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 Gould Dolan. She's a professor of psychology and neuroscience at the University of California at Berkeley. Gould'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? Gould 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. Gould thinks, among other things, psychedelics may be able to help patients recovering from strokes. We started the conversation talking about the origin of Gould's quest to understand how psychedelics work. About 10

years ago, when I started my lab, there were starting to be some hints that psychedelics were having these remarkable effects in all kinds of diseases that didn't seem terribly connected to each other, right? So addiction and depression and PTSD, and the people who study those diseases each have their way of studying them and modeling them and animals. And they're fyloed into different spaces. And yet, we were starting to hear hints that 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 assays we use, but even what brain regions might be important, right? The depression people were focused on the hippocampus and the prefrontal cortex. The PTSD people were focused on the amygdala. The addiction people were focused on the nucleus. The Cummins, 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 seem 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? Right.

So critical periods are something that neuroscientists have known about for almost 100 years. They were first described in 1935 by Conrad Lorenz who was describing an imprinting behavior in baby geese. So basically 48 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 if there's a crazy scientist around, it might be to the crazy scientist. There are photos of the baby geese following him around, right? In fact, as if he were a Mamagoose. 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 48 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 another 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. 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, once 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't respond to it and so you're blind forever. And so we have been looking probably for the last 100 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. It's more speculative than speculating, right? Like, we're not going to speculate, but we're tempted to speculate. So I appreciate that, right? Like, this is clearly speculative. It's based on research in mice. But why are you tempted to speculate that psychedelics may reopen critical periods in the brain?

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 induce this altered state of consciousness. So we discovered a critical period in 2019 for social reward 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 900 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 Ibogaine and ketamine, none of which are like particularly pro-social, nobody's, you know, doing a 30 person cuddle puddle on Ibogaine, right? Even though they don't have this pro-social property, they are all also able 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 deduce 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. 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 ideas that there's a, there's some set of critical periods for learning social behavior from language to norms and that those close over the course of childhood and adolescence.

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 energetically to always be having to learn from your social environment. 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 wash genes that the cool kids are wearing,

right? And now you wear whatever acid wash genes you want, right? That's

right. I wear mom genes that are acid washed.

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 returns. 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?

Yeah. So basically as soon as we got this result, I reached out to every single person that I know who works on critical 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 2019 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, 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 other 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? 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 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 it 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 going to totally break everything. So why even bother?

Right. And I, you know, I called it the multi 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 multi 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 multi brain problem is that they are context specific. So it's not that psychedelics 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.