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

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

• 0:00
  Speaker 1: Howdy, Extraordinaries!
• 0:01
  Speaker 2: As you might expect from the title of the episode,
• 0:03
  Speaker 2: today we're talking about addiction. We're going to be talking
• 0:06
  Speaker 2: about sensitive topics like drug use, drug abuse, and suicide.
• 0:11
  Speaker 2: So please decide now if this episode is a good
• 0:13
  Speaker 2: fit for you or for kiddos who might be within earshot.
• 0:24
  Speaker 2: According to the Substance Abuse and Mental Health Services Administration,
• 0:28
  Speaker 2: In 2024, among people 12 and older, about 17% of us,
• 0:33
  Speaker 2: or nearly 50 million people in the United States, struggled
• 0:37
  Speaker 2: with addiction. What is it that drugs do to our
• 0:40
  Speaker 2: brains that make them so addictive? And why is it
• 0:43
  Speaker 2: that some of us can try these drugs once and
• 0:45
  Speaker 2: then leave them alone, while others of us become hooked?
• 0:49
  Speaker 2: And what happens to our brains long-term after we've become
• 0:52
  Speaker 2: addicted to a drug of abuse? Well, it wouldn't be
• 0:55
  Speaker 2: an episode of DKEU if we didn't say, we don't know,
• 0:59
  Speaker 2: at least a few times throughout the episode. But today,
• 1:02
  Speaker 2: we're bringing on a guest who will give us the
• 1:04
  Speaker 2: latest insights into our understanding of addiction.
• 1:08
  Speaker 1: Welcome to Daniel and Kelly's Addictive Universe.
• 1:10
  Speaker 3: Addictive Universe Hi, I'm Daniel.
• 1:24
  Speaker 4: I'm a particle physicist who likes to think and write
• 1:27
  Speaker 4: about aliens, and I have several very healthy, habit-forming, non-addictive behaviors.
• 1:33
  Speaker 1: Hello, I'm Kelly Wienersmith.
• 1:34
  Speaker 2: I study parasites and space, and I certainly have the
• 1:37
  Speaker 2: kind of personality where I worry that if I.
• 1:39
  Speaker 1: Were to ever try a bad drug that I could
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  Speaker 1: get addicted.
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  Speaker 4: Really? All right, so my question for you today, Kelly,
• 1:45
  Speaker 4: is what is something in your life that you've given up?
• 1:49
  Speaker 1: That I've given up?
• 1:51
  Speaker 4: Other than cleaning Zach's office.
• 1:54
  Speaker 3: Oh, man.
• 1:54
  Speaker 1: Yeah, I threw my hands up at that one.
• 1:55
  Speaker 2: He actually, he told me the other day that it's
• 1:59
  Speaker 2: not fair that we keep harping on the Doritos bag
• 2:01
  Speaker 2: because he did clean that up.
• 2:04
  Speaker 1: But the rest of the office.
• 2:07
  Speaker 4: The point of those jokes is not the Doritos bag specifically.
• 2:10
  Speaker 4: It's what the Doritos bag stands for.
• 2:12
  Speaker 1: Represents.
• 2:13
  Speaker 2: I know.
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  Speaker 1: I think he's missing the point there. But let's see.
• 2:16
  Speaker 1: What did I give up?
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  Speaker 2: There was a time where I was having a glass
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  Speaker 2: of wine every night.
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  Speaker 1: And then it was two glasses of wine.
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  Speaker 2: And then I realized I was starting to think about
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  Speaker 2: how I was really looking forward to the glasses of wine.
• 2:29
  Speaker 2: And then I started thinking about my family history and
• 2:32
  Speaker 2: our relationship with alcohol.
• 2:33
  Speaker 1: Not my parents.
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  Speaker 2: They both make great choices about alcohol. But a couple
• 2:37
  Speaker 2: generations out from that. And I decided I don't need
• 2:41
  Speaker 2: a glass of wine at night. And so I stopped
• 2:44
  Speaker 2: my evening glass of wine. I'll still have a glass
• 2:46
  Speaker 2: of wine sometimes if I go out to dinner with
• 2:47
  Speaker 2: friends or something. But I felt myself drifting in a
• 2:51
  Speaker 2: direction that I felt was maybe not the right direction
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  Speaker 2: for me.
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  Speaker 1: What about you?
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  Speaker 4: Yeah, I have friends who feel the same way and
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  Speaker 4: they do things like dry January where they're just like,
• 3:01
  Speaker 4: I'm just going to not have any for a month
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  Speaker 4: just to prove to myself that I can.
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  Speaker 3: Yeah.
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  Speaker 4: And, uh, in my case, that was never something I
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  Speaker 4: was doing all the time, but there was a period
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  Speaker 4: in my life when I was, um, enjoying banana peels
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  Speaker 4: quite regularly. And I decided, you know what, I'm going
• 3:16
  Speaker 4: to see if I can take a break. And I
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  Speaker 4: did about six or seven years ago and, um, still
• 3:22
  Speaker 4: on that break.
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  Speaker 2: Did you feel better when you went on that break
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  Speaker 2: or was it, why are you still on that break?
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  Speaker 4: Yeah, no good reason. I just, uh, didn't feel like
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  Speaker 4: going back. I mean, um, Maybe I have fewer crazy
• 3:34
  Speaker 4: ideas to inspire my research, but....
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  Speaker 1: You're still doing all right. You're still doing all right.
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  Speaker 4: I'm still doing all right. When I start running out
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  Speaker 4: of research ideas, then I'll dip back into that. But
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  Speaker 4: until then, I'm staying clean.
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  Speaker 5: All right.
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  Speaker 1: Well, I think you could just go on a jog
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  Speaker 1: and that might That might help you.
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  Speaker 4: That's Kelly's answer to everything. Have you tried jogging?
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  Speaker 2: Have you got on a jog? And the funny thing
• 3:58
  Speaker 2: is I haven't jogged. I've given up jogging apparently because
• 4:01
  Speaker 2: I haven't done that in a while. I've just been
• 4:03
  Speaker 2: too busy. I got to get back to jogging.
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  Speaker 4: But exercise is a fascinating one because there are people
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  Speaker 4: who exercise very regularly and are addicted to it to
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  Speaker 4: the point where like, maybe it's not so healthy. It's
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  Speaker 4: okay to take a day off kind of a thing.
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  Speaker 3: Yeah. Yeah.
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  Speaker 4: It's fascinating. Where even healthy seeming habits can be overdone.
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  Speaker 1: Yeah, yeah.
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  Speaker 2: I think it depends a lot on your personality. I
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  Speaker 2: certainly am capable of overdoing.
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  Speaker 1: Just about everything.
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  Speaker 2: And in a lot of cases, I can funnel that
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  Speaker 2: towards productive activities where it doesn't do me too much harm.
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  Speaker 2: But I think I've been lucky in that way.
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  Speaker 4: But enough of our clueless speculation. Neither of us are
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  Speaker 4: giving you advice about how to live your life. And
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  Speaker 4: we're not medical doctors, so we shouldn't be talking about this. Instead,
• 4:43
  Speaker 4: we decided to invite somebody on the show who does
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  Speaker 4: know what they're talking about and can give us the
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  Speaker 4: actual cutting edge scientific basis for addiction.
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  Speaker 2: Yes, and our motivation for doing this, in addition to
• 4:54
  Speaker 2: just happening to know a person who studies addiction and
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  Speaker 2: is awesome, is that we had two questions from listeners
• 5:00
  Speaker 2: focused on addiction. And so let's go ahead and listen
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  Speaker 2: to those questions now.
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  Speaker 3: Hey, Daniel and Kelly.
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  Speaker 5: Greetings from beautiful Kombucha Ridge, Blacksburg, Virginia. I've got a
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  Speaker 5: question for y'all, which is mostly for Kelly this time,
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  Speaker 5: and it's about addiction. If I don't drink my coffee
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  Speaker 5: in the morning, I get a gnarly headache.
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  Speaker 4: Why is this?
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  Speaker 5: Being addicted to coffee seems like it may be overall
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  Speaker 5: good for human health, so continuing my morning ritual isn't
• 5:24
  Speaker 5: much of an internal struggle. However, for addictions that are
• 5:27
  Speaker 5: detrimental to our health, what is the mechanism that causes
• 5:31
  Speaker 5: otherwise rational people to continue these self-destructive habits, like tobacco
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  Speaker 5: or other more nefarious substances? Thanks as always for your
• 5:39
  Speaker 5: awesome pods. Can't wait to hear y'all break it down.
• 5:41
  Speaker 3: Hi, Kelly and Daniel.
• 5:44
  Speaker 6: I guess my question distills down to why we get
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  Speaker 6: addicted to sugar when it's so harmful to us in
• 5:52
  Speaker 6: so many ways and how is that if ketones are
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  Speaker 6: so good for you and make you feel so much
• 5:59
  Speaker 6: better how is it nobody seems to be addicted to
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  Speaker 6: ketones that'd be an interesting one for.
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  Speaker 4: Me and one of my favorite things about living in
• 6:09
  Speaker 4: the sort of faculty ghetto at UC Irvine is that
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  Speaker 4: I just happen to know people nearby who study this
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  Speaker 4: and that and the other thing and so They're a
• 6:17
  Speaker 4: great resource because also they're too polite to say no
• 6:20
  Speaker 4: when we invite them on the podcast.
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  Speaker 1: Hooray!
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  Speaker 2: So let's go ahead and get our guest who couldn't
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  Speaker 2: say no on the show.
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  Speaker 3: Dr.
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  Speaker 2: Marcella Wood is a professor and chair of the Neurobiology
• 6:32
  Speaker 2: and Behavior Department at the University of California, Irvine. His
• 6:35
  Speaker 2: lab works on understanding what's happening in our brains when
• 6:38
  Speaker 2: we form long-term memories with the goal of helping us
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  Speaker 2: combat memory loss related to aging and neurogenerative.
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  Speaker 1: Diseases like Alzheimer's.
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  Speaker 2: His lab also explores how drug abuse impacts memory circuits
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  Speaker 2: in the brain and seeks to use this information to
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  Speaker 2: help prevent relapse.
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  Speaker 1: Welcome to the show.
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  Speaker 3: Thank you so much. It's a pleasure to be here.
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  Speaker 2: Well, the first question that I really need to know
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  Speaker 2: the answer to is that I wrote Daniel and Katrina
• 7:02
  Speaker 2: to be like, do you all know anyone who studies addiction?
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  Speaker 2: And they were like, our neighbor studies addiction. So the
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  Speaker 2: first thing I need to know is what is it
• 7:09
  Speaker 2: like living next to Daniel and Katrina? And is it
• 7:13
  Speaker 2: a problem that they are members of this weekly bean club?
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  Speaker 3: It's fantastic living next to each other.
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  Speaker 1: Okay, that's great.
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  Speaker 3: Absolutely. Oh, that's it?
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  Speaker 1: No insights?
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  Speaker 3: Yeah.
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  Speaker 4: Our boys used to play a lot in the street
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  Speaker 4: behind our house. That's true. And I remember going over
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  Speaker 4: there like, Silas, it's time to come home. It's dinner time.
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  Speaker 4: And he's like, no, I need a drink of water.
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  Speaker 4: And I'd be like, well, we have water at home.
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  Speaker 4: And he's like, the water at Marcella's house is so
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  Speaker 4: much better.
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  Speaker 3: Okay. I did not know that. That's great.
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  Speaker 4: We actually left a Google review on your house saying
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  Speaker 4: the water here is excellent. Yeah, five stars.
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  Speaker 3: That is hilarious. All right.
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  Speaker 1: All right.
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  Speaker 2: We'll transition into more serious topics. So we had a
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  Speaker 2: handful of listener questions specifically about addiction, but they were
• 8:00
  Speaker 2: asking about different kinds of addiction.
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  Speaker 4: Sure.
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  Speaker 1: But let's start with just like, what is the general
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  Speaker 1: definition of addiction? Yeah.
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  Speaker 3: So first, in order to understand addiction and put it
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  Speaker 3: into its context, I like to think about what our brain...
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  Speaker 3: actually evolved to do and why drugs of abuse do
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  Speaker 3: what they do. And so to kind of put it
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  Speaker 3: into the right context, it's useful to think of the
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  Speaker 3: reward system and the reward circuitry in your brain. What
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  Speaker 3: does it do? What is it there for? How did
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  Speaker 3: it evolve? And basically the reward circuitry in our brain
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  Speaker 3: has evolved and designed to allow us to remember and
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  Speaker 3: respond to things that we did right. So things that
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  Speaker 3: are good for our own survival, and the survival of
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  Speaker 3: our species. So those two things are critically, critically important.
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  Speaker 3: And our brain has evolved to meet that requirement.
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  Speaker 4: So my brain is rewarding me for buying that chocolate
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  Speaker 4: bar at Trader Joe's because it's good for all of humanity,
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  Speaker 4: you're saying.
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  Speaker 3: Potentially. Depends on what chocolate means to you. And I agree.
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  Speaker 3: Chocolate means a lot to me. So for example, things
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  Speaker 3: like food, sex... social bonding, all those kinds of things,
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  Speaker 3: if we do correctly, our brain rewards us for it
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  Speaker 3: and uses a neurotransmitter called dopamine to say, hey, yeah,
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  Speaker 3: we did this thing and we need to do that
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  Speaker 3: again because it was really good. And dopamine release in
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  Speaker 3: the reward circuitry is our motivator. It's telling us, yeah,
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  Speaker 3: we did the right thing at the right time and
• 9:39
  Speaker 3: we need to remember that. And so the reward circuitry
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  Speaker 3: in the brain is intimately tied in with the learning
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  Speaker 3: and memory circuitry. So that's why my lab works on
• 9:48
  Speaker 3: both of these things together. You can't dissociate addiction and
• 9:52
  Speaker 3: reward behaviors from learning and memory. They're intimately tied together.
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  Speaker 4: That seems so obvious now because rewards... only work if
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  Speaker 4: you remember them, right?
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  Speaker 3: Yeah, exactly. And so we do something right and our
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  Speaker 3: brain releases dopamine and the dopamine levels change how the
• 10:12
  Speaker 3: neurons in our brain talks to each other. And then
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  Speaker 3: those signals then go to the prefrontal cortex in our
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  Speaker 3: brain That's our decision-making area. And it says, okay, yeah,
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  Speaker 3: what we did was great. We're going to do that again,
• 10:25
  Speaker 3: or we're going to plan how to do it again.
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  Speaker 3: So we can try and travel into the future and say,
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  Speaker 3: in the past, we did this right. Now in the future,
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  Speaker 3: we're going to do it right again. And it's good
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  Speaker 3: for us. So that's the kind of foundational context of
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  Speaker 3: what your brain does. And then drugs of abuse, unfortunately,
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  Speaker 3: tap into all of that. And so drugs of abuse
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  Speaker 3: and different drugs have different mechanism of action, but what
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  Speaker 3: they all do is they hijack that reward circuitry. And
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  Speaker 3: then they trick your brain into thinking, whatever that was,
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  Speaker 3: that was 10 times better, a thousand times better, a
• 11:01
  Speaker 3: million times better than food, than sex, than social bonding,
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  Speaker 3: all these natural rewards. And so now the brain sends
• 11:10
  Speaker 3: that signal to the prefrontal cortex for decision-making and it says, Well,
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  Speaker 3: whatever that was, the neurotransmitter levels were so different and
• 11:18
  Speaker 3: so important that now we have to pursue that. That
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  Speaker 3: has to be better for us. It has to be
• 11:24
  Speaker 3: better for our survival, the species, etc. Because the neurotransmitter
• 11:30
  Speaker 3: levels change so much. And so that's what grabs your brain.
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  Speaker 2: So I'm thinking of a drug like cocaine and cocaine,
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  Speaker 2: like the plants that cocaine comes from, maybe don't benefit
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  Speaker 2: from us getting addicted to them.
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  Speaker 1: Although maybe we do.
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  Speaker 2: Maybe we grow a lot more cocaine plants because we're addicted.
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  Speaker 2: But like, why does cocaine have this compound that does
• 11:50
  Speaker 2: this to our brain? Is that because it benefits cocaine
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  Speaker 2: plants in some way and they're hijacking our brain for
• 11:55
  Speaker 2: their own benefit? Or is it just like this just
• 11:57
  Speaker 2: was an unhappy coincidence?
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  Speaker 3: Yeah, that's a fantastic question that I have actually never
• 12:01
  Speaker 3: been asked. Hmm. So cocoa plants, they grow naturally all
• 12:07
  Speaker 3: throughout South America, four or five different countries that have
• 12:10
  Speaker 3: huge production. And the cocoa plants have that base compound
• 12:15
  Speaker 3: for cocaine. It's very, very little in the leaves. And
• 12:19
  Speaker 3: perhaps by animals chewing on that and then getting a
• 12:22
  Speaker 3: very little bit of sensation of, yeah, that's great, that
• 12:26
  Speaker 3: helps that plant propagate. I don't know, actually.
• 12:30
  Speaker 5: Okay.
• 12:30
  Speaker 4: So you've described how our brain... gives rewards in response
• 12:35
  Speaker 4: to certain behaviors and how some drugs can short circuit that,
• 12:39
  Speaker 4: giving you that reward or an enhanced version of that
• 12:42
  Speaker 4: reward without those behaviors. But what about the addiction part?
• 12:45
  Speaker 4: Like that describes how this is fun, this tastes good,
• 12:49
  Speaker 4: or this feels great. But isn't there more to addiction
• 12:52
  Speaker 4: than something about it that's biological or psychological?
• 12:55
  Speaker 3: Yeah, absolutely. And we can talk about this as this
• 12:59
  Speaker 3: conversation goes. It's really difficult. for people to understand what
• 13:03
  Speaker 3: drugs of abuse do and how it becomes a disorder.
• 13:07
  Speaker 3: And is it really a disorder? Some people actually argue
• 13:09
  Speaker 3: about is it a brain disorder or not? And the
• 13:12
  Speaker 3: reason comes back to what you asked, Daniel, that when
• 13:15
  Speaker 3: we first experience drugs of abuse, it's voluntary. It might
• 13:19
  Speaker 3: be a pain medication like opioids. Frequently, it starts with
• 13:23
  Speaker 3: pain management. But opioids, they do two things. One, they
• 13:29
  Speaker 3: release the brakes on that dopamine release and the dopamine
• 13:33
  Speaker 3: neuron function. So it's like releasing the emergency brake on
• 13:37
  Speaker 3: a car or not having brakes there. You can go
• 13:40
  Speaker 3: a lot faster. It's a lot better. The second thing
• 13:43
  Speaker 3: that opioids do is they engage hedonic feel-good response. So
• 13:49
  Speaker 3: with those two things in play, your brain has a
• 13:52
  Speaker 3: real hard time saying no to it. And it wants
• 13:55
  Speaker 3: it more. And so you start to... get this pattern
• 13:58
  Speaker 3: of continuously taking it and continuously seeking it. And some
• 14:03
  Speaker 3: people can still stop after months, years, a decade, they
• 14:08
  Speaker 3: can stop. But others continue down a more compulsive path.
• 14:13
  Speaker 3: Part of your reward circuitry has to do with habits
• 14:16
  Speaker 3: and compulsive habits and patterns of action. And so, that
• 14:21
  Speaker 3: part of the reward then starts to get rewired so
• 14:25
  Speaker 3: that someone starts to compulsively search and take drugs of
• 14:30
  Speaker 3: abuse like opioids. And then what happens is the brain
• 14:34
  Speaker 3: starts to compensate for that. So your brain does not
• 14:37
  Speaker 3: want to have dopamine release constantly flooding the neurons and
• 14:42
  Speaker 3: having the neurons constantly activated. It can become neurotoxic. So
• 14:48
  Speaker 3: your brain starts to decrease levels of the receptors where
• 14:52
  Speaker 3: the drugs bind to. So your brain decreases those receptors,
• 14:56
  Speaker 3: tries to fight this constant push by the drugs of abuse.
• 15:00
  Speaker 3: And then what happens is people start to have these
• 15:04
  Speaker 3: anhedonia type effects where normal rewards aren't pleasurable anymore. Food
• 15:10
  Speaker 3: is not pleasurable. Sex is not pleasurable. Even taking your
• 15:14
  Speaker 3: drug of abuse isn't pleasurable, but you're scratching that itch
• 15:17
  Speaker 3: to get it.
• 15:18
  Speaker 4: Wait, I never realized that. You're saying if you become
• 15:21
  Speaker 4: addicted or if you overstimulate, then other activities, which normally
• 15:26
  Speaker 4: would give you a pleasurable feeling, start to feel less fun?
• 15:30
  Speaker 3: Right. Oh my gosh. And this is a whole other conversation.
• 15:35
  Speaker 3: It's almost similar to what some people, not all people,
• 15:39
  Speaker 3: some people experience on GLP-1. GLP-1, which I don't know
• 15:44
  Speaker 3: if you've heard, has been affecting people that are addicted
• 15:47
  Speaker 3: to alcohol. And probably other drugs as well. Alcohol is
• 15:51
  Speaker 3: where the story first broke. And now there are clinical
• 15:54
  Speaker 3: trials trying to understand how does GLP-1 agonists affect alcohol
• 15:58
  Speaker 3: and drug pursuit. But there are some people that are
• 16:01
  Speaker 3: being affected because it affects dopamine function in the brain.
• 16:05
  Speaker 3: You don't feel like pursuing food anymore. But the other
• 16:09
  Speaker 3: consequence is you don't feel like pursuing other things either.
• 16:12
  Speaker 3: So you get anhedonic. There's the anhedonia, depression. And so
• 16:16
  Speaker 3: people are trying to figure out, is that a dose-dependent effect?
• 16:19
  Speaker 3: Is it a drug-specific effect? Like one company makes this
• 16:22
  Speaker 3: type of agonist, et cetera. So there are all these
• 16:26
  Speaker 3: competing things happening in the brain.
• 16:28
  Speaker 2: So is that like, if you're on GLP-1, you're not
• 16:32
  Speaker 2: only less interested in eating, but you're also less interested
• 16:35
  Speaker 2: in alcohol? Or are you more interested in alcohol?
• 16:38
  Speaker 3: Yes. Less. Yeah. Less. And it's not all people.
• 16:41
  Speaker 4: Okay.
• 16:42
  Speaker 3: It depends on a lot of factors, but there are
• 16:45
  Speaker 3: subsets of people that that's exactly what they feel. They
• 16:48
  Speaker 3: don't want to pursue food. They don't want to pursue alcohol,
• 16:51
  Speaker 3: but they don't want to pursue anything. That dopamine motivation
• 16:54
  Speaker 3: signal isn't coming through.
• 16:56
  Speaker 2: And are we able to predict like, you know, so
• 16:59
  Speaker 2: lots of people are prescribed opioids for pain. Some of
• 17:02
  Speaker 2: them become addicted. Some of them don't. And lots of
• 17:04
  Speaker 2: people get GLP-1s.
• 17:06
  Speaker 1: Some people.
• 17:07
  Speaker 2: become less interested in things like alcohol.
• 17:09
  Speaker 1: Some don't.
• 17:09
  Speaker 2: Can we predict how people are going to respond to
• 17:12
  Speaker 2: this stuff? Do we understand individual variability in this stuff?
• 17:15
  Speaker 3: Yeah, that's a great question. And that's a huge area
• 17:18
  Speaker 3: of investigation because in some aspects of basic research, it's
• 17:24
  Speaker 3: really hard to get at the genetics and the individual
• 17:26
  Speaker 3: genetic variability.
• 17:28
  Speaker 1: Mm-hmm.
• 17:29
  Speaker 3: On the other side, humans are highly variable. And we
• 17:34
  Speaker 3: can get into epigenetics, which my lab studies on, and
• 17:36
  Speaker 3: that speaks to persistence, but it also speaks to this
• 17:39
  Speaker 3: individual variability. And so, it's really hard to tie down
• 17:45
  Speaker 3: who might be susceptible and who might not be. That's
• 17:48
  Speaker 3: a great, great area of investigation right now in science.
• 17:52
  Speaker 4: You've sketched out this sort of cartoon version of how
• 17:55
  Speaker 4: the brain works. Thank you for making it accessible to us.
• 17:58
  Speaker 4: But I also wonder how much of that is our
• 18:02
  Speaker 4: speculation and how much of that is really grounded in
• 18:05
  Speaker 4: measurement and theory and understanding the brain itself, which to
• 18:09
  Speaker 4: my limited understanding remains a mystery, even at a fairly
• 18:13
  Speaker 4: basic level. Like, do we know how these things really
• 18:16
  Speaker 4: work at the neuronal level and the prefrontal cortex and
• 18:18
  Speaker 4: all that stuff?
• 18:19
  Speaker 5: Yeah, yeah.
• 18:20
  Speaker 3: So through basic research, Two things here. One, we know
• 18:24
  Speaker 3: that when classifying a drug of abuse as addictive, you
• 18:29
  Speaker 3: can go across species and you can see that almost
• 18:32
  Speaker 3: all species will self-administer a drug of abuse, like cocaine, opioids.
• 18:38
  Speaker 3: A lot of species will self-administer if given the opportunity
• 18:42
  Speaker 3: to do so.
• 18:43
  Speaker 4: So there are like labs out there that give rats
• 18:45
  Speaker 4: cocaine or like birds cocaine or.
• 18:48
  Speaker 5: Yeah.
• 18:50
  Speaker 3: And so because the rewards circuitry in the brain is
• 18:54
  Speaker 3: one of the oldest circuits in the brain. So, for example,
• 18:59
  Speaker 3: I'm working with a professor at UCLA right now trying
• 19:03
  Speaker 3: to understand how opioid neurotransmitter system evolved. So, one of
• 19:08
  Speaker 3: the things we're looking at are hagfish, which are one
• 19:10
  Speaker 3: of the oldest, oldest animals out there.
• 19:13
  Speaker 1: Slimiest.
• 19:15
  Speaker 5: Yeah.
• 19:15
  Speaker 4: Are those the ones that produce like incredible volumes of slime?
• 19:18
  Speaker 3: Yeah. So we're trying to sequence the DNA of hagfish
• 19:22
  Speaker 3: right now to understand how these gene sets evolve, duplicated, specialized.
• 19:28
  Speaker 4: And so I never thought I'd be asking this question,
• 19:30
  Speaker 4: but what does a hagfish do when it snorts cocaine?
• 19:32
  Speaker 3: That we don't know.
• 19:36
  Speaker 4: Somebody's got to do the experiment.
• 19:39
  Speaker 3: They have the receptors.
• 19:40
  Speaker 5: Yeah.
• 19:41
  Speaker 3: So going back to your question, A lot of the
• 19:44
  Speaker 3: mode of action has been well characterized. We know what
• 19:47
  Speaker 3: the receptors are. Once you identify the receptors, you can see, okay,
• 19:51
  Speaker 3: where are those receptors in the brain? So that then
• 19:54
  Speaker 3: starts to tell you the circuitry. And then people have
• 19:57
  Speaker 3: been studying the circuitry at many, many different levels. So
• 20:01
  Speaker 3: we know what brain regions, we know what cell types
• 20:04
  Speaker 3: in those brain regions, we know the acute chronic effects
• 20:08
  Speaker 3: of different drugs. All that is really well worked out.
• 20:12
  Speaker 3: I think one of the real unknown domains in addiction is, again,
• 20:17
  Speaker 3: coming back to what you asked, where does the persistence
• 20:20
  Speaker 3: come from? How is it that you can experience a
• 20:24
  Speaker 3: drug of abuse, for example, like methamphetamine, and that leaves
• 20:28
  Speaker 3: a molecular signature in your brain for decades?
• 20:32
  Speaker 4: Wow. Wow.
• 20:33
  Speaker 3: Right? How does that happen? And so there are very,
• 20:36
  Speaker 3: very few molecular mechanisms that can give you that, and
• 20:39
  Speaker 3: epigenetic mechanisms is one of those. And that can explain,
• 20:43
  Speaker 3: and I'll talk about epigenetics in a minute if you want,
• 20:45
  Speaker 3: but epigenetic mechanisms can explain how a single event or
• 20:50
  Speaker 3: a pattern of events can be encoded and stay persistently
• 20:54
  Speaker 3: encoded in the brain. And that happens throughout your body.
• 20:57
  Speaker 3: Your body uses these mechanisms for development and differentiation of
• 21:01
  Speaker 3: different cell types and tissues. So your brain uses these
• 21:05
  Speaker 3: mechanisms as well. But then somebody can be abstinent for
• 21:09
  Speaker 3: decades and then a certain cue, a signal, a context
• 21:15
  Speaker 3: will trigger the reward pathway to re-engage and the person
• 21:20
  Speaker 3: will seek the drug. But then because of absence of
• 21:25
  Speaker 3: the drug, the tolerance that they had developed a long
• 21:28
  Speaker 3: time ago isn't there anymore. And yet they will take
• 21:33
  Speaker 3: the same amount of drug that they used to, and
• 21:35
  Speaker 3: that is the kind of thing that leads to overdose deaths.
• 21:38
  Speaker 3: And so there are all these aspects of abstinence, what
• 21:41
  Speaker 3: happens during abstinence, how does that persist through decades? How
• 21:47
  Speaker 3: does relapse occur? How do we stop relapse? All those
• 21:51
  Speaker 3: kinds are the major open questions in the field of
• 21:54
  Speaker 3: substance use and use disorders.
• 21:56
  Speaker 1: And those are some pretty important questions.
• 21:58
  Speaker 3: Yeah.
• 21:59
  Speaker 2: We haven't on the show before talked about epigenetics, I
• 22:02
  Speaker 2: don't think. So could you go ahead and explain what
• 22:05
  Speaker 2: epigenetics is?
• 22:06
  Speaker 3: Yeah. So epi means above, and genetics, your genome. So
• 22:11
  Speaker 3: it's literally above the level of your DNA. So your
• 22:14
  Speaker 3: genome is your DNA. And your DNA, we know exactly
• 22:19
  Speaker 3: what that looks like. We can sequence every individual person's
• 22:23
  Speaker 3: DNA and we will know exactly what it looks like.
• 22:26
  Speaker 3: And your DNA has a very fixed level of information capacity.
• 22:33
  Speaker 3: And that encodes all your genes, how those genes are
• 22:36
  Speaker 3: turned on and when, and gives rise to our blueprint, right?
• 22:39
  Speaker 3: Our body, our function. But then the epigenome, it's a
• 22:45
  Speaker 3: collection of chemical modifications on the DNA that And the
• 22:49
  Speaker 3: proteins that wrap the DNA. So for example, if you
• 22:52
  Speaker 3: took just one cell of your body, you have 46
• 22:56
  Speaker 3: chromosomes in that one cell. And so that nucleus is
• 23:01
  Speaker 3: microscopic and has 46 chromosomes. So if you unravel those
• 23:06
  Speaker 3: chromosomes and put them head to tail, you would have
• 23:09
  Speaker 3: six feet of DNA.
• 23:10
  Speaker 1: That's crazy.
• 23:11
  Speaker 3: Six feet. Six feet. Wow. In this microscopic nucleus.
• 23:15
  Speaker 4: All rolled up inside every single cell. Amazing.
• 23:17
  Speaker 3: And so- The DNA gets wrapped around these proteins and compacted,
• 23:22
  Speaker 3: massively compacted. It's about a 10,000-fold level of compaction. If
• 23:28
  Speaker 3: you took a piece of paper and folded it in
• 23:29
  Speaker 3: half and folded that in half and that in half,
• 23:32
  Speaker 3: you can do that seven or eight times. This is 10,000-fold.
• 23:36
  Speaker 3: It's a number our brain can't really comprehend. And so
• 23:39
  Speaker 3: all your genes are in that tight little mix. And
• 23:42
  Speaker 3: so you have to access and turn on your genes
• 23:45
  Speaker 3: to And your epigenome does that. Your DNA is totally fixed.
• 23:49
  Speaker 3: So a liver cell has the exact same DNA as
• 23:52
  Speaker 3: a kidney cell. But a liver cell is only expressing
• 23:56
  Speaker 3: genes for liver function. Kidney cell is only expressing kidney genes.
• 24:01
  Speaker 3: All the other genes are repressed. They're shut down by
• 24:05
  Speaker 3: an epigenetic mechanism that controls this. So your epigenome controls
• 24:10
  Speaker 3: how your genes are turned on and off and regulated.
• 24:14
  Speaker 3: And here's the crazy part. Your DNA gets these little
• 24:18
  Speaker 3: chemical modifications. The protein that helps compact the DNA gets
• 24:23
  Speaker 3: little modifications. That whole collection of modifications is called your epigenome.
• 24:28
  Speaker 3: Every epigenetic modification is a metabolite. So our diet, our experience,
• 24:35
  Speaker 3: our sleep, our stress, the pesticides that we eat in
• 24:39
  Speaker 3: our food, all get integrated into that platform. And that's
• 24:43
  Speaker 3: how we adapt. Within our lifespan, right? So there's evolutionary
• 24:48
  Speaker 3: adaptation that takes eons. And then there's within-organismal adaptation to
• 24:54
  Speaker 3: your life experience. And the crazy thing is people think
• 24:58
  Speaker 3: that the epigenome can also be a source of heritable experience.
• 25:03
  Speaker 4: That you could pass it on to people. Right.
• 25:05
  Speaker 3: So things that your grandparents experienced would be epigenetically inherited
• 25:10
  Speaker 3: by you. And it can skip generations. So these are
• 25:13
  Speaker 3: all things that people don't understand. The phenomena have been observed.
• 25:17
  Speaker 3: They exist. But we don't understand the mechanism.
• 25:19
  Speaker 4: So if my grandparents had some amazing transformational chocolate bar
• 25:24
  Speaker 4: 100 years ago, that could have been somehow encoded and
• 25:27
  Speaker 4: passed down to me and led to me appreciating chocolate
• 25:30
  Speaker 4: even more?
• 25:31
  Speaker 3: Potentially. And so where they've shown that to be true
• 25:35
  Speaker 3: is with odors associated with fear responses. And so that
• 25:40
  Speaker 3: you can track within a species, but across generations. A
• 25:43
  Speaker 3: grandchild of a grandparent that had an odor associated with
• 25:49
  Speaker 3: a terrifying experience, they'll be weary of that odor for
• 25:54
  Speaker 3: no reason. They've never experienced the fear component.
• 25:56
  Speaker 4: Wow.
• 25:57
  Speaker 3: But we don't know how that works.
• 25:58
  Speaker 2: I remember I had read about, I think it was
• 26:00
  Speaker 2: Michael Meany's experiments on how moms treated their babies and
• 26:04
  Speaker 2: how that impacted the way they responded to stress for
• 26:05
  Speaker 2: the rest of their lives. And I learned about that
• 26:07
  Speaker 2: right before I got pregnant. And every time I got
• 26:10
  Speaker 2: stressed out, I was like, no, I'm going to ruin
• 26:12
  Speaker 2: my daughter. And then that stressed me out even more.
• 26:15
  Speaker 2: And it was this like feedback. And eventually my husband
• 26:17
  Speaker 2: was like, you gotta, here's some ice cream, calm down.
• 26:19
  Speaker 1: And I was like, all right. And I'd feel better,
• 26:21
  Speaker 1: but all right, let's take a break.
• 26:24
  Speaker 2: And when we get back, we'll unpack epigenetics a little
• 26:27
  Speaker 2: bit more.
• 26:47
  Speaker 1: And we're back. And let's start with a question from Daniel.
• 26:50
  Speaker 4: So this idea of epigenetics and remembering things, Does that
• 26:54
  Speaker 4: mean that, for example, if somebody lives next to a
• 26:57
  Speaker 4: bunch of very nice bean eaters, that their children and
• 27:01
  Speaker 4: their children's children might have a particular response to the
• 27:06
  Speaker 4: aroma of digested beans?
• 27:10
  Speaker 1: Fear response?
• 27:11
  Speaker 3: Honestly, I don't know. Yeah.
• 27:16
  Speaker 4: All right.
• 27:16
  Speaker 3: That's hilarious, though.
• 27:18
  Speaker 4: That was a joke question, but I wanted to say
• 27:19
  Speaker 4: more about this sort of state-of-the-art-of-knowledge thing. about where this
• 27:22
  Speaker 4: information is stored. Because in the case of genetics, it's obvious,
• 27:25
  Speaker 4: it's the DNA, that's where it's stored. In the case
• 27:28
  Speaker 4: of epigenetics, you pointed to molecular fingerprints and the sort
• 27:32
  Speaker 4: of information around the genome. What is the context in
• 27:36
  Speaker 4: which this can be written and read and impact the
• 27:40
  Speaker 4: behavior and the life of a creature?
• 27:43
  Speaker 3: Where this is happening physically is on the DNA itself.
• 27:48
  Speaker 3: So DNA can obtain a modification called methylation. So the
• 27:52
  Speaker 3: DNA gets methylated. And that's just a little tiny chemical
• 27:57
  Speaker 3: group that gets added to DNA. And that tiny, tiny
• 28:00
  Speaker 3: little chemical group can absolutely change gene expression. It can
• 28:04
  Speaker 3: shut it down, or in some cases, it can help
• 28:06
  Speaker 3: turn it on. So an excellent example of this is
• 28:10
  Speaker 3: going back to pregnancy, Kelly. Mm-hmm. When a mom is pregnant,
• 28:14
  Speaker 3: she'll frequently be prescribed supplemental folic acid, right? And so
• 28:20
  Speaker 3: a lot of moms will take supplemental folic acid. And
• 28:23
  Speaker 3: the reason is folic acid is a methyl donor. That
• 28:27
  Speaker 3: little chemical group that gets added to DNA, it's a
• 28:30
  Speaker 3: methyl donor. And so folic acid supplementation prevents spina bifida.
• 28:36
  Speaker 3: And so you have normal spinal cord development and whatnot
• 28:39
  Speaker 3: when you've supplemented. You prevent any potential harm from malnutrition
• 28:44
  Speaker 3: or not having enough of the right type of nutrients
• 28:47
  Speaker 3: for that epigenetic mechanism to be engaged. Another example of
• 28:51
  Speaker 3: that is with rheumatoid arthritis. When you have severe rheumatoid arthritis,
• 28:57
  Speaker 3: you get put on a drug called methotrexate. It's an anti-inflammatory,
• 29:01
  Speaker 3: helps people quite a bit. But usually insurance companies require
• 29:05
  Speaker 3: people to be on it for a couple of years
• 29:07
  Speaker 3: before they get moved on to biologicals like antibodies, which
• 29:10
  Speaker 3: work better. So methotrexate, one of the problems is it
• 29:13
  Speaker 3: causes memory formation problems. And the reason is methotrexate is
• 29:19
  Speaker 3: affecting that DNA methylation pool. And so people that are
• 29:23
  Speaker 3: on methotrexate will frequently supplement with folic acid for their memory.
• 29:28
  Speaker 3: So these epigenetic mechanisms are heavily used during development. And
• 29:33
  Speaker 3: they're also heavily used by our adult brain past development
• 29:38
  Speaker 3: and those physical entities exist on the DNA itself, as
• 29:42
  Speaker 3: well as the proteins that the DNA wraps around to
• 29:44
  Speaker 3: get compacted into the nucleus of a cell.
• 29:47
  Speaker 2: Is there ever a good reason for your brain to
• 29:51
  Speaker 2: be less good at forming memories?
• 29:53
  Speaker 1: Or is this always.
• 29:53
  Speaker 2: Just you have a deficit of something you need, and
• 29:56
  Speaker 2: that's why you have the problem and you have to
• 29:58
  Speaker 2: take folic acid?
• 29:59
  Speaker 3: Brilliant question. So for the longest time, my lab, we
• 30:03
  Speaker 3: were obsessed with trying to understand how are long-term memories
• 30:06
  Speaker 3: formed and how do they persist? And we thought if
• 30:09
  Speaker 3: we can answer that question, we can understand things like PTSD, addiction,
• 30:13
  Speaker 3: et cetera. And after about 10 years of work, we
• 30:16
  Speaker 3: realized that we had accidentally discovered the opposite. We had
• 30:20
  Speaker 3: discovered enzymes that control epigenetic machinery that prevent you from
• 30:27
  Speaker 3: encoding everything. And we found out by accident because when
• 30:30
  Speaker 3: we mess with those enzymes, animals can encode sub-threshold learning events.
• 30:37
  Speaker 3: Learning events that would not be encoded into long-term memory
• 30:39
  Speaker 3: are perfectly encoded into long-term memory and persistently. And so
• 30:44
  Speaker 3: when you modulate the epigenetic machinery, you absolutely massively control
• 30:50
  Speaker 3: learning and memory.
• 30:51
  Speaker 1: Wow.
• 30:52
  Speaker 3: And again, that's what drugs of abuse do as well.
• 30:55
  Speaker 3: And so going back to what you asked with the memory,
• 30:59
  Speaker 3: Our brain is very selective at what it encodes. And
• 31:03
  Speaker 3: we do not want it encoding everything. We want it
• 31:07
  Speaker 3: to encode the most important things that happen to us.
• 31:12
  Speaker 3: For example, if you're crossing the street and you're jaywalking
• 31:16
  Speaker 3: and you almost get hit by a car, your brain
• 31:18
  Speaker 3: will instantly encode that event. It will release a stress hormone.
• 31:23
  Speaker 3: The stress hormone immediately engages the epigenetic machinery. adjust it
• 31:27
  Speaker 3: so that you kick on gene expression that allows your
• 31:30
  Speaker 3: neurons to change their structure and function and they encode
• 31:34
  Speaker 3: everything that you experienced that day. What kind of car
• 31:36
  Speaker 3: almost killed you, what you were wearing that day, what
• 31:39
  Speaker 3: you had for breakfast, whoever remembers that, unless you eat
• 31:42
  Speaker 3: the exact same thing like I do every single breakfast,
• 31:45
  Speaker 3: what street it was, what time of the day, you
• 31:48
  Speaker 3: encode all that. It's a flash memory. But normally that
• 31:51
  Speaker 3: doesn't happen. Normally it's very difficult for us to encode things.
• 31:55
  Speaker 3: So like, med students going through organic chemistry. It's awful
• 32:00
  Speaker 3: trying to memorize all that organic chemistry. Your brain isn't
• 32:03
  Speaker 3: designed to do that. It doesn't want to do that.
• 32:05
  Speaker 3: So it takes repetitive, spaced out training to be able
• 32:08
  Speaker 3: to encode things like that.
• 32:10
  Speaker 4: It is awful.
• 32:11
  Speaker 3: Totally agree.
• 32:12
  Speaker 1: You took organic chemistry as a physicist?
• 32:15
  Speaker 3: Why did you do.
• 32:16
  Speaker 1: That to yourself?
• 32:17
  Speaker 4: I didn't take organic chemistry because it is awful.
• 32:20
  Speaker 3: Oh, I see.
• 32:20
  Speaker 4: But I think you're saying that it's good to be
• 32:23
  Speaker 4: able to forget things. Otherwise, we'd be like awash in
• 32:26
  Speaker 4: a bunch of boring details.
• 32:28
  Speaker 3: Yeah.
• 32:28
  Speaker 4: And we should be remembering the important stuff. That's the
• 32:30
  Speaker 4: answer to Kelly's question, is that there's a lot of
• 32:33
  Speaker 4: our lives that are forgettable, unfortunately.
• 32:35
  Speaker 3: Yeah. We would not be able to give the right
• 32:38
  Speaker 3: salience to things, whether good or bad. Everything would be
• 32:41
  Speaker 3: the same.
• 32:42
  Speaker 4: And this is something I don't think I understood before.
• 32:45
  Speaker 4: You're saying essentially that our personalities and our memories are
• 32:48
  Speaker 4: not just encoded in our neural structure. As a physicist
• 32:53
  Speaker 4: who thinks about machine learning and training and stuff, I
• 32:56
  Speaker 4: think about networks learning and all that is encoded in
• 32:58
  Speaker 4: the weights and the structure of the network. You're saying
• 33:01
  Speaker 4: it's more than just the neurons and the structure and
• 33:03
  Speaker 4: the relationships in our brain. There's this whole chemical overlay,
• 33:07
  Speaker 4: this epigenetic overlay that also affects our behavior because it
• 33:11
  Speaker 4: affects our memory. That's like totally brand new knowledge to
• 33:15
  Speaker 4: me today. Wow.
• 33:16
  Speaker 3: I remember a while ago reading a yeast genetics paper.
• 33:19
  Speaker 3: And so people studying yeast gave yeast a particular food source.
• 33:23
  Speaker 3: The yeast would use that food source and then it
• 33:27
  Speaker 3: engages transcription factors for the metabolic machinery to use the
• 33:30
  Speaker 3: food source. And then you take the food source away.
• 33:33
  Speaker 3: And there are all these epigenetic modifications that remain. And
• 33:37
  Speaker 3: so yeast geneticists would call that short-term or long-term memory,
• 33:40
  Speaker 3: depending on how long those chemical modifications on the epigenome lasted.
• 33:45
  Speaker 3: So then, well, why? Why would a yeast care about
• 33:48
  Speaker 3: that or a yeast geneticist care about that? It's because
• 33:51
  Speaker 3: that type of molecular memory then allows a yeast that
• 33:56
  Speaker 3: has experienced the food source once to experience it a
• 33:58
  Speaker 3: second time. Their metabolic machinery is ready to use it immediately.
• 34:02
  Speaker 3: And they can out-compete a naive yeast.
• 34:04
  Speaker 5: Wow.
• 34:05
  Speaker 3: So it gives them an adaptive advantage. And so that's
• 34:08
  Speaker 3: an epigenetic molecular memory that then allows that yeast to
• 34:13
  Speaker 3: have an adaptive advantage.
• 34:16
  Speaker 4: So I promise I'm going to get us back to addiction.
• 34:17
  Speaker 4: But first, I have to ask you a crazy-sounding question,
• 34:19
  Speaker 4: which is, so then if you read science fiction novels
• 34:22
  Speaker 4: where they're scanning people's brains and uploading them to the
• 34:25
  Speaker 4: cloud to live forever, are you thinking... You also got
• 34:28
  Speaker 4: to scan their epigenetics. Otherwise it's not the same person.
• 34:31
  Speaker 3: Oh, absolutely. Absolutely. Yeah.
• 34:34
  Speaker 2: You two need to collaborate on a sci-fi novel. So
• 34:40
  Speaker 2: to bring us back to addiction is, is the connection here.
• 34:42
  Speaker 2: So you mentioned that people who managed to get themselves
• 34:46
  Speaker 2: off of drugs of abuse years later can get triggered.
• 34:50
  Speaker 1: Is that epigenetics making that happen?
• 34:53
  Speaker 3: In part, in part for sure. So we know that
• 34:56
  Speaker 3: drugs of abuse and consistent use can change the circuitry
• 35:01
  Speaker 3: in a very persistent way. And we can measure those
• 35:04
  Speaker 3: changes in all sorts of ways. So we know that happens.
• 35:07
  Speaker 3: We know it's persistent. And one of the only ways
• 35:10
  Speaker 3: that cells can change their function and maintain that difference
• 35:14
  Speaker 3: is through epigenetic regulation. And that's what we see in development.
• 35:18
  Speaker 3: When we develop and our bodies develop, certain parts of
• 35:21
  Speaker 3: our body take on a specific function like the liver
• 35:24
  Speaker 3: or the kidney. and forevermore stay that function. And so
• 35:27
  Speaker 3: that's what's happening to the reward system. It's experienced this
• 35:31
  Speaker 3: drug of abuse for who knows how long. It's adapted
• 35:35
  Speaker 3: and changed persistently. And that fundamental change then puts the
• 35:39
  Speaker 3: brain at risk to relapse, either due to experience the
• 35:44
  Speaker 3: drug again, like having a drink after being sober for decades,
• 35:49
  Speaker 3: seeing a cue or a context, For a cocaine user,
• 35:52
  Speaker 3: that can be a rolled up dollar bill. It can
• 35:54
  Speaker 3: be a snow-capped mountain. It can trigger somebody with cocaine
• 35:58
  Speaker 3: use disorder.
• 35:59
  Speaker 4: You mean because they did cocaine on a snow-capped mountain
• 36:02
  Speaker 4: once before or because a snow-capped mountain looks like it
• 36:05
  Speaker 4: has cocaine on it?
• 36:05
  Speaker 3: It reminds them of the powder. Wow. Yeah.
• 36:09
  Speaker 4: Wow, fascinating. So then in your view, is addiction biological?
• 36:14
  Speaker 4: Is it psychological? Is there even a distinction? Is all
• 36:18
  Speaker 4: of psychology just biological?
• 36:20
  Speaker 3: Yeah, so I think it's a mix of that. I
• 36:23
  Speaker 3: spend most of my time studying it at a molecular
• 36:26
  Speaker 3: and epigenetic level, but there's absolutely a psychosocial component to it.
• 36:32
  Speaker 3: As humans, we are very social animals. And one thing
• 36:36
  Speaker 3: that in neuroscience still drives me insane is In neuroscience,
• 36:39
  Speaker 3: we always study an individual brain. Always. Whether it's animal research,
• 36:44
  Speaker 3: human research, it's an individual brain. But our brains never
• 36:47
  Speaker 3: evolved to work individually. Our brains evolved to interact with
• 36:51
  Speaker 3: other brains.
• 36:52
  Speaker 5: Always.
• 36:53
  Speaker 3: They're always interacting with other brains. And that's the success
• 36:56
  Speaker 3: of a species. And so, with addiction, it's not only
• 37:01
  Speaker 3: the chemical component and the molecular component, but there's a
• 37:05
  Speaker 3: very large social component to it as well. And it
• 37:09
  Speaker 3: has a genetic component as well. So the heritability of
• 37:13
  Speaker 3: addiction is the same as diabetes, hypertension. The genetic risk
• 37:20
  Speaker 3: is similar to those diseases. But people argue with addiction
• 37:27
  Speaker 3: being a disorder or a disease because you can have
• 37:32
  Speaker 3: addiction be part of your life for quite a long
• 37:34
  Speaker 3: time and then become abstinent. and never, ever return to
• 37:38
  Speaker 3: that drug of abuse. And that can't happen with Alzheimer's disease, right? Right.
• 37:43
  Speaker 3: Or Huntington's disease. If you have that disease, you don't
• 37:48
  Speaker 3: just stop all of a sudden. It doesn't just go away.
• 37:51
  Speaker 3: It will always be there. So people get into these
• 37:53
  Speaker 3: arguments of disease or not disease, etc.
• 37:57
  Speaker 4: So then is there a distinction in your mind between
• 37:59
  Speaker 4: things that are habit-forming and things that are addictive? Like
• 38:03
  Speaker 4: you just said that you can have addictions, which then
• 38:05
  Speaker 4: you just walk away from. So, for example, I eat
• 38:08
  Speaker 4: chocolate regularly. I don't think I'm addicted to chocolate. I've
• 38:11
  Speaker 4: gone for periods without doing chocolate.
• 38:14
  Speaker 1: Doing chocolate.
• 38:15
  Speaker 4: Doing chocolate. Hitting chocolate. Without my chocolate dealer coming to
• 38:22
  Speaker 4: my house. So, is there a distinction there between habit
• 38:25
  Speaker 4: forming and addiction? People also say, for example, marijuana is
• 38:29
  Speaker 4: not addictive. It's habit forming. Is that a meaningful distinction?
• 38:33
  Speaker 4: What does it mean?
• 38:34
  Speaker 3: Well, yeah. I have trouble with. splitting hairs like that
• 38:38
  Speaker 3: because people use these terms in different ways. But I
• 38:42
  Speaker 3: think undoubtedly part of the circuitry in the mesolimbic pathway
• 38:48
  Speaker 3: that is the reward circuitry, there's a habit component. And
• 38:52
  Speaker 3: we know from experiments that you can adjust those habit
• 38:56
  Speaker 3: mechanisms to transform into compulsive drug taking. And so although
• 39:03
  Speaker 3: habits and habit formation might be part of it. That's
• 39:08
  Speaker 3: all it is. It's just part of it. And it
• 39:10
  Speaker 3: might be in series with developing a compulsive disorder, but
• 39:15
  Speaker 3: it might not be. There's so many different components to this.
• 39:19
  Speaker 3: It's hard to tell what's a stronger driver in one
• 39:22
  Speaker 3: person versus another person.
• 39:23
  Speaker 4: So you're saying it is possible to have a healthy
• 39:28
  Speaker 4: relationship with chocolate and also to have chocolate every day.
• 39:32
  Speaker 3: I think so.
• 39:32
  Speaker 4: I want a scientific blessing for my chocolate habit here.
• 39:36
  Speaker 3: Having the same chocolate problem, uh, I want to believe
• 39:40
  Speaker 3: in that, too.
• 39:43
  Speaker 2: So now that you've gone into all of this nuance
• 39:46
  Speaker 2: to explain to us that like that social stuff also matters,
• 39:49
  Speaker 2: but I'm going to still try to go back and
• 39:51
  Speaker 2: simplify things for a second. So we've been trying to
• 39:54
  Speaker 2: look at how addiction impacts the brain.
• 39:57
  Speaker 1: Where are we in our.
• 39:58
  Speaker 2: Ability to use medications to try to tinker with the
• 40:02
  Speaker 2: brain to undo the damage that's been done? Five years
• 40:05
  Speaker 2: from now, will we be giving drug addicts a bunch
• 40:08
  Speaker 2: of folic acid or withholding folic acid because it was
• 40:11
  Speaker 2: an epigenetics thing? Where are we in being able to
• 40:14
  Speaker 2: give people medications to help with this kind of stuff?
• 40:17
  Speaker 1: Yeah.
• 40:18
  Speaker 3: So there are several approaches. There are pharmacological approaches. So
• 40:23
  Speaker 3: for example, with opioid addiction, a frontline medication is naloxone.
• 40:29
  Speaker 3: And that's an inhibitor. It binds to the receptor and
• 40:32
  Speaker 3: it blocks the opioid from being able to hit the receptor.
• 40:35
  Speaker 3: And so you can prevent someone from ODing. You can
• 40:38
  Speaker 3: rescue their breathing. That's why it's a frontline defense. But
• 40:42
  Speaker 3: then longer treatment, there's buprenorphine and methadone, which also hit
• 40:47
  Speaker 3: those receptors. They give a little bit of the euphoria,
• 40:51
  Speaker 3: but they're much, much safer. And so other countries use
• 40:54
  Speaker 3: those much more than the United States for treatment of
• 40:57
  Speaker 3: opioid addiction. Things like cocaine, there's almost nothing out there
• 41:02
  Speaker 3: for cocaine. People are trying to use your own immune
• 41:06
  Speaker 3: system to fight cocaine use disorder and methamphetamine use disorder,
• 41:11
  Speaker 3: where you can get your immune system to create antibodies
• 41:14
  Speaker 3: against the drug, and then the drug can't bind the
• 41:17
  Speaker 3: receptor or the transporter or whatever, whatever its mode of
• 41:20
  Speaker 3: action is. So that's been somewhat successful. People are using
• 41:26
  Speaker 3: electromagnetic stimulation in the brain. That's been successful for like
• 41:30
  Speaker 3: antidepressant resistant depression. And it works in addiction in some areas.
• 41:36
  Speaker 4: Wait, are you talking about like zapping people's brains?
• 41:39
  Speaker 3: Yeah.
• 41:40
  Speaker 5: Wow.
• 41:41
  Speaker 4: And my, again, very limited understanding is that we don't
• 41:44
  Speaker 4: really understand why that works. It's just kind of like
• 41:46
  Speaker 4: a thing we've tried on people and we've seen that
• 41:49
  Speaker 4: it kind of does work. Or do we understand why
• 41:52
  Speaker 4: applying electric shocks to the brain can help in this situation?
• 41:54
  Speaker 3: I don't know enough about that area. I'd be afraid
• 41:57
  Speaker 3: to speculate too much on the mode of action, how
• 42:01
  Speaker 3: it works, how persistent it works. That's what I would
• 42:04
  Speaker 3: want to know. We can see short-term effects, but how
• 42:07
  Speaker 3: do those short-term effects really translate into long-term? did that
• 42:11
  Speaker 3: one or very specific dosing of electromagnetic stimulation cause long-term
• 42:18
  Speaker 3: effects or was it just temporary? I can totally see
• 42:21
  Speaker 3: a mechanism for temporary. I don't understand exactly how it'd
• 42:24
  Speaker 3: be specific for long-term, but maybe that's known. I don't know. Okay.
• 42:28
  Speaker 2: So electromagnetic stimulation, I think there was at least one
• 42:31
  Speaker 2: more thing you were going to tell us about.
• 42:33
  Speaker 4: Chocolate therapy. Wasn't it chocolate therapy?
• 42:36
  Speaker 3: Oh yeah. Sorry. That, that was actually the, the, um,
• 42:39
  Speaker 3: Cardiobehavioral therapy. So using social groups, social support, those are huge.
• 42:44
  Speaker 3: And then there's also, and this is controversial in the
• 42:47
  Speaker 3: United States, but using monetary reward in place of drug
• 42:53
  Speaker 3: to stay clean.
• 42:54
  Speaker 4: Wow.
• 42:54
  Speaker 3: And that kind of management works extremely well.
• 42:57
  Speaker 4: Paying people not to take drugs.
• 42:59
  Speaker 3: Exactly. And you can just saying it makes you understand
• 43:03
  Speaker 3: why a lot of people are against it.
• 43:07
  Speaker 2: I can imagine if you factor in the cost of
• 43:09
  Speaker 2: supporting somebody with an addiction, if you could just give
• 43:12
  Speaker 2: them that money and they'd stop, that might be better
• 43:14
  Speaker 2: for everybody.
• 43:15
  Speaker 3: Right. No, the money's peanuts to run those programs compared
• 43:18
  Speaker 3: to the over $ 1 to $ 4 trillion that costs just
• 43:22
  Speaker 3: the United States to deal with addiction.
• 43:23
  Speaker 4: Wow.
• 43:24
  Speaker 1: A year.
• 43:25
  Speaker 4: Well, it's a similar argument for like universal basic income
• 43:28
  Speaker 4: or universal health care. Preventative costs are always smaller.
• 43:32
  Speaker 3: Exactly.
• 43:33
  Speaker 2: Well, our listeners had questions about coffee and sugar and
• 43:37
  Speaker 2: a couple other addictive stimulants.
• 43:39
  Speaker 1: And so let's take a break. And when we come back,
• 43:41
  Speaker 1: we'll get to their questions. All right, we're back.
• 44:03
  Speaker 2: And so one thing that I'm dying to know is
• 44:05
  Speaker 2: we've been talking about drugs of abuse, but how do
• 44:08
  Speaker 2: drugs of abuse differ from something like my addiction to
• 44:12
  Speaker 2: scrolling on Instagram or.
• 44:14
  Speaker 1: My addiction to coffee in the morning or Daniel's?
• 44:17
  Speaker 2: Massive addiction that's apparently all he thinks about to chocolate.
• 44:22
  Speaker 4: You mean very healthy habit-forming behavior.
• 44:24
  Speaker 1: That's right, yes.
• 44:26
  Speaker 3: Yeah, so, and this, I won't probably speak too much
• 44:30
  Speaker 3: because I don't know enough about natural things like sugar, etc.
• 44:36
  Speaker 3: Drugs of abuse have an absolutely outscaled effect on the
• 44:39
  Speaker 3: neurotransmitter systems and the circuitry in the brain. Things like sugar,
• 44:44
  Speaker 3: people say, oh, you become addicted to sugar. And we
• 44:47
  Speaker 3: continuously escalate our sugar intake. And yeah, sugar is a
• 44:51
  Speaker 3: problem in our American diet. But the impact on metabolism
• 44:57
  Speaker 3: as a whole is massive. And so trying to then
• 45:01
  Speaker 3: parse out, okay, what changed in the whole milieu of
• 45:06
  Speaker 3: metabolism from increasing sugar and compulsive sugar intake that led
• 45:12
  Speaker 3: to more is really hard to pinpoint. Other things like gambling,
• 45:18
  Speaker 3: Social media, there was a huge lawsuit that I think
• 45:22
  Speaker 3: Meta just lost for social media and trapping adolescents into
• 45:28
  Speaker 3: social media addiction, right? So there must be aspects of
• 45:33
  Speaker 3: that that are true. It's definitely true for gambling. These things,
• 45:37
  Speaker 3: social media, gambling, they also release that neurotransmitter. And one
• 45:42
  Speaker 3: reason is because of something called prediction error. So dopamine
• 45:46
  Speaker 3: in your brain, is not really thought of as, oh,
• 45:49
  Speaker 3: it's a pleasurable molecule, the pleasure molecule. People mislabel it
• 45:53
  Speaker 3: that way. Oh, you had this amazing meal. We released
• 45:57
  Speaker 3: all this dopamine. That's why it tastes so good. That's
• 46:01
  Speaker 3: not really it. It's the increase in dopamine is a
• 46:04
  Speaker 3: motivation seeker. It tells us and motivates us to go
• 46:08
  Speaker 3: get it. And so with gambling and social media, The
• 46:14
  Speaker 3: dopamine is acting as a prediction error in that you
• 46:18
  Speaker 3: got a better than expected reward. And so for gambling,
• 46:21
  Speaker 3: you know you're going to lose a lot. But every
• 46:24
  Speaker 3: once in a while, you're going to hit.
• 46:25
  Speaker 5: Yeah.
• 46:26
  Speaker 3: And when you hit, that high is awesome because your
• 46:28
  Speaker 3: prediction error, you kept expecting, you know, lose, lose, lose, lose.
• 46:33
  Speaker 3: But when you hit and you hit big, it's a
• 46:36
  Speaker 3: massive bonus, like, ah, dopamine, so much release. It's going
• 46:40
  Speaker 3: to drive us to go do that again because it
• 46:42
  Speaker 3: was great. It was a great experience, right? Social media,
• 46:47
  Speaker 3: when people post something that goes viral, same thing. All
• 46:51
  Speaker 3: of a sudden, attention, people saying great things about you, blah, blah, blah,
• 46:56
  Speaker 3: and people get addicted to that and keep pursuing it.
• 46:59
  Speaker 3: And that can be very detrimental, especially in teenagers. where
• 47:04
  Speaker 3: the whole reward circuitry, the learning and memory circuitry in
• 47:08
  Speaker 3: a teenager is still evolving. There's a very complex hormonal
• 47:12
  Speaker 3: kind of control of how the brain is continuing to
• 47:15
  Speaker 3: develop during adolescence. And that's when we're hitting all these
• 47:20
  Speaker 3: kids with pretty bad diets in some cases, social media constantly.
• 47:28
  Speaker 3: All the news people see is fantastical and blown out
• 47:32
  Speaker 3: of proportion. and clickbait, right? It's either amazingly incredible or
• 47:38
  Speaker 3: it's horrific and world destroying, right? That's how our media
• 47:42
  Speaker 3: is pitched to us now so that we'll actually click
• 47:45
  Speaker 3: on it. And so, when the brain starts to see
• 47:47
  Speaker 3: all of this, it gets confused. The neurotransmitter, all it
• 47:51
  Speaker 3: is is a prediction error. It can't assess value of
• 47:55
  Speaker 3: what you're looking at and what you're doing, really, right?
• 47:58
  Speaker 3: And that's where all those social constructs, psychosocial behavior, your
• 48:02
  Speaker 3: support group, your family, your friends, that's where all that
• 48:05
  Speaker 3: becomes really, really important. It helps your brain and that
• 48:09
  Speaker 3: collection of brains figure out how to respond to these things.
• 48:13
  Speaker 2: Wow.
• 48:13
  Speaker 4: So when you say the dopamine is the prediction error
• 48:16
  Speaker 4: and that it's not like the reward, It's the thing
• 48:19
  Speaker 4: that motivates you to go back and like put down
• 48:22
  Speaker 4: another 20 bucks on blackjack.
• 48:24
  Speaker 3: Yeah.
• 48:24
  Speaker 4: Because it's anticipating the occasional big hit.
• 48:28
  Speaker 3: Right.
• 48:29
  Speaker 5: I see.
• 48:29
  Speaker 3: And then we keep pursuing that big hit. Yeah. And
• 48:33
  Speaker 3: it's the same thing that thrill seekers do, extreme skiing.
• 48:37
  Speaker 3: I grew up doing extreme skiing.
• 48:39
  Speaker 4: Cool.
• 48:40
  Speaker 3: And I just kept looking for that bigger cliff, more
• 48:44
  Speaker 3: inclined just to get that rush. And you start pursuing
• 48:47
  Speaker 3: more and more dangerous things until you start breaking bones.
• 48:50
  Speaker 3: And then you get either too old or you stop
• 48:54
  Speaker 3: or you die.
• 48:54
  Speaker 2: I am way less exciting. For me, the big hit
• 49:00
  Speaker 2: is when a goat post comes up on Instagram.
• 49:02
  Speaker 1: And I'm like, goats! That's what's exciting for me. But
• 49:07
  Speaker 1: I stay here. Did you break bones?
• 49:10
  Speaker 3: I got pretty lucky. But I'm 54 years old right now,
• 49:15
  Speaker 3: and I damaged my MCL in January. I hit a
• 49:18
  Speaker 3: tree in March. Oh. but I still love to ski.
• 49:21
  Speaker 3: So it's all good. Good luck. You learn how to fall.
• 49:27
  Speaker 4: So maybe that's a good transition to studies of how
• 49:31
  Speaker 4: we avoid or leave addictive behaviors. So when Marcelo has
• 49:36
  Speaker 4: been skiing and getting that fix of that thrill of like, wow,
• 49:39
  Speaker 4: I just did something stupid and survived, and then you
• 49:42
  Speaker 4: stop doing it. You were talking earlier about the basic
• 49:45
  Speaker 4: mechanisms of addiction involve obviously the reward and then the
• 49:49
  Speaker 4: habit formation, but then the sort of desensitivity to it.
• 49:52
  Speaker 4: Is it that last part that's crucial for the difficulty
• 49:56
  Speaker 4: of leaving the addictive behavior?
• 49:59
  Speaker 3: Yeah, I think as the brain kind of switches to
• 50:01
  Speaker 3: this compulsive approach, it's battling, one, the anhedonia, the lack
• 50:08
  Speaker 3: of reward for natural rewards and the normal things that
• 50:11
  Speaker 3: you do that should be pleasurable, like the goats, right?
• 50:15
  Speaker 3: That's a natural, normal thing that should be fun.
• 50:18
  Speaker 1: That's right.
• 50:19
  Speaker 3: And I don't know what's wrong with people that don't
• 50:21
  Speaker 3: like goats.
• 50:21
  Speaker 4: Obvious evolutionary benefits.
• 50:26
  Speaker 1: There are some crazy people out there.
• 50:28
  Speaker 3: Yeah, yeah. So your brain starts to battle that. And
• 50:32
  Speaker 3: then your brain has also changed the levels of receptors
• 50:37
  Speaker 3: and all these compensatory things that lead to tolerance and sensitization.
• 50:42
  Speaker 3: incubation of craving. The longer you're away from something, the
• 50:45
  Speaker 3: more you crave it. That's a wild mechanism. And so
• 50:49
  Speaker 3: it really becomes important trying to find how you normalize
• 50:52
  Speaker 3: those things. How do you get back to normal rewards
• 50:56
  Speaker 3: being stimulating again? And time and time again, one of
• 51:01
  Speaker 3: the most important things is social interaction. That means more
• 51:05
  Speaker 3: to your brain than most other things. But it gets
• 51:10
  Speaker 3: harder and harder for us to do that. So like,
• 51:11
  Speaker 3: for example, in the pandemic, addiction and overdose deaths skyrocketed.
• 51:17
  Speaker 4: Wow.
• 51:18
  Speaker 3: Because we were isolated. We're socially isolated. So it was
• 51:21
  Speaker 3: a very scary problem when thinking about addiction. Now that
• 51:24
  Speaker 3: things have normalized a bit more, it's gotten better. But
• 51:28
  Speaker 3: this is also one of the concerns about our online
• 51:31
  Speaker 3: lives and how fake our online lives can be. It
• 51:35
  Speaker 3: all comes back down to Trying to find normal pleasures
• 51:40
  Speaker 3: would be rewarding. And can you maintain that? And for
• 51:44
  Speaker 3: some people, that's exercise. Exercise is great. Getting into that
• 51:47
  Speaker 3: habitual exercise starts to re-transform how your brain responds. And
• 51:52
  Speaker 3: exercise affects all the epigenetic machinery as well. It affects
• 51:56
  Speaker 3: how your metabolism reacts. And so you can use those
• 51:58
  Speaker 3: things to help modify.
• 52:01
  Speaker 4: And so somebody who's become addicted to coffee in the
• 52:03
  Speaker 4: morning and then stops coffee and gets headaches, Your advice is,
• 52:08
  Speaker 4: even though you don't feel like going to speak to
• 52:10
  Speaker 4: anybody now because you're miserable, what you really should do
• 52:13
  Speaker 4: is go talk to your neighbors. Yes.
• 52:17
  Speaker 3: Although coffee and headaches are a bit different mechanism.
• 52:22
  Speaker 2: Do we understand that mechanism? Because I think our listener
• 52:25
  Speaker 2: wanted to know why they get a headache when they
• 52:27
  Speaker 2: try to wean themselves off coffee.
• 52:29
  Speaker 3: Yeah, I remember looking this up a long time ago.
• 52:31
  Speaker 3: I don't quite remember, but it does have to do
• 52:33
  Speaker 3: with vasoconstriction and caffeine and vasoconstriction. But I can't remember
• 52:37
  Speaker 3: the exact mechanism.
• 52:38
  Speaker 1: Okay.
• 52:39
  Speaker 3: So when you're not having your coffee at the right time,
• 52:43
  Speaker 3: miss it by a couple hours, you start to get
• 52:45
  Speaker 3: a headache. It's because the blood pressure in your brain
• 52:47
  Speaker 3: has changed.
• 52:47
  Speaker 4: That makes sense.
• 52:50
  Speaker 2: It feels all the more imperative then to get coffee
• 52:53
  Speaker 2: if you're like, oh my gosh, the pressure in my
• 52:55
  Speaker 2: brain is increasing.
• 52:56
  Speaker 1: I need to go get coffee. And so now I
• 52:59
  Speaker 1: will never be late for my coffee again.
• 53:00
  Speaker 4: Yep. What do you think is the future of this field?
• 53:04
  Speaker 4: What do you think we're going to be able to
• 53:06
  Speaker 4: do in 15 or 30 years that we can't do
• 53:08
  Speaker 4: today to help people with addiction?
• 53:10
  Speaker 3: Yeah, so I think two or three things might be incredible.
• 53:15
  Speaker 3: One is trying to understand who will develop addiction and
• 53:19
  Speaker 3: who will not. How do you help people self-identify that
• 53:25
  Speaker 3: they have the genetics or the behavioral psychosocial environment where
• 53:31
  Speaker 3: they really are much more high at risk and to
• 53:34
  Speaker 3: be educated in that. Education goes a long way in addiction.
• 53:39
  Speaker 3: Two is for things like epilepsy, there are some incredible
• 53:45
  Speaker 3: closed loop circuit devices that as soon as someone's like
• 53:50
  Speaker 3: hippocampus is about to have a seizure, the device starts
• 53:53
  Speaker 3: to register the neuronal spiking and then dampen it down
• 53:56
  Speaker 3: so the person doesn't seize. And so as we identified
• 54:00
  Speaker 3: the reward, circuitry that triggers relapse and the cell types
• 54:05
  Speaker 3: and the firing patterns, those types of mechanisms could theoretically
• 54:09
  Speaker 3: be used so that as someone's brain starts to trigger relapse,
• 54:13
  Speaker 3: that device shuts it down and prevents it.
• 54:15
  Speaker 4: Wow.
• 54:16
  Speaker 3: And then the third, science fiction, but this is working
• 54:20
  Speaker 3: in other domains, is.
• 54:21
  Speaker 4: Robotic goats?
• 54:23
  Speaker 5: No.
• 54:23
  Speaker 4: Okay.
• 54:25
  Speaker 3: CRISPR editing. And so we now know, for example, in
• 54:28
  Speaker 3: sickle cell anemia, you can do CRISPR editing and It's
• 54:32
  Speaker 3: quite successful.
• 54:33
  Speaker 4: So you mean changing people's genes, basically gene therapy?
• 54:36
  Speaker 5: Right.
• 54:36
  Speaker 4: Wow.
• 54:37
  Speaker 3: It's in vivo gene therapy within the organism. And there
• 54:41
  Speaker 3: are ways that that is starting to evolve dramatically in science.
• 54:45
  Speaker 3: And so is that a future for addiction therapy? Maybe not.
• 54:50
  Speaker 3: But like you said, it's 15, 20, 30 years out there.
• 54:54
  Speaker 4: I can't see any way that could ever go wrong.
• 54:57
  Speaker 4: So that sounds great. No, never, never.
• 55:01
  Speaker 2: I like it when you're the wet blanket, Daniel. It's
• 55:03
  Speaker 2: usually my job. It's very refreshing when you take up
• 55:07
  Speaker 2: the torch.
• 55:09
  Speaker 5: All right.
• 55:10
  Speaker 2: Well, Marcelo, thank you very much for being on the show.
• 55:12
  Speaker 2: I had a ton of fun. Thank you for putting
• 55:14
  Speaker 2: up with living next to Daniel. That must be a
• 55:17
  Speaker 2: lot of fun. A real roller coaster. And I assume
• 55:20
  Speaker 2: whenever there's a problem.
• 55:21
  Speaker 3: Now I know where I can get my chocolate.
• 55:22
  Speaker 4: That's right.
• 55:23
  Speaker 3: Yeah.
• 55:23
  Speaker 2: I was going to say, I assume whenever there's like
• 55:24
  Speaker 2: a neighborhood level problem, if you just bring Daniel enough chocolate,
• 55:27
  Speaker 2: he'll get on your side.
• 55:29
  Speaker 4: That's a bean. That counts as a bean.
• 55:31
  Speaker 3: That's right.
• 55:32
  Speaker 1: Okay.
• 55:33
  Speaker 3: All right.
• 55:33
  Speaker 1: Well, thank you very much for joining us.
• 55:35
  Speaker 4: All right. Appreciate it. Thanks, Marcelo.
• 55:37
  Speaker 3: That was wonderful. Thank you. Whoa. That was super interesting.
• 55:40
  Speaker 5: I'd never heard of the epigenome before. So, understanding how
• 55:45
  Speaker 5: the human body becomes accustomed to drugs makes sense in
• 55:48
  Speaker 5: that context, but I still don't think I understand the
• 55:51
  Speaker 5: withdrawal part of my question. If I don't drink coffee,
• 55:54
  Speaker 5: my withdrawal symptom is a headache. If a person addicted
• 55:57
  Speaker 5: to a more serious drug abstains, then they could experience
• 55:59
  Speaker 5: significantly more extreme effects than a headache. I'd love to
• 56:03
  Speaker 5: understand what's causing that. Phrased differently, why, as a coffee drinker,
• 56:07
  Speaker 5: does my brain's blood pressure change and give me a
• 56:10
  Speaker 5: headache if I skip caffeine for the day? Thank you, Daniel, Kelly,
• 56:14
  Speaker 5: and Dr. Marcelo Sweetwater-Wood for an incredible episode. What a
• 56:18
  Speaker 5: great deep dive into a fascinating topic.
• 56:21
  Speaker 3: Yeah, I listened to the episode.
• 56:22
  Speaker 6: It seems that nobody's addicted to sugar, and it's just
• 56:26
  Speaker 6: a habit that is a strong habit. Not quite sure
• 56:30
  Speaker 6: where the dividing line between addiction and a strong habit
• 56:33
  Speaker 6: would be. But as a follow-up question, I wonder if
• 56:37
  Speaker 6: the addiction or strong habit to ketones might be anorexia.
• 56:41
  Speaker 3: I don't know. Anyway, very interesting episode. Thank you very much. Cheers.
• 56:46
  Speaker 4: Bye-bye. Thanks everybody for listening. Please go and do us
• 56:56
  Speaker 4: a favor and rate the show on whatever podcast app
• 56:59
  Speaker 4: you're using. It really helps people find us.
• 57:01
  Speaker 2: Daniel and Kelly's Extraordinary Universe is edited by the amazing
• 57:05
  Speaker 2: Matt Kesselman.
• 57:06
  Speaker 4: He really is a wizard. You can also find us
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• 57:16
  Speaker 2: You can email us at questions at DanielAndKelly.org. We really
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• 57:27
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• 57:33
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