Addiction (featuring Dr. Marcelo Wood)

Daniel and Kelly interview Dr. Marcelo Wood about what addiction does to our brains, why some of us become addicted to drugs while others don't, what drugs do to our brains in the long term, and more. See omnystudio.com/listener https://omnystudio.com/listener for privacy information.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Daniel Whiteson?

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• 3:43Daniel Whiteson?

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• 4:15Kelly Weinersmith?

  Howdy, extraordinaries. As you might expect from the title of the episode, today we're talking about addiction. We're going to be talking about sensitive topics like drug use, drug abuse and suicide. So please decide now if this episode is a good fit for you or for kiddos who might be within earshot.

• 4:39Kelly Weinersmith?

  According to the Substance Abuse and Mental Health Services Administration, in 2024, among people 12 and older, about 17% of us, or nearly 50 million people in the United States, struggled with addiction. What is it that drugs do to our brains that make them so addictive? And why is it that some of us can try these drugs once and then leave them alone while others of us become hooked? And what happens to our brains long-term after we've become addicted to a drug of abuse? Well, it wouldn't be an episode of DKEU if we didn't say, we don't know, at least a few times throughout the episode. But today, we're bringing on a guest who will give us the latest insights into our understanding of addiction.

• 5:23Kelly Weinersmith?

  Welcome to Daniel and Kelly's Addictive Universe.

• 5:39Daniel Whiteson?

  Hi, I'm Daniel. I'm a particle physicist who likes to think and write about aliens and I have several very healthy habit-forming non-addictive behaviors.

• 5:48Kelly Weinersmith?

  Hello, I'm Kelly Weinersmith. I study parasites and space and I certainly have the kind of personality where I worry that if I were to ever try a bad drug, that I could get addicted.

• 5:58Daniel Whiteson?

  Really? All right. So my question for you today, Kelly, is what is something in your life that you've given up?

• 6:04Kelly Weinersmith?

  That I've given up?

• 6:06Daniel Whiteson?

  Other than cleaning Zach's office.

• 6:08Kelly Weinersmith?

  Oh, man. Yeah, I threw my hands up at that one. He actually, he told me the other day that it's not fair that we keep harping on the Doritos bag because he did clean that up. But, but the rest of the office.

• 6:21Daniel Whiteson?

  The point of those jokes is not the Doritos bag specifically. It's what the Doritos bag stands for.

• 6:27Kelly Weinersmith?

  Represents. I know. I think he's missing the point there. But let's see, what did I give up? There was a time where I was having a glass of wine every night and then it was two glasses of wine and then I realized I was starting to think about how I was really looking forward to the glasses of wine. And, and then I started thinking about my family history and our relationship with alcohol. Not my parents, they both make great choices about alcohol, but a couple generations out from that. And I decided I don't need a glass of wine at night. And so I stopped my evening glass of wine. I also have a glass of wine sometimes if I go out to dinner with friends or something, but I felt myself drifting in a direction that I felt was maybe not the right direction for me. What about you?

• 7:11Daniel Whiteson?

  Yeah, I have friends who feel the same way and they do things like Dry January, where they're just like, I'm just going to not have any for a month just to prove to myself that I can.

• 7:20Kelly Weinersmith?

  Yeah.

• 7:20Daniel Whiteson?

  And in my case, that was never something I was doing all the time. But there was a period in my life when I was enjoying banana peels quite regularly and I decided, you know what, I'm going to see if I can take a break. And I did about six or seven years ago and still on that break.

• 7:39Kelly Weinersmith?

  Did you feel better when you went on that break? Or was it, why are you still on that break?

• 7:43Daniel Whiteson?

  Yeah, no good reason. I just didn't feel like going back. I mean, maybe I have fewer crazy ideas to inspire my research, but.

• 7:53Kelly Weinersmith?

  You're still doing all right. You're still doing all right.

• 7:55Daniel Whiteson?

  I'm still doing all right. When I start running out of research ideas, then I'll dip back into that. But until then, I'm staying clean.

• 8:04Kelly Weinersmith?

  All right. Well, I think you could just go on a jog and that might, that might help you, but.

• 8:08Daniel Whiteson?

  That's Kelly's answer to everything. Have you tried jogging?

• 8:12Kelly Weinersmith?

  Have you gone on a jog? And the funny thing is I haven't jogged. I've given up jogging apparently because I haven't done that in a while. I've just been too busy. I got to get back to jogging.

• 8:20Daniel Whiteson?

  But exercise is a fascinating one because there are people who exercise very regularly and are addicted to it to the point where like, maybe it's not so healthy. It's okay to take a day off, kind of a thing.

• 8:31Kelly Weinersmith?

  Yeah.

• 8:31Daniel Whiteson?

  Yeah, it's fascinating. Where even healthy seeming habits can be overdone.

• 8:36Kelly Weinersmith?

  Yeah, yeah. I think it depends a lot on, on your personality. I certainly am capable of overdoing just about everything. And in a lot of cases, I can funnel that towards productive activities where it doesn't do me too much harm. But I think I've been lucky in that way.

• 8:50Daniel Whiteson?

  But enough of our clueless speculation. Neither of us are giving you advice about how to live your life and we're not medical doctors, so we shouldn't be talking about this. Instead, we decided to invite somebody on the show who does know what they're talking about and can give us the actual cutting-edge scientific basis for addiction.

• 9:06Kelly Weinersmith?

  Yes, and our motivation for doing this, in addition to just happening to know a person who studies addiction and is awesome, is that we had two questions from listeners focused on addiction. And so let's go ahead and listen to those questions now.

• 9:19Daniel Whiteson?

  Hey, Daniel and Kelly. Greetings from beautiful Kambucha, Rich, Blacksburg, Virginia. I've got a question for y'all, which is mostly for Kelly this time, and it's about addiction. If I don't drink my coffee in the morning, I get a gnarly headache. Why is this? Being addicted to coffee seems like it may be overall good for human health, so continuing my morning ritual isn't much of an internal struggle. However, for addictions that are detrimental to our health, what is the mechanism that causes otherwise rational people to continue these self-destructive habits like tobacco or other more nefarious substances? Thanks as always for your awesome pods. Can't wait to hear y'all break it down. Hi, Kelly and Daniel.

• 9:59Daniel Whiteson?

  I guess my question distills down to why we get addicted to sugar when it's so harmful to us in so many ways and.

• 10:09Daniel Whiteson?

  How is that if ketones are so good for you and make you feel so much better? How is it nobody seems to be addicted to ketones? That'd be an interesting one for me. And one of my favorite things about living in the sort of faculty ghetto at UC Irvine is that I just happen to know people nearby who study this and that and the other thing. And so they're a great resource because also they're too polite to say no when we invite them on the podcast.

• 10:36Kelly Weinersmith?

  Hooray. So let's go ahead and get our guest who couldn't say no on the show. Dr. Marcelo Wood is a professor and chair of the neurobiology and behavior department at the University of California Irvine. His lab works on understanding what's happening in our brains when we form long-term memories with the goal of helping us combat memory loss related to aging and neurogenerative diseases like Alzheimer's. His lab also explores how drug abuse impacts memory circuits in the brain and seeks to use this information to help prevent relapse. Welcome to the show.

• 11:09Daniel Whiteson?

  Thank you so much. It's a pleasure to be here.

• 11:11Kelly Weinersmith?

  Well, the first question that I really need to know the answer to is that I wrote Daniel and Katrina to be like, do y'all know anyone who studies addiction? And they were like, our neighbor studies addiction. So the first thing I need to know is what is it like living next to Daniel and Katrina? And is it a problem that they are members of this weekly bean club?

• 11:32Daniel Whiteson?

  It's fantastic living next to each other.

• 11:34Kelly Weinersmith?

  Okay, that's great.

• 11:36Daniel Whiteson?

  Absolutely.

• 11:37Kelly Weinersmith?

  Oh, that's it? No insights?

• 11:39Daniel Whiteson?

  Yeah. Our boys used to play a lot in the street behind our houses. That's true. And I remember going over there like, Silas, it's time to come home. It's dinnertime. And he's like, no, I need a drink of water. And I'd be like, well, we have water at home. And he's like, the water at Marcella's house is so much better. I did not know that. That's great. We actually left a Google review on your house saying, the water here is excellent. Yeah, five stars. That is hilarious.

• 12:06Kelly Weinersmith?

  All right, all right. We'll transition into more serious topics. So we had a handful of listener questions specifically about addiction, but they were asking about different kinds of addiction.

• 12:17Daniel Whiteson?

  Sure.

• 12:18Kelly Weinersmith?

  But let's start with just like, what is the general definition of addiction?

• 12:21Daniel Whiteson?

  Yeah. So first, in order to understand addiction and put it into its context, I like to think about what our brain actually evolved to do and why drugs of abuse do what they do. And so to kind of put it into the right context, it's useful to think of the reward system and the reward circuitry in your brain. What does it do? What is it there for? How did it evolve? And basically, the reward circuitry in our brain has evolved and designed to allow us to remember and respond to things that we did right. So things that are good for our own survival and the survival of our species.

• 13:01Daniel Whiteson?

  So those two things are critically, critically important, and our brain has evolved to meet that requirement. So my brain is rewarding me for buying that chocolate bar at Trader Joe's because it's good for all of humanity, you're saying? Potentially. Depends on what chocolate means to you. And I agree, chocolate means a lot to me. So for example, things like food, sex, social bonding, all those kinds of things, if we do correctly, our brain rewards us for it and uses a neurotransmitter called dopamine to say, hey, yeah, we did this thing and we need to do that again because it was really good.

• 13:44Daniel Whiteson?

  And dopamine release in the reward circuitry is our motivator. It's telling us, yeah, we did the right thing at the right time and we need to remember that. And so the reward circuitry in the brain is intimately tied in with the learning and memory circuitry. Oh. So that's why my lab works on both of these things together. You can't dissociate addiction and reward behaviors from learning and memory. They're intimately tied together. That seems so obvious now because rewards only work if you remember them, right? Exactly. Yeah. And so we do something right and our brain releases dopamine and the dopamine levels

• 14:26Daniel Whiteson?

  change how the neurons in our brain talks to each other. And then those signals then go to the prefrontal cortex in our brain. That's our decision-making area. And it says, okay, yeah, what we did was great. We're going to do that again, or we're going to plan how to do it again. So we can try and travel into the future and say, in the past, we did this right. Now in the future, we're going to do it right again and it's good for us. So that's the kind of foundational context of what your brain does. And then drugs of abuse, unfortunately, tap into all of that. And so drugs of abuse and different drugs have a different mechanism of action, but what they all do is they hijack that reward circuitry.

• 15:09Daniel Whiteson?

  And then they trick your brain into thinking, whatever that was, that was 10 times better, 1,000 times better, a million times better than food, than sex, than social bonding, all these natural rewards. And so now the brain sends that signal to the prefrontal cortex for decision-making and says, well, whatever that was, the neurotransmitter levels were so different and so important that now we have to pursue that. That has to be better for us. It has to be better for our survival, the species, et cetera, because the neurotransmitter levels change so much. And so that's what grabs your brain.

• 15:48Kelly Weinersmith?

  So I'm thinking of a drug like cocaine and cocaine, like the plants that cocaine comes from, maybe don't benefit from us getting addicted to them, although maybe we do. Maybe we grow a lot more cocaine plants because we're addicted. But like, why, why does cocaine have this compound that does this to our brain? Is that because it benefits cocaine plants in some way and they're hijacking our brain for their own benefit? Or is it just like, this just was an unhappy coincidence?

• 16:14Daniel Whiteson?

  Yeah, that's a fantastic question that I have actually never been asked.

• 16:17Kelly Weinersmith?

  Oh.

• 16:18Daniel Whiteson?

  So cocoa plants, they grow naturally all throughout South America, four or five different countries that have huge production. And the cocoa plants have that base compound for cocaine. It's very, very little in the leaves and perhaps by animals chewing on that and then getting a very little bit of sensation of, yeah, that's, that's great, that helps that plant propagate. I don't know, actually.

• 16:45Kelly Weinersmith?

  Okay.

• 16:46Daniel Whiteson?

  So you've described how our brain gives rewards in response to certain behaviors and how some drugs can short-circuit that, giving you that reward or an enhanced version of that reward without those behaviors. But what about the addiction part? Like that describes how this is fun, this tastes good, or this feels great. But isn't there more to addiction? There's something about it that's biological or psychological? Yeah, absolutely. And we can talk about this and as this conversation goes, it's really difficult for people to understand what drugs of abuse do and how it becomes a disorder. And is it really a disorder? Some people actually argue about, is it a brain disorder or not?

• 17:26Daniel Whiteson?

  And the reason comes back to what you asked, Daniel, that when we first experience drugs of abuse, it's voluntary. It might be a pain medication like opioids. Frequently, it starts with pain management. But opioids, they do two things. One, they release the brakes on that dopamine release and the dopamine neuron function. So it's like releasing the emergency brake on a car or not having brakes there, you can go a lot faster. It's a lot better. The second thing that opioids do is they engage hedonic feel-good response. So with those two things in play, your brain has a real hard time saying no to it and it wants it more.

• 18:10Daniel Whiteson?

  And so you start to get this pattern of continuously taking it and continuously seeking it. And some people can still stop after months, years, a decade, they can, they can stop. But others continue down a more compulsive path. Part of your reward circuitry has to do with habits and compulsive habits and patterns of action. And so that part of the reward then starts to get rewired so that someone starts to compulsively search and take drugs of abuse like opioids. And then what happens is the brain starts to compensate for that.

• 18:51Daniel Whiteson?

  So your brain does not want to have dopamine release constantly flooding the neurons and having the neurons constantly activated. It can become neurotoxic. So your brain starts to decrease levels of the receptors where the drugs are bind to. So your brain decreases those receptors, tries to fight this constant push by the drugs of abuse. And then what happens is people start to have these anhedonia-type effects where normal rewards aren't pleasurable anymore. Food is not pleasurable. Sex is not pleasurable. Even you're taking your drug of abuse isn't pleasurable, but you're scratching that itch to get it. Wait, I never realized that.

• 19:35Daniel Whiteson?

  You're saying if you become addicted or if you overstimulate, then...

• 19:39Daniel Whiteson?

  Other activities which normally would give you a pleasurable feeling start to feel less fun?

• 19:45Daniel Whiteson?

  Right.

• 19:46Daniel Whiteson?

  Oh, my gosh.

• 19:47Daniel Whiteson?

  And this is a whole other conversation. It's almost similar to what some people, not all people, some people experience on GLP-1. GLP-1, which I don't know if you've heard, has been affecting people that are addicted to alcohol and probably other drugs as well. Alcohol is where the story first broke. And now there are clinical trials trying to understand how does GLP-1 agonists affect alcohol and drug pursuit? But there are some people that are being affected because it affects dopamine function in the brain. You don't feel like pursuing food anymore. But the other consequence is you don't feel like pursuing other things either. So you get anadonic. There's anadonia, depression.

• 20:31Daniel Whiteson?

  And so people are trying to figure out, is that a dose-dependent effect? Is it a drug-specific effect? Like, one company makes this type of agonist, et cetera. So there are all these competing things happening in the brain.

• 20:43Kelly Weinersmith?

  So is that like, if you're on GLP-1, you're not only less interested in eating, but you're also less interested in alcohol? Or are you more interested in alcohol? Yes.

• 20:53Daniel Whiteson?

  Less. Yeah, and less. And it's not all people. It depends on a lot of factors. But there are subsets of people that that's exactly what they feel. They don't want to pursue food. They don't want to pursue alcohol. But they don't want to pursue anything. That dopamine motivation signal isn't coming through.

• 21:11Kelly Weinersmith?

  And are we able to predict, like, you know, so lots of people are prescribed opioids for pain. Some of them become addicted, some of them don't. And lots of people get GLP-1s. Some people become less interested in things like alcohol, some don't. Can we predict how people are going to respond to this stuff? Do we understand individual variability in this stuff?

• 21:30Daniel Whiteson?

  Yeah, that's a great question, and that's a huge area of investigation. Because in some aspects of basic research, it's really hard to get at the genetics and the individual genetic variability. On the other side, you know, humans are highly variable. And even, and we can get into epigenetics, which my lab studies on, and that speaks to persistence, but it also speaks to this individual variability. And so it's really hard to tie down who might be susceptible and who might not be. That's a great, great area of investigation right now in science.

• 22:06Daniel Whiteson?

  You've sketched out this sort of cartoon version of how the brain works. Thank you for making it accessible to us. But I also wonder how much of that is our speculation? And how much of that is really grounded in measurement and theory and understanding the brain itself? Which, to my limited understanding, remains a mystery even at a fairly basic level. Like, do we know how these things really work at the neuronal level and the prefrontal cortex and all that stuff?

• 22:34Daniel Whiteson?

  Yeah, yeah. So through basic research, two things here. One, we know that when classifying a drug of abuse as addictive, you can go across species. And you can see that almost all species will self-administer a drug of abuse, like cocaine, opioids. A lot of species will self-administer if given the opportunity to do so.

• 22:58Daniel Whiteson?

  So there are like labs out there that give rats cocaine or like birds cocaine?

• 23:03Daniel Whiteson?

  Yeah. And so, because the reward circuitry in the brain is one of the oldest circuits in the brain. So, for example, I'm working with a professor at UCLA right now, trying to understand how opioid neurotransmitter system evolved. So one of the things we're looking at are hagfish, which are one of the oldest, oldest animals out there.

• 23:28Kelly Weinersmith?

  Slimiest.

• 23:29Daniel Whiteson?

  Yeah.

• 23:30Daniel Whiteson?

  Are those the ones that produce like incredible volumes of slime?

• 23:33Kelly Weinersmith?

  Yeah.

• 23:34Daniel Whiteson?

  So we're trying to sequence the DNA of hagfish right now to understand how these genes sets evolved, duplicated, specialized.

• 23:43Daniel Whiteson?

  And so, I never thought I'd be asking this question, but what does a hagfish do when it snorts cocaine?

• 23:48Daniel Whiteson?

  Now, we don't know.

• 23:49Daniel Whiteson?

  Somebody's got to do the experiment.

• 23:52Daniel Whiteson?

  They have the receptors.

• 23:55Daniel Whiteson?

  Yeah.

• 23:56Daniel Whiteson?

  So going back to your question, a lot of the mode of action has been well-characterized. We know what the receptors are. Once you identify the receptors, you can see, okay, where are those receptors in the brain? So that then starts to tell you the circuitry. And then people have been studying the circuitry at many, many different levels. So we know what brain regions, we know what cell types in those brain regions, we know the acute chronic effects of different drugs. All that is really well-worked out. I think one of the real unknown domains in addiction is, again, coming back to what you asked, where does the persistence come from? How is it that you can experience a drug of abuse?

• 24:40Daniel Whiteson?

  For example, like methamphetamine, and that leaves a molecular signature in your brain for decades?

• 24:47Kelly Weinersmith?

  Wow.

• 24:48Daniel Whiteson?

  Right? How does that happen? And so there are very, very few molecular mechanisms that can give you that. And epigenetic mechanisms is one of those. And that can explain, and I'll talk about epigenetics in a minute if you want, but epigenetic mechanisms can explain how a single event or a pattern of events can be encoded and stay persistently encoded in the brain. And that happens throughout your body. Your body uses these mechanisms for development and differentiation of different cell types and tissues. So your brain uses these mechanisms as well. But then, somebody can be abstinent for decades, and then a certain cue, a signal, a context

• 25:30Daniel Whiteson?

  will trigger the reward pathway to reengage, and the person will seek the drug. But then because of absence of the drug, the tolerance that they had developed a long time ago, isn't there anymore. And yet, they will take the same amount of drug that they used to. And that is the kind of thing that leads to overdose deaths. And so there are all these aspects of abstinence, what happens during abstinence? How does that persist through decades? How does relapse occur? How do we stop relapse? All those kinds are the major open questions in the field of substance use and use disorders.

• 26:11Kelly Weinersmith?

  And those are some pretty important questions.

• 26:13Daniel Whiteson?

  Yeah.

• 26:14Kelly Weinersmith?

  We haven't, on the show before, talked about epigenetics, I don't think. So could you go ahead and explain what epigenetics is?

• 26:20Daniel Whiteson?

  Yeah. So epi means above, and genetics, your genome. So it's literally above the level of your DNA. So your genome is your DNA. And your DNA, we know exactly what that looks like. We can sequence every individual person's DNA, and we will know exactly what it looks like.

• 26:41Daniel Whiteson?

  Right.

• 26:42Daniel Whiteson?

  And your DNA has a very fixed level of information capacity. And that encodes all your genes, how those genes are turned on and when, and gives rise to our blueprint, right? Our body, our function. But then, the epigenome, it's a collection of chemical modifications on the DNA and the proteins that wrap the DNA. So for example, if you took just one cell of your body, you have 46 chromosomes in that one cell. And so that nucleus is microscopic and has 46 chromosomes. So if you unravel those chromosomes and put them head to tail, you would have six feet of DNA.

• 27:26Kelly Weinersmith?

  That's crazy.

• 27:27Daniel Whiteson?

  Six feet, six feet in this microscopic nucleus.

• 27:29Daniel Whiteson?

  All rolled up inside every single cell. Amazing.

• 27:32Daniel Whiteson?

  And so, the DNA gets wrapped around these proteins and compacted, massively compacted. It's about a 10,000-fold level of compaction. Like, if you took a piece of paper and folded it in half, and folded that in half, and that in half, you can do that seven or eight times. This is 10,000-fold. It's a number our brain can't really comprehend. And so all your genes are in that tight little mix. And so you have to access and turn on your genes, and your epigenome does that. Your DNA is totally fixed, so a liver cell has the exact same DNA as a kidney cell. But a liver cell is only expressing genes for liver function, kidney cell is only expressing kidney genes.

• 28:16Daniel Whiteson?

  All the other genes are repressed, they're shut down by an epigenetic mechanism that controls this. So your epigenome controls how your genes are turned on and off and regulated. And here's the crazy part. Your DNA gets these little chemical modifications, the protein that helps compact the DNA gets little modifications. That whole collection of modifications is called your epigenome. Every epigenetic modification is a metabolite. So our diet, our experience, our sleep, our stress, the pesticides that we eat in our food, all get integrated into that platform. And that's how we adapt within our lifespan, right?

• 29:01Daniel Whiteson?

  So there's evolutionary adaptation, that takes eons. And then there's within-organismal adaptation to your life experience. And the crazy thing is, people think that the epigenome can also be a source of heritable experience.

• 29:18Daniel Whiteson?

  That you could pass it on to people.

• 29:20Daniel Whiteson?

  Right. So things that your grandparents experienced would be epigenetically inherited by you, and it can skip generations. So these are all things that people don't understand. The phenomena have been observed, they exist, but we don't understand the mechanism.

• 29:34Daniel Whiteson?

  So if my grandparents had some like amazing transformational chocolate bar 100 years ago, that could have been somehow encoded and passed down to me and led to me appreciating chocolate even more?

• 29:45Daniel Whiteson?

  Potentially. And so where they've shown that to be true is with odors associated with fear responses. And so that you can track within a species but across generations. A grandchild of a grandparent that had an odor associated with a terrifying experience, they'll be weary of that odor for no reason. They've never experienced the fear component.

• 30:11Daniel Whiteson?

  Wow.

• 30:12Daniel Whiteson?

  But we don't know how that works.

• 30:13Kelly Weinersmith?

  I remember I had read about, I think it was Michael Meany's experiments on how moms treated their babies and how that impacted the way they responded to stress for the rest of their lives. And I learned about that right before I got pregnant. And every time I got stressed out, I was like, no, I'm going to ruin my daughter. And then that stressed me out even more. And it was this like feedback. And eventually, my husband was like, you gotta, here's some ice cream, calm down. And I was like, all right. And I'd feel better. But all right, let's take a break. And when we get back, we'll unpack epigenetics a little bit more.

• 30:52Daniel Whiteson?

  Hey, I'm Niall Rogers, producer, songwriter, guitarist, and co-founder of the group Chic. A great song has a way of defining a moment, a moment of joy, heartbreak, or anything in between. This fall, I'll be driving across the country, dropping in on some of the coolest, most fascinating artists working today. We'll go deep into their lives and careers and hear what it was like before the moment that made them. From hitmakers like Miguel...

• 31:25Speaker 04

  That last year, finishing that record was the hardest experience of my life. Regardless of how everyone else buys into this, I believe in this and I'm gonna push.

• 31:37Daniel Whiteson?

  To rising stars like Alex Warren.

• 31:40Speaker 04

  You know, a song is a story and the verse is setting the scene. And for me, at least, it's allowing me to be personal and vulnerable with the audience, whether it's about my wife and I'm being vulnerable about her, or it's about, you know, my parents and I'm being vulnerable to them. And it's almost like a cinematic piece in a way where each song tells that beautiful story.

• 31:58Daniel Whiteson?

  It's gonna be one hell of a trip. Experience Before the Moment, a Lincoln Original Series on the iHeartRadio app, YouTube, or wherever you get your podcasts.

• 32:11Speaker 03

  This is Jason Tipp from Hoops Tonight with Jason Tipp. Buy smart, drive for less, and trade for more. That's Toyota Ford ability. And it starts with a great deal on an off-road ready Tacoma or half-ton Tundra, two of Toyota's longest-lasting trucks, combining power for work, tech for adventures, and style in between. Built on a reputation for quality and reliability, Toyota trucks are known for holding their value, which can mean big savings when it's time for your next Toyota. So get a great deal today and great value tomorrow. Shop toyota.com for more. Toyota, let's go places.

• 32:42Daniel Whiteson?

  The biggest game of the season, right here, right now. Starts Saturday strong. It's Big Noon Saturday on Fox. And here we go. It all starts at 10 Eastern with Big Noon Kickoff, live with an epic pregame. The crowd, the atmosphere, this is what makes it special. Then it's America's number one game. What a hit. The best pregame, the best announcers, the biggest games. Down the sideline, touchdown. It's Big Noon Saturday, noon Eastern on Fox.

• 33:12Speaker 05

  This is Hoda Kotb from Joy 101 with Hoda Kotb. Halloween has a funny way of making you buy things you'd never normally buy. A 10-foot skeleton? Sure. A full-size fog machine? Why not. Three bags of candy that somehow become six bags of candy? It happens. Which brings me to the Chase Freedom Flex Card, the savvy decision that will earn you more cash back on the everyday purchases, plus the extraordinary Halloween tricks and treats. With Freedom Flex, you earn even more treats on your Halloween and everyday needs. You get 5% cash back on popular rotating quarterly categories, 3% on dining and drugstores, and 1% on all other purchases. More ways to earn, more ways to get rewarded. That's

• 33:55Speaker 05

  no tricks, all treats. More ways to earn, more ways to get rewarded. So sign up for the Chase Freedom Flex Card. Learn more at chase.com/getflex. This is a paid collaboration with Chase Freedom Flex. Cards issued by JP Morgan Chase Bank, N.A. Member, FDIC. Subject to credit approval. Offer subject to change. Terms apply.

• 34:19Speaker 04

  Sometimes the most important safety decision happens before you even know you're in danger.

• 34:24Speaker 03

  Someone had called in, had a young family and had a job displacement, was talking about canceling their service. Our agent walked them through, helped them meet a goal financially that they could still maintain. It was no more than 24 to 72 hours after they had a carbon monoxide leak.

• 34:42Speaker 01

  Whoa.

• 34:43Speaker 03

  Family of four, five or so. If it would have been shut off, that leak wouldn't have been detected and the story could have gone significantly worse there.

• 34:51Speaker 04

  And being a grown up means making sure your home and family are protected. This week, we show you how that's done in an episode sponsored by ADT Blue.

• 34:59Speaker 03

  We want people to be protected and we want to work with people to make sure that they're protected. Life throws curveballs at you, but what's most important is keeping people protected as much as we can.

• 35:09Speaker 04

  Listen to new episodes of Grown Up Stuff on the iHeartRadio app, Apple Podcasts, and wherever you get your podcasts.

• 35:28Kelly Weinersmith?

  And we're back. And let's start with a question from Daniel.

• 35:31Daniel Whiteson?

  So this idea of epigenetics and remembering things, does that mean that, for example, if somebody lives next to a bunch of very nice bean eaters, that their children and their children's children might have, you know, a particular response to the aroma of digested beans?

• 35:51Kelly Weinersmith?

  Fear response?

• 35:52Speaker 03

  Honestly, I don't know. Yeah.

• 35:57Speaker 03

  That's hilarious.

• 35:59Daniel Whiteson?

  That was a joke question, but I want to understand more about this sort of state of the art of knowledge about where this information is stored. Because in the case of genetics, it's obvious, it's the DNA, that's where it's stored. And the case of epigenetics, you pointed to molecular fingerprints and the sort of information around the genome. Like, what is the context in which this can be written and read and impact?

• 36:20Speaker 04

  Yeah.

• 36:21Daniel Whiteson?

  You know, the behavior and the life of a creature?

• 36:23Daniel Whiteson?

  Yeah. And so where this is happening physically is on the DNA itself. So DNA can obtain a modification called methylation. So the DNA gets methylated. And that's just a little tiny chemical group that gets added to DNA. And that tiny, tiny little chemical group can absolutely change gene expression. It can shut it down, or in some cases, it can help turn it on. So an excellent example of this is, going back to pregnancy, Kelly, when a mom is pregnant, she'll frequently be prescribed supplemental folic acid.

• 36:59Daniel Whiteson?

  Mm-hmm.

• 37:00Daniel Whiteson?

  Right? And so a lot of moms will take supplemental folic acid. And the reason is, folic acid is a methyl donor. That little chemical group that gets added to DNA, it's a methyl donor. And so folic acid supplementation prevents spina bifida. And so you have normal spinal cord development and whatnot when you've supplemented. You prevent any potential harm from malnutrition or not having enough of the right type of nutrients for that epigenetic mechanism to be engaged. Another example of that is with rheumatoid arthritis. When you have severe rheumatoid arthritis, you get put on a drug called methotrexate. It's

• 37:41Daniel Whiteson?

  an anti-inflammatory, helps people quite a bit. But usually, insurance companies require people to be on it for a couple of years before they get moved on to biologicals like antibodies, which work better. So methotrexate, one of the problems is it causes memory formation problems. And the reason is, methotrexate is affecting that DNA methylation pool. And so people that are on methotrexate will frequently supplement with folic acid for their memory. So these epigenetic mechanisms are heavily used during development, and they're also heavily used by our adult brain, past development. And those physical entities exist on the

• 38:21Daniel Whiteson?

  DNA itself, as well as the proteins that the DNA wraps around to get compacted into the nucleus of a cell.

• 38:28Kelly Weinersmith?

  Is there ever a good reason for your brain to be less good at forming memories? Or is this always just you have a deficit of something you need and that's why you have the problem and you have to take folic acid?

• 38:40Daniel Whiteson?

  Brilliant question. So for the longest time, my lab, we were obsessed with trying to understand how are long-term memories formed and how do they persist? And we thought, if we can answer that question, we can understand things like PTSD, addiction, et cetera. And after about 10 years of work, we realized that we had accidentally discovered the opposite. We had discovered enzymes that control epigenetic machinery that prevent you from encoding everything.

• 39:09Kelly Weinersmith?

  Huh.

• 39:10Daniel Whiteson?

  And we found out by accident, because when we mess with those enzymes, animals can encode sub-threshold learning events, learning events that would not be encoded into long-term memory, are perfectly encoded into long-term memory.

• 39:23Kelly Weinersmith?

  Huh.

• 39:23Daniel Whiteson?

  And persistently. And so when you modulate the epigenetic machinery, you absolutely, massively control learning and memory.

• 39:32Kelly Weinersmith?

  Wow.

• 39:33Daniel Whiteson?

  And again, that's what drugs of abuse do as well. And so going back to what you asked, with the memory... Our brain is very selective at what it encodes. And we do not want it encoding everything. We want it to encode the most important things that happen to us. For example, if you're crossing the street and you're jaywalking and you almost get hit by a car, your brain will instantly encode that event. It will release a stress hormone. The stress hormone immediately engages the epigenetic machinery, adjusts it so that you kick on gene expression that allows your neurons to change their structure and function. And they encode everything that you experienced that day. What kind of car almost killed you?

• 40:19Daniel Whiteson?

  What you were wearing that day? What you had for breakfast? Whoever remembers that? Unless you eat the exact same thing like I do every single breakfast. What street it was? What time of the day? You encode all that. It's a flash memory. And but normally that doesn't happen. Normally, it's very difficult for us to encode things. So like med students going through organic chemistry. It's awful trying to memorize all that organic chemistry. Your brain isn't designed to do that. It doesn't want to do that. So it takes repetitive spaced out training to be able to encode things like that.

• 40:51Daniel Whiteson?

  It is awful. Totally agree.

• 40:53Kelly Weinersmith?

  You took organic chemistry as a physicist? Why did you do that to yourself?

• 40:58Daniel Whiteson?

  I didn't take organic chemistry because it is awful. But I think you're saying that it's good to be able to forget things. Otherwise, we'd be like awash in a bunch of boring details.

• 41:09Daniel Whiteson?

  Yeah.

• 41:09Daniel Whiteson?

  And we should be remembering the important stuff. That's the answer to Kelly's question is that there's a lot of our lives that are forgettable, unfortunately.

• 41:16Daniel Whiteson?

  Yeah, we would not be able to give the right salience to things, whether good or bad. Everything would be the same.

• 41:23Daniel Whiteson?

  And this is something I don't think I understood. You're saying essentially that our personalities and our memories are not just encoded in our neural structure. Like, you know, as a physicist who thinks about machine learning and training and stuff, I think about networks, learning and all that is encoded in the weights and the structure of the network. You're saying it's more than just the neurons and the structure and the relationships in our brain. There's this whole chemical overlay, this epigenetic overlay that also affects our behavior because it affects our memory.

• 41:53Daniel Whiteson?

  Yeah.

• 41:53Daniel Whiteson?

  That's like totally brand new knowledge to me today. Wow.

• 41:57Daniel Whiteson?

  I remember a while ago, reading a yeast genetics paper. And so people studying yeast gave yeast a particular food source. The yeast would use that food source. And then it engages transcription factors for the metabolic machinery to use the food source. Then you take the food source away. And there are all these epigenetic modifications that remain. And so yeast geneticists would call that short term or long term memory, depending on how long those chemical modifications on the epigenome lasted. So then, well, what, why? Why would a yeast care about that? Or a yeast geneticist care about that? It's because that type of molecular memory then allows a yeast that has experienced the food source once, they experience it a second time.

• 42:40Daniel Whiteson?

  Their metabolic machinery is ready to use it immediately. And they can out compete a naive yeast.

• 42:45Daniel Whiteson?

  Wow.

• 42:46Daniel Whiteson?

  And so it gives them an adaptive advantage. And so that's an epigenetic molecular memory that then allows that yeast to have a adaptive advantage.

• 42:57Daniel Whiteson?

  So I promise I'm going to get us back to addiction. But first I have to ask you a crazy sounding question, which is, so then if you read science fiction novels where they're like scanning people's brains and uploading them to the cloud to live forever, are you thinking, you also got to scan their epigenetics, otherwise it's not the same person?

• 43:11Daniel Whiteson?

  Oh, absolutely. Absolutely.

• 43:15Kelly Weinersmith?

  You two need to collaborate on a sci fi novel.

• 43:20Kelly Weinersmith?

  So to bring us back to addiction, is the connection here? So you mentioned that people who managed to get themselves off of drugs of abuse years later can get triggered. Is that epigenetics making that happen?

• 43:34Daniel Whiteson?

  In part, in part, for sure.

• 43:36Kelly Weinersmith?

  Okay.

• 43:36Daniel Whiteson?

  So we know that drugs of abuse and consistent use can change the circuitry in a very persistent way. And we can measure those changes in all sorts of ways. So we know that happens. We know it's persistent. And one of the only ways that cells can change their function and maintain that difference is through epigenetic regulation. And that's what we see in development. When we develop and our bodies develop, certain parts of our body take on a specific function, like the liver, the kidney, and forevermore stay that function. And so that's what's happening to the reward system. It's experienced this drug of abuse for who knows how long. It's adapted and changed persistently.

• 44:18Daniel Whiteson?

  And that fundamental change then puts the brain at risk to relapse. Either due to experience the drug again, like having a drink after being sober for decades, seeing a cue or a context for a cocaine user. That can be a rolled up dollar bill. It can be a snow capped mountain can trigger somebody with cocaine use disorder.

• 44:40Daniel Whiteson?

  You mean because like they did cocaine on a snow capped mountain once before? Or because a snow capped mountain looks like it has cocaine on it?

• 44:46Daniel Whiteson?

  It reminds them of the powder.

• 44:48Daniel Whiteson?

  Wow.

• 44:49Daniel Whiteson?

  Yeah.

• 44:50Daniel Whiteson?

  Wow, fascinating. So then, in your view, is addiction biological? Is it psychological? Is there even a distinction? Is all the psychology just biological?

• 45:01Daniel Whiteson?

  Yeah, so I think it's a mix of that. You know, I spend most of my time studying it at a molecular and epigenetic level. But there's absolutely a psychosocial component to it. As humans, we are very social animals. And one thing that in neuroscience still drives me insane is in neuroscience, we always study an individual brain. Always, whether it's animal research, human research, it's an individual brain. But our brains never evolved to work individually. Our brains evolved to interact with other brains. Always, they're always interacting with other brains. And that's the success of a species. And so with addiction, it's not only the chemical component and the molecular component,

• 45:45Daniel Whiteson?

  but there's a very large social component to it as well. And it has a genetic component as well. So the heritability of addiction

• 45:55Daniel Whiteson?

  Oh, yeah.

• 45:56Daniel Whiteson?

  is the same as diabetes, hypertension. The genetic risk is similar to those diseases. But people argue with addiction being a disorder or a disease because you can have addiction be part of your life for quite a long time and then become abstinent and never ever return to that drug of abuse. And that can't happen with Alzheimer's disease.

• 46:23Daniel Whiteson?

  Right.

• 46:23Daniel Whiteson?

  Right. Or Huntington's disease. If you have that disease, you don't just stop all of a sudden. It doesn't just go away. It will always be there. So people get into these arguments of disease or not disease, et cetera.

• 46:38Daniel Whiteson?

  So then is there a distinction in your mind between things that are habit forming and things that are addictive? Like you just said that you can have addictions, which then you just walk away from. You know, so for example, I eat chocolate regularly. I don't think I'm addicted to chocolate. I've gone for periods without doing chocolate.

• 46:54Kelly Weinersmith?

  Doing chocolate.

• 46:58Daniel Whiteson?

  Hitting chocolate. You know, without my chocolate dealer coming to my house. So is there a distinction there between habit forming and addiction? You know, people also say, for example, you know, marijuana is not addictive. It's habit forming. Is that a meaningful distinction? What does it mean?

• 47:14Daniel Whiteson?

  Ah, well, yeah, I have trouble with splitting hairs like that. Because we, people use these terms in different ways.

• 47:22Daniel Whiteson?

  Okay.

• 47:22Daniel Whiteson?

  But I think undoubtedly part of the circuitry in the mesolimbic pathway that is the reward circuitry, there's a habit component. And we know from experiments that you can adjust those habit mechanisms to transform into compulsive drug taking. And so although habits and habit formation might be part of it, that's all it is. It's just part of it. And it might be in series with developing a compulsive disorder, but it might not be. There are so many different components to this. It's hard to tell what's a stronger driver in one person versus another person.

• 48:05Daniel Whiteson?

  Hmm. So you're saying it is possible to have a healthy relationship with chocolate and also to have chocolate every day?

• 48:12Daniel Whiteson?

  I think so.

• 48:13Daniel Whiteson?

  I want a scientific blessing for my chocolate habit here.

• 48:17Daniel Whiteson?

  Having the same chocolate problem.

• 48:21Daniel Whiteson?

  I wouldn't believe in that, too.

• 48:24Kelly Weinersmith?

  So now that you've gone into all of this nuance to explain to us that like that social stuff also matters, but I'm gonna still try to go back and simplify things for a second. So we've been trying to look at how addiction impacts the brain. Where are we in our ability to use like medications to try to tinker with the brain to like undo the damage that's been done? Like, you know, five years from now, will we be giving drug addicts a bunch of folic acid or withholding folic acid because it was like an epigenetics thing? Or yeah, so where are we in being able to give people medications to help with this kind of stuff?

• 48:58Daniel Whiteson?

  Yeah, so there are several approaches. There are pharmacological approaches. So for example, with opioid addiction, a frontline medication is naloxone. And that's an inhibitor. It binds to the receptor and it blocks the opioid from being able to hit the receptor. And so you can prevent someone from ODing, you can rescue their breathing. That's why it's a frontline defense. But then longer treatment, there's buprenorphine and methadone, which also hit those receptors. They give a little bit of the euphoria, but they're much, much safer. And so other countries use those much more than the United States for treatment of opioid addiction.

• 49:40Daniel Whiteson?

  Things like cocaine, there's almost nothing out there for cocaine. People are trying to use your own immune system to fight cocaine use disorder and methamphetamine use disorder, where you can get your immune system to create antibodies against the drug. And then the drug can't bind the receptor or the transporter or whatever, whatever its mode of action. So that's been somewhat successful. People are using electromagnetic stimulation in the brain. That's been successful for like antidepressant resistant depression. And it works in addiction in some areas.

• 50:17Daniel Whiteson?

  Wait, are you talking about like zapping people's brains?

• 50:20Daniel Whiteson?

  Yeah.

• 50:20Daniel Whiteson?

  Wow. My, again, very limited understanding is that we don't really understand why that works. It's just kind of like a thing we've tried on people and we've seen that it kind of does work? Or do we understand why applying electric shocks to the brain can help in this situation?

• 50:35Daniel Whiteson?

  I don't know enough about that area. I'd be afraid to speculate too much on the mode of action.

• 50:41Daniel Whiteson?

  Okay.

• 50:42Daniel Whiteson?

  How it works, how persistent it works. That's what I would want to know. We can see short-term effects, but how do those short-term effects really translate into long-term? Did that one or very specific dosing of electromagnetic stimulation cause long-term effects? Or was it just temporary? I can totally see a mechanism for temporary. I don't understand exactly how it'd be specific for long-term. But maybe that's known. I don't know.

• 51:09Kelly Weinersmith?

  Okay, so electromagnetic stimulation. I think there was at least one more thing you were going to tell us about.

• 51:14Daniel Whiteson?

  Chocolate therapy, wasn't it chocolate therapy?

• 51:17Daniel Whiteson?

  Oh, yeah, sorry. That was actually the cognitive behavioral therapy. So using social groups, social support, those are huge. And then there's also, and this is controversial in the United States, but using monetary reward in place of drug to stay clean.

• 51:35Kelly Weinersmith?

  Wow.

• 51:35Daniel Whiteson?

  And that kind of management works extremely well.

• 51:38Daniel Whiteson?

  Paying people not to take drugs.

• 51:40Daniel Whiteson?

  Exactly. And you can, just saying it makes you understand why a lot of people are against it.

• 51:48Kelly Weinersmith?

  I can imagine if you factor in the cost of supporting somebody with an addiction.

• 51:52Daniel Whiteson?

  Yeah.

• 51:53Kelly Weinersmith?

  If you could just give them that money and they'd stop, that might be better for everybody.

• 51:56Daniel Whiteson?

  Right. No, the money's peanuts to run those programs compared to the over one to four trillion dollars that costs just the United States to deal with addiction.

• 52:05Kelly Weinersmith?

  Wow.

• 52:05Daniel Whiteson?

  A year.

• 52:06Daniel Whiteson?

  Well, it's a similar argument for like universal basic income or, you know, universal healthcare preventative costs are always smaller.

• 52:13Daniel Whiteson?

  Exactly.

• 52:14Kelly Weinersmith?

  Well, our listeners had questions about coffee and sugar and a couple other addictive stimulants. And so let's take a break. And when we come back, we'll get to their questions.

• 52:33Speaker 03

  Hey, I'm Nile Rodgers, producer, songwriter, guitarist, and co-founder of the group Sheik. A great song has a way of defining a moment, a moment of joy, heartbreak, or anything in between. This fall, I'll be driving across the country, dropping in on some of the coolest, most fascinating artists working today. We'll go deep into their lives and careers and hear what it was like before the moment that made them. From hit makers like Miguel.

• 53:07Speaker 02

  That last year, finishing that record was the hardest experience of my life, regardless of how everyone else buys into this. I believe in this and I'm gonna push.

• 53:18Speaker 03

  To rising stars like Alex Warren.

• 53:21Speaker 02

  You know, a song is a story and the verse is setting the scene. And for me, at least, it's allowing me to be personal and vulnerable with the audience,

• 53:29Speaker 03

  whether it's about my wife and I'm being vulnerable about her, or it's about, you know, my parents and I'm being vulnerable to them. And it's almost like a cinematic piece in a way where each song tells that beautiful story. It's gonna be one hell of a trip. Experience Before the Moment, a Lincoln original series on the iHeartRadio app, YouTube, or wherever you get your podcasts.

• 53:52Speaker 02

  This is Colin Cowherd from the Colin Cowherd Podcast. Buy smart, drive for less, and trade for more. That's Toyota Ford ability. All starts with a great deal on an off-road ready Tacoma or a half-ton Tundra, two of Toyota's most capable and longest-lasting trucks. Built on a reputation for quality and reliability, Toyota trucks are known for holding their value, which could mean big savings when it's time for your next Toyota. For a great deal today to a great value tomorrow, shop toyota.com. Toyota, let's go places.

• 54:24Speaker 03

  The biggest game of the season, right here, right now. Starts Saturday strong. It's Big Noon Saturday on Fox. And here we go. It all starts at 10 Eastern with Big Noon Kickoff, live with an epic pregame. The crowd, the atmosphere, this is what makes it special. Then it's America's number one game. What a hit. The best pregame, the best announcers, the biggest games.

• 54:48Speaker 04

  Down the sideline, touchdown.

• 54:50Speaker 03

  It's Big Noon Saturday, noon Eastern on Fox.

• 54:54Speaker 04

  This is Hoda Kotb from Joy 101 with Hoda Kotb. Halloween has a funny way of making you buy things you'd never normally buy. A 10-foot skeleton? Sure. A full-size fog machine? Why not? Three bags of candy that somehow become six bags of candy? It happens. Which brings me to the Chase Freedom Flex Card, the savvy decision that will earn you more cash back on the everyday purchases, plus the extraordinary Halloween tricks and treats. With Freedom Flex, you earn even more treats on your Halloween and everyday needs. You get 5% cash back on popular rotating quarterly categories, 3% on dining and drugstores, and 1% on all other purchases. More ways to earn, more ways to get rewarded. That's no tricks, all treats.

• 55:39Speaker 04

  More ways to earn, more ways to get rewarded. So sign up for the Chase Freedom Flex Card. Learn more at chase.com/getflex. This is a paid collaboration with Chase Freedom Flex. Cards issued by JP Morgan Chase Bank, N A member FDIC. Subject to credit approval. Offer subject to change. Terms apply. Sometimes the most important safety decision happens before you even know you're in danger.

• 56:06Speaker 01

  Someone had called in, had a young family and had a job displacement, was talking about canceling their service. Our agent walked them through, helped them meet a goal financially that they could still maintain. It was no more than 24 to 72 hours after they had a carbon monoxide leak. Whoa. Family of four, five or so. If it would have been shut off, that leak wouldn't have been detected and the story could have gone significantly worse there.

• 56:33Speaker 04

  And being a grown up means making sure your home and family are protected. This week, we show you how that's done in an episode sponsored by ADT Blue.

• 56:41Speaker 01

  We want people to be protected and we want to work with people to make sure that they're protected. Life throws curveballs at you, but what's most important is keeping people protected as much as we can.

• 56:50Speaker 04

  Listen to new episodes of Grown Up Stuff on the iHeartRadio app, Apple Podcasts, and wherever you get your podcasts.

• 57:09Kelly Weinersmith?

  All right, we're back. And so one thing that I'm dying to know is we've been talking about drugs of abuse, but how do drugs of abuse differ from something like my addiction to scrolling on Instagram, or my addiction to coffee in the morning, or Daniel's massive addiction, that's apparently all he thinks about, to chocolate?

• 57:27Daniel Whiteson?

  You mean very healthy habit-forming behavior?

• 57:31Kelly Weinersmith?

  That's right, yes.

• 57:32Daniel Whiteson?

  Yeah, so, and this, I won't probably speak too much, because I don't know enough about natural things like sugar, etc. Drugs of abuse have an absolutely outscaled effect on the neurotransmitter systems and the circuitry in the brain. Things like sugar, people say, oh, you become addicted to sugar, and we continuously escalate our sugar intake. And yeah, sugar is a problem in our American diet, but the impact on metabolism as a whole is massive. And so trying to then parse out, okay, what changed in the whole milieu of

• 58:13Daniel Whiteson?

  metabolism from increasing sugar and compulsive sugar intake that led to more is really hard to pinpoint. Other things like gambling, social media, there was a huge lawsuit that I think Meta just lost for social media, and trapping adolescents into social media addiction, right? So there must be aspects of that that are true. It's definitely true for gambling. These things, social media, gambling, they also release that neurotransmitter. And one reason is because of something called prediction error. So dopamine in your brain is not really

• 58:56Daniel Whiteson?

  thought of as, oh, it's a pleasurable molecule, the pleasure molecule, people mislabel it that way. Oh, you had this amazing meal, we released all this dopamine, that's why it tastes so good. That's not really it. It's, the increase in dopamine is a motivation seaper. It tells us and motivates us to go get it. And so with gambling and social media, the dopamine is acting as a prediction error in that you got a better-than-expected reward. And so for gambling, you know you're gonna lose a lot, but every once in a while you're gonna hit.

• 59:32Daniel Whiteson?

  Yeah.

• 59:33Daniel Whiteson?

  And when you hit, that high is awesome, because your prediction error, you kept expecting, you know, lose, lose, lose, lose. But when you hit, and you hit big, it's a massive bonus, like, ah, dopamine, so much release, it's gonna drive us to go do that again, because it was great. It was a great experience, right? Social media, when people post something that goes viral, same thing. All of a sudden, attention, people saying great things about you, blah, blah, blah, and people get addicted to that and keep pursuing it. And that can be very detrimental, especially in teenagers, where the whole reward circuitry, the learning and memory circuitry in a teenager is still evolving.

• 1:00:17Daniel Whiteson?

  There's a very complex hormonal kind of control of how the brain is continuing to develop during adolescence. And that's when we're hitting all these kids with, you know, pretty bad diets, in some cases, social media, constantly, all the news people see is fantastical and blown out of proportion and clickbait, right? It's either amazingly incredible, or it's horrific and world-destroying, right? That's how our media is pitched to us now, so that we'll actually click on it. And so when the brain starts to see all of this, it gets confused. The neurotransmitter, all it is, is a prediction error. It can't assess value

• 1:01:02Daniel Whiteson?

  of what you're looking at and what you're doing, really, right? And that's where the, all those social constructs, psychosocial behavior, your support group, your family, your friends, that's where all that becomes really, really important. It helps your brain and that collection of brains figure out how to respond to these things.

• 1:01:20Daniel Whiteson?

  Wow. So when you say the dopamine is the prediction error, and that it's not like the reward, it's the thing that motivates you to go back and like, put down another 20 bucks on blackjack?

• 1:01:31Daniel Whiteson?

  Yeah.

• 1:01:31Daniel Whiteson?

  Because it's anticipating the occasional big hit?

• 1:01:35Daniel Whiteson?

  Right.

• 1:01:36Daniel Whiteson?

  I see.

• 1:01:36Daniel Whiteson?

  And then we keep pursuing that big hit. Yeah. And it's the same thing that thrill-seekers do, extreme skiing. I grew up doing extreme skiing.

• 1:01:46Kelly Weinersmith?

  Cool.

• 1:01:47Daniel Whiteson?

  And I just kept looking for that bigger cliff, more inclined, just to get that rush. And you start pursuing more and more dangerous things until you start breaking bones, and then you get either too old, or you stop, or you die.

• 1:02:02Kelly Weinersmith?

  I am way less exciting. For me, the big hit is when a goat post comes up on Instagram, and I'm like, goats! And that's, that's what's exciting for me. But I stay here. Did you break bones?

• 1:02:17Daniel Whiteson?

  I got pretty lucky. But I'm 54 years old right now, and I damaged my MCL in January. I hit a tree in March, but I still love to ski. So it's all good.

• 1:02:30Kelly Weinersmith?

  Good luck.

• 1:02:32Daniel Whiteson?

  You learn how to fall.

• 1:02:33Daniel Whiteson?

  So maybe that's a good transition to studies of how we avoid or leave addictive behaviors. So when Marcelo's been skiing, getting that fix of that thrill of like, wow, I just did something stupid and survived, you know, and then you stop doing it. You were talking earlier, the basic mechanisms of addiction involve, obviously, the reward, and then the habit formation, but then the sort of desensitivity to it. Is it that last part that's crucial for the difficulty of leaving the addictive behavior?

• 1:03:05Daniel Whiteson?

  Yeah, I think as the brain kind of switches to this compulsive approach, it's battling, one, the anhedonia, the lack of reward for natural rewards and the normal things that you do that should be pleasurable, like the goats, right? That's a natural, normal thing that should be fun.

• 1:03:24Kelly Weinersmith?

  That's right.

• 1:03:26Daniel Whiteson?

  And I don't know what's wrong with people that don't like goats.

• 1:03:29Daniel Whiteson?

  Obvious evolutionary benefits.

• 1:03:30Kelly Weinersmith?

  There are some crazy people out there.

• 1:03:34Daniel Whiteson?

  Yeah, yeah. So your brain starts to battle that, and then your brain has also changed the levels of receptors and all these compensatory things that lead to tolerance and sensitization. Incubation of craving, the longer you're away from something, the more you crave it. That's a wild mechanism. And so it really becomes important trying to find how you normalize those things. How do you get back to normal rewards being stimulating again? And time and time again, one of the most important things is social interaction. That means more to your brain than most other things. But it gets harder and harder for

• 1:04:18Daniel Whiteson?

  us to do that. So like, for example, in the pandemic, addiction and overdose deaths skyrocketed.

• 1:04:24Daniel Whiteson?

  Wow.

• 1:04:25Daniel Whiteson?

  Because we were isolated, we're socially isolated. So it was a very scary problem when thinking about addiction. Now that things have normalized a bit more, it's gotten better. But this is also one of the concerns about our online lives and how fake our online lives can be. It all comes back down to trying to find normal pleasures be rewarding, and can you maintain that? And for some people, that's exercise. Exercise is great.

• 1:04:53Daniel Whiteson?

  Yeah.

• 1:04:54Daniel Whiteson?

  And getting into that habitual exercise starts to retransform how your brain responds. And exercise affects all the epigenetic machinery as well. It affects how your metabolism reacts. And so you can use those things to help modify.

• 1:05:07Daniel Whiteson?

  And so somebody who's like, become addicted to coffee in the morning, and then stops coffee and gets headaches, your advice is, even though you don't feel like going to speak to anybody now, because you're miserable, what you really should do is go talk to your neighbors.

• 1:05:21Daniel Whiteson?

  Yes. Although coffee and headaches are a bit different mechanism.

• 1:05:27Kelly Weinersmith?

  Do we understand that mechanism? Because I think our listener wanted to know why they get a headache when they try to wean themselves off coffee.

• 1:05:35Daniel Whiteson?

  Yeah, I remember looking this up a long time ago, and I don't quite remember, but it does have to do with vasovisconstriction, and caffeine and vasovisconstriction. But I can't remember the exact mechanism.

• 1:05:46Kelly Weinersmith?

  Okay.

• 1:05:46Daniel Whiteson?

  So when you're not having your coffee at the right time, miss it by a couple hours, you start to get a headache, it's because the blood pressure in your brain has changed.

• 1:05:55Daniel Whiteson?

  Hmm, that makes sense.

• 1:05:57Kelly Weinersmith?

  It feels all the more imperative then to get coffee, if you're like, oh, my gosh, the pressure in my brain is increasing, I need to go get coffee, and so now I will never be late for my coffee again.

• 1:06:08Daniel Whiteson?

  Yep.

• 1:06:08Daniel Whiteson?

  What do you think is the future of this field? What do you think we're gonna be able to do in 15 or 30 years that we can't do today to help people with addiction?

• 1:06:17Daniel Whiteson?

  Yeah, so I think two or three things might be incredible. One is trying to understand who will develop addiction and who will not. How do you help people self-identify that they have the genetics or the behavioral psychosocial environment where they really are much more high at risk, and to be educated in that?

• 1:06:42Daniel Whiteson?

  Yeah.

• 1:06:43Daniel Whiteson?

  Education goes a long way in addiction. Two is, for things like epilepsy, there are some incredible closed-loop circuit devices that, as soon as someone's, like hippocampus is about to have a seizure, the device starts to register the neuronal spiking, and then dampen it down so the person doesn't seize. And so as we identified the reward circuitry that triggers relapse, and the cell types and the firing patterns, those types of mechanisms could theoretically be used so that as someone's brain starts to trigger relapse, that device shuts it down and prevents it.

• 1:07:22Daniel Whiteson?

  Wow.

• 1:07:23Daniel Whiteson?

  And then the third, science fiction, but, you know, this is working in other domains, is-

• 1:07:28Daniel Whiteson?

  Robotic goats?

• 1:07:29Daniel Whiteson?

  No, okay. CRISPR editing. And so we now know, for example, in sickle cell anemia, you can do CRISPR editing, and it's quite successful.

• 1:07:40Daniel Whiteson?

  So you mean changing people's genes, basically gene therapy?

• 1:07:43Daniel Whiteson?

  Right.

• 1:07:43Daniel Whiteson?

  Wow.

• 1:07:44Daniel Whiteson?

  It's in vivo gene therapy within the organism, and there are ways that that is starting to evolve dramatically in science. And so is that a future for addiction therapy? Maybe, but it's, like you said, it's 15, 20, 30 years out there.

• 1:08:01Daniel Whiteson?

  I can't see any way that could ever go wrong. So that sounds great.

• 1:08:05Daniel Whiteson?

  No, never, never.

• 1:08:09Kelly Weinersmith?

  I like it when you're the wet blanket, Daniel. It's usually my job. It's very refreshing when you take, take up the torch.

• 1:08:17Kelly Weinersmith?

  All right, well, Marcelo, thank you very much for being on the show. I had a ton of fun. Thank you for putting up with living next to Daniel. That must be a lot of fun, a real roller coaster. And I assume whenever there's a problem.

• 1:08:28Daniel Whiteson?

  Now I know where I can get my chocolate.

• 1:08:30Kelly Weinersmith?

  That's right. Yeah, I was gonna say, I assume whenever there's like a neighborhood level problem, if you just bring Daniel enough chocolate, he'll get on your side, it sounds like.

• 1:08:36Daniel Whiteson?

  That's a bean. That counts as a bean.

• 1:08:38Kelly Weinersmith?

  That's right. Okay. All right. Well, thank you very much for joining us.

• 1:08:42Daniel Whiteson?

  All right. Appreciate it. Thanks, Marcelo.

• 1:08:44Daniel Whiteson?

  That was wonderful. Thank you.

• 1:08:46Daniel Whiteson?

  Whoa, that was super interesting. I'd never heard of the epigenome before. So, understanding how the human body becomes accustomed to drugs makes sense in that context, but I still don't think I understand the withdrawal part of my question. If I don't drink coffee, my withdrawal symptom is a headache. If a person addicted to a more serious drug abstains, then they could experience significantly more extreme effects than a headache. I'd love to understand what's causing that. Phrased differently, why, as a coffee drinker, does my brain's blood pressure change and give me a headache if I skip caffeine for the day? Thank you, Daniel, Kelly, and Dr. Marcelo Sweetwater Wood for an incredible episode. What a great deep dive into a fascinating topic.

• 1:09:28Speaker 02

  Yeah, I've listened to the episode. It seems that nobody's addicted to sugar and it's just a habit that is a strong habit. Not quite sure where the dividing line between addiction and a strong habit would be. But as a follow up question, I wonder if the addiction or strong habit to ketones might be anorexia? I don't know. Anyway, very interesting episode. Thank you very much. Cheers. Bye bye.

• 1:10:01Daniel Whiteson?

  Thanks, everybody, for listening. Please go and do us a favor and rate the show on whatever podcast app you're using. It really helps people find us.

• 1:10:08Kelly Weinersmith?

  Daniel and Kelly's Extraordinary Universe is edited by the amazing Matt Kesselman.

• 1:10:13Daniel Whiteson?

  He really is a wizard. You can also find us online on Blue Sky, Instagram, and X, D and K Universe. Come engage with us.

• 1:10:23Kelly Weinersmith?

  You can email us at [email protected]. We really do want to hear from you.

• 1:10:29Daniel Whiteson?

  And you can find our website, www.danielandkelly.org, where you'll also find an invitation to join our Discord, where everybody comes and talks about the amazing universe.

• 1:10:40Kelly Weinersmith?

  And we also have the most amazing moderators. This is an iHeart Podcast. Thanks for joining us.

• 1:10:49Kelly Weinersmith?

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