interesting developmental questions as to why, you know, how willpower develops over our lifespan. And also why we have, like, age restrictions for when to get up on. Yeah, I mean, in a perfect world, you know, you would basically wait until you're able to control yourself. Yeah, in a perfect world. All right, so I think this is a good spot to stop for a second. And anyone want to ask any questions? Yeah. You've been emphasizing that all of the drugs that abuse target the dopamine system. But you've also been emphasizing that lots of other things target the dopamine system. Absolutely. Like food and sex, as well as lots of drugs to which people do not become addicted. Yes. And so clearly the dopamine system isn't the answer to what makes a drug addictive. Right. Otherwise, we'd be addicted to chocolate cake. Right. To good movies. Right. And to DMT. And all kinds of other things. Right. So what do you need to do to kind of partial that out and get down to what accounts for it? It's been taught as well as opposed to, we like it. Yeah, absolutely. That's a fantastic question. I mean, and one of the reasons I really like that question is because what you've done is you've taken the first two thirds of research on addiction and said, okay, now we're going to jump ahead to that. So it used to be that everyone focused on dopamine and said, oh yeah, if we just get a dopamine blocking drug we're going to block addiction. Yeah. But the side effect is you don't like chocolate cake anymore and you don't like movies anymore. Right. And so obviously we don't want to stop that. And so there's a huge number of other, well, so there's a number of different answers to that question. One is that there are a huge number of other brain circuits that are potentially involved. And again, I have a slide actually for this. Here we go. So when we talk about addiction, so there's a lot of, we're talking about modern theories of addiction, right? And so when we talk about addiction, we're not actually just talking about just getting a reward anymore. We're actually talking about when the reward, the drive to get the reward takes over, right? And makes us sort of inflexible and unable to control ourselves. And that's really what the essence of the addiction is. And frankly, you know, if you talk to people who have drug abuse problems, addiction problems, in late stages of addiction, a lot of times they're not even enjoying it, right? They're not actually getting that rewarding feeling anymore from the drug. They are just trying to maintain it. And so that's when we talk about coming up with treatments for addiction, really going after that reward drive or the dopamine drive is really not feasible. That's not really a great strategy. What we really want to study is some of these late stage components that produce the inflexibility or the compulsiveness is one way that we describe it. And there are other brain systems, in particular the brain stress systems. There's a lot of interest in the brain stress systems these days. So there are things like, I don't want to get too jargony or technical, but things like cortical drug and releasing factor and Kappa opioids and things like that. They're considered to be... George Ku is the director of the National Institute on Alcohol Abuse and Alcoholism. He's a famous neuroscientist. And he has this whole model of addiction that he calls the dark side. If you read any of the literature, you will read a million different reviews called the dark side of addiction, which is basically saying that by the time we get to the point of addiction, we're not looking for rewards anymore. We're going into the stress part and you're basically trying to relieve stress and get out of it. And so I think that's where a lot of modern neuroscience is actually looking for treatments for addiction. It's actually looking into these changes that occur in the stress system, maybe at the same time as the reward and the motivation components are happening. But it's not just dopamine that produces these kinds of behaviors. The short version is we don't totally know yet. And one of the reasons is because there has historically been such an emphasis on drugs as rewards that we've focused so much on that that we kind of neglected everything else surrounding it. But now that we're actually starting to look at what other components of addiction are relevant. Now we've got all these other brain targets. Another thing actually that you reminded me of is there's been some really interesting research looking at the timing of when something hits your dopamine system as to what kind of influence it has on your behavior. Some things produce a very slow rise in your dopamine and that might be something like eating good food or something like that. Other things produce very rapid and sharp elevations. And those sharp elevations, the spiking is a term that is used can actually produce more of an addictive like profile. So if you give, for example, if you give a rat two forms of cocaine, slow onset cocaine, you sort of dribble it into their bloodstream slowly. They don't develop really addictive behaviors related to the drug. But if you give them a shot, a really fast shot, they will go crazy. They will be super motivated for the drug and it will have very highly rewarding properties ultimately leading to something like addiction. So the timing of how these drugs or other things affect your brain are very influential as well. So it's not just the brain systems, but it's also the dynamics of how they're engaged and what they're doing to. So that's the long version of we've got a lot of work to figure this out. We have a question on prayer. Yes, in regards to the non-drug forms of addiction, Gamble, who's asked what it hurt? Can't believe the brain does it have the same compulsive strength? That's a really good question also. It has similar. I want to be careful about saying it has the same. It also depends on what part of your brain you're looking at and what system. But these things, things like gambling or internet or sex do have very profound influences over the same pathways that the drugs are tapping into. One of the reasons that casinos are designed the way they are is basically because the flashing lights and the odds of you not getting with that one time that you do when people study this in the lab they'll put humans in brain scanners and look at the dynamics of their brain, fMRI scanners. And they'll have them do gambling tasks. You can't really give somebody a shot of cocaine in the scanner, but you can give them a gambling task. And when you give them a gambling task the same parts of the brain are light up. So the dopamine neurons are activated they're releasing dopamine and particularly if you do sort of the same ratios that they do in the casino where you lose, you lose, you lose, you lose, bang you win and there's flashing lights very powerfully reinforcing and it does actually engage the same parts of the brain. And one of the things I think that your question gets at is, you know, our brains didn't evolve to like heroin, right? Our brains didn't, you know, it's not that that's some sort of evolutionary adaptive feature, right? What's happening is that our addictions or the internet, you know, to get addicted to the internet these are tapping into natural systems that we already have, right? So the brain systems that are involved in positively responding to a drug of abuse are actually the same brain systems that are very largely overlapping brain systems as what are responsible for getting, you know, highly caloric food because that's what we evolved to do, right? This is one reason why, you know, squirrels don't use drugs, right? Because, you know, unless we trick them into doing so. But the most part our animals don't really use drugs because they've evolved to go and get food and that's what their brains are doing. But when, you know, because we're advanced and we've come up with, I guess, creative ways to tap into these brain structures we're basically hijacking these natural reward pathways and using them to sort of increase the amount of positive reinforcement that we get. So I think that there is actually a very similar, I am hesitating a little bit because there's obviously going to be some subtle differences, but there are a lot of commonalities and if it's set up the right way you can get a very drug-like brain response to something like a casino win or, you know, or sexually arousing stimuli, for example. Alright, so let's go through a couple more questions and then we'll come back to the audience. So you show this slide where you see when people start using drugs but is there some research that tells us what kind of people are going to become addicted? Is there something genetic? Is there something about the environment? So yeah, that's, I mean, again these are the questions, right? These are the important questions and it kind of gets back at some of the questions that you asked before. There's a lot of factors that influence proclivity to use drugs. Which drugs people use? And also, you know, proclivity to risk behavior, right? Proclivity to seek out high-fat foods, right? More than others. And so there are differences among people. I think that's what doesn't have to be said, right? The question is what causes those differences and I think this is getting back to some of the questions that we addressed earlier. There are genetic components. There are environmental components. One of the statistics that people talk about is that lots of people try different drugs in use. For the most part, the numbers of people depends on the drug, but for the most part it's usually only 20 to 25% of long-term users who actually develop what psychiatrists would refer to as addiction. And so the question is why? What's, you know, what's unique about that? And it could be a genetic issue. It could be a developmental issue. It's very likely a combination of those things. People are also interested. It turns out that if you study lab animals, mice and rats, if you give lab rats cocaine, about 25% of them will develop what we call addiction-like behaviors. So they will keep pressing the lever for cocaine even if there's no cocaine available, or even if there's a shock that's associated with cocaine. But it's not all rats that will do this. Only about 25%, 20 to 25% of them. And it turns out that's about the same number in humans that will actually go and meet diagnostic criteria for addiction. So there's something about individual differences that's underlying this. Does the specific drug change this kind of ratio of people who become addicted? It fluctuates a little bit. It definitely depends on the drug a little bit. And there are other factors too. Drug availability, right? We see a lot more alcohol addiction than we do other drugs of abuse. Well one reason is because alcohol is a lot more widely available, right? People start drinking at a very young age. They might not have exposure to other drugs of abuse until later. So again, that's another factor is when you actually start using drugs, these drugs have a very profound effect on the development of your brain. And so, you know, when you start using drugs at an earlier age, that's going to have an influence on your ability to use drugs at a later date. I don't want to dodge the question too, too much, but it's just such a complicated question. There's so many factors. One of the things that's really hot topic right now is this term called epigenetics. And this idea that you're actually passing genetic information on from one generation to the next, but environmentally influenced genetic information. And so one thought is that parents who use drugs can have changes in their genes that can actually go and influence their offspring. And so there's a lot of really complex interactive factors that play a role in this. And thus becoming addicted to one drug will lead you to, or increase your chances of becoming addicted to a second drug. The gateway hypothesis. Yeah, right. Again, it depends. There is a possibility. So there's the possibility that you can get cross-drug sensitization, sort of the concept that people talk about. Where you increase your reward seeking, you increase risky behavior. There's a high coincidence between people who drink and people who smoke, right? There's a high coincidence between people who take other drugs and smoking and alcohol. What we don't know is, is that a biological phenomenon? Or is it just that, you know, you're running with a crowd that drinks and smokes and somebody's got some cocaine so everybody tries it, right? So we don't totally know. But again, we can go back to sort of animals. One nice thing about studying this in animal models is that we don't have the social component, right? We can extract that and just look at the biological component. And it turns out that, you know, animals that are are high drug users of one particular type sometimes will also be high drug users. But not always. And there's actually a lot of really interesting research in humans and animals that, for example, opiate users, so heroin and other users, are in a lot of ways different from psychostimulant users, cocaine users, and or emphatomy, methamphetamine users. And they do it in different places. So opiate users tend to be use opiates in, more like in the home or in small groups, whereas psychostimulant users tend to be doing it out in the world and being more active. So there's, you know, again, this kind of gets the cultural and social aspects of the drug use, which may be also influenced by the genetic components as well. How about the opposite hypothesis that, for example, there's a wide belief that marijuana use is somehow preventing people from becoming addicted to opiates. Yeah, I mean, marijuana is an interesting drug. I think that it's so controversial right now as to whether or not marijuana has a addictive profile at all. I think that, for the most part, the literature suggests that yes, it does. But how? And after how much? And, you know, we don't have the same history of researching marijuana that we have other drugs of abuse. Right now, obviously this is a hugely hot topic with this being legalized in Massachusetts and other states. I think we're about to see, you know, a massive experiment being done in society, right? We know what effect widespread alcohol use has because alcohol is everywhere in every culture, right? But something like marijuana is not necessarily. It's not nearly as widespread though. It's becoming that way. Why marijuana might prevent opioid abuse might be just a divergence issue, right? So that people are basically getting a certain amount of pain relief or relaxation or, you know, some other psychoactive properties from the marijuana and so they don't actually ultimately go and need to use the opiates as much. Now, it's this question. I want to be a little bit careful. I don't want to be in a situation where I'm saying, you should use marijuana, not opiates. You know, A, I'm not a doctor. And B, you know, these are complicated issues and the cultural belief, right, is that marijuana is a safer drug than heroin. And I think that's, you know, understandable. I think that there is a lot of interest in understanding, based on scientific research, if this is actually true, you know, how much marijuana use is bad? Is, can you reach the same level of problematic marijuana use as you can with opiates? We don't, you know, or other drugs. We don't know the answer yet. And so that's why, you know, we're all kind of aware of the fact that kind of people think of marijuana as sort of a safe drug, safer than other drugs, but we just don't have the data on it yet. And we really, you know, be careful. Alright, so we're running out of time, but we'll open the floor for more questions. Yeah. So I have a question in regards to the age as to when somebody might experiment with it. It could be a drug, but it could also be something social. Sure. So is there a theory, evolutionarily speaking, why the prefrontal cortex is not developed until the 25 when everybody is experimenting so much earlier? Doesn't make any sense, right? No. I mean, it's like natural selection, which will thin out the herd, some will die in the car. I like that theory. No, actually, that is an awesome question. And there's actually there's some work that's being done right now that is proposing that it is actually evolutionary. Because what you want to do when you're young is you want to explore, right? You want to go out and see what you want to find the best reward possible. You want to go out and find mates, right? You want to go out and experience all the different things in the world so that you can start making informed decisions about them. You know, and that might be in humans, it might also be in animals, too. And so one thought, I don't know if this has been proven yet, but one hypothesis is that the brakes develop a little bit slower so that you have that freedom to go and explore. Because exploring and having these exposure to experiences can actually be a very good thing, you know, if it's safe and if it doesn't need to car crashes. Right, right, exactly. You don't have to stick your hand in the fire. Don't stick your hand in the fire. I just talked to him. I learned that I should stick my hand in the fire. But, you know, that's one way that you learn, right? Is by trying things out. And so in order to build a model of the world, you have to have experiences. And so if you had something that prevented you from having experiences, you really wouldn't have a very thorough model of the world. That's one theory, you know. Whether or not there's also the thinning of the herd hypothesis as well, you know, that's another possibility. You know, there's a lot of, it could also be just developmentally, you know, we need to be protected longer, right? And so it's basically a consequence of our prolonged brain development that requires us to be in a culture or in a family or somebody that can actually protect us from doing crazy things. So the other question is, is it just that regularly available drugs of choice are more new to us than maybe thousands of years ago? Like we have a career that is regularly available now as a modern culture. I'm just wondering if that starting to as we more understand that we put limits on when alcohol can be consumed at 21-year-olds and still the brains are not formed properly. So is it just that it's a newer more readily available thing that within the last, you know, say a thousand years or so is a thing I don't know. Again, these are great questions. It kind of hits at this societal interaction with the biology, right? And, you know, one of the things you think about is something like the industrial revolution, right? Basically, when our lives started becoming easier, right, we didn't have to go out and work in the field as much, you know, basically spend all day working and then go home and pass out, right? That's when you start seeing a lot more widespread problematic drug use. Like I said, there's always been drug use historically and there's always been problematic drug use. I actually was looking and apparently Alexander the Great died probably because of complications of excessive alcohol use. So, you know, there's always been issues with this. But if drugs are readily available, if we don't have as much of a need to go out and, you know, work to get our food or hunt to get our food or something like that, then we're going to have a higher likelihood of wanting to use these drugs to tap into these brain systems. I mean, again, this is sort of my pet beliefs based on what I've read in the literature. It's something that I've done any particular study on. But it makes sense that we see a rise in problematic use of drugs or, you know, things like the internet, right, or cell phones or whatever, right? We didn't have those before, right? So, of course that's your experiment right there is that, you know, there was no problematic internet use before there's the internet. But as soon as we have it, wow, if you got a way to cause problems with it, right? So that now we, you know, people are actually getting clinically diagnosed with internet use disorders. So we basically come up with really clever ways to entertain ourselves and then get excessive. And I'm sure it's the case with drugs of abuse and other things as well. Alright, so it seems we've run out of time but if you guys want to ask more questions, we'll stay a bit... Yeah, I'm happy to answer more questions. Thank you all for coming guys. Thank you.