Daniel and Kelly’s Extraordinary Universe - Addiction (featuring Dr. Marcelo Wood)

Episode Date: September 10, 2026

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 for privacy information.

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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. Welcome to Daniel and Kelly's addictive universe. 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. Hello, I'm Kelly Wintersmith. 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. Really? All right. So my question for you today, Kelly, is what is something in your life that you've given up?

That I've given up. Other than cleaning Zach's office. 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. Okay. But the rest of the office.

The point of those jokes is not the Doritos bag specifically. It's what the Doritos bag stands for, Zach. 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 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'll still 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? 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. Yeah. 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. Did you feel better when you went on that break? Or was it, why are you still on that break? 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 you're still doing all right. You're still doing all right. 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. All right. Well, I think you could just go on a jog and that might, that might help you. That's Kelly's answer to everything. Have you tried jogging?

Have you got 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've got to get back to jogging. But exercise is a fascinating one because there are people who exercise bear 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.

Yeah. Yeah. Yeah, it's fascinating. Where even healthy seeming habits can be overdone. Yeah. Yeah. I think it depends a lot 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. But enough of our clueless speculation. Neither of us are giving you advice about how to live your life. 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. Yes.

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. Hey, Daniel Kelly. Greetings from beautiful kombucha, Rich, Blacksburg, Virginia. I've got a question for you 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. I guess my question distills down to why we get addicted to sugar when it's so harmful to us in so many, any ways. And 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. Hooray! So let's go ahead and get our guest who couldn't say no on the show. Dr. Marcella 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.

Thank you so much. It's a pleasure to be here. Well, the first question that I really need to know the answer to is that I wrote Daniel and Katrina to be like, do you 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? It's fantastic living next to each other.

Okay, that's great. Absolutely. Oh, that's it? No insights? 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 is time to come home.

It's dinner time. 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 Marcellus house is so much better. Okay. 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. 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. Sure. But let's start with just like what is the general definition of addiction?

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. 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. It 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. 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. 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. And so we do something right, and our brain releases dopamine and the dopamine levels 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 different mechanism of action. But what they all do is they hijack that reward circuitry. And then they trick your brain into thinking, whatever that was, that was 10 times better, a thousand times better, a million times better than food, then sex, than social bonding, all these natural rewards. And so now the brain sends that signal to the prefront cortex for decision making.

And he 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 changed so much. And so that's what grabs your brain. 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? Yeah, that's a fantastic question that I have actually never been asked. Oh. 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 great, that helps that plant propagate. I don't know, actually. Okay. 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?

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 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? And the reason comes back to what you asked, Daniel, that when we first experienced 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 the 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. 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 stop. But others continue down a more compulsive path. Part of your reward secretary 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. 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 abine 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 anadonia-type effects where normal rewards aren't pleasurable. 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. You're saying if you become addicted or if you over-stimulate, then other activities, which normally would give you a pleasurable feeling, start to feel less.

fun? Right. Oh my gosh. It's, and this is a whole other conversation. It's almost similar to what some people, not all people, some people experience on GLP1, right? GLP1, which I don't know if you've heard, it has been affecting people that are addicted to alcohol and probably other drugs as well. Alcohol is where the story first broke, and now they're 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 consequences, you don't feel like pursuing other things either. So you get anadonic. There's anadonia, depression, 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 agonists, etc. So, There are all these competing things happening in the brain. So is that like if you're on GLP1, you're not only less interested in eating, but you're also less interested in alcohol? Or are you more interested in alcohol? Yes. 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.

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 ones. 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? 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, 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. 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. Yeah. Like, do we know how these things really work at the neuronal level and the pre-level and the pre-year?

frontal cortex and all that stuff. 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. So there are labs out there that give rats cocaine or like birds, cocaine or... Yeah. And so because the reward circuitry in the brain is one of the oldest circuits in the brain.

Uh-huh. 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. Slimiest. Yeah. Are those the ones that produce, like, incredible volumes of slum?

Yeah, gross. So we're trying to sequence the DNA of hagfish right now to understand how these gene sets evolved, duplicated, specialized. And so I never thought I'd be asking this question, but what does a hagfish do when it snorts cocaine? That we don't know. Somebody's got to do the experiment. They have the receptors.

Yeah, all right. 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 ask, where does the persistence come from? How is it that you can experience a drug of abuse, for example, like methamphetamine, and that leaves a molecular signature in your brain for decades? Wow. Wow.

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

will trigger the reward pathway to re-engage and a 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 is 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. And those are some pretty important questions. Yeah. We haven't on the show before talked about epigenetics, I don't think. So could you go ahead and explain what epigenetics is?

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. Right. 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. That's crazy. Six feet. Six feet. Wow. In this microscopic nucleus. All rolled up inside every single cell. Amazing.

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 full. 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 is a kidney cell. But a liver cell is only expressing genes for liver function. Kidney cell is only expressing kidney genes. All the other genes are repressed. They're shut down by an epigenetic mechanism that controls this. So your epigenome control. 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. 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. That you could pass it on to people. Right. So things that your grandparents experience 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. 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? 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. Wow. But we don't know how that works. I remember I had read about, I think it was Michael Meaney'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 got to, 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. Where you go.

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And this is Big Lives. Listen to Big Lives on the IHeart Radio app, Apple Podcasts, or wherever you get podcasts. And we're back and let's start with a question from Daniel. So this idea of epigenetics and remembering things, does that mean that, for example, if somebody lives neck to a bunch of very nice bean eaters that their children and their children's children might have a particular response to the aroma of digested beans. Fear response? Honestly, I don't know.

Yeah. That's hilarious. That was a joke question. But I wanted to say 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.

In 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 the behavior and the life of a creature? 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. 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 epigenite 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 an anti-flammatory, 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 metotrexate 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 DNA itself, as well as the proteins that the DNA wraps around to get in compacted into the nucleus of a cell. 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? 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.

it, we had discovered enzymes that control epigenetic machinery that prevent you from encoding everything. Huh. And we found out by accident because when we mess with those enzymes, animals can encode subthreshold learning events, learning events that would not be encoded into long-term memory, are perfectly encoded into long-term memory. Huh. And persistently.

And so when you modulate the epigenetic machinery, you absolutely massively. control learning and memory. Wow. 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 to encoding everything. We want it to encode the most important things that happened 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, adjust 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, 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. 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 train to be able to encode things like that. It is awful.

Totally agree. You took organic chemistry as a physicist? Why did you do that to yourself? I didn't take organic chemistry because it is awful. Oh, I see. But I think you're saying that it's good to be able to forget things. Otherwise, we'd be like a wash and a bunch of boring details. Yeah.

And we should be remembering the important stuff. That's the answer to Kelly's question. There's a lot of our lives that are forgettable, unfortunately. Yeah. We would not be able to give the right salience to things, whether good or bad. Everything would be the same. And this is something I don't think I understood. You're saying essentially that our personality,

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.

Yeah. That's like totally brain knowledge to me today. Wow. 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. And 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-term modifications on the epigenome lasted. So then, well, 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. Their metabolic machinery is ready to use it immediately. And they can outcompete a naive yeast. Wow. And so it gives them an adaptive advantage. And so that's an epigenetic molecular memory that then allows, allows that yeast to have an adaptive advantage.

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? Oh, absolutely. Absolutely. Yeah.

You two need to collaborate on a sci-fi novel. So to bring us back to addiction, is the connection? 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? In part, in part for sure. Okay. 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 or 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. 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. You mean because they did cocaine on a snow-capped mountain once before, or because a snow-capped mountain looks like it has cocaine on it?

It reminds them of the powder. Wow. Yeah. Wow, fascinating. So then in your view, is addiction biological? Is it psychological? Is there even a distinction? Is all psychology just biological? 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, right? 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, 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 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, 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, etc. 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. Doing chocolate. Doing chocolate. 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? Well, yeah, I have trouble with. splitting hairs like that, because people use these terms in different ways. 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's so many different components to this. It's hard to tell what's a stronger driver in one person versus another person. So you're saying it is possible to have a healthy relationship with chocolate and also to have chocolate every day. I think so. I want a scientific blessing for my chocolate habit here. Yeah. Having the same chocolate problem, I would have believed in that too. 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 going to 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? 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, receptor. And so you can prevent someone from Odine, 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. 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, it's 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. Are you talking about like zapping people's brains?

Yeah. Wow. And 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? I don't know enough about that area. I'd be afraid to speculate too much on the mode of action, 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 caused long-term effects, or was it just temporary? I can totally see a mechanism for temporary. I don't understand exactly how it be specific for long-term. But maybe that's known. I don't know. Okay, so electromagnetic stimulation. I think there was at least one more thing you were going to tell us.

about? Chocolate therapy. Wasn't it chocolate therapy? Oh, yeah, sorry. That was actually the, the, um, cognitive behavioral therapy. So using social group, social support, those are huge. And then there's also, and this is controversial in the United States, but using, um, monetary reward in place of drug to stay clean. Wow. And that kind of management works extremely well. Paying people not to take drugs. Exactly. And you can just saying it makes you understand. why a lot of people are against it. I can imagine if you factor in the cost of supporting somebody within addiction, if you could just give them that money and they'd stop, that might be better for everybody.

Right. No, the money's peanuts to run those programs compared to the over $1 to $4 trillion that costs just the United States to deal with addiction. Wow. A year. Well, it's a similar argument for like universal basic income or, you know, universal health care, preventative costs are always smaller. Exactly.

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. The music you love. Your favorite radio stations. Everywhere you go. The podcasts everyone's talking about. All in one place.

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Hey, it's Bobby Bones. Join me in former NFL quarterback Matt Castle every Wednesday on our podcast, lots to say with me, Bobby Bones, and Matt Castle. We also bring in friends, they're mostly Matt's friends, who are current or former NFL players, some of the biggest names in music and entertainment, and then we have some really great conversations that can pretty much go anywhere. The great Pac-Man Jones. After the game, the whole national task force for police officers was at the stadium. Like, hey, buddy, yeah, you, Adam. Come up.

And one of my favorite segments we do is called situational awareness, where Bobby and I give each other real-life situations and figure out what we'd actually do. You're in training camp, and the rookie quarterback has one good throwing session in front of the media. Suddenly, everybody online says he should start over you, week one. How do you handle this? You just go back out to practice the next day and wait for him to mess up. Listen to lots to say with Bobby Bones and Matt Castle on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. This is Jay Valentine.

I've spent my career on the executive side of this industry, multi-platinum songs, building artists, and building business. And alongside my brother tank, the superstar R&B singer, songwriter, and producer, we've created something special, the R&B Money Podcast. This is not just a podcast. It's a safe space where artists, executives, and fans of R&B music come to reminisce. Pull back the curtain and tell the stories that shape this culture. The real history behind the hits. That was Hood famous. Yeah.

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And I'm Alice Gregory. Together we set out to interview everyone who got one of Patriot and Michael's letters, as one married couple trying to understand another. Listen to death of an artist on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. All right, we're back. 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? You mean very healthy habit-forming behavior. That's right. Yes. Yeah. So, and this, I won't probably speak too much because I don't know enough about natural things like sugar, et cetera. 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 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 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 seeper. 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 expect your reward. And so for gambling, you know you're going to lose a lot, but every once in a while you're going to hit. 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, oh, dopamine, so much release, it's going to 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. 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 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 of what you're looking at and what you're doing, really. Right. And that's where 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. So when you say the dopamine is the prediction error and that it's not the reward, it's the thing that motivates you to go back and put down another 20 bucks on Blackjack. Yeah. Because it's anticipating the occasional big hit. Right. I see. And then we keep pursuing that big hit.

Mm-hmm. Yeah. And it's the same thing that thrill seekers do, extreme skiing. I grew up doing extreme skiing. Cool. 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 stop.

or you die. I am way less exciting. For me, the big hit is when a goat post comes up on Instagram. And I'm like, goats! That's what's exciting for me. But I stay here. Did you break bones? 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. Good luck. You learn how to fall. So maybe that's a good transition to studies of how we avoid or leave addictive behaviors. So when Marcello's been skiing and getting that fix of that thrill of like, wow, I just did something stupid and survived.

And then you stopped 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? Yeah, I think as the brain kind of switches to this compulsive approach, it's battling, one, the anedonia, 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. That's right.

And I don't know what's wrong with people that don't like goats. evolutionary benefits. There are some crazy people out there. 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 know. 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 us to do that. So like, for example, in the pandemic, addiction and overdose deaths skyrocketed. Wow. Because we were isolated. We're socially isolated. So it was a very scary problem when thinking about addiction. Now the 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. And getting into that habitual exercise, it starts to re-transform how your brain response. 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. 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. Yes. Although coffee and headaches are a bit different mechanism.

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

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. That makes sense. 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.

What do you think is the future of this field? What do you think we're going to be able to do in 15 or 30 years that we can't do today to help people with addiction? 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 yeah 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. Wow. And then the third, science fiction, but, you know, this is working in other domains is... Robotic goats? 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. So you mean changing people's genes, basically gene therapy.

Right. Wow. It's in-devo 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. I can't see any way that could ever go wrong. So that sounds great. No, never, never. I like it when you're the wet blanket, Daniel. It's usually my job. It's very refreshing when you take up the torch. 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... Well, now I know where I can get my chocolate. That's right. Yeah, I was going to 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. That's a bean. That counts as a bean. That's right. Okay. All right. Well, thank you very much for joining us. All right. Appreciate it. Thanks, Marcel.

That was wonderful. Thank you. you. Whoa, that was super interesting. I 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 and they could experience significantly more extreme effects than a headache, I'd love to understand what's causing that. Fries 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. Marcello's Sweetwater Wood for an incredible

episode. What a great deep dive into a fascinating topic. 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. I'm 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. 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. Daniel and Kelly's Extraordinary Universe is edited by the amazing Matt Kesselman. He really is a wizard. You can also find us online on Blue Sky, Instagram, and X, D&K Universe. Come engage with us.

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Hey, it's Bobby Bones. Join me and former NFL quarterback Matt Castle. Every Wednesday on our podcast, lots to say with me, Bobby Bones and Matt Castle. You're in training camp, and the rookie quarterback has one good throwing session in front of the media. Suddenly, everybody online says he should start over you week one.

How do you handle this? You just go back out to practice the next day and wait for him to mess up. Listen to lots to say with Bobby Bones and Matt Castle on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. Hey, what's up? I'm Tony Gonzalez. And I'm October Gonzalez.

But you can call me Toby. We want you to join us on our new podcast, No Safe Words with October and Tony Gonzalez. We get real about marriage, parenthood, sex, divorce, and all the nitty-gritty stuff we all think about, but just don't say out loud. You're probably just going to be some rich guy and he's going to whisk you away.

Oh, this is awkward. Listen to No Safe Words with October and Tony Gonzalez on the IHeart Radio app, Apple Podcast, or wherever you. you get your podcast. It's the US Open, which means the tennis world is about to lose its mind, and I'm here for every second of it. Join me, Renee Stubbs, on the Renee Stubbs tennis podcast as I break it all down.

The matches that matter, the drama that doesn't, and the stories everyone's talking about. No cliches, no sugar coding, just host analysts from someone who's actually been there. Coco looking real good. Her serve looks so much smoother than it has in the past. I was really happy to see eager back to what she looked like a couple of years ago when she was winning dominantly. Listen to the Renee Stubbs tennis podcast on the IHart Radio app, Apple Podcasts, or wherever you get your podcasts.

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