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No one starts as a sensitized individual when they start taking drugs, just as you say, they take it for the pleasure of the drugs, for the social milieu to fit in for all the various reasons a person might. But it's not a sensitized want at that point. And many people, most people who start taking drugs are not going to develop sensitized wants. There's a lot of individual differences in vulnerability to sensitization of this dopamine system. And many people are fairly resistant at street doses. So they don't become very sensitized. But some individuals are susceptible, some very, very susceptible. And if they're taking drugs, especially if they're taking them in sort of a binge like fashion, you know, like on weekends, not on the weekdays, but then on the weekends again, sort of spaced apart binges. That's the ideal sort of recipe for developing sensitization of the brain. Mesolimbic dopamine system.
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If someone has a problem with substance use disorder, please call one call placement. That's 888-831-1581.
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And if we can't help you, we'll make a referral to someone who can.
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Please, we're out of time.
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One call placement is affiliated with Carrera
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B
Treatment Wellness and Spa and One Method treatment centers. Dr. Kent Berridge is a professor of psychology and neuroscience at the University of Michigan whose groundbreaking research helped change the way we understand addiction, pleasure, motivation and the brain's reward system. He's best known for developing the wanting versus liking theory of addiction, which explores why people continue chasing substances or behaviors even when they no longer truly enjoy them. His work has helped shape conversations around addiction, dopamine, cravings and recovery across both science and mental health. Doctor, thank you for coming on the show today. It's a blessing to all of us. Your work is mainly about why human beings chase things. Drugs, food, sex, gambling success, even when those things stop making them happy.
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A
Yes, I think that's true. I mean, it's something we stumbled into. I've always been interested in pleasure and desire, you know, motivation and emotion. But the difference between wanting and liking is just something we stumbled into. We weren't expecting it.
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B
Well, it's actually brilliant because it applies to the boots on the ground and people who are treating people. So it's absolutely. And the science doesn't always correlate, believe me, but this, this actually does. It's beautiful. All right, doctor I've sat across from thousands of addicts and one thing I've seen over and over is people Using drugs they don't even seem to enjoy anymore. They look miserable, they hate themselves, and then they still go on to use again. Is that exactly what your work explains?
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A
That is exactly what our work explains. You know, that would be sort of the poster child for incentive sensitization forms of addiction.
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B
You helped introduce the idea of wanting versus liking. Can you explain the difference and why that distinction matters so much in addiction?
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A
Well, I have to say that when I began my career decades ago, I didn't think there really was a difference. You know, at that time, we all thought there was a unitary brain reward system sort of centered on dopamine, mesolimbic, dopamine, and that it would cause both liking and wanting. That the two words were basically synonyms for the same psychological process of reward. It's something you want and something you like. There was lots of evidence for that. And my beginnings were intended to add just a little bit more evidence to the dopamine as pleasure liking hypothesis. And I was disappointed that I couldn't do it. In our hands, we were asking the question a little bit differently from earlier studies by others. And in our hands, dopamine was not pleasure liking.
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B
What I want to say to you, though, is, in my experience, and help me out at first, you know, there's a choice to be made to pick up. There is no addiction yet. Okay. And at first it's all fun. And then you graduate to fun with problems.
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A
Yeah.
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B
And then you graduate to all problems. And I think your work, correct me if I'm wrong, is in the. In the area of graduating to all problems.
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A
I think that's right. I mean, our hypo. Our work instead of sensitization. No one starts as a sensitized individual when they start taking drugs. I mean, just as you say, they take it for the pleasure of the drugs, for the social milieu to fit in for all the various reasons a person might. But it's not a sensitized want at that point. That's right. And many people, most people who start taking drugs are not going to develop sensitized wants. They're. There's a lot of individual differences in vulnerability to sensitization of this dopamine system. And many people are fairly resistant at street doses. So they don't become very sensitized. But some individuals are susceptible. Some very, very susceptible. And if they're taking drugs, especially if they're taking them in sort of a binge like fashion, you know, like on weekends, not on the weekdays, but then on the weekends, again, sort of spaced apart Binges. That's the ideal sort of recipe for developing sensitization of the brain mesolimbic dopamine system. If they're vulnerable to do it and if they're taking drugs and doing that to sensitize, then their wants are going to be focused on the drug taking.
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B
Excellent. So what's the difference between the people that go on to become addicted and the ones that don't?
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A
Well, the individual difference is there's a number of sources. I mean, genes have a lot to do with it. In fact, genes are probably the biggest single contributor. This is true for people.
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B
Bullets, not environment.
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A
Well, environment. Environment has a lot to do with whether one's taking drugs. Absolutely. And how one takes it. But the vulnerability to sensitization is mostly genetics coupled with a few other factors like certain pre exist pre exposures to certain kinds of environmental things like major stresses in life that can also predispose towards sensitization and produce even cross sensitization. So that when they do take drugs, even the first time, they might have a sensitized respons.
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B
Because sometimes, correct me if I'm wrong. Yes, it's the genes. A lot of time. A lot of the time. But doesn't it need a specific event to kick that off?
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A
Oh, absolutely. That's right. Even with the genetic vulnerability, we're still not sensitized. We're just vulnerable to becoming sensitized. And drugs are good sensitizing agents. If we're vulnerable to sensitizing, you know, and it turns out that it's all kinds. Well, not all, but many, many kinds of drugs. Psychostimulants like amphetamine, opioids, like heroin, alcohol, nicotine, all of these sensitize.
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B
Well, let's talk about that for a second. Because they're different drugs. Right.
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A
Very different.
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B
And you haven't. You're not a drug addict. You don't. You're not in recovery or any of that. Right? That's.
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A
That's right.
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B
Okay. And I am. I lost two and a half decades to drug addiction and I've given probably just a little over 10,000 people back to their loved ones. And one of the things when I was reading up about you was omitted and I'm sure you know this, but I wanted to get your thoughts on it. So with certain drugs and heroin isn't one of them because you're sleeping through your high. Okay. Just like the other opioids and a lot of benzos too. Okay. But co. And a lot of the reasons or the cues. Right. That you talk about And I call it. It's just calling you. Right. But you give a much better description of it. A lot of it is the sex. Dr. It's. It's so. Because these drugs go with sex, and. And that's the cue that pulls them in, even though they don't want to do it anymore and even though they don't like it anymore. What's. What's your thinking on that?
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A
Well, I think that's reasonable for. For many people that, you know, drugs and sex together are going to become sort of a constellation, and the cues for both are going to feed in cooperatively and trigger the same kind of very, very int. There was a study a number of years ago of. Of CO users who were showing hypersexuality and kind of developing compulsive sexual pursuit, possibly induced by their co. You needed a study.
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B
You needed a study for that?
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A
Well, you know, once it's in the scientific literature, then we can cite it, you know, otherwise, it's anecdotes from.
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B
It's like, did you do a study on that? Like, oxygen is helpful for breathing?
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A
Well, sure. More recently, you know, a lot of. A lot. But. Well, a fair number of Parkinson's patients who are being prescribed the new medications, the new dopamine direct agonist medications are developing behavioral compulsions. And in men, sexual compulsive pursuit of pornography and sex is very, very common. Little less common in women, but it can happen in both. So this is inducing sort of sex compulsions in people who were not very compulsive personalities to begin with, who didn't have the sex compulsions or drug compulsions compulsions. Yet it's dopamine stimulation that's doing it. So, yes, these things go together.
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B
Thank you. What do most people completely misunderstand about dopamine and pleasure?
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A
Well, the biggest misunderstanding is the belief that dopamine is pleasure. It's a belief that I had once I held fervently and I used to. That's the belief.
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B
That's the belief that's mainstream right now.
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A
Oh, yeah, that. Well, it's a meme. It started, you know, in the late 1970s and early 1980s. The big champion of it was Roy Wise, who was an excellent neuroscientist in Montreal at that time. And he had many experiments that would show. They were animal experiments. What he would do is he would block dopamine with a dopamine suppressing drug, an antipsychotic drug that blocks dopamine receptors. And he would find that rats who had been working for Food reward or sex reward, or drug reward, or brain stimulation, electrode reward, which is a reward that rats will work for any of these rewards. Once they had the dystopian blockade, they gradually abandoned those rewards as though the pleasure of the rewards had drained out of them and they were no longer pleasant. He called this extinction mimicry, because it's what happens. It looked like what happens, this gradual decay. If you simply just stopped giving them the reward, they gradually cease working.
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B
But they relapse. They relapse.
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A
Well, they relapse. If you, if you. That's right. So if you take, take them home for the weekend, then bring them back next week and give them a chance, then they do relaps. That's right. They'll start working again. But, but if you, each time give them the dopamine blockade, gradually they will cease to relapse. They will abandon these kinds of things. So even this, this he called anhedonia, that is the lack of pleasure, the dopamine blockade was producing the lack of pleasure. And if dopamine blockade takes away the pleasure, it meant that dopamine itself was causing the pleasure. This was the basis for the hypothesis. He had clever experiments that kind of ruled out a few alternative interpretations, and I believed it. My very first dopamine study was really a collaboration with Roy Wise, and I intended to just give him one more little bit of evidence for dopamine pleasure. And it totally failed in our hands. We were asking a different, in a different kind of way.
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B
That's magnificent. That's magnificent. Do addicts eventually stop chasing pleasure and start chasing relief?
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A
People who have had the experience of addiction or talk a lot with people, addiction are best qualified to say, but my, my impression is that a lot of people do take drugs for the pleasure. A lot of other people do take drugs to relieve anxiety and distress and other various forms of distress that are going on in life. Some people start taking drugs for these reasons, but they then become sensitized. And these people, even if you took away the pleasure, even if you took away the withdrawal and distress, these people could still have compulsive wanting to take the drugs again and again.
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B
And it's because they don't know how to live. Dr. They don't know how to live. You've been doing this a long time. You get into some, you get into a learned helplessness, right? And this is. They just give up. That's what that is. And sometimes they start off right with the pleasure, and then because they're using drugs, their life gets worse and worse. And Worse, they're creating wreckage and then the depression sets in. And the depression begets more drugs and the more drugs beget more, more depression.
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A
Right. So that's the cycle of relieving distress. And that could happen even without sensitized wanting or could accompany sensitized wanting. But the difference is going to be if they're sensitized wanting, then even if you could sort of relieve their distress, you know, put them in a five star luxury hotel and give them everything they want and take away the problems
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B
in their going to drink out of the mini bar.
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A
Well, right. If they're sensitized, they can go through all of this and you could even take away the drugs for this month or two, but they're still going to relapse when they come out. These are the sensitized individuals whose wanting in a sense, becomes irrational because it's no longer linked to distress relief, it's no longer linked to pleasure. It may confuse even the person who's doing it. They may not have a reason. But this system doesn't need reasons. It operates by psychological rules, not by cognitive rational reasons.
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B
So I know the answer to this on the ground, but I'm interested in knowing scientifically what this is. Do addicts eventually stop chasing pleasure and start chasing relief and if so, when in their arc?
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A
Well, I'm sure many addicts do stop chasing pleasure and do start chasing relief. And my guess would be that this would happen especially when distress is sort of mounting either because of their addiction or and heavy drug use, problems in life and withdrawal, sorts of syndromes or for other reasons. Once, once distress is high, then that gives you another reason to take drugs. But that's still different from a sensitized want.
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B
That's, that's right.
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A
It is possible to have this distress relief motive without being sensitized.
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B
Yet what's actually happening in the brain in the seconds before somebody relapses, especially after they've been sober for years,
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A
if they have a sense, if they've sensitized their mesolimbic dopamine system, that's what's happening is when they think of taking drugs kind of vividly imagine it, or if they're encountering cues related to taking drugs, this triggers hyperreactivity, a hyperactivation in the dopamine system itself and in the structures that it's connected to. In neuroimaging studies of addiction, what this looks like is sort of of lighting up to a very intense degree of these brain limbic emotional reward structures like the nucleus accumbens. And prefrontal cortex. When the person's looking at the drug cues, it lights up much higher than a person who would just be a recreational user. It's this intense limbic activation. And psychologically what it's causing is a very, very intense desire, far more intense than most of us experience in our day to day lives. We're all capable of that kind of intensity of desire, but many of us will never actually experience it. A sensitized person can experience it triggered by drug cues especially, and even intensified further if they're encountering those cues in a moment of psychological stress or emotional excitement. So the intensity can actually be kind of surprising on certain occasions because it's rising above what a person's used to coping with. Cue triggered wanting. That's the essence of this addictive, urgent.
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B
Are you saying this separate and apart? Are you saying that the dopamine receptor is not the pleasure center of the brain?
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A
The dopamine receptor is not the pleasure center of the brain. We, we all thought it was, and some people still think it is.
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B
What is?
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A
The dopamine neurons are talking to other neurons, say in the nucleus accumbens. Some of those nucleus accumbens neurons with opioid receptors or endocannabinoid receptors, they can cause true intense pleasure. Usually the dopamine system is working with them sort of hand in glove. It's a circuit, but they are separable components. And when dopamine system is hyperactive on its own without acting on these pleasure opioid and cannabinoid and other neurotransmitter systems, then you get the wanting, excessive wanting that's detaching from liking even in the absence of intense pleasure.
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B
So the science in Anything is typically 10 to 15 years ahead of the practice. Okay, it's, that's across the board. Why is, why is your definition of this in totality not adopted by the mainstream yet?
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A
Well, many reasons, I think. I mean, one is that the notion that dopamine is the pleasure neurotransmitter, that's a meme that, you know, as we said, it began 40 years ago. And it is, and it's partly true because it's a reward neurotransmitter. Reward is pleasure. Yes. But it's also wanting. They do go together. So dopamine's contributing that wanting side to reward. It's still part of the reward system. The meme is so powerful that it's just never going to go away. I think even in neuroscience, there are some people who still will adopt it, although usually not people who are really in addiction neuroscience anymore. So that's a mistake that we just have to live with.
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B
Yeah, that's is must be crazy making for you. You've got the evidence. And this reminds me of the saying, you got to get sober for yourself. You got to want it. And nothing could be less true. Okay, nothing's killed more people than that statement. But yet that's the statement. And it's been parroted by this one to the next one to the next one throughout history. And this feels to me like it's the same thing.
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A
Yeah, I think that's fair. And, you know, there may be reasons why people say that, even if it's not the final answer.
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B
They're intellectually lazy. That's the answer.
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A
Well, but there are for the dopamine pleasure notion. I mean, in defense of the people who say it, it is true that when you encounter something pleasant, you know, tasty food, a drug or other pleasant event, dopamine systems activate. They do activate. So they go along with the pleasure. Now, the question is whether they're causing the pleasure or whether they're being caused by the pleasure. To make you want to even further this thing that's caused the pleasure, usually many people don't get to that stage of asking that question.
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B
Why is the distinction so important?
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A
Well, the distinction is important because when you turn on dopamine systems particularly selectively, you get intense wanting, but you do not intensify the pleasure. This is what we began to find out.
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B
It's calling you. It's. It's caught. That's why I say it's calling you. That's the part that's calling you, not the part. It's the part that's creating the wanting, not the pleasure. That's the distinction.
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A
Absolutely right. There's a lot of disappointments along the way. I mean, I really wanted dopamine to be pleasure when I started out. And when in our hands, we were asking a little bit differently. The earlier experiments had been how much would animals work for these rewards? And they wouldn't work if you suppressed dopamine. How much would they consume? Well, they wouldn't consume if you suppressed dopamine. We were asking a little bit more, starting with the pleasure of taste. The way parents would ask their newborn infants for thousands of years, does the infant like the kinds of foods we eat by giving just a little taste of that food to the infant and seeing does the baby sort of smile like it slips, or does the baby gape and shake its head and, you know, really not like that food. Great apes have similar facial expressions. Chimpanzees and orangutans. Monkeys also do. And it turns out that even rats, which are omnivores like us, that is, they like sweet and fatty and salty foods. They don't like bitter foods. So they'll eat just about the same foods that we eat. They'll show some of the same facial expressions to sugar and then opposite facial expressions to bitter. When we started with dopamine, we started suppressing dopamine or taking it away. And we expected the positive liking reactions to sugar to go down, and it never did. Then we started turning on the dopamine system, say, with an electrode to stimulate the dopamine neurons. And this made animals eat five times more than normal. It would make the rats eat eight times more than normal. And people thought they ate more because they liked the food more. But when we looked at the facial expressions, they didn't like the food more. In fact, they kind of showed a little more disgusting, but they still ate eight times more than usual.
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B
The reason being. The reason being is because I saw a rat the size of a cat in New York dragging a whole pizza, like a large pizza. It was. I was like. I was shocked by it. I was like, what the hell is this? That's why, right?
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A
Yeah, rats like pizza. They want pizza just like humans in that regard.
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B
All right, you say.
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A
But the one liking thing is, it's probably fair to say the field didn't believe us for about 10 years. But then some drug studies, clever drug studies by a number of people. One great example is Marco Layton in Montreal in the early 2000s. He was giving people volunteers who would participate in the study they could get free. And he asked them, how much do you like this coke? And how much do you want to take a little bit more once you've taken this first dose. And he gave them low dose or medium dose or high dose. And the more. The higher the dose they took, the more they liked the co. Made sense. And the higher the dose they took, the more they wanted to take even more. Makes you want it even more again.
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B
That was a study. That was the study.
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A
Well, this is the half the study. The second half is he gave them the. But he simultaneously suppressed their dopamine with a dopamine blocking drug or. And when he now asked them, how much do you like the CO and how much do you want it? He was wondering if the dopamine blockade would suppress the liking rating. He probably still believed the dopamine pleasure hypothesis.
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B
What was the drug that, that inter. That interrupted the dopamine.
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A
He did it in a couple of ways. One was to give a neuroleptic drug. It might have been haloperidol or pemazide, or it might have been another antipsychotic, dopamine. It's a dopamine receptor D2 blocker. It blocks D2 dopamine receptors. The other way he did it was to ask them just before this experiment to drink a certain amino acid cocktail that competes with the synthesis of dopamine in the brain and it essentially stops the synthesis of dopamine for the next few hours.
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B
I want to look at all of these drugs because there is nothing standard in this industry, okay, that blocks the receptor for co. Okay. And I'm not saying that there isn't, doctor, I'm saying that it isn't used. And I'm doing this 20 years and I had to talk to a world renowned scientist, okay, to get this. And I can promise you no one else in my industry is talking to people like you. So you just, if this is true, you just helped so many people. Because I'm going to scream it from the mountaintop.
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A
Well, it's an antipsychotic. It's the same drug that's prescribed for schizophrenia. And people don't really enjoy taking this drug.
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B
Wait, wait, wait, hold on. We do off label stuff all the time. What's the problem?
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A
Well, for the. It didn't block the pleasure, but it did reduce the wanting to take more coffee. So it was human confirmation that it was suppressing selectively wanting. Now there's many. There's several kinds of dopamine receptors. And these drugs just block the D2 kind. There's a D1 kind of. And within them there's several subcategories. So it's blocking maybe half the dopamine receptors. But people who are prescribed for schizophrenia who have to take it every day, they find that it kind of drains a lot of the zest out of life, the incentive salience of life. When you walk out on a morning and the world is inviting. That's a dopamine kind of want. That's a very adaptive, good kind of dopamine want. But antipsychotics block that, you know, so life becomes less interesting, less engaging under these drugs. And also sometimes there can be movement side effects if a person takes these drugs for years. So you probably would not have people willing to take these drugs.
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B
You've said cues can trigger craving years later. The neighborhood, the smell, the people, the music. Is that why environment matters so much in recovery?
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A
Yes, I think so. I mean the life is a constellation of cues, you know, in context. The place that we are in where we have taken drugs. Particular things, sights and smells and touches of things that have been associated with the drugs, these can really trigger it. Now it isn't the cues themselves, it's the cues acting on a brain system that's, that's ready to be hyper reactive. So and since sensitization lasts for years, once it's induced of this dopamine system, that's the brain system there. I mean for all of us. To kind of put it in a way that I think everybody would understand whether they've taken drugs or not. You know, if, if we're hungry and we're walking down the street before lunch and we haven't eaten and we're not really particularly thinking of food, but now we smell food and we think, wow, that's nice, I would love to have something to eat. And maybe even particularly that, that thing that I'm smelling, that's a cue triggering this kind of limbic dopamine response and giving us a good start, strong urge or want to eat. But if we've had a big lunch and we're walking down the same street and we smell the same smells, it's not likely to trigger an urge to
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B
wanting because we're not in the wanting stage.
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A
Well, the brain is not ready to respond with that, with dopamine activation if the cue is the same but the brain's response is different.
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B
Because you're full.
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A
Because you're full. That's right. So hunger, satiety, these are temporary states.
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B
So there's no wanting if you're full.
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A
That's right. There's no wanting for food if you're full. Now there's, you can still have other wants because the society for food isn't going to suppress wanting for other things. Sensitization is a more permanent kind of hunger like state that can last in a person. So that's why years later, even in a rat, if you give sensitize them and then you don't give them drugs for a year, you come back a year later, they're still sensitized. That's half a lifetime for a rat because they only live for two years. Same thing. If you take a person and they haven't taken drugs again, Marco Layton in Montreal has done this. If you give them drugs and sensitize them and ask them to come back a year later, put them in a PET scanner, they are still sensitized a year later, even though they haven't taken drugs in the year since you first sensitize them. So once you're sensitized, it lasts a long time because you can't.
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B
Because you can't unring a bell.
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A
Do you know you can't unring this bell? You know, it is conceivably decades and decades and decades. Maybe as we hit our. You know, as we hit later in life, dopamine systems start to die in everybody. We, most of us will never develop Parkinson's disease because the dopamine death is slow and we'll die of something else before we lose enough dopamine to be Parkinson's. But we are losing it after age 30 or so. And it may be that later decades, a person can shake what they couldn't shake earlier. But sensitization is persistent, and sometimes it can last decades. I think.
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B
So that's the science behind relapse.
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A
Yeah, I think so, yes. For. For anyone who's sensitized, that's the science behind relapse.
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B
It took me three years just to get 30 days sober. Because if I drove by a hotel or one of the many dope dealers, Right. My best intentions, it could have been I was sober, like, three weeks. Right?
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A
Right.
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B
But I'd fold every time. I remember there was a time where there was a girl who was sick, and I needed to bring her milk. I don't know why. Okay. But I wanted to bring her some milk, and she wanted it. And so I'm. I go to get the milk. I've got the milk in the car. I'm on my way to see this girl. I've got 29 days sober. I didn't make it. I didn't make it. I drove by a motel. Right. It set off the phenomenon of craving. And I was. And I was on a run for another five and a half months.
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A
It's a classic story, and I think many people could resonate to that.
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B
Yeah. All right. What are your thoughts on GLP1s
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A
encouraging, both for weight loss and for potentially giving up drug use. It's better than anything that's come down the pike previously. So, you know, there's anecdotal reports already, there are some studies already that suggest it's reducing opioid cravings, alcohol craving. It's not a magic bullet. It doesn't work for everybody, and neither does it help weight loss for everybody. But it helps a number, a good number, and it helps more than previous medications. So I'd say it's very encouraging. So far.
- [29:52]
B
It takes away all the noise around the food. It takes away all the noise around smoking. I was smoking a ton of cigars a day. I'm lucky if I can smoke two now and I don't even finish them. Okay. We've been putting people on this since the day we opened two and a half years ago. Okay. And we've gotten tremendous results from it. Now there's not enough people on it. Okay. For it to not be anecdotal.
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A
Yeah.
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B
Okay.
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A
No, absolutely. And the animal experiments, neuroscience experiments support it absolutely too. The drugs, the GLP1 agonists, they're acting on hunger satiety centers in the brain stem and hypothalamus, but they're also acting in this dopamine system, the mesolimbic dopamine system. Even micro injections of droplets of these drugs into the dopamine system of rats will suppress their craving for food and suppress their craving for drugs preference and things of that sort. So it's acting directly in the mesolimbic system when it can get there. Some of these GLP1 agonists are able to penetrate the blood brain barrier and get to all of these targets. Other GLP1 agonists are not so good at getting to, through the blood brain barrier. So they can't get all the brain, but they still can get to the brainstem and hypothalamic little parts that don't have a blood brain barrier. And those parts seem to also modulate and suppress the dopamine system's response to these cues. So in the animal studies, absolutely supports the, the human anecdotes. It, it works to suppress these cravings. And when does it get to the pre.
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B
When does it get to the cortex?
- [31:32]
A
Well, the meso, the mesolimbic system that's really generating the wants. It's mostly below the cortex, not entirely, but say, you know, 75% below the cortex. But there are parts of the cortex, the frontal cortex, that can participate in this too. In the orbital frontal cortex and insular cortex, parts of the human, in the very front and a little bit to the side of the frontal lobe, these can connect up and participate too. And these also would be, I think, showing suppressed responses. I mean, that'll be mostly in the human FMRI studies to see that suppression of that cue induced craving responses. But I think that's happening.
- [32:08]
B
A lot of families watching addiction, active addiction, wonder, why would somebody destroy their own life over and over again? What do you wish these people, these parents, understood about this?
- [32:26]
A
Well, the intensity of these sensitized ones, in my view, can become compulsive, rising to an intensity that is arguably compulsive. Now this. That's a controversial assertion, and it's not.
- [32:40]
B
That's exactly the way it happens. And if it's controversial, okay, these people don't know what they're talking about, because you're exactly right.
- [32:49]
A
As an example, in the last two years, there are two books by very good philosophers. Owen Flanagan is a philosopher at Duke University, and he's a former recovered alcoholic and benzodiazepine user himself. And Hannah Picard at Johns Hopkins University. Both of their books in this last two years argue that addiction is not compulsive. The reason they do that is they say, well, addicts, they can postpone drug use if they have to. In a circumstance, if you reward them for not taking drugs, they might reduce their drug taking. And to earn the rewards, if you have fairly severe punishments.
- [33:24]
B
That's semantics. Dr. That's semantics. And the reason it's semantics is because, sure, if you're not using in the moment, it may or may not be compulsive. Once you start. Once you start using, you don't have it. It's got you. So I think it's semantics because at that point, it is compulsive.
- [33:45]
A
Well, I absolutely agree with you on that point. And both for some animal experimental evidence that we have and some human evidence from other domains, the animal evidence is we can. Recently we've been trying to get a sense of not only what controls the intensity of wants, but also what controls the target of want. Why does one person want this drug or that drug? Why do some people come addicted to drugs and others to sex and gamblings and things of that sort? And what we're doing is what's called optogenetic brain stimulation, where a laser light can activate neurons. Here we're doing it in the amygdala, which is kind of a part that recognizes it perceives the world, visual and other percepts, and it kind of puts the motivational value on them, but it turns on the dopamine system. So what we're doing is activating this amygdala. Whenever a rat, say, works for a sugar pellet, or whenever it works for intravenous or intravenous or. And here's the compulsive part. Whenever it approaches a nasty shock rod, which is an electric rod, it sticks out of the wall and the rat does not have to touch it, but a normal rat will touch it once, maybe twice. Get an electric Shock and then we'll stay far away from it as possible and may even bury it with sand that's in the cage. It's a defensive response that they do. That's a normal rat. But the rat who has this amygdala activation paired with the shock rod gets a shock, comes back, is really curious, is fascinated by this rod that shocked it is hovers over it, gets another shock, hovers over it, gets another shock, puts its mouth on it, gets another shock. It may get 20 shocks, up to 20 shocks in a half hour session. Then if it gets more than 20, if it gets to 20, we take it out so that it won't hurt, hurt itself any further. This is a rat who's compulsively seeking this rod that hurts it. There's no pleasure at all. But the rats who have the amygdala stimulation paired with sugar, they become sugar addicts who ignore intravenous or intravenous opioids.
- [35:35]
B
Sugar. They rather have sugar than co.
- [35:39]
A
If they've had this stimulation. If we've paired this. If we take a different rat and we pair the stimulation with co, it becomes who ignores sugar and run.
- [35:46]
B
You know what I want to know because this is. You said something that I've never thought about in 20 years. I know people use. You've got addicts and then you, they're specialists. And then you've got benzo people and they're specialists. Alcoholics are specialists, Co users are specialists or specialists. There's some overlap, but true cocaine addicts are disgusted by meth. Okay. But I've never considered why some people gravitate to CO and some do you know why that is?
- [36:27]
A
Well, I think there are two reasons. One reason is, is that they're seeking different things, you know, very pleasant and kind of sedating and makes all the bad things go in life go away is slightly different. It's going to brighten up the world, make things really attractive or interesting and. But it's a very different experience. People who are seeking these different experiences might take it for that reason. But the second reason is the reason why some of my rats are sugar addicts, others are remifent addicts or CO addicts and others are shock rod compulsive addicts who keep shocking themselves. And that's because once if they're going to be sensitized, if we can create this sensitized excessive wanting, it can be assigned by the brain to a particular target. And once it's assigned, it kind of sticks to that target. So a person could have true sensitized wanting for. And a different person could have true sensitized wanting for. Even when they're no longer seeking the very different pharmacological effects so much now they've got a kind of similar urge, a similar excessive want that incentive sensitization has caused in them. It's just directed towards different targets because of their experiences.
- [37:35]
B
Can someone be neurologically hijacked and still responsible for their choices?
- [37:42]
A
Well, I think the answer is yes. Although, you know, when we're inducing these kind of compulsive wants, then it's. I think we have to be understanding that the intensity of the temptation they're experiencing is much stronger.
- [37:54]
B
It's biology.
- [37:56]
A
It's biology. But even with an intense, intense temptation. I mean, here's an intense temptation that anyone could experience, and that is if we were starved and starved and starved. We all want food when we're hungry. But if a person starved and starved and starved, the intensity of their want for food is far exceeding ours. You know, in World War II in the United States, there was what was called the Minnesota Starvation Study. It was happening because there were conscientious objectors who didn't want to go and fight in. In the armed forces. And they. It wasn't really socially acceptable to do that, to be a conscious objector, but they were given a choice. They could participate in this study as volunteers, and then they wouldn't be have any jail sentences or anything. They participated. They were motivated because their friends were fighting and sometimes dying, and they wanted to participate. The government knew that people were starving around the world. And the question was, how could you help these people afterwards? Could you take a starved person, bring them back to health? To answer that question, they needed to have starved people. So this is why the volunteers near Minneapolis were so starving. And if you see photos of these men, they look like concentration camp prisoners.
- [39:04]
B
The ribs really.
- [39:05]
A
They're really starved down now. They could go into Minneapolis sometimes on leave. They couldn't eat. And they had a buddy system because the temptation to defect was so high with donut shops and things that you couldn't send them in by themselves, even though they're motivated to participate. Even with the buddy system going into. At a time, some of them would defect and have to be kicked out of the study. Others who didn't defect, they were written up in a medical journal and they would take the little food from the cafeteria that they had and they would save one little crumb and take it back to their barracks and sort of obsess over it. This little crumb of food. They would read cookbooks with what the physician who wrote the study says, with sort of like pornography interest, with obsessive pornographic interests, looking at this cookbook. And some of them developed eating disorders later in life once. Once they had recovered. This is an intensity of temptation that any of us are capable of. And all of those guys were put into. And it's so strong that some of them defected, not all of them. Right. Some of them were able to resist. But if all of us were put into this temptation and we were sent into Minneapolis to smell donut shops and hamburgers frying time after time, how many of us would succeed in, say, not defecting on 100 visits? Over 100 visits, never defecting once Some of us would give in to the temptation. This is the kind of temptation that I think a sensitized addict could be imagined to experience for the drug cues that tempt them. So we're asking something that's out of the ordinary when we're asking to resist. It is possible there are behavioral strategies and cognitive strategies that may help, including 12 steps programs that may help resist this temptation. But it isn't easy. And of course, not everybody can succeed.
- [40:53]
B
Who did this study?
- [40:54]
A
Doctor, I can send you. I can send you the citation for it.
- [40:58]
B
Whoever did it. Now we know who coined the phrase food porn, right?
- [41:04]
A
It was sort of the earliest demonstration of food porn. That's right.
- [41:08]
B
I just want to see if a big shot like you would say food porn. All right. Do behavioral addictions like gambling, gaming, social media, and pornography activate similar reward systems?
- [41:20]
A
I now think that the answer is yes for some individuals who have gambling or addictions or pornography addictions or some of these other behavioral addictions. If you had asked me 15 years ago, I would have said I thought the answer was no. The reason 15 years ago, I thought the answer was no is because we know something about the biological neural mechanisms of how drugs can sensitize the dopamine system. We know some of the neural, even cellular, molecular events that's happening. And I would have thought, well, how. How is sensitization happening in the absence of drugs that you're not triggering these same mechanisms? But I should have remembered 15 years ago. I should have remembered that 30 years ago, my colleague, the co author of the addiction incentive sensitization addiction hypothesis, Terry Robinson, he had been showing that he could sensitize rats even without drugs by stressful experiences. A stressful experience would stress sensitize them. And then if you later gave them drugs for the first time, they Would already be sensitized, their mesolimbic dopamine system. Some individuals, I think, can sensitize readily without drugs. They're that vulnerable. And what's convinced me in the last 15 years that it's happening in these behavioral addictions are two things. One is FMRI studies of people with gambling addiction or people with sex pornography addiction. Some people with binge eating disorders, Some people with other behavioral addictions, Internet, who are showing in FMRI neuroimaging studies the same kind of limbic hyper reactivity to their addictive cues that a drug addict shows to drug cues. This is looking like a sensitized response. The other reason that makes me think this is happening and it's for real Is what we mentioned before, that some behavioral addictions like gambling, pornography and sex pursuit shopping drug use is being created in people who never would have done this before. That is Parkinson's patients who are being prescribed the direct agonist newer medications in conjunction with L dopa, the old medication that induces behavioral addictions of this sort in anywhere from 10 to 40% of people who are taking it it, depending on how intense you'd want to draw the cutoff for these urges. And if a person shows one of these Parkinson's patients, shows one of these compulsions, There's a fairly good chance they're going to show a second. And a third collection of a constellation really of behavioral addictions Creating it by dopamine stimulation in people who were not at all behavioral addicts before. This says, yes, it is the same system. It's following the same rules. It's the same mesolimbic dopamine system. It's the same hyper reactivity to the addictive cues that creates that really intense sensitized want.
- [43:56]
B
If the wanting system stays sensitized for years, what actually helps calm it down Is it. Time, Relationships, structure, purpose, treatment, service, you know, what do you think? I mean, I wrote a book on transcendence Because I have the experience of knowing that a very, very small percentage of people actually transcend addiction. It's just not who they are anymore. Okay, so if you can explain that and the question I just asked you, that would be extremely helpful.
- [44:39]
A
Well, I think many of the traditionally effective therapies, They've been mostly cognitive, behavioral, psychological therapies, 12 step programs rather than medications before the GLP1 agonist came along. Most of these are really not so much calming down the sensitized wanting system, but rather giving ways to cope with it and to deal with it without taking drugs. Mindfulness Kinds of approaches where you kind of recognize the cue triggered urgent and you feel it, but you look at it, you kind of experience and you don't act on it right away. You try to put a little space between the urge and the action. Mesolimbic dopamine systems, they are naturally ready to trigger action. This is why Parkinson's disease is also associated with dopamine systems. Motive and motor, that is motive and movement, they kind of go together in the brain and it's naturally one lead cell to the other. But cognitive behavioral strategies may give us a way to put a little space between them so we can have the urge and not necessarily act upon it in that way. It's possible maybe that the new GLP1 agonists and other drugs that come along that pathway might actually help reduce the cravings themselves. The intensity of the Cutrich urges, which would of course be a wonderful adjunct.
- [45:58]
B
It does. And then that gives you the space to actually make a decision with support in a safe, supportive, contained environment. That is, that gives you the space that you're talking about.
- [46:13]
A
Right. So the combination of these newer medications together with cognitive behavioral mindfulness or 12 step program strategies might be the best way to go.
- [46:23]
B
We hear a lot about personalized medicine today. Do you think addiction treatment eventually needs to become more individualized based on brain science?
- [46:34]
A
Well, I'm not a physician, I'm not an MD. I'm a PhD neuroscientist and psychologist who does basic kind of neuroscience research, mostly in animals. So medical approaches, it's not my bailiwick. I would imagine though that there will be, there will be certainly room for this. I mean the GLP1 agonist, they're certainly wonderfully encouraging, as we've said, but they don't work for everybody. I mean for some they produce too much nausea. For others they just.
- [47:02]
B
That's that in my experience, that's the Ozempic, not the Zeppelin. The Zeppelin people are really not that I'm promoting that bound. Okay. But it's. That is in our experience makes it so that you're not nauseous.
- [47:18]
A
But yeah, I think you're right. That's right. And I think you're. The newer ones will also kind of even reduce nausea further so that less of a problem. That will be good. Yet still, not everybody even shows the weight loss effect. You know, most people, many people do, but some people take the drugs and don't.
- [47:33]
B
Some, some people on a microdose. Dr. They're, they're not taking it for weight loss. They're Taking it for cholesterol and.
- [47:43]
A
No, that's fair.
- [47:44]
B
Yeah. And, and, and to get the noise around drugs to dissipate and stuff like that. So. Yeah, but I didn't know, I didn't know it didn't work for everybody on. Or is it just the nausea? The nausea where they stopped taking it?
- [48:02]
A
I think both of those things are happening. The nausea is one story, but the failure to actually lose weight or to reduce cravings for drugs, I think that may happen for some individuals too.
- [48:12]
B
You know, you're right, you're right, you're right. There's two people that I know that are not losing weight on this.
- [48:18]
A
Okay, so, so if it is, then there will be a place to kind of tailor and maybe find other approaches. I mean, there's, there's several of these receptors. GLP1 is one receptor, but there's several in the family that drugs are now targeting. And, and sometimes the drugs are now going to go in combination for two receptors, which may be more effective. So there is room to tailor and possibly based on individualized analyses, including maybe genetic analyses, it will be possible to diagnose eventually.
- [48:46]
B
How is AI help you in your work?
- [48:53]
A
Well, I'm coming towards the end of my career, so I'm sort of, kind of a little bit too, too late for the AI, But I think, you
- [48:59]
B
know what, that, you know what you just told me that you were Coach Nick Saban and you saw the nil thing going on and you said, I'm going to cut and run before this nonsense. So.
- [49:10]
A
Well, I think, I think AI is going to be really, really helpful in so many ways, both in clinical work and in basic research work. So it's, it's a wonderful thing, but it's still kind of bubbling up and just beginning to. Being, being applied. My work has not used it, but I think it has a lot of promise.
- [49:28]
B
Can I ask you a personal question? Why do you, why are you ending. Why are you coming to the end of something if you're clearly a thought leader in this? And, you know, we got to keep moving when we're older because you, you lose, you, you lose purpose and that's, it's like losing your legs. Once you lose your legs, you're done, you know.
- [49:56]
A
Well, I, I'm not going to actually retire for a few more years. I'm still going to participate intellectually and write in the things on, on these themes, but I'm closing down my research lab which has been, you know, optogenetic research and other brain manipulation in animals to, to do it. And the reason I'm doing that is. Well, I'm 69. I've had a lab here at the University of Michigan for 40 years. That's a good long time. National funding for scientific research is going down and there are new junior colleagues who are coming up and who need funding and who need lab space and things of that sort. So I, I've had a good run and I think it's about time that, you know, I, I step aside and leave, make room for people who are coming up in this way. The resources are limited.
- [50:37]
B
Are you going to, are you going to give a lot of that equipment to the young guys that you've been mentoring and so they can.
- [50:42]
A
Yes, my lab in the last few months has been sort of picked over by colleagues here.
- [50:46]
B
Good for you. Good for you. You're a good man. All right.
- [50:49]
A
Well, it's a natural thing.
- [50:51]
B
Do you think the brain can heal after long term addiction?
- [50:56]
A
Sensitization lasts a long time, but it may. It's not clear that it lasts forever, and it may be that it does decline in some. It is also possible to develop cognitive behavioral strategies to deal with urges. Finally, I think, you know, for. For some there's other changes in the brain that go along with heavy drug use, and some of them may be reversible and healing possible. There is evidence that that can happen. So, yes, I think healing can happen. Not everything perhaps heals, but for many people, most, and perhaps for a lot of people, all things can heal.
- [51:32]
B
Right? Right. What fascinates you most right now about the neuroscience of addiction that we still don't fully understand?
- [51:41]
A
Well, I mean, I've been struck by surprises all throughout my career. Originally I thought dopamine was pleasure and then turned out not to be. It was only the wanting for the pleasure. Other things that have come up is, I think addiction neuroscience has a lot of understanding of things that change the intensity of addictive urges. But we still don't have a good sense of what controls the target of urges. You know, that's why we're doing the optogenetic studies with cocaine, the shock rot, to try to get a better sense of what's controlling the target. For normally, for most of us who are not addicted, as we said, when you're hungry, you want food. If you're thirsty, you may not want dry food, but you want to drink. At other moments, you want something else. A third thing, the focus of wanting changes from moment to moment. For most of us in addiction, the focus becomes sort of fixed and more intense. For this one thing. So what's controlling this focus both in the natural situation and the addicted situation? That's why we're doing the amygdala and mesolimbic.
- [52:40]
B
How does kill so many people but didn't kill that rat? How do you get, how do you get rats addicted to when the tiniest amount can kill people?
- [52:55]
A
Right. Well, it's the dose. The tiniest amount of the really potent ones, like some of the newer opioids that are being coming along. Even more potent than car and others. Even more potent. You're right. A tiny little crumb can kill, but it's the dose. I mean, if you could cut that crumb into smaller crumbs and just give the really small crumb, that wouldn't kill. It's the dose. The thing about opioids is that they activate the reward pleasure system very potently. Yes. But they also simultaneously suppress the part of the brain that controls your breathing. That's right. Every breath we take is triggered by the brain. It's commanded by the brain. A little nucleus in the brain stem. And opioids suppress that. And the doses that are most enjoyed are the same doses that are becoming lethal. You know, it would be great if the doses that were enjoyed were lower than the lethal doses then people would take.
- [53:49]
B
But doctor, I, I didn't. I did. That's not my experience. My experience is you, you develop a tolerance for the drug. That's why you've got kids now, straight A students that aren't using that go to the rave on the weekend. They don't have the tolerance. So their buddy who's the drug addict, he's fine, he's high and they drop dead.
- [54:13]
A
No, you're absolutely right. Tolerance does develop. Absolutely. So yes, new users who take the same dose may die. Whereas experienced user, habitual user is not. Tolerance also is partly cue controlled and context controlled. There is such a thing where even an experienced user, if they take the same dose in a whole new setting, the dose that wouldn't really subdue them in the usual setting is more lethal in the new setting. That's kind of conditioned tolerance. But even a very experienced user who gets a crumb of, you know, a fairly good crumb effect that's going to suppress the tolerance is not going to protect them.
- [54:51]
B
How many rats did you kill?
- [54:52]
A
We don't kill them because we control the dose. We know the dose.
- [54:55]
B
Really? Not even, not even an accidental overdose?
- [54:58]
A
Well, we say. We say that's right because we kind of space out. We say once you've Earned it. Now you have to wait a couple minutes. It's a fast acting. Well, Remy, it's a fast acting. You have to wait 10 minutes before you get the next one. Now you can. Okay, now 10.
- [55:10]
B
You know, it's. Do you know what? Do you know what? That's so good to know, Doctor, because the. When you go to court, when you have a drug addict who's died at the hands, murdered at the hands of a dealer, okay, I. I call it murder. But the part that I'm interested in is if you can be mindful enough to mete out the dose that will not kill a rat, then you can argue that it's intentional or grossly negligent every single time, because.
- [56:01]
A
I'm sorry, it's negligent. But it really hinges on the super potency of these new opioids. You know, with. With heroin, it could be kind of predicted the dose effect and people knew what they were dealing with. That's right. Kind of measure out the dose. But once you've got things like car, which can clump, you know, even if it's the. The dealers have intended to mix it into the. To the hair and other things. But if there's a clump of car that remains in, a person gets that clump, that's the lethal dose. So, you know, if it was a drug company, they would take special, special measures to make sure it was all evenly distributed. But the clumps in what's being sold on the street, clumps can be still there. And that's what's lethal.
- [56:40]
B
Yeah. All right, last question. After spending your entire career studying desire, pleasure, and motivation, what do you think healthy wanting actually looks like in human life?
- [56:54]
A
Oh, healthy wanting is essential. The same dopamine system that's causing addiction in all of us every day is giving us zest for life. It's making life worth living in a real way. It's giving us the healthy desires to engage in life and pursue things that are good for us and good for others. So it's a wonderful system. We would be. We wouldn't have evolved without it. It's a crucial system, but it can sort of go into a hyperactive mode in certain situations, in certain individuals, and that's where problems begin to arise.
- [57:30]
B
Is there anything left unsaid, anything you want to say?
- [57:35]
A
Well, there are. There are other sides, other faces of the wanting system. You know, we've been focused on addiction, which is reasonable, but there's other kind of clinical conditions that dopamine and this wanting system is Relevant to, like in depression and schizophrenia. They've been always considered in textbook psychiatry to have anhedonia as one of their symptoms. Anhedonia where things in the world are not worth pursuing. But it turns out if you ask them the pleasure of these things, they often will give you normal pleasure ratings for many of these patients. But they don't want them. They're not engaging, they're not worth pursuing. In the view of this person. It's sort of a suppression of the wanting system. And so new words to replace anhedonia, words like avolition are sometimes being applied to those patients. A loss of will, a loss of wanting to kind of say. And the last thing which kind of came as a surprise to me, but I think it's very interesting is this wanting system incentive salience. It can also overlap with a certain kind of fearful anxiety salience. And you know, when people are given, say, with schizophrenia, they're prescribed potent antipsychotic drugs that block dopamine D2 receptors. Sometimes they block serotonin receptors too, but they all block the dopamine D2 receptors. Sometimes this is given to kind of reduce paranoia and the intensity of that sort of where something grabs your attention and it's a threat and you weave it into the delusion that the police are following you, that someone's out to get you, or something of that sort. The dopamine wanting system has a kind of aversive, fearful salience mode that's distinguishable from its incentive salience mode, but it can flip a little bit back and forth. People who take amphetamine, you know, for the euphoric effects of that, but they can flip into amphetamine psychosis and which can involve paranoia. So this is something. It's a sort of double dual face of the dopamine motivational salience system. We don't quite understand fully how it's flipping, but it's fascinating that it can, and we'd love to understand that better.
- [59:32]
B
It is. All right. Not that you want to be found, but this is the question I ask everybody at the end. Where can people find you?
- [59:43]
A
Well, I'm on the Internet here. I'm here at the University of Michigan with an email address at the University of Michigan. I'm not a clinician. I can't. I'm not qualified to give any kind of clinical advice at all. My role has simply been to try to find out what in the brain does want psychologically through these basic research experiments.
- [60:01]
B
What a blessing that you came here today. Everybody's better off for it. We're going to look into those drugs. Okay. Because I. I still can't believe that the mainstream is the way it is, and it hasn't evolved any. This is just in every area we've evolved.
- [60:23]
A
Yeah, well, the pendulum has moved. I think the understanding has improved in the mainstream. But, you know, there's pockets and there's other pockets that don't.
- [60:32]
B
All right, thank you so much for coming. I really appreciate it, everyone. See you next Tuesday.
- [60:39]
A
We're out of time. Please subscribe on YouTube, click the thumbs up and leave a comment. Please subscribe on Apple Podcast and Spotify and leave a rating and a review and share the we're out of time podcast with others you know who will get value out of it. See you next Tuesday.