The Ecstasy of an Open Brain

Summary

Radiolab Episode Summary: "The Ecstasy of an Open Brain"

Radiolab, produced by WNYC Studios and hosted by Lulu Miller and Latif Nasser, delves into the fascinating interplay between neuroscience and human behavior in the episode titled "The Ecstasy of an Open Brain." This episode explores the concept of critical periods in brain development and investigates how psychedelics like MDMA and LSD can potentially reopen these windows, offering groundbreaking therapeutic possibilities.

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Introduction to Critical Periods

The episode begins with Molly Webster introducing the concept of critical periods, specific windows during which the brain is exceptionally receptive to certain environmental stimuli, allowing for rapid and profound learning. Gould Dolan, a neuroscientist and former teenager, frames her personal adolescent struggles—like bullying and social anxiety—as inspirations for her scientific inquiry into how these critical periods shape our behaviors and habits.

Notable Quote:

Gould Dolan ([02:24]): "Critical periods are windows of time when the brain is specifically sensitive to its environment and it can learn really well and really strong from that environment."

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Understanding Critical Periods

Webster elaborates on critical periods by referencing Conrad Lorenz's classic study on imprinting in geese, where goslings form lasting attachments within 48 hours of hatching. This phenomenon highlights how certain behaviors and preferences are hardwired during these fleeting phases.

Notable Quote:

Molly Webster ([03:07]): "There are critical periods for language, vision, touch, motor learning. Basically, for everything the brain has to learn that isn’t encoded in your genes."

As adults, while the brain maintains some plasticity, these critical periods largely close, making it challenging to relearn or unlearn behaviors and recover from neurological injuries.

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Reopening Critical Periods with Psychedelics

Dolan and Webster introduce their pioneering research at Johns Hopkins University, where they explore the possibility of reopening critical periods in adult brains using psychedelics. Their initial experiments with mice revealed that administering MDMA in a social context could restore a juvenile-like sensitivity to social rewards in adult mice.

Experimental Insights:

• MDMA Administration: When adult mice were given MDMA alongside their social environment, they exhibited behaviors akin to juvenile mice, showing enhanced social learning ([12:22]).
• Broader Psychedelic Effects: Further experiments demonstrated that other psychedelics, including LSD, psilocybin, and ketamine, also reopened critical periods, suggesting a class-wide effect rather than one specific to MDMA's prosocial properties.

Notable Quote:

Molly Webster ([16:54]): "The trip... the mystical experience is really just what it feels like to reopen critical periods."

This revelation challenges the prevailing notion that psychedelics' profound effects are exclusive to human mystical experiences, positing instead that these experiences might stem from a fundamental biological mechanism of brain plasticity.

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Therapeutic Implications

The ability to reopen critical periods has profound implications for treating various neuropsychiatric conditions:

1. Post-Traumatic Stress Disorder (PTSD): MDMA-assisted psychotherapy has shown remarkable results, with patients often requiring only a few sessions to achieve lasting relief, compared to traditional therapies that require ongoing treatment.

   Notable Quote:

   Molly Webster ([23:02]): "It's not just that something is happening at the receptor level... it's that... the reconfiguring that's the cure. It's the learning that's the cure."

2. Depression: Psilocybin and other psychedelics may facilitate rapid and sustained improvements in depressive symptoms by enabling the brain to reorganize and establish new neural pathways.

3. Stroke Recovery: The most ambitious application discussed is using psychedelics to reopen critical periods for motor learning in stroke patients, potentially enhancing the efficacy of physical therapy and improving motor function recovery.

   Clinical Trial Plans:

   Molly Webster ([33:39]): "We're going to try and reopen [critical periods] in those people and see what happens to their ability to pair that psychedelic with physical therapy."

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Ethical and Practical Considerations

Reopening critical periods, while promising, introduces ethical and practical challenges:

• Vulnerability: Individuals may become more susceptible to environmental influences, necessitating controlled settings to prevent potential harm.

  Notable Quote:

  Molly Webster ([28:04]): "You should take care of yourself like you're four. Don't expose yourself to anything that you wouldn't take your four-year-old to."

• Limitations on Usage: There may be a finite number of times psychedelics can effectively reopen critical periods before diminishing returns occur, highlighting the need for strategic therapeutic applications.

• Contextual Sensitivity: The environment in which psychedelics are administered plays a crucial role in determining the outcomes, emphasizing the importance of pairing these substances with appropriate therapeutic contexts.

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Future Directions and Potential

The research spearheaded by Dolan and Webster opens the door to a myriad of possibilities beyond mental health, including treatments for:

• Traumatic Brain Injuries
• Neurodegenerative Diseases
• Sensory Processing Disorders

Their concept of psychedelics as "master keys" for unlocking various critical periods suggests that with the right context, these substances could revolutionize our approach to brain plasticity and healing.

Notable Quote:

Molly Webster ([36:31]): "If we're right about this Master Key business, then there are a lot of other diseases that psychedelics are not being explored for that really we should be thinking about."

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Conclusion

Radiolab's "The Ecstasy of an Open Brain" masterfully intertwines personal narratives, scientific exploration, and ethical discourse to shed light on the transformative potential of psychedelics in neuroscience. By challenging traditional models of mental health treatment and proposing innovative therapeutic avenues, the episode underscores the profound impact that understanding and manipulating critical periods can have on human health and behavior.

Final Notable Quote:

Molly Webster ([37:29]): "These drugs are extremely powerful medicines and we need to treat them with respect."

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This episode serves as a compelling exploration of the nexus between brain development, critical periods, and the therapeutic possibilities unlocked by psychedelics, offering listeners a deep dive into cutting-edge neuroscience research with real-world implications.

Transcript

[Latif Nasser]

Radiolab is supported by Dell Shop Dell Technologies Black Friday event for their lowest prices of the year. The Future is on sale today with limited time deals on select PCs like the XPS 16 that accelerate AI with Intel Core Ultra processors. Black Friday is their biggest sale of the year and the best time to upgrade. But it's only here for a limited time. Shop [e-mail] deals that's Dell.com Radiolab is brought to you by Progressive Insurance. Do you ever think about switching insurance companies to see if you could save some cash? Progressive makes it easy to see if you could save when you bundle your home and auto policies. Try [e-mail] Progressive Casualty Insurance Company and affiliates. Potential savings will vary. Not available in all states.

[Molly Webster]

Listeners support it. WNYC Studios.

[Latif Nasser]

Hey, it's Latif here with a quick note. Today we have the second installment in the series where we just sort of let ourselves fall into a conversation between our own senior correspondent, Molly Webster and a scientist who's working on the front edge of something, if not exactly news, something deeply and delightfully new. So here we go.

[Molly Webster]

Wait.

[Gould Dolan]

You're listening. Okay. All right.

[Latif Nasser]

Okay.

[Molly Webster]

All right.

[Gould Dolan]

You're listening to Radio Lab Radiolab from wnyc.

[Molly Webster]

See? Yep. 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, 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.

[Gould Dolan]

I'm Molly Webster, this is Radiolab. And that was Gould Dolan, a neuroscientist and former teen. But unlike maybe the rest of us former teens, Gould's very familiar teenage struggle would end up at the center of her scientific work and lead to new ways of seeing the moments in our lives when our most basic habits and behaviors emerge and then get locked in. And it all starts with something called critical periods. Okay, so for, like, us, you know, yokels over here, like, what is a critical learning period?

[Molly Webster]

Yeah, so critical periods are windows of time when the brain is specifically 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, oh, so cute.

[Gould Dolan]

We did an episode on it at one point. Yeah.

[Molly Webster]

So, yeah. So Conrad Lorenz, what he noticed is that within 48 hours of hatching, a little geese will goose. Well, gosling, I don't know.

[Gould Dolan]

Goss goose, I don't know.

[Molly Webster]

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. Or if it's 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.

[Gould Dolan]

And when was that discovered?

[Molly Webster]

So that was in, I think 1935. And then since 1935, we've discovered dozens of other critical periods.

[Gould Dolan]

Wow.

[Molly Webster]

There's critical periods for language, there's critical periods for vision, there's critical periods for touch, for, you know, motor learning. There's critical periods basically for everything that the brain has to learn that isn't encoded in your genes.

[Gould Dolan]

And do we associate those critical periods with being a baby?

[Molly Webster]

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. Motor learning is a little bit longer because you're still learning a lot of motor things pretty far along.

[Gould Dolan]

And then, you know, neuroscience often makes me feel like I just started falling behind at like three months old. Because you're just like, oh, that window closed and that window closed and that window closed. I'm like, I'd like to think I'm 40 and the world is still my oyster, but perhaps not.

[Molly Webster]

Yeah, well, I mean, definitely when I've talked about this with some people, they get a little offended. Cause 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 they are noticing everything. It's like shoes. What 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 be always in that open, vulnerable state forever. 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.

[Gould Dolan]

And you're like, oh, look at the flower.

[Molly Webster]

Oh, look at the butterfly. I love your tooth. It's awesome, right? But the ability to reopen critical periods has been something that neuroscience has been looking for for almost a hundred years because we realized that 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.

[Gould Dolan]

Wow, this is creating such a feeling of urgency in me. So critical periods are great for learning and learning fast. They make us super spongy and absorbent to the world around us. But the fact that they close makes it hard to relearn something we've lost or to unlearn something that's getting in our way. But Gul, in her first lab at Johns Hopkins University, actually uncovered a whole new way of thinking about that problem. And weirdly, it all comes down to peer pressure.

[Molly Webster]

My postdoc, who had studied very early brain development, was really interested in studying, you know, how social behavior changes over maturation. 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, really. And he was like, no, no, I really want to do this development thing. And then I was like, well, you know, I do remember being bullied as a teenager. You know, maybe there's something here.

[Gould Dolan]

You were peer pressured into peer pressure?

[Molly Webster]

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 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 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, 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.

[Gould Dolan]

So Guel and her team, they get a bunch of mice at all different ages, and they observe them very, very closely. And she basically confirms sort of what we see anecdotally in humans, that teen mice pay attention to their friends more, they learn from their friends more. But then they opened the tiny mouse brains, and what they saw is that mice, just like humans, have oxytocin, this sort of feel good chemical that's released when we're around friends or loved ones. And they saw that the neurons in the teen mouse brains were more susceptible and sensitive to oxytocin. And so it seemed like, oh, this is a biological neurological critical period.

[Molly Webster]

And then right away, we were like, okay, we need to figure out a way to reopen it.

[Gould Dolan]

Wait, they reopen?

[Molly Webster]

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. Sensory deprivation can reopen touch critical periods. It's just not a very clinically useful way of doing it. Right. Like, it's just not. Yeah.

[Gould Dolan]

I was like, how long do I have to be deprived? Molly's over here looking at her calendar. Like, what do I want to fix?

[Molly Webster]

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 prosocial behavior. You know, kids were taking these drugs and going to raves and doing, you know, 60 person cuddle puddles, but also.

[Gould Dolan]

Love a cuddle puddle.

[Molly Webster]

Yeah, I mean, it is. It's a very powerful, 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 reopen this critical period by triggering this massive oxytocin release that could prepare the neuron to learn from its social environment again.

[Gould Dolan]

So they go back to the lab, back to the mice who this time are going to go on a little trip.

[Molly Webster]

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.

[Gould Dolan]

Would you like peek in with a secret telescope to see what their behavior was like in those two days?

[Molly Webster]

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?

[Gould Dolan]

I mean, I'm not sure, maybe the mouse got acid washed genes or something unbeknownst to us.

[Molly Webster]

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, okay, 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. 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 betting, it's like, oh, I like this betting. Because I remember that all my buddies like this betting, and that's where I found my buddies is on this betting. So I like this betting, not this other betting. Right? 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.

[Gould Dolan]

And what ghoul and her team saw is that the adult brains on mdma, they actually went back to that sensitive teenage like brain state.

[Molly Webster]

So can I tell you what we were wrong about there? I don't know if I told you this.

[Gould Dolan]

Oh my God. Sure.

[Molly Webster]

Yeah. So at the end of that paper in 2019, we were like, okay, great, we understand this now. It's because MDMA is prosocial. But we also knew that MDMA belonged to this larger group of compounds that are all psychedelic, right? And so I was like, let's just test it with lsd. 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 pro social effect that MDMA has. Right. 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, okay, well what about like ketamine? And it did it. And basically all of the psychedelics are doing it.

[Gould Dolan]

Like the fact that it's a drug that induces social behavior is not why you're seeing social results. It's about the class of drugs of psychedelics.

[Molly Webster]

That's right, that's right. It's the psychedelics part of it, not the prosocial 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. 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. And what I think is that this seeing God, this mystical experience is really just what it feels like to reopen critical periods.

[Gould Dolan]

Just to put that in context, it's like a dude tripping in a corner is in a way having the same experience as like a wide eyed baby soaking up their world or a teenager who cares so much about what everyone else thinks of them. And it's not just that they're experiencing in the same way, it's that there's an underlying deep biological mechanism that's being shared in all of those situations. And if you can tap into that mechanism, there are some very real world practical things that you might be able to do. Which we'll get into right after this break. Radiolab is supported by BetterHelp. As many of us are reflecting on what we're thankful for this month. We often forget to express gratitude to someone very near and dear to us, ourselves. It can be hard or not always at the top of our minds to remind ourselves that we're doing our best to make sense of the world and to live our lives and that it's not easy. So let this be a reminder to send some love and thanks to the people in your life, including you. If you need some guidance with this, therapy can help. Working with a therapist can be a great way to reflect and develop coping mechanisms, among other valuable tools. If you're thinking of starting therapy, give BetterHelp a try. It's entirely online, designed to be convenient, flexible, and suited to your schedule. So just fill out a brief questionnaire to get matched with a licensed therapist and switch therapists anytime for no additional charge. Let the gratitude flow with BetterHelp. Visit betterhelp.com Radiolab today to get 10% off your first month. That's BetterHelp. H E L P.com Radiolab.

[Latif Nasser]

Radiolab is supported by Made in Cookware As a Radiolab listener, you know we like to nerd out and explore things like how seagulls from the 1970s shook up our understanding of what's natural in all of us animals and how far the moon actually is. The usual Made In Cookware is into exploration too, creating products that help us answer questions like have you wanted to cook lobster but balked because the process seemed too intimidating? When it comes to picking the right ones and what tools you need to dig in, it can seem like a lot. Armed with Made In's Stainless Clad stock pot and their how to Cook Lobster blog post, there's no need to be afraid. With their professional grade stainless clad, carbon steel, nonstick and enameled cast iron cookware collections, Made in lets you focus on memorable meals. Cook like a pro with Made In. For full details, visit madeincookware.com that's M A D E incookware.com hey, Jon Favreau here.

[Gould Dolan]

There's no shortage of political takes in 2024, but quantity doesn't cut it. We need a better conversation about the latest, biggest election of our lives. On Pod Save America, me and my co hosts cut through the noise to help you figure out what matters and.

[Latif Nasser]

How you can help.

[Gould Dolan]

Every Tuesday, Wednesday, and Friday, Pod Save America is breaking down the political news that makes us laugh, cry, and snap our laptops in half. Expensive year for laptops. Make sure to check out new episodes of Pod Save America on your favorite podcast platform or our YouTube channel now. I'm Molly Webster. This is Radiolab. We are back in the saddle with neuroscientist Gul Dolan. She's been telling us about how psychedelics can reopen critical periods in the brain, and where it goes from here, in a way, just gets more practical. Because I think we've all been hearing about studies in which psychedelics are curing various afflictions so, like MDMA is helping with ptsd or psilocybin, AKA magic mushrooms, can help with depression. And Gould says that she thinks her study, the one that she did with mice, that it might be able to provide a clue about how those treatments are doing, what they do.

[Molly Webster]

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. 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.

[Gould Dolan]

That's very interesting that in a way, it's not the psychedelic. I mean, it is. The presence of the psychedelic is allowing something else in the brain, like an experience or whatever, to have an action.

[Molly Webster]

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.

[Gould Dolan]

Who knew? I'm settling in.

[Molly Webster]

Okay. Yeah, settle in. 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. 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 Wellbutrin, when they go off of Wellbutrin, they go back to smoking. And people who follow that model find that to be an acceptable solution. 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. 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 that thing that's happening is enabling a reconfiguration of all of the synapses that are relevant to the trauma. And that is the cure. It's the reconfiguring that's the cure. It's the learning that's the cure.

[Gould Dolan]

Gould says that when you use a psychedelic in the right context, it actually opens up the brain at a cellular level so that the neurons can reorganize themselves. And in that reorganization, they can create new patterns and new pathways that allow for learning and maybe even healing. So really what these drugs do is create a window of opportunity. How long was that period seemingly open for?

[Molly Webster]

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 and, AKA the trip. The trip. Right.

[Gould Dolan]

The length of the trip.

[Molly Webster]

The length of the trip is proportional. 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 two days, and then by a week, it's closed. Psilocybin and MDMA keep it open for two weeks and close by three weeks. LSD keeps it open for three weeks, closed by four weeks. And then there's sort of a rockstar psychedelic, which most people haven't heard of, called ibogaine. And that the trip lasts anywhere from 36 to 72 hours.

[Gould Dolan]

Wow. Okay.

[Molly Webster]

And ibogaine reopens the critical period for at least four weeks. And we haven't tested the closure. We haven't found the closure because everyone.

[Gould Dolan]

Had to, like, go home for dinner. And you're like, we can't. We can't test this anymore. I mean, it's just sort of interesting because you think even four days, four days, two weeks, more than a month. Like, are you just in those moments, like, vulnerable to everything? It just feels like the next couple of weeks, like, solidly matter.

[Molly Webster]

Yes, solidly matter and solidly vulnerable. So it's possibly a missed therapeutic opportunity, but it's also possibly a time when we could do great harm to people because there's. They're sort of vulnerable to information coming in the way that children are. And then we've, you know, kind of thrown them back into their lives and possibly re. Exposed them to whoever has been traumatizing them, and that we could potentially lock in some really bad things.

[Gould Dolan]

It's funny. It's. Yeah, I think about, I mean, recreational psychedelics use. People are doing it all the time, at least in my world. And like now I just like want to be like, okay, for the next two weeks if you could, you know, be careful or maybe go. If you go take a yoga class if you really want to learn that technique or something. I don't know. It's just the vulnerability part of it feels. And vulnerability has such a negative connotation. But I do think it goes both ways of like, it just, you're vulnerable, you're malleable, you're open. That feels like a double edged sword.

[Molly Webster]

Yep. To me, these drugs are extremely powerful medicines and we need to treat them with respect. I, you know, really feel like if you see these drugs as powerful ways to restore, you know, 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. Like, don't expose yourself to anything that you wouldn't take your four year old to.

[Gould Dolan]

Horror.

[Molly Webster]

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.

[Gould Dolan]

Master key.

[Molly Webster]

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. 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.

[Gould Dolan]

Wow. Okay.

[Molly Webster]

But you know, when I first started talking about this master keys idea, people were just like rolling their eyes.

[Gould Dolan]

Oh, really?

[Molly Webster]

Yeah. Oh, for sure. 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.

[Gould Dolan]

Anyway, it's social. Mammals are social.

[Molly Webster]

Yeah. And we still care about social. It's just, you know, social. It's an emotion.

[Gould Dolan]

What's like the hardcore critical period that would.

[Molly Webster]

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 period. 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, 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. It's just horrible. 500,000 people a year are debilitated in the United States, and stroke is much more common in other countries. So it's a worldwide massive burden.

[Gould Dolan]

And just real quick, why is motor neuron like the top of the mountain for critical periods?

[Molly Webster]

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.

[Gould Dolan]

Whoa.

[Molly Webster]

And neurons in the motor cortex are not able to regenerate. So once they're gone, they're gone. 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. That's a hard thing because, you know, they've got a job already and they've.

[Gould Dolan]

Been doing that job for 70 years, potentially. You know.

[Molly Webster]

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.

[Gould Dolan]

So the main thing that Gould's team is focused on right now is designing a clinical trial for stroke patients. What they know is that generally after a stroke, the critical learning window is open for about two to three months, and then it closes.

[Molly Webster]

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.

[Gould Dolan]

Keep the PT going.

[Molly Webster]

Keep it going. 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.

[Gould Dolan]

Hard and fast, shut, hard, close.

[Molly Webster]

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, say your trial works.

[Gould Dolan]

That you see that if you have a stroke and I give you MDMA and for two weeks, we do stuff, and you can gain motor neuron skills back. That's great. But imagine that you don't gain all your skills back. So then you're like, okay, well, I'm gonna do MDMA again. Keep the window open for two weeks. So I get a month out of this. Right? Two doses. I get a month where I'm open. I'm wondering is if you hit a point where the mdma, your brain's, like, used to it.

[Molly Webster]

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 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.

[Gould Dolan]

Yeah. It makes me think that depending on how your stroke stuff comes out, that I want everyone to save at least one MDMA trip for themselves, you know, for when they're older.

[Molly Webster]

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.

[Gould Dolan]

Hmm. I sort of want to run out of here, and I'm not sure if I want to do MDMA with a therapist or if I just want to do MDMA and cuddle with people for two weeks, you know, or if I just don't want to do MDMA at all, like, maybe go hide in a cave for a while.

[Molly Webster]

Yeah, totally.

[Gould Dolan]

I don't know.

[Molly Webster]

For me, personally, the thing that I'm most excited about is, you know, if we're right about this Master Ki business business, then what it means is that there's a lot of other diseases that psychedelics are not being explored for that really we should be thinking about. Right. So as a whole new avenue that will have implications for, you know, people with cochlear implants, people with traumatic brain injury, you know, all kinds of other diseases that really right now we just don't have any therapy for.

[Gould Dolan]

This episode was reported by me, Molly Webster. It was produced by the amazing Sindhu Nana Sambindhan. There was production help from me and Timmy Broderick and fact checking was by Emily Krieger. I want to give a huge thank you shout out to Gul Dolan who is now at the University of California, Berkeley and talked to me multiple, multiple times. Special thanks also go to Charles, Philip and David Herman and a special shout out to Rahman Nardu who is in the lab of Gould. Dolan is the postdoc we referenced earlier in the piece, the one who said, you know, let's study peer pressure. Finally, if you want that spongy brain juice, you should check out our newsletter. It's got content, extra content, insider content, fun pictures, staff wrecks. You can go to radiolab.org newsletter and sign up or check out the link on the show Notes. That's the show folks. I'm Molly Webster, this is Radiolab. Catcha later.

[Latif Nasser]

Hi, I'm David and I'm from Baltimore, Maryland. Radiolab was created by Jad Abumrad and is edited by Soren Wheeler. Lulu Miller and Latif Nasser are our co hosts. Dylan Keefe is our Director of Sound design. Our staff includes Simon Adler, Jeremy Bloom, Becca Bressler, W. Harry Fortuna, David Gable, Maria Paz Gutierrez, Sindhu Nyanam Sambandan, Matt Kielty, Annie McEwen, Rebecca Lacks, Alex Neeson, Sara Khari, Sarah Sandbach, Arianne Wack, Pat Walters and Molly Webster. Our fact checkers are Diane Kelly, Emily Krieger and Natalie Middleton.

[Gould Dolan]

Hi, this is Ellie from Cleveland, Ohio. Leadership support for Radiolab Science programming is provided by the Gordon and Betty Moore Foundation Science Sandbox Assignments Foundation Initiative and the John Templeton Foundation. Foundational support for Radiolab was provided by the Alfred P. Sloan Foundation.

[Molly Webster]

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[Gould Dolan]

Every home NYCNow delivers the most up to date local news from WNYC in Gothamist. Every morning, midday and evening with three updates a day. Listeners get breaking news, top headlines and in depth coverage from across New York City by sponsoring programming like NYC Now. You'll reach our community of dedicated listeners with premium messaging and an uncluttered audio experience. Visit sponsorship.wnyc.org to get in touch and find out more.