Pushkin. Let's talk about psychedelics. It's been a few years since the FDA approved the use of ketamine to treat depression in certain patients. Later this year, the FDA may also approve the use of MDMA in combination with therapy to treat PTSD post traumatic stress disorder, and researchers around the world are studying other powerful psychedelics like psilocybin, ibogaine, and LSD. It's been clear for a long time that these are very powerful drugs, and it's becoming clear that these drugs may be particularly helpful in certain contexts. But still less clear is a very big, very important question, how exactly do psychedelics work. I'm Jacob Goldstein and this is What's Your Problem, the show where I talk to people who are trying to make technological progress. My guest today is goul Dolan. She's a professor of psychology and neuroscience at the University of California at Berkeley. Goule's problem is summed up in a phrase from a paper that she co authored last year in the journal Nature. She's trying to identify quote, a common neurobiological mechanism that can account for the shared therapeutic effects of psychedelics. In other words, why do all these very different drugs seem to have similar powerful effects on the brain. Goole has a theory about this, about why all these different drugs seem to have similar effects, and if she's right, it could mean that psychedelics used in the right context, may be useful beyond mental illness. Goul thinks, among other things, psychedelics may be able to help patients recod from strokes. We started the conversation talking about the origin of Ghul's quest to understand how psychedelics work.

Pushkin. Let's talk about psychedelics. It's been a few years since the FDA approved the use of ketamine to treat depression in certain patients. Later this year, the FDA may also approve the use of MDMA in combination with therapy to treat PTSD post traumatic stress disorder, and researchers around the world are studying other powerful psychedelics like psilocybin, ibogaine, and LSD. It's been clear for a long time that these are very powerful drugs, and it's becoming clear that these drugs may be particularly helpful in certain contexts. But still less clear is a very big, very important question, how exactly do psychedelics work. I'm Jacob Goldstein and this is What's Your Problem, the show where I talk to people who are trying to make technological progress. My guest today is goul Dolan. She's a professor of psychology and neuroscience at the University of California at Berkeley. Goule's problem is summed up in a phrase from a paper that she co authored last year in the journal Nature. She's trying to identify quote, a common neurobiological mechanism that can account for the shared therapeutic effects of psychedelics. In other words, why do all these very different drugs seem to have similar powerful effects on the brain. Goole has a theory about this, about why all these different drugs seem to have similar effects, and if she's right, it could mean that psychedelics used in the right context, may be useful beyond mental illness. Goul thinks, among other things, psychedelics may be able to help patients recod from strokes. We started the conversation talking about the origin of Ghul's quest to understand how psychedelics work.

About ten years ago when I started my lab, you know, there were starting to be some hints that psychedelics were having these remarkable effects in you know, all kinds of diseases that didn't seem terribly connected to each other, right, so addiction and depression and PTSD, and you know, the people who study those diseases each have their way of studying them and modeling them in animals, and they're they're siloed into different spaces. And yet we were starting to hear hints that, you know, it didn't matter which psychedelic they were kind of interchangeably showing some promise in all of these different areas that seem unconnected to each other. I mean not just in terms of what behavioral essays we use, but even sort of what brain regions might be important. Right, Like, the depression people were focused on the hippi campus and the frontal cortex.

About ten years ago when I started my lab, you know, there were starting to be some hints that psychedelics were having these remarkable effects in you know, all kinds of diseases that didn't seem terribly connected to each other, right, so addiction and depression and PTSD, and you know, the people who study those diseases each have their way of studying them and modeling them in animals, and they're they're siloed into different spaces. And yet we were starting to hear hints that, you know, it didn't matter which psychedelic they were kind of interchangeably showing some promise in all of these different areas that seem unconnected to each other. I mean not just in terms of what behavioral essays we use, but even sort of what brain regions might be important. Right, Like, the depression people were focused on the hippi campus and the frontal cortex.

The PTSD people.

The PTSD people.

Were focused on the amygdala, the you know, the addiction people were focused on the nucleus, thecumbents, and they were just sort of all over the place, and yet there seemed to be this overlap. But when we then discovered that all of the psychedelics seemed to be doing the same thing, it sort of began to settle in that this explanation that we came up with could account for why all of these diseases that look so different from each other could be responding to psychedelics in a therapeutic way.

Were focused on the amygdala, the you know, the addiction people were focused on the nucleus, thecumbents, and they were just sort of all over the place, and yet there seemed to be this overlap. But when we then discovered that all of the psychedelics seemed to be doing the same thing, it sort of began to settle in that this explanation that we came up with could account for why all of these diseases that look so different from each other could be responding to psychedelics in a therapeutic way.

So should we start the explanation with talking about critical periods? Is that a reasonable place to start. Let's start with critical periods. What's the critical period?

So should we start the explanation with talking about critical periods? Is that a reasonable place to start. Let's start with critical periods. What's the critical period?

Right?

Right?

So, critical periods are something that you know, neuroscientists have known about for almost one hundred years. They were first described in nineteen thirty five by Conrad Lorenz, who was describing and imprinting behavior in baby geese, So basically, forty eight hours after they hatch from their eggs, they will imprint onto anything that is moving around in their immediate environment. So typically this would be their mother, but you know, if there's a crazy scientist around, it might be to the crazy scientist.

So, critical periods are something that you know, neuroscientists have known about for almost one hundred years. They were first described in nineteen thirty five by Conrad Lorenz, who was describing and imprinting behavior in baby geese, So basically, forty eight hours after they hatch from their eggs, they will imprint onto anything that is moving around in their immediate environment. So typically this would be their mother, but you know, if there's a crazy scientist around, it might be to the crazy scientist.

And there are photos of the baby geese following him around right in fact, as if he were a mamma goose.

And there are photos of the baby geese following him around right in fact, as if he were a mamma goose.

Yeah, exactly.

Yeah, exactly.

And so but that window of time where they're so sensitive to their environment and they form these lasting attachments only lasts about forty eight hours, and then afterwards they don't. They're not sensitive to their environment in the same way. They're not learning from their environment in the same way. And that window of time Conrad Lorenz called it the critical period. And since that time we've discovered literally dozens of other critical periods. So there are critical periods for rewiring the visual system, critical periods for touch, critical periods for movement, critical periods for language. Language is probably the one that most people are familiar with. If they try to learn enough their language when they were older, it's much harder and you always have an accent compared to the language you learn as a child, and so neuroscientists have known about these critical periods for a long time, and we've had this idea that maybe the reason that we're so bad at curing diseases of the brain, neuropsychiatric illnesses and neurological diseases, is because by the time we get around to correcting whatever is the underlying problem, the relevant critical period.

And so but that window of time where they're so sensitive to their environment and they form these lasting attachments only lasts about forty eight hours, and then afterwards they don't. They're not sensitive to their environment in the same way. They're not learning from their environment in the same way. And that window of time Conrad Lorenz called it the critical period. And since that time we've discovered literally dozens of other critical periods. So there are critical periods for rewiring the visual system, critical periods for touch, critical periods for movement, critical periods for language. Language is probably the one that most people are familiar with. If they try to learn enough their language when they were older, it's much harder and you always have an accent compared to the language you learn as a child, and so neuroscientists have known about these critical periods for a long time, and we've had this idea that maybe the reason that we're so bad at curing diseases of the brain, neuropsychiatric illnesses and neurological diseases, is because by the time we get around to correcting whatever is the underlying problem, the relevant critical period.

Has already closed.

Has already closed.

And so the classic example of this is if you are born with bilateral cataracts in your eyes and you don't have them removed by the time you're aged five or so, then you will be blind forever because even if you remove the cataracts, wants the ability of the visual part of the brain to adapt to the corrected visual environment. Once the critical period has closed, it can't adapt again, and so even though the impediment is removed, the brain can respond to it, and so you're blind forever. And so we have been looking, probably for the last one hundred years or so for ways to reopen critical periods, with the idea that if we could reopen them, we could potentially cure or do a better job of correcting some of these impairments later in life.

And so the classic example of this is if you are born with bilateral cataracts in your eyes and you don't have them removed by the time you're aged five or so, then you will be blind forever because even if you remove the cataracts, wants the ability of the visual part of the brain to adapt to the corrected visual environment. Once the critical period has closed, it can't adapt again, and so even though the impediment is removed, the brain can respond to it, and so you're blind forever. And so we have been looking, probably for the last one hundred years or so for ways to reopen critical periods, with the idea that if we could reopen them, we could potentially cure or do a better job of correcting some of these impairments later in life.

So in this Nature paper, that you published last year. You write, it's tempting to speculate that the altered state of consciousness shared by all psychedelics reflects the subjective experience of reopening critical periods. Let me say, first of all, I like, it's tempting to speculate. It's like, you're not even speculating.

So in this Nature paper, that you published last year. You write, it's tempting to speculate that the altered state of consciousness shared by all psychedelics reflects the subjective experience of reopening critical periods. Let me say, first of all, I like, it's tempting to speculate. It's like, you're not even speculating.

It's more speculative than speculating, right, Like, we're not going to speculate, but we're tempted to speculate. So and I appreciate that, right, Like, this is clearly speculative, it's based on research and mice. But why are you tempted to speculate that psychedelics may reopen critical periods in the brain?

It's more speculative than speculating, right, Like, we're not going to speculate, but we're tempted to speculate. So and I appreciate that, right, Like, this is clearly speculative, it's based on research and mice. But why are you tempted to speculate that psychedelics may reopen critical periods in the brain?

Right?

Right?

So, the reason that we're tempted to speculate this is because, you know, one of the other things that brings together psychedelics as a group of drugs is that they all induced this altered state of consciousness. So we discovered a critical period in twenty nineteen for Social rewards learning. It was a brand new critical period. Although you know, there was a lot of literature from human studies suggesting that such a critical period should exist, but it just took doing it. In nine hundred mice to be able to formally demonstrate it. So we did that. We showed that there's this social critical period, and originally we showed that MDMA was able to reopen this critical period. And we thought because MDMA is characterized by having this pro social property that makes it different from the other psychedelics in that, you know, it's altered state of consciousness, plus you know, cuddle puddles and empathy, right, and so we thought it's because of that pro social property of MDMA that it's able to open this social critical period. But then when we figured out that well LSD and I began and KETYMI, none of which are like particularly pro social, nobody's you know, doing a thirty person cuddle puddle on I begin right, even though they don't have this pro social property, they are all also able.

So, the reason that we're tempted to speculate this is because, you know, one of the other things that brings together psychedelics as a group of drugs is that they all induced this altered state of consciousness. So we discovered a critical period in twenty nineteen for Social rewards learning. It was a brand new critical period. Although you know, there was a lot of literature from human studies suggesting that such a critical period should exist, but it just took doing it. In nine hundred mice to be able to formally demonstrate it. So we did that. We showed that there's this social critical period, and originally we showed that MDMA was able to reopen this critical period. And we thought because MDMA is characterized by having this pro social property that makes it different from the other psychedelics in that, you know, it's altered state of consciousness, plus you know, cuddle puddles and empathy, right, and so we thought it's because of that pro social property of MDMA that it's able to open this social critical period. But then when we figured out that well LSD and I began and KETYMI, none of which are like particularly pro social, nobody's you know, doing a thirty person cuddle puddle on I begin right, even though they don't have this pro social property, they are all also able.

To open this critical period.

To open this critical period.

And so that was our first hint that maybe the common property is between psychedelics that accounts for this altered state of consciousness that they all induce is the common property of inducing critical period reopening.

And so that was our first hint that maybe the common property is between psychedelics that accounts for this altered state of consciousness that they all induce is the common property of inducing critical period reopening.

And so specifically, can you just talk a little bit more about the specific critical period in mice that you're looking at here, right?

And so specifically, can you just talk a little bit more about the specific critical period in mice that you're looking at here, right?

So, we're measuring something called social condition place preference, which is just an assay to measure the ability of the mice to learn from their social environments. And so that ability changes over time, and as they get older, they stop learning from their social environment. And so this developmental change relates to why we think teenagers are so much more susceptible to peer pressure than adults. We think it relates to why you're so much more sensitive to learning the rules of your culture when you're young, so you know, you learn what's polite.

So, we're measuring something called social condition place preference, which is just an assay to measure the ability of the mice to learn from their social environments. And so that ability changes over time, and as they get older, they stop learning from their social environment. And so this developmental change relates to why we think teenagers are so much more susceptible to peer pressure than adults. We think it relates to why you're so much more sensitive to learning the rules of your culture when you're young, so you know, you learn what's polite.

So it's basically the idea is that there's a critical there is some set of critical periods for learning social behavior from language to norms, and that that those clothes over the course of childhood and adolescents.

So it's basically the idea is that there's a critical there is some set of critical periods for learning social behavior from language to norms, and that that those clothes over the course of childhood and adolescents.

That's right, that's right.

That's right, that's right.

And we think that that critical period, like other critical periods like language, you know, is curtailed as you get older because basically it's sort of expensive energe to always be having to learn from your social environment.

And we think that that critical period, like other critical periods like language, you know, is curtailed as you get older because basically it's sort of expensive energe to always be having to learn from your social environment.

You know, I like to.

You know, I like to.

Think back on my teenage years and you know, mostly I'm relieved that they're over, because you know, it was time consuming and energetically exhausting to you know, have to care about the exact right shade of acid washed genes that the cool kids are wearing.

Think back on my teenage years and you know, mostly I'm relieved that they're over, because you know, it was time consuming and energetically exhausting to you know, have to care about the exact right shade of acid washed genes that the cool kids are wearing.

Right, and now you wear whatever acid wash genes you want, right, that's right.

Right, and now you wear whatever acid wash genes you want, right, that's right.

I wear mom jeans that are acid washed.

I wear mom jeans that are acid washed.

And so then you find that when you give psychedelics to an old mouse, they're able to the.

And so then you find that when you give psychedelics to an old mouse, they're able to the.

Learning that they were doing in juvenile in their juvenile period return, so they're able to learn again like a juvenile.

Learning that they were doing in juvenile in their juvenile period return, so they're able to learn again like a juvenile.

Have you tested this theory on other critical periods in mice or on other animals?

Have you tested this theory on other critical periods in mice or on other animals?

Yeah, So basically, as soon as we got this this result, I reached out to every single person that I know who works on critics periods, and I was like, do you have a critical period that you want to try and reopen? Because I think we might have accidentally stumbled on the master key for unlocking critical periods, and so we're working on it. We definitely have some collaborations going. But in the meantime between sort of when we first have this twenty nineteen paper and then this summer, there have been some hints that other critical periods are being reopened by say ketamine. There are two papers showing that ketamine, if given back to back to back to back can reopen the critical period for ocular dominance plasticity, which is this visual critical period that we've learned so much about the mechanisms about. So that's a first hint, and we are working feverishly to see if we can reopen other critical periods like motor learning for stroke. We're doing that in both mice and in humans. We're working on some language critical periods in collaboration with some of the labs. So you know, the jury is still out, but there's some other reasons to make us think that we're on the right track with this idea about the master key.

Yeah, So basically, as soon as we got this this result, I reached out to every single person that I know who works on critics periods, and I was like, do you have a critical period that you want to try and reopen? Because I think we might have accidentally stumbled on the master key for unlocking critical periods, and so we're working on it. We definitely have some collaborations going. But in the meantime between sort of when we first have this twenty nineteen paper and then this summer, there have been some hints that other critical periods are being reopened by say ketamine. There are two papers showing that ketamine, if given back to back to back to back can reopen the critical period for ocular dominance plasticity, which is this visual critical period that we've learned so much about the mechanisms about. So that's a first hint, and we are working feverishly to see if we can reopen other critical periods like motor learning for stroke. We're doing that in both mice and in humans. We're working on some language critical periods in collaboration with some of the labs. So you know, the jury is still out, but there's some other reasons to make us think that we're on the right track with this idea about the master key.

When you say master key in this context, in this context, exactly what do you mean?

When you say master key in this context, in this context, exactly what do you mean?

So I guess what I mean is is that when I was a graduate student, we were a little bit in a debate with another lab that was proposing that there would be some drug or manipulation that you could do that could reopen all critical periods, and that you could just give that drug and it would it would it would be the master key, right and for unlocking all of these critical periods. And at the time, I remember being really skeptical of that idea, and I thought, well, anything that can do that to the brain is either going to induce amnesia, cause seizure, or disrupt the structural integrity of the brain. And I thought that because of what we knew about, you know, basically the mechanisms that constrain critical periods to these windows of time, like like.

So I guess what I mean is is that when I was a graduate student, we were a little bit in a debate with another lab that was proposing that there would be some drug or manipulation that you could do that could reopen all critical periods, and that you could just give that drug and it would it would it would be the master key, right and for unlocking all of these critical periods. And at the time, I remember being really skeptical of that idea, and I thought, well, anything that can do that to the brain is either going to induce amnesia, cause seizure, or disrupt the structural integrity of the brain. And I thought that because of what we knew about, you know, basically the mechanisms that constrain critical periods to these windows of time, like like.

You couldn't work without breaking the brain. The only way to reopen the critical period is the master key is like a sledgehammer that's just gonna totally break everything. So why even bother.

You couldn't work without breaking the brain. The only way to reopen the critical period is the master key is like a sledgehammer that's just gonna totally break everything. So why even bother.

Right, And I you know, I called it the Melti brain problem, right, And so then when we when we started getting these results for the psychedelics, I was, I started thinking, well, how come we're not running into the Melty brain problem? And I think, and this is at this point still speculative, and we're we're actively pursuing this line of research. So I don't want to overstate the case. But my hunch is that the way that we are able to circumvent, or the way that psychedelics specifically are circumventing, the Melty brain problem is that they are context specific. So it's not that psychdelics are causing reopening of all critical periods everywhere in the brain all at the same time. It seems to be that they are not you know, destroying or melting the brain, because they're only making available for modification the subset of synapses, circuits, memories, and grams that are have been recently activated, and that is why they have this constraint of being context dependent.

Right, And I you know, I called it the Melti brain problem, right, And so then when we when we started getting these results for the psychedelics, I was, I started thinking, well, how come we're not running into the Melty brain problem? And I think, and this is at this point still speculative, and we're we're actively pursuing this line of research. So I don't want to overstate the case. But my hunch is that the way that we are able to circumvent, or the way that psychedelics specifically are circumventing, the Melty brain problem is that they are context specific. So it's not that psychdelics are causing reopening of all critical periods everywhere in the brain all at the same time. It seems to be that they are not you know, destroying or melting the brain, because they're only making available for modification the subset of synapses, circuits, memories, and grams that are have been recently activated, and that is why they have this constraint of being context dependent.

So this is this is why your thesis is they will psychedels will be helpful when paired with interventions like therapy, but not by themselves.

So this is this is why your thesis is they will psychedels will be helpful when paired with interventions like therapy, but not by themselves.

Well, this is.

Well, this is.

This is the explanation we have for why the psychedelics aren't breaking the the brain rather than I mean, basically, the clinical data is driving this idea that in fact the context matters, right.

This is the explanation we have for why the psychedelics aren't breaking the the brain rather than I mean, basically, the clinical data is driving this idea that in fact the context matters, right.

But it's a potential mechanistic explanation for that.

But it's a potential mechanistic explanation for that.

Clinical well that feature, that's right, it's a mechanistic explanation for a clinical description, which you know, I don't think is going to be the case for every single application that psychedelics might be used for. So, for example, I think the critical period idea nicely explains why MDMA assisted psychotherapy works. If we're able to demonstrate that we can correct motor impairments following stroke with psychedelics paired with physical therapy, then that'll be a nice other explanation.

Clinical well that feature, that's right, it's a mechanistic explanation for a clinical description, which you know, I don't think is going to be the case for every single application that psychedelics might be used for. So, for example, I think the critical period idea nicely explains why MDMA assisted psychotherapy works. If we're able to demonstrate that we can correct motor impairments following stroke with psychedelics paired with physical therapy, then that'll be a nice other explanation.

That's a huge idea. You've just dropped in the middle of a list, by the.

That's a huge idea. You've just dropped in the middle of a list, by the.

Way, right, So, by the way, that's also quite quite speculative.

Way, right, So, by the way, that's also quite quite speculative.

After the break, how gool plans to test this hypothesis that psychedelics may help patients recovering from strokes. Let's just talk about how we get from this sort of you know, seems like psychedelics reopen one critical period in mice to like, can this idea be helpful in humans?

After the break, how gool plans to test this hypothesis that psychedelics may help patients recovering from strokes. Let's just talk about how we get from this sort of you know, seems like psychedelics reopen one critical period in mice to like, can this idea be helpful in humans?

Right?

Right?

You must know the aphorism mice lie and primates exaggerate. I was thinking of that one.

You must know the aphorism mice lie and primates exaggerate. I was thinking of that one.

I mean, I think that a little bit of why it's so hard to translate this stuff from mouse studies to human studies so far is that mostly what they've been used for is non psychiatric disease, and so it's really sort of impossible to measure or to recapitulate all of the features of a psychiatric disease.

I mean, I think that a little bit of why it's so hard to translate this stuff from mouse studies to human studies so far is that mostly what they've been used for is non psychiatric disease, and so it's really sort of impossible to measure or to recapitulate all of the features of a psychiatric disease.

In a mouse. Right, Like if.

In a mouse. Right, Like if.

PTSD is mostly in humans and females is caused by you can't really model rape in a mouse, right, And so there are all these other features of the illness that you know, you can try and approximate by fear learning, but you're not really going to capture the salient elements. And so this is kind of why I think an important test case of this idea of the master key is to switch away from neuropsychiatric disease and move into neurological disease, because then you know, we can explicitly test this learning model. Right if we switch to a neurological disease like stroke, and we're able to show that if we give psychedelics and pair it with physical therapy, we are able to restore motor learning. But if we give psychedelics and then just send them on home without any additional physical therapy, then nothing really is going to happen. That I think would be an explicit test of this idea that what the mechanism at work here is about learning and memory rather than a magic bill that corrects an underlying biochemical imbalance.

PTSD is mostly in humans and females is caused by you can't really model rape in a mouse, right, And so there are all these other features of the illness that you know, you can try and approximate by fear learning, but you're not really going to capture the salient elements. And so this is kind of why I think an important test case of this idea of the master key is to switch away from neuropsychiatric disease and move into neurological disease, because then you know, we can explicitly test this learning model. Right if we switch to a neurological disease like stroke, and we're able to show that if we give psychedelics and pair it with physical therapy, we are able to restore motor learning. But if we give psychedelics and then just send them on home without any additional physical therapy, then nothing really is going to happen. That I think would be an explicit test of this idea that what the mechanism at work here is about learning and memory rather than a magic bill that corrects an underlying biochemical imbalance.

Well, yes, I mean that's the side of it, addressing this debate that you're involved in, but also going on there presumably if you're able to do this test in stroke patients, is if psychedelics plus physical therapy after a stroke leads to better recovery than physical therapy alone. That's great. I mean, I don't even care about the mechanism at that point, right, Like, is somebody going to do a phase one safety trial soon? Like is somebody going to give stroke patients psychedelics?

Well, yes, I mean that's the side of it, addressing this debate that you're involved in, but also going on there presumably if you're able to do this test in stroke patients, is if psychedelics plus physical therapy after a stroke leads to better recovery than physical therapy alone. That's great. I mean, I don't even care about the mechanism at that point, right, Like, is somebody going to do a phase one safety trial soon? Like is somebody going to give stroke patients psychedelics?

We are, we are working on it.

We are, we are working on it.

Right after this call, I have a meeting to try and secure funding to make that happen. So we are on it, and we are actually doing it in parallel with mouth studies for mechanism. And you know, I understand why people are so much more jazzed about you know the clinical outcomes and you know the real world impacts of these things. But I have to say, I think mechanism should not be underestimated as an important way of understanding this, because we never would have even come up with this idea of thinking about stroke if we hadn't thought of the mechanism. Right, So, if we the mechanism is what is leading us to speculate, if this mechanism is true, then these other diseases should respond in this predictable way.

Right after this call, I have a meeting to try and secure funding to make that happen. So we are on it, and we are actually doing it in parallel with mouth studies for mechanism. And you know, I understand why people are so much more jazzed about you know the clinical outcomes and you know the real world impacts of these things. But I have to say, I think mechanism should not be underestimated as an important way of understanding this, because we never would have even come up with this idea of thinking about stroke if we hadn't thought of the mechanism. Right, So, if we the mechanism is what is leading us to speculate, if this mechanism is true, then these other diseases should respond in this predictable way.

There was a better way I could have framed that, And I apologize. I mean, what I really mean is, yes, it's it's useful and big to learn the mechanism. But like helping stroke patients get better is also a huge deal. Would perhaps be diplomatic way to say that.

There was a better way I could have framed that, And I apologize. I mean, what I really mean is, yes, it's it's useful and big to learn the mechanism. But like helping stroke patients get better is also a huge deal. Would perhaps be diplomatic way to say that.

I mean, I don't mind the undiplomatic way, because that's I've been dealing with this right from the beginning.

I mean, I don't mind the undiplomatic way, because that's I've been dealing with this right from the beginning.

Right.

Right.

So, the first time I presented this critical period idea at a meeting, it was in Portugal, and you know, the room was full of people who were already doing clinical trials for psilocybin for depression and MDMA for PTSD, and they were already very much invested in the idea that it was going to work based on some underground therapists results and anecdotal reports, some of their you know, pilot studies, and they were like, why do we need mechanism?

So, the first time I presented this critical period idea at a meeting, it was in Portugal, and you know, the room was full of people who were already doing clinical trials for psilocybin for depression and MDMA for PTSD, and they were already very much invested in the idea that it was going to work based on some underground therapists results and anecdotal reports, some of their you know, pilot studies, and they were like, why do we need mechanism?

Who cares?

Who cares?

We know it's going to work, and going backwards to look in mice seems silly.

We know it's going to work, and going backwards to look in mice seems silly.

We know it's going to work. It's just the way to die.

We know it's going to work. It's just the way to die.

And I said at that time it was like, mechanism matters, and there are going to be a million different ways that we might fail if we don't understand exactly how these drugs are working. And basically that prediction ended up being true because the two people who were represented in that room were on the one side, the people arguing for, you know, let's just use psilocybin like a next generation SSRI, and their trial failed. And then the other half of the room where people who were saying, no, we need to pair it with psychotherapy, and their trial was successful. And our mechanism, we think explains the difference between them.

And I said at that time it was like, mechanism matters, and there are going to be a million different ways that we might fail if we don't understand exactly how these drugs are working. And basically that prediction ended up being true because the two people who were represented in that room were on the one side, the people arguing for, you know, let's just use psilocybin like a next generation SSRI, and their trial failed. And then the other half of the room where people who were saying, no, we need to pair it with psychotherapy, and their trial was successful. And our mechanism, we think explains the difference between them.

Is there an animal model you can use is to test your hypothesis that in stroke patients psychedelics plus physical therapy would work better than physical therapy alone.

Is there an animal model you can use is to test your hypothesis that in stroke patients psychedelics plus physical therapy would work better than physical therapy alone.

Yes, So basically, one of the people I reached out to when you know, we first got this critical period result for all of the psychedelics. We're two neurologists at John Hopkins, so Steve Zeiler and John Krackauer, and Steve Zyler especially had been working on developing a mouse model of stroke. And what he has shown is that just like in human patients with stroke, right after the stroke, there is a critical period that gets reopened and some amount of physical therapy is able to restore function, but that that is time limited. So in my you know, within seven days after the stroke, they're no longer able to learn. In humans that's a little bit longer. So you know, in humans. After your stroke, you're able to benefit from therap physical therapy for about two months. At about three months it goes away, and that window of time, you know, it's closure. And people have thought about, well, you know, nobody has dreamed big that we might be able to reopen it. But people have tried to do other manipulations that might keep it open longer, you know, by enriching the environment, by you know, giving them SSRIs, and none of those things have worked.

Yes, So basically, one of the people I reached out to when you know, we first got this critical period result for all of the psychedelics. We're two neurologists at John Hopkins, so Steve Zeiler and John Krackauer, and Steve Zyler especially had been working on developing a mouse model of stroke. And what he has shown is that just like in human patients with stroke, right after the stroke, there is a critical period that gets reopened and some amount of physical therapy is able to restore function, but that that is time limited. So in my you know, within seven days after the stroke, they're no longer able to learn. In humans that's a little bit longer. So you know, in humans. After your stroke, you're able to benefit from therap physical therapy for about two months. At about three months it goes away, and that window of time, you know, it's closure. And people have thought about, well, you know, nobody has dreamed big that we might be able to reopen it. But people have tried to do other manipulations that might keep it open longer, you know, by enriching the environment, by you know, giving them SSRIs, and none of those things have worked.

It's the injury of the stroke itself is inducing the brain to reopen the critical period that has been closed since childhood, and that allows people to whatever, try and relearn language, try and relearn motor skills whatever they have lost in the stroke. Obviously not always successfully.

It's the injury of the stroke itself is inducing the brain to reopen the critical period that has been closed since childhood, and that allows people to whatever, try and relearn language, try and relearn motor skills whatever they have lost in the stroke. Obviously not always successfully.

That's right.

That's right.

And basically until this this psychedelic idea came around, the most effective way to reopen the critical period for motor learning after stroke was to give another stroke, which is not you know, very therapeutically viable, right Like, nobody wants to hear their stroke with another stroke. So this idea is testable and we are in parallel testing it in collaboration with the Xylor lab. This is not a social critical period this is a motor critical period. So let's test the idea that in this context what matters is the motor learning or the practicing a motor task, not the social And so we're testing that and combining with different psychedelics, but we're comparing all of those different conditions to test this idea in mice, and then in parallel, we will do the study to look at you know, trying to reopen in humans.

And basically until this this psychedelic idea came around, the most effective way to reopen the critical period for motor learning after stroke was to give another stroke, which is not you know, very therapeutically viable, right Like, nobody wants to hear their stroke with another stroke. So this idea is testable and we are in parallel testing it in collaboration with the Xylor lab. This is not a social critical period this is a motor critical period. So let's test the idea that in this context what matters is the motor learning or the practicing a motor task, not the social And so we're testing that and combining with different psychedelics, but we're comparing all of those different conditions to test this idea in mice, and then in parallel, we will do the study to look at you know, trying to reopen in humans.

And so the mouse study is underway now, and you're trying to get funding for the human study, that's right. And then once you have the money, then you go to the institutional review board and say can we do this?

And so the mouse study is underway now, and you're trying to get funding for the human study, that's right. And then once you have the money, then you go to the institutional review board and say can we do this?

Yeah, you know, everything's queued up and wow, you know, everything is basically ready to go.

Yeah, you know, everything's queued up and wow, you know, everything is basically ready to go.

We just need the money.

We just need the money.

So non trivial, but it's a lot probably surmountable.

So non trivial, but it's a lot probably surmountable.

Yeah, yeah, I mean it's a lot of money.

Yeah, yeah, I mean it's a lot of money.

We're asking for a million dollars to run, you know, a safety trial and about twenty people. And then if that phase one trial goes well. The way the trial is designed is that it will allow us to collect just a little bit of in addition to how well this patient population, right, because these are older people who have other medical issues, so we just want to be double sure that you know, these drugs are safe in this population. But the way we've designed the trial is it'll give us some hints about efficacy, so we'll test, you know, a little bit of you know, their ability to recover motor function. And the most important thing about the human trial and the way that I the reason that I paired up with Steve and John is because they have actually developed a sort of gamified virtual reality context for delivering this physical therapy. It's a virtual reality kind of room, and the cameras track the person's body position in space, and as they move their arm around, a dolphin on a screen moves around, and it's sort of a fun way to get people to practice moving. But it's also a little bit more play like, which is more the way that we learn during our childhood. So there's this shift in the way we learn between childhood and adulthood from exploratory learning to sort of goal directed exploitatory learning, and so we want to kind of mimic that as much as possible, to make it fun and to make it not be goal directed.

We're asking for a million dollars to run, you know, a safety trial and about twenty people. And then if that phase one trial goes well. The way the trial is designed is that it will allow us to collect just a little bit of in addition to how well this patient population, right, because these are older people who have other medical issues, so we just want to be double sure that you know, these drugs are safe in this population. But the way we've designed the trial is it'll give us some hints about efficacy, so we'll test, you know, a little bit of you know, their ability to recover motor function. And the most important thing about the human trial and the way that I the reason that I paired up with Steve and John is because they have actually developed a sort of gamified virtual reality context for delivering this physical therapy. It's a virtual reality kind of room, and the cameras track the person's body position in space, and as they move their arm around, a dolphin on a screen moves around, and it's sort of a fun way to get people to practice moving. But it's also a little bit more play like, which is more the way that we learn during our childhood. So there's this shift in the way we learn between childhood and adulthood from exploratory learning to sort of goal directed exploitatory learning, and so we want to kind of mimic that as much as possible, to make it fun and to make it not be goal directed.

They're already doing that sort of psychedelic adjacent sounding thing where your arm is a dolphin and you're playing. They're doing that without psychedelics, and you're like, let's definitely add some psychedelics to that. I mean, is that not to be glib about it, but they're already doing that without psychedelics.

They're already doing that sort of psychedelic adjacent sounding thing where your arm is a dolphin and you're playing. They're doing that without psychedelics, and you're like, let's definitely add some psychedelics to that. I mean, is that not to be glib about it, but they're already doing that without psychedelics.

That's right.

That's right.

So they have developed that whole paradigm to test the efficacy of that sort of gamified environment compare to standard of care, because standard of care is really mostly just teaching patients how to say the other hand, to zip their zipper and brush their hand. It's really compensatory, not trying to bring back the lost motor function. And so they've done head to head studies of the virtual reality game version versus standard of care during that open state, of the normal open state of the critical beers, so right after the stroke. They've shown that there's better outcomes if they use this gamified version. And so now we're saying, okay, let's take all those people who didn't get the optimal therapy right after their stroke, people who had a stroke a year ago, and go back and see if we can reopen this critical period and then give them what we think is the better therapy in terms of this virtual reality.

So they have developed that whole paradigm to test the efficacy of that sort of gamified environment compare to standard of care, because standard of care is really mostly just teaching patients how to say the other hand, to zip their zipper and brush their hand. It's really compensatory, not trying to bring back the lost motor function. And so they've done head to head studies of the virtual reality game version versus standard of care during that open state, of the normal open state of the critical beers, so right after the stroke. They've shown that there's better outcomes if they use this gamified version. And so now we're saying, okay, let's take all those people who didn't get the optimal therapy right after their stroke, people who had a stroke a year ago, and go back and see if we can reopen this critical period and then give them what we think is the better therapy in terms of this virtual reality.

We'll be back in a minute with the lightning round. Okay, let's finish with the lightning round.

We'll be back in a minute with the lightning round. Okay, let's finish with the lightning round.

Okay.

Okay.

What's your biggest professional disagreement with your mother.

What's your biggest professional disagreement with your mother.

Whether psychedelics can cure allergies?

Whether psychedelics can cure allergies?

Go on.

Go on.

Okay, Well, so my mother is an allergy and immunologist clinician. She's retired now, but you know, I've told her this crazy idea that we had about psychedelics and she was like, no, that's not how it works. And the idea is based on the fact that, you know, there's some evidence to support the notion that allergy happens because you know, the immune system, the part of the immune system that's normally supposed to fight off parasitic infections, is being underutilized by our modern diets, which are put more parasite free than our evolutionary history, and so it's sort of left jobless and it's looking for a job. And my idea is that, well, maybe the brain is assigning the job and saying that dog barked at you, that's scary, that's the threat to go after that immune system, and that if that's a learned association that the brain decided that it could unlearn it too.

Okay, Well, so my mother is an allergy and immunologist clinician. She's retired now, but you know, I've told her this crazy idea that we had about psychedelics and she was like, no, that's not how it works. And the idea is based on the fact that, you know, there's some evidence to support the notion that allergy happens because you know, the immune system, the part of the immune system that's normally supposed to fight off parasitic infections, is being underutilized by our modern diets, which are put more parasite free than our evolutionary history, and so it's sort of left jobless and it's looking for a job. And my idea is that, well, maybe the brain is assigning the job and saying that dog barked at you, that's scary, that's the threat to go after that immune system, and that if that's a learned association that the brain decided that it could unlearn it too.

By reopening this critical period.

By reopening this critical period.

It's totally speculative.

It's totally speculative.

I have to say, like, I don't believe it enough where I'm like out, you know, doing psychedelics and snuggling up to a horse.

I have to say, like, I don't believe it enough where I'm like out, you know, doing psychedelics and snuggling up to a horse.

I would love to cure my horse allergies. But I don't. I don't believe it enough to go for it.

I would love to cure my horse allergies. But I don't. I don't believe it enough to go for it.

I think it's a testable hypothesis that we should study.

I think it's a testable hypothesis that we should study.

And your and your mom believes it even less than you do.

And your and your mom believes it even less than you do.

That's right.

That's right.

Yes, what's your favorite portrayal of a psychedelics of a psychedelic experience in you know, in whatever, in a book, in a movie, in music.

Yes, what's your favorite portrayal of a psychedelics of a psychedelic experience in you know, in whatever, in a book, in a movie, in music.

I really still have a soft spot in my heart for the Huxley description of him staring at a chair, because you know, as a scientist, I have to say that one really resonates. Like I'm not a religious person, mystical experiences, that stuff doesn't really resonate with me. But he's staring at a chair and sort of being mesmerized by the you know, asymptotic distribution of chair molecules the further away you get from the chair, and then the Huxley molecules the further and then you know, the two of them sitting on each other and suddenly they're inert they're intermixed, and Huxley is the chair.

I really still have a soft spot in my heart for the Huxley description of him staring at a chair, because you know, as a scientist, I have to say that one really resonates. Like I'm not a religious person, mystical experiences, that stuff doesn't really resonate with me. But he's staring at a chair and sort of being mesmerized by the you know, asymptotic distribution of chair molecules the further away you get from the chair, and then the Huxley molecules the further and then you know, the two of them sitting on each other and suddenly they're inert they're intermixed, and Huxley is the chair.

I mean that that resonates.

I mean that that resonates.

But have you ever taken psychedelics for work?

But have you ever taken psychedelics for work?

I don't know.

I don't know.

Yeah, I don't really want to talk about that or answer that question.

Yeah, I don't really want to talk about that or answer that question.

Mine totally reasonable. Do you have any advice for people who are considering taking psychedelics recreationally.

Mine totally reasonable. Do you have any advice for people who are considering taking psychedelics recreationally.

Yeah, it would say that, you know, these are powerful medicines and that we should honor and respect their power, and that they're doing something. If we're right, they're doing something very big to the brain, and that this transformation should not be taken lightly. And you know, I would also emphasize that our studies suggest that once you reopen these critical periods, especially with psilocybin, MDMA and LSD, they stay open for several weeks after the acute effects of the drug wear off, and so you're gonna be in a in a sort of vulnerable state that's reminiscent of childhood. And I would say be very very cautious about who you expose yourself to during that period. You know, if you're in a traumatic relationship, it's probably a good idea to stay away from your traumatizer for a couple of weeks after you've taken the drug, you know. I think that we can learn a lot from the history of these drugs.

Yeah, it would say that, you know, these are powerful medicines and that we should honor and respect their power, and that they're doing something. If we're right, they're doing something very big to the brain, and that this transformation should not be taken lightly. And you know, I would also emphasize that our studies suggest that once you reopen these critical periods, especially with psilocybin, MDMA and LSD, they stay open for several weeks after the acute effects of the drug wear off, and so you're gonna be in a in a sort of vulnerable state that's reminiscent of childhood. And I would say be very very cautious about who you expose yourself to during that period. You know, if you're in a traumatic relationship, it's probably a good idea to stay away from your traumatizer for a couple of weeks after you've taken the drug, you know. I think that we can learn a lot from the history of these drugs.

You know.

You know.

Charles Manson is a good example of somebody who gave psychedelics to people and then used it to, you know, when they were in this vulnerable state, which presumably lasted for a long time, to indoctrinate them into his way of thinking, and turned a bunch of hippies into killers who were going to, you know, induce helter skelter to save the world. This is the sort of awesome power of these drugs that we need to be very mindful of and not treat them like little toys.

Charles Manson is a good example of somebody who gave psychedelics to people and then used it to, you know, when they were in this vulnerable state, which presumably lasted for a long time, to indoctrinate them into his way of thinking, and turned a bunch of hippies into killers who were going to, you know, induce helter skelter to save the world. This is the sort of awesome power of these drugs that we need to be very mindful of and not treat them like little toys.

Anything else, anything else we should talk about. I know you've got to go. I don't want to keep you, but if there's anything else you want to say.

Anything else, anything else we should talk about. I know you've got to go. I don't want to keep you, but if there's anything else you want to say.

Please, I think we covered a lot, super fun. Thank you so much, any.

Please, I think we covered a lot, super fun. Thank you so much, any.

Thanks one million dollars.

Thanks one million dollars.

Gool Dolan is a professor of psychology and science at UC Berkeley. Today's show was produced by Gabriel Hunter Cheng. It was edited by Lyddy Jean Kott and engineered by Sarah Bruguier. You can email us at problem at Pushkin dot Fm. I'm Jacob Goldstein and we'll be back next week with another episode of What's Your Problem.

Gool Dolan is a professor of psychology and science at UC Berkeley. Today's show was produced by Gabriel Hunter Cheng. It was edited by Lyddy Jean Kott and engineered by Sarah Bruguier. You can email us at problem at Pushkin dot Fm. I'm Jacob Goldstein and we'll be back next week with another episode of What's Your Problem.