Gül Dölen
Appearances
Radiolab
The Ecstasy of an Open Brain
If we gave MDMA in a social context, then it was able to reopen the critical period. But not if we gave MDMA in an isolation context. So in the case where they were by themselves having MDMA, They did not reopen their social critical period. Context matters, right? It's not like people are going to Burning Man and just having a dance party and coming back cured of their PTSD.
Radiolab
The Ecstasy of an Open Brain
It's the right, if you give MDMA in the right context. So if you pair MDMA with therapy, then you get these remarkable results.
Radiolab
The Ecstasy of an Open Brain
Well, so let me just unpack that in two different ways, because I do think that this is, to me, where the crux of the debate right now is. I think there's sort of, I mentioned... Who knew?
Radiolab
The Ecstasy of an Open Brain
Okay. Yeah, settling. So the crux of the debate seems to be, you know, what I call the biochemical imbalance model of psychiatric illness and the learning model. And so the biochemical imbalance model is, it basically says, if you are depressed, it's because of a biochemical imbalance in serotonin. And all we have to do to make you undepressed is restore that balance, right?
Radiolab
The Ecstasy of an Open Brain
The problem is, is that that approach has only provided symptomatic cures, right? So people who are on SSRIs, You know, when they come off of them, they go back to being depressed. People who are on Welbutrin, when they go off of Welbutrin, they go back to smoking. And people who follow that model find that to be an acceptable solution.
Radiolab
The Ecstasy of an Open Brain
But the psychedelics, they have these remarkable results where people, instead of taking, you know, one a day for years and years and years, the MDMA-assisted psychotherapy trials, it's three pills total. And those... No longer adaptive habits become available for relearning, for updating to the current circumstances. And six months later, the underlying condition is resolved.
Radiolab
The Ecstasy of an Open Brain
So what people describe with psychedelics is it's like it was 20 years of therapy in one day. And I think that our critical period idea really provides an explanation. It's not just that something is happening at the receptor level. that is rebalancing a biochemical imbalance. It's that thing that's happening is enabling a reconfiguration of all of the synapses that are relevant to the trauma.
Radiolab
The Ecstasy of an Open Brain
And that is the cure. It's the reconfiguring that's the cure. It's the learning that's the cure.
Radiolab
The Ecstasy of an Open Brain
This is probably the coolest part of this paper. There's this proportionality between the duration of the acute subjective effects of the psychedelics in humans. A.K.A.
Radiolab
The Ecstasy of an Open Brain
The length of the trip in humans is proportional to the duration of the open state that we can induce of this social critical period in mice. So, for example, ketamine keeps the critical period open for, you know, two days and then, you know, by a week it's closed. Psilocybin and MDMA keep it open for two weeks and closed by three weeks. LSD keeps it open for three weeks, closed by four weeks.
Radiolab
The Ecstasy of an Open Brain
And then there's sort of a rock star psychedelic, which most people haven't heard of, called Ibogaine. And that, the trip lasts anywhere from 36 to 72 hours. Wow. Okay. And Ibogaine reopens the critical period for at least four weeks. And we haven't tested the closure yet. We haven't found the time.
Radiolab
The Ecstasy of an Open Brain
Yeah. So critical periods are windows of time when the brain is especially sensitive to its environment and it can learn really well and really strong from that environment. Probably the best way to understand that is to think about the first critical period that was described. I think a lot of people have heard of it. It's imprinting behavior in geese. So this is so cute.
Radiolab
The Ecstasy of an Open Brain
Yes, solidly matter and solidly vulnerable. So it's possibly a mistherapeutic opportunity, but it's also possibly a time when we could do great harm to people because they're suggestible. They're sort of vulnerable to information coming in the way that children are. And then we've
Radiolab
The Ecstasy of an Open Brain
you know, kind of thrown them back into their lives and possibly re-expose them to whoever's been traumatizing them and that we could potentially lock in some really bad things.
Radiolab
The Ecstasy of an Open Brain
Yeah. To me, these drugs are extremely powerful medicines, and we need to treat them with respect. I really feel like if you see these drugs as powerful ways to restore that childlike sense of wonder and vulnerability, In the two weeks after you do a psychedelic, you should take care of yourself like you're four, right?
Radiolab
The Ecstasy of an Open Brain
Like, don't expose yourself to anything that you wouldn't take your four-year-old to. Hmm.
Radiolab
The Ecstasy of an Open Brain
You know, from my point of view as a neuroscientist, maybe these psychedelics are master keys for unlocking all kinds of critical periods. What a crazy phrase. Master key. Yeah. Yeah, right. All we have to do to change which critical period gets reopened is change the context. So if you want to reopen a social critical period, you give it in a social context.
Radiolab
The Ecstasy of an Open Brain
If you want to open it in a motor critical period, you give it in a motor context, right? So maybe the RAVE is a great way to open a motor context critical period, but not necessarily an inner directed PTSD kind of critical period. Wow. OK, but, you know, when I first started talking about this master keys idea, people were just like rolling their eyes. Oh, really? Yeah. Oh, for sure.
Radiolab
The Ecstasy of an Open Brain
That your critical period is just a baby critical period. It's not like the serious, hardcore critical periods that matter clinically. You know, you're just it's just easy to open because it's the door isn't closed that hard on that one anyway.
Radiolab
The Ecstasy of an Open Brain
Yeah. And we still care about social. It's just, you know, social. It's an emotion.
Radiolab
The Ecstasy of an Open Brain
So yeah. So Conrad Lorenz, what he noticed is, is that within 48 hours of hatching, a little geese will goose will gosling. I don't know. I don't know. Anyway, geese will form a long lasting attachment to whatever is moving around in their immediate environment. And so typically this is their mom. But if the mom isn't there, it could be another mom.
Radiolab
The Ecstasy of an Open Brain
So the hardcore one is vision. And since we first started making the case that psychedelics are reopening this critical period, there have been a couple of other papers from other labs showing that actually they can reopen. Well, ketamine is the one that people have looked at. But I think there's now another paper out about LSD. suggesting that they can reopen ocular dominance critical periods.
Radiolab
The Ecstasy of an Open Brain
So the visual critical period can also be reopened. But the most hardcore one is motor, right? So movement. And this is the one that matters for stroke. And just so you know, reopening this motor critical period after stroke has been, you know, a goal of clinicians. And it's kind of where good ideas go to die, right? Like...
Radiolab
The Ecstasy of an Open Brain
People have been trying to do this for stroke for a long time because roughly a million Americans a year get a stroke and half of them are debilitated for life afterwards, right? They die. It's just horrible. 500,000 people a year are debilitated in the United States. And stroke is, you know, much more common in other countries. So it's a worldwide massive burden.
Radiolab
The Ecstasy of an Open Brain
I mean, we don't really understand how it happens. But basically, what we think is, is that when the stroke happens, the brain region that is encoding, let's say it's a hand movement, that those neurons that are encoding that hand movement die. And neurons in the motor cortex are not able to regenerate. So once they're gone, they're gone. Right.
Radiolab
The Ecstasy of an Open Brain
And so what we think has to happen in order to recover from a motor injury is that the nearby neurons that are encoding, say, the arm or the elbow or the upper arm, those neurons have to get repurposed and have to learn how to do finger, even though they're normally doing elbow. Yeah. That's a hard thing because, you know, they've got a job already.
Radiolab
The Ecstasy of an Open Brain
And they've been doing that job for 70 years potentially, you know. That's right. That's right. And so that's why we think it's so hard. And right after a stroke, if you want to reopen the critical period again, so far the best way to do that is to give another stroke, which is not clinically useful, right? Like nobody wants to cure stroke by getting another stroke.
Radiolab
The Ecstasy of an Open Brain
And then it closes. So we think that after they've, you know, done as much as they can during that two months, three months after the stroke with the physical therapy, but they haven't recovered full motion yet, we can give them psychedelics and keep it open a little bit longer. Keep the PT going. Keep it going.
Radiolab
The Ecstasy of an Open Brain
Actually, though, in the first version of this trial, what we're going to do is we're going to take people who had a stroke over a year ago. So their critical period is closed down. Hard and fast shut. Hard closed. And then we're going to try and reopen in those people and see what happens to their ability to pair that psychedelic with physical therapy this time instead of psychotherapy.
Radiolab
The Ecstasy of an Open Brain
Or if it's, you know, Conrad Lorenz, it could be a scientist. But then after that 48 hour time window is over. They can be exposed to all kinds of things in their environment and they won't form that lasting attachment. So that little window of time where they're so sensitive to their environment and they can form this lifelong attachment is what he coined the phrase critical period.
Radiolab
The Ecstasy of an Open Brain
There is evidence that there is only so many times that you can take these psychedelics before they stop working in this way. There's evidence, you know, anecdotally from... recreational users who estimate that you've got about 20 or 30 really big MDMA trips and then you're done and it loses its magic after that.
Radiolab
The Ecstasy of an Open Brain
Right, right. Yeah, I agree. I'm hopeful. I mean, we don't know. This is really, I'm speculating now. But if this is the case, maybe you use up all of your MDMA slots, but you've never done Ibogaine. And so you can still have an Ibogaine in reserve that you could tap into to reopen. But, you know, this remains to be seen. Hmm.
Radiolab
The Ecstasy of an Open Brain
For me personally, the thing that I'm most excited about is, you know, if we're right about this master key business, then what it means is, is that there's a lot of other diseases that psychedelics are not being explored for that really we should be thinking about. Right.
Radiolab
The Ecstasy of an Open Brain
that will have implications for people with cochlear implants, people with traumatic brain injury, all kinds of other diseases that really right now we just don't have any therapy for.
Radiolab
The Ecstasy of an Open Brain
And when was that discovered? So that was in, I think, 1935. And then since 1935, we've discovered dozens of other critical periods. Wow. There's critical periods for language. There's critical periods for vision. There's critical periods for touch, for motor learning. There's critical periods basically for everything that the brain has to learn that isn't encoded in your genes.
Radiolab
The Ecstasy of an Open Brain
Yes. Mostly it's, I mean, not just babies. There are, you know, different windows depending on what you're trying to learn at the time. So, you know, vision, the critical period peaks around three or four years old. By five or six, it's closed. Language stays open probably six, seven, eight, and then it's closed.
Radiolab
The Ecstasy of an Open Brain
Motor learning is a little bit longer because you're still learning a lot of motor things pretty far along.
Radiolab
The Ecstasy of an Open Brain
Yeah. Well, I mean, I definitely when I've talked about this with some people, they get a little offended because they're like, what do you mean? I'm open minded. I'm open minded and I'm 40. And it's like, yeah, you're open minded, but you're not a sponge the way that a child is a sponge. Right. Like if you've ever watched a kid try and get out the door on a snow day, it's brutal, you know, like.
Radiolab
The Ecstasy of an Open Brain
They are noticing everything. It's like shoes, wet shoes. Look at this dust bunny. You know, every single leaf is like a magical kingdom full of possibility. And they're just noticing it all. And so, you know, they need to close because it's not it's not very adaptive to to be always in that open, vulnerable state forever.
Radiolab
The Ecstasy of an Open Brain
And if you're trying to make your way through a saber tooth tiger infested area, it's probably better to be, you know, a habit based, efficient, you know. And you're like, oh, look at the flower. Oh, look at the butterfly. I love your tooth. It's awesome. But yeah.
Radiolab
The Ecstasy of an Open Brain
The ability to reopen critical periods has been something that neuroscience has been looking for for almost 100 years because we realized that, you know, the reason that we're so bad at curing diseases of the brain is because by the time we get around to fixing the underlying problem, the relevant critical periods have all closed.
Radiolab
The Ecstasy of an Open Brain
My postdoc, who had studied very early brain development, was really interested in studying how social behavior changes over time. And he was like, what if critical periods is the basis of this change in peer pressure behavior in juveniles versus adults? And at first I was like, that's kind of a boring project. And he was like, no, no, I really want to do this development thing.
Radiolab
The Ecstasy of an Open Brain
And then I was like, well, you know. I do remember being bullied as a teenager. You know, maybe there's something here. You were peer pressured into peer pressure. Yeah, basically. Yeah. I mean, it was just to take it back a second. I mean, part of the reason that I think I've gone back and tried to interpret why did I struggle so much with fitting in when I was in middle school and,
Radiolab
The Ecstasy of an Open Brain
You know, if I really think about it, it's because when I was younger, I was so obsessed with being in the right in-group and knowing the exact right shade of acid-wash jeans the cool kids were wearing. And I had this idea that maybe we care so much more about—
Radiolab
The Ecstasy of an Open Brain
who's in our social group and our social environment because we're learning from our social environment much more when we're younger than when we're older. And so that was sort of my own personal intuition about why there might be such a thing as a critical period for social reward learning. But of course,
Radiolab
The Ecstasy of an Open Brain
In the human literature, they can't do a comprehensive study of one type of social behavior across 15 different ages, looking at hundreds of people at each age. It would cost way too much money. But I knew that we could do that kind of experiment in mice.
Radiolab
The Ecstasy of an Open Brain
And then right away we were like, OK, we need to figure out a way to reopen it. Wait, they reopen? Yes. And that's interesting because one of the earliest ways that people figured out that you could reopen critical periods was deprivation. So visual deprivation, for example, can reopen visual critical periods. Auditory deprivation can reopen auditory critical periods.
Radiolab
The Ecstasy of an Open Brain
Sensory deprivation can reopen touch critical periods. It's just not a very clinically useful way of doing it. Right.
Radiolab
The Ecstasy of an Open Brain
And so. We were looking around for different ways to reopen it. And we knew that MDMA was a psychedelic drug that was special and different from most other psychedelics because it had this ability to induce pro-social behavior. You know, kids were taking these drugs and going to raves and doing, you know, 60-person cuddle puddles.
Radiolab
The Ecstasy of an Open Brain
I don't know about you, but I found being a teenager and, you know, going into puberty very difficult. You know, I was bullied by the mean girls, the popular girls at school and had to eat lunch by myself. And I remember having a tearful conversation with my mother and she was like, don't worry. It'll pass. You think that this is the whole world right now.
Radiolab
The Ecstasy of an Open Brain
Yeah. I mean, it's a very powerful drug, and it does have these very profound effects on people. So then we thought, well, if MDMA is able to induce a massive release of oxytocin, which there was some evidence from other labs showing that, we thought maybe this would be a really cool way to
Radiolab
The Ecstasy of an Open Brain
to reopen this critical period by triggering this massive oxytocin release that could prepare the neuron to learn from its social environment again.
Radiolab
The Ecstasy of an Open Brain
In this experiment, we were giving the MDMA and then waiting for two days. So they're no longer actively tripping. They're no longer actively cuddle puddling or doing anything like that.
Radiolab
The Ecstasy of an Open Brain
No, we could have, but we didn't. Okay. I don't know if you've seen people on psychedelics, but unless there's a DJ, you know, they can look very boring on the outside, right?
Radiolab
The Ecstasy of an Open Brain
Unbeknownst to us. So, no, so it wasn't like that. Basically, what happened was is that then they had a how-much-do-you-care-about-social-interaction quiz, essentially. Like, we tested them on... Can you learn from your social group again? So we say, OK, here's two new types of bedding. And we want you to tell us which one you like better by how much time you spend on them.
Radiolab
The Ecstasy of an Open Brain
And when we did that test, these were adult animals. But the ones that had gotten MDMA two days later when they go into the bedding, it's like, oh, I like this bedding because I remember that all my buddies like this bedding and that's where I found my buddies is on this bedding. So I like this bedding, not this other bedding, right?
Radiolab
The Ecstasy of an Open Brain
When they received the MDMA in a social context with their friends, suddenly they all cared, right? Like they suddenly they were learning from their social environment again as if they were teenagers.
Radiolab
The Ecstasy of an Open Brain
So can I tell you what we were wrong about there? I don't know if I told you this. Oh, my God.
Radiolab
The Ecstasy of an Open Brain
Yeah. So at the end of that paper in 2019, we were like, OK, great. We understand this now. It's because MDMA is pro-social. But we also knew that MDMA belonged to this larger group of people. compounds that are all psychedelic, right? And so I was like, let's just test it with LSD.
Radiolab
The Ecstasy of an Open Brain
And suddenly all of the animals who had received LSD were also doing social reward learning like they were juveniles again. And I was like, okay, this is weird. I don't understand why this is because, you know, nobody's doing LSD and then, you know, doing a 30-person cuddle puddle. You know, people who do LSD don't have this, like, acute prosocial effect that MDMA has. Right.
Radiolab
The Ecstasy of an Open Brain
So it's that's strange. Let's test a couple of others in case. So then we did it with psilocybin and we got the same thing. And then we were like, OK, well, what about like ketamine? And it did it. And basically all of the psychedelics are doing it.
Radiolab
The Ecstasy of an Open Brain
But in a few years, you'll be off in the bigger world and you'll see that there are a lot more people and you'll fit in better and it'll be fine.
Radiolab
The Ecstasy of an Open Brain
That's right. That's right. It's the psychedelics part of it, not the pro-social effects of MDMA that make it able to reopen this critical period. You know, when I first started working on psychedelics, so this was about 10 years ago, the fad was, look, everything cool that psychedelics do, you really have to study in a human.
Radiolab
The Ecstasy of an Open Brain
There's no way that you're ever going to be able to get at that mystical experience that what is a mouse seeing God even look like? You know, you're just not going to be able to, you're just never going to be able to get to the heart of the cool stuff if you study it in animals. And I think that this critical period explanation is the first one where we can really challenge that worldview.
Radiolab
The Ecstasy of an Open Brain
And what I think is that this seeing God, this mystical experience is really just what it feels like to reopen critical periods.