Addiction (featuring Dr. Marcelo Wood)

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2:16This product is not intended to diagnose treat cure or prevent any disease. It's fall in Jeep country, and during the driving to fall sales event, get a great deal on four by fours that refuse to be contained, like Jeep Wrangler, confidence built into every drive with the most awarded SUV ever, Jeep Grand Cherokee, and freedom that can't be denied, with the open air freedom in Jeep Gladiator. After 85 years, it's no surprise that Jeep became America's SUV brand. Get a great deal during the Jeep driving to fall sales event. Jeep is one more awards over its lifetime than any other SUV brand, even the Jeep Grill or Registered trademarts of FCA-US LLC. 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 your shot. According to the Substance Abuse and Mental Health Services Administration,

3:17in 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 DK EU 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

4:17several very healthy, habit-forming non-addictive behaviors. Hello, I'm Kelly Wiener-Smith. 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 in that one. He actually, he told me the other day that it's not fair that we keep harping on the Doritos back, because he did clean that up, but the rest of the office. The point of those jokes is not the Doritos bag specifically. The Doritos bag stands for, Zach. We're a presence. 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

5:19about 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 love 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, whether it's just like, I'm just going to not have any for a month just approved to myself that I can. 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. Oh, 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,

6:22maybe 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'm did backing to that, but until then, I'm staying clean. All right, why I think you could just go on a jog, and that might, that might help you, but that's killing me. 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 got to get back to jogging. 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. Yeah, it's fascinating. We're even healthy, seeming habits can be overdone. 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. But enough of our clueless speculation,

7:26neither of us are giving you advice about how to live your life and we're not medical doctors. We shouldn't be talking about this. Instead, we decided to invite somebody on the show who doesn't know what they're talking about and can give us the actual cutting-edge scientific basis for addiction. 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. Hey Daniel Kelly, greetings from beautiful kombucha rich blackspurg, 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.

8:29Can'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 ways. How is that if key tones are so good for you and make you feel so much better? How is it? Nobody seems to be addicted to key tones. That'd be an interesting month 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 there are great resource because also they're too polite to say no when we invite them on the podcast. Great. So let's go ahead and get our guests 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

9:32and neuro generative 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. The 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? 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, time to come home is 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 Marcelo's house is so much better. I did not know that. That's great. We actually left a Google review on your house saying

10:36the water here is excellent. Yeah, five stars. That is hilarious. All right. All right. Well, 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 have abused you, 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? Therefore, 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.

11:39And our brain has evolved to meet that requirement. So my brain is rewarding me for buying that chocolate bar of 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. 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

12:40addiction 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. Yeah, right? Exactly. Yeah. 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 at different mechanism of action. But what they all do is they hijack that reward circuitry.

13:44And 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, than sex, than social bonding, all these natural rewards. And so now the brain sends that signal to the prefrontal cortex for decision making. 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 change 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

14:46just was an unhappy coincidence? Yeah, that's a fantastic question that I have actually never been asked. So cocoa plants, they grow naturally all throughout South America for 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. Then helps that plant propagate. I don't know actually. Okay. So you've described how our brain gives rewards and 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 than something about it that's biological or psychological? Yeah, absolutely. And we can talk about this and as this conversation goes,

15:49it'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 it. Is it a brain disorder or not? 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 breaks 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,

16:55years, a decade 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. 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 anodonia type effects where normal rewards aren't pleasurable anymore.

17:59Food 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. Well, I never realized that. You're saying if you become addicted or if you overstimulate, then other activities which normally would give you pleasurable feeling start to feel less fun. Right. Oh my god. 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. 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 their clinical trials trying to understand how does GLP1 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

18:59pursuing other things either. So you get anodonic. There's anodonia, 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 agonist, 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 GLP1s. Some people become less interested in things like alcohol. Some don't. Can we predict how people are

20:01going to respond to this stuff? Do we understand individual variability in this stuff? 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, 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, theory, and understanding the brain itself, which to my limit understanding remains a mystery, even at a fairly basic level.

21:02Like, do we know how these things really work at the neuronal level and the prefrontal 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, interesting opioids. A lot of species will self administer if given the opportunity to do so. So there's like labs out there that give rats cocaine, 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 is one of the oldest, oldest animals out there. Slimeist. Yeah. Are those the ones that

22:05produce like incredible volumes of slime? Yeah, correct. So we're trying to sequence the DNA of hagfish right now to understand how these gene sets evolve, duplicated, specialized. And so I never thought I'd be asking this question, but what does a hagfish do when it's snorts cocaine? Now we don't know. Somebody's got to do the experiment. Yeah. They have the receptors. Yeah. All right. So going back to your question, a lot of the motive 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?

23:10How 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 reengage, and the person will seek the drug. But then because of absence of the drug, the tolerance that

24:16they 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 stock 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. And your DNA has a very fixed level of information capacity. And that encodes all your

25:23genes. How those genes are turned on and when and gives rise to our our blueprint, right? Our body our function. But then the epigenum, 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 that nucleus has is microscopic. And as 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. And 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 could 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

26:28genes 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's kidney cell. But a liver cell is only expressing genes for liver function. Kidney cells only expressing kidney genes. 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

27:31that's how we adapt within our lifespan. Right. So there's evolution, air 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. You could then you could pass it on to people. Yeah. 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 grand

28:34child 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. But we don't know how that works. I remember I had read about I think it was Michael Mene'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 hear some ice cream come 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. What if your soda actually did something for you? Introducing Skypop Protein Soda. Skypop Protein Soda has 10 grams of complete protein, zero sugar, and real delicious soda taste. Skypop

29:36Protein Soda. Reach for the sky. Get your skypop protein soda now at Target, Rouse, or Go Puff. Hey everyone, it's the Jonas Brothers with the Hey Jonas podcast. We've been catching up with some great friends Paul Rod and Michael Bubley, Seth Meyers, Nile Horan, Jake Shane, and making some new friends while getting into what's really like to have sisters, like Alex Nassian Earl. She likes to control everyone and tell everyone to do that. Okay, well control is a harsh word. I would say that's a harsh word. I am more outspoken. Growing up a lot of the times because she was so quiet, I would speak for like the both of us. Now I'm working on like thinking a mom is really not a good taking before I speak. And Joey King. You know if your like mom is yelling at your sibling and even if you're annoyed with your sibling, you just like won't let that slide. It's like you only can yell at your sibling. I'm like you can't do that here. That is not a lot of talk about her like that. I just like about it. Plus we've been taking your calls, listening to your voice mails and giving advice, or at least trying to. So if you've got catching up to do now is the perfect time. Listen to Hey Jonas on the iHeart Radio app Apple

30:38podcasts or wherever you get your podcasts. Is there an epidemic against literature? More specifically, Black literature. Our books are being banned, scanned by AI and destroyed. I'm Jack Weiss-Peace Thomas and on this season of the Black Lit podcast, we're outside asking some of the custodians of our stories, teachers and our modern day writers why? They don't want to hold bunch of little elevators, smock them access and Martin Luther King's on the way out. They want to build children who have no empathy. That's really the ultimate goal. We want books that don't make white kids feel bad. So is the war on literacy and information or our ability to connect? Well people with a know how sexy reading is and how fun they could be and not always associated with education. It could be in a state, it could be entertainment and that is the beauty of reading. It can be all of those things. And considering this is Black Reading Month, the only real question is what are you reading next? Listen to Black Lit from the Black Effect podcast network on our iHeart

31:43Radio app Apple Podcast or wherever you get your podcasts. Dear Hunnies, this is goodbye. In February of 2024, celebrated illustrator and children's book author, patron authors and her husband Michael, nailed letters to dozens of friends and family members to let them know that they had died by suicide. By the time you get the shalliter book, Petra and I will be dead. Next stop, Wonderland. Patra and Michael were by all accounts healthy, happy and in love. Why did they do it? And what did it do to the people they left behind? I would have given a million reasons to not leave this world had I known. I keep coming back to a truly hope that Patra was a thousand percent on board with the plan. Do you think of him as having killed her? Yes, I do. I hold my core responsible for my mother's death. I'm Leon Nevock. And I'm Alice Gregory. Together, we set out to interview everyone who got one of Patra and Michael's letters as one married couple trying to

32:46understand another. Listen to death of an artist on the iHeart Radio app Apple podcasts or wherever you get your podcasts. It's fall in jeep country and during the driving to fall sales event, get a great deal on four by fours that refuse to be contained like jeep rankler, confidence built into every drive with the most awarded SUV ever, jeep grand Cherokee, and freedom that can't be denied with the open air freedom and jeep gladiator. After 85 years, it's no surprise that jeep became America's SUV brand. Get a great deal during the jeep driving to fall sales event. Jeep is one more awards over its lifetime than any other SUV brand, jeep and the jeep grill register trademarts of FCAUS LLC. 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 next to a bunch of very nice bean eaters, their children and their children's children might have a particular response

33:52to the aroma of digested beans. Fear response. Honestly, I don't know. Yeah. All right. That's hilarious though. That was a joke question, but I want to just add more about the 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 in red and impact? Yeah. You know, the behavior and the life of a creature. 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.

34:54So an excellent example of this is going back to pregnancy, Kelly. When a mom is pregnant, she'll frequently be prescribed supplemental folic acid. 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 epigenate 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

35:56antibodies, 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 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 our long-term memories formed and how do they persist. And we thought if

36:56we can answer that question, we can understand things like PTSD, addiction, etc. 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. 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. And persistently. And so when you modulate the epigenetic machinery, you absolutely massively control learning and memory. 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 encode everything. We want it to encode the most important things that happen to us. For example,

38:00if 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, 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 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 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

39:06it is awful. 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. 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. Yeah. We would not be able to give the right salient, stiff 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 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. This is whole chemical overlay, this epigenetic overlay that also affects our behavior because it affects our memory. That's like totally bringing knowledge to me today. Wow. I remember a while ago reading a yeast genetics paper. And so people studying yeast

40:08gave 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 those chemical modifications on the epigenome last it. 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 that yeast to have an adaptive advantage. So I promise I'm going to get it 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

41:12them 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 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 of the kidney and forever

42:12more stay that function. And so that's what's happening to the reward system. It's experienced the struggle 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 used to sort. You mean because like they did cocaine on a snow capped mountain once before or because the 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 the psychology just biological? Yeah. So I think it's a mix of that. I spend most of my time studying it at a molecular

43:13and 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. I 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

44:15or 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 all 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. 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. Hitting chocolate. Without my chocolate dealer coming to my house. So is there a distinction there between habit forming and addiction? People also say for example, marijuana is not addictive.

45:17It's habit forming. Is that a meaningful distinction? What does it mean? Ah, 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 mesolumbic pathway that is the reward circuitry. There's a habit component. And we know from experiments that you can adjust 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 and one person versus another person. So you're saying it's possible to have a healthy relationship with chocolate and also to have chocolate every day.

46:19I think so. I want a scientific blessing for my chocolate happy here. Having the same chocolate problem, I want to believe in that too. So now that you've gone on 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 undo the damage that's been done? 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. So where are we and 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 no-lockson. And that's an inhibitor. It binds to the receptor and it blocks the opioid from being able to hit the receptor.

47:22And so you can prevent someone from Odin. 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 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 motive action. So that's been somewhat successful. People are using electromagnetic stimulation in the brain. That's been successful for like anti-depressant resistant depression and it works in addiction in some areas. Are you talking about like zapping

48:25people'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 motive 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 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. 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 cadre of behavioral therapy.

49:27So using social group, 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. 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. So I can imagine if you factor in the cost of supporting somebody within addiction, yeah, 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 one to four trillion dollars that cost just the United States to deal with addiction. Wow. A year. Well, it's a similar argument for universal basic income or universal healthcare, 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,

50:28we'll get to their questions. 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. You mean very healthy, habit-forming behavior. That's right. Yes. Yeah. So in 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 and the brain. Things like sugar, people say,

51:32oh, 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 a manager's 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 released that neurotransmitter. And one reason is because of something called prediction error.

52:32So 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 seeker. 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 going to lose a lot. But everyone's told you're going to hit. Yeah. 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.

53:37Same 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 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, 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 of what you're looking at

54:42and 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 then 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. Yeah. Because it's anticipating the occasional big hit. Right. I see. And then we keep pursuing that big hit. And it's the same thing that thrill seekers do, extreme skiing. I grew up doing extreme skiing. 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 then you get either too old or you stop or you die.

55:45I am way less exciting. For me, the big hit is when a goat post comes up on Instagram and I'm like, oh, 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 Marcelo has been skiing and getting that fix, that thrill of like, wow, I just did something stupid and survived. 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? Yeah. I think is the brain kind of switches to this

56:49compulsive approach. It's battling one, the the anodonia, 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. Obvious 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 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

57:49things 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 that 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 starts to re-transform 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. And so somebody who's like become addicted to coffee in the morning and then stops

58:52coffee 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. Well, their 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 basal constriction and caffeine and basal constriction. 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. 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. Yeah. And so now I will never be late for my coffee again. Yep. What do you think is the future of this field? What do you think we're going to be able to do

59:52in 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. 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

1:00:58starts 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. Chris Paredity. And so we now know for example in sickle cell anemia you can do crisper editing and it's quite successful. So you mean changing people's genes, basically gene therapy? Right. It's indivo 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, 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.

1:02:03That must be a lot of fun. Real roller coaster. And I assume whenever there's a problem, now you know where I can get my chocolate. Yeah, it's 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. 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, Marcelo. That was wonderful. Thank 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. Freeze differently. Why, as a coffee drinker, does my brains 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,

1:03:04what 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, not quite sure where the dividing line between addiction and a strong habit would be, but there's a follow-up question. I wonder if the addiction or strong habits 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 at 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. You can email us at questions at Daniel and Kelly.org. We really do want to hear from you. And you can find our website

1:04:10www.DanielandKelly.org where you'll also find an invitation to join our discord where everybody comes and talks about the amazing universe. And we also have the most amazing moderators. This is an iHeart podcast. Thanks for joining us. This is an iHeart podcast. Guaranteed Human.