Show Notes

Octopuses and humans have very little in common. It’s not just a matter of their eight limbs and cool camouflage—we haven’t had a shared ancestor for more than half a billion years, before dinosaurs walked the earth. But there’s one surprising thing we do seem to share: MDMA makes us both a lot cuddlier. For neuroscientist Gül Dölen, this was a huge insight into the powerful role psychoactive drugs can play in animal social behavior. Now a pioneer in the burgeoning field of psychedelic research at UC Berkeley, Dölen discusses her quest to understand how these drugs could be harnessed as tools in learning and therapeutics. 

Further reading: 

• Gül Dölen’s 2019 Nature paper “Oxytocin-dependent reopening of a social reward learning critical period with MDMA”
• Gül Dölen’s 2018 Current Biology paper “A Conserved Role for Serotonergic Neurotransmission in Mediating Social Behavior in Octopus”
• UC Berkeley Center for the Science of Psychedelics launches new online course on “Psychedelics and the Mind”
• Altered States, a new podcast from from PRX and the UC Berkeley Center for the Science of Psychedelics about “what science can tell us about psychedelics and what psychedelics can tell us about ourselves”

This episode was written and hosted by Leah Worthington and produced by Coby McDonald. 

Special thanks to Pat Joseph, Nathalia Alcantara, and Gül Dölen. Art by Michiko Toki and original music by Mogli Maureal. Additional music from Blue Dot Sessions.

Transcript: 

LEAH WORTHINGTON: 

We’ve all heard the expression “kids’ brains are like sponges.” They learn to ride bikes, speak languages, pick up crafts, and make new friends like it’s the easiest thing in the world. If you’re anything like me, you watch them with enormous envy. If my brain is a sponge, it’s more like that thin, crusty one that I should have tossed a few weeks ago. Smells moldy. Honestly makes the dishes dirtier. What I wouldn’t give to go back to sponge-brain and collect a few more languages, conquer my fear of skiing, maybe unlearn a bit of unhealthy social conditioning… But, amazingly, new research into drug therapy has shown some potential for doing just that—reawakening the brain’s malleability. 

That’s where neuroscientist Gül Dölen comes in. Since undergrad, Gül has been captivated by the ability of certain drugs to stimulate critical brain processes. She describes drugs like LSD and MDMA as “consciousness-changing” for their ability to “dramatically alter people’s ability to process the world, see the world differently.” It’s not just about the trip itself, she says, but about what comes after, what can happen when you change the way someone processes the world. Now a professor at UC Berkeley and a pioneer in the burgeoning field of psychedelic research, she’s on a quest to understand how these psychedelics might hold the key for recreating that youthful brain sponginess, in really powerful and even therapeutic ways. 

Her research has involved asking questions like, how might psychedelic-assisted treatment help people do everything from regaining vision to learning new languages to recovering from strokes? Also: what happens when you give an eight-limbed, aggressively antisocial, manipulative killer—also known as an octopus—a dose of ecstasy? Spoiler: It’s weirdly similar to what happens in humans.

[MUSIC IN]

LEAH: This is The Edge, produced by California magazine and the Cal Alumni Association. I’m your host, Leah Worthington.

In today’s episode, we’re thrilled to have Gül Dölen, a professor of psychology and neuroscience, best known for her work using psychedelic drugs to study animal social behavior and neural plasticity. Gül, who joined the UC Berkeley faculty earlier this year, is also the Renee and Bob Parsons Endowed Chair in the Berkeley Center for the Science of Psychedelics. And you’re in for a real treat because today she’s here to talk about octopus intelligence, drug therapy, and how psychedelics may be the so-called “master key” to unlocking critical periods of learning.

[MUSIC OUT]

LEAH: So, I will admit that in preparing for this interview and talking with my colleagues, we’ve been referring to you as the octopus psychedelic researcher.

GÜL: Wow. I mean, I’m glad that that is an easy way to remember who I am. But I’m hoping that by the end of this podcast, you can start to think of me as the critical periods lady. Because the octopus work is great, and it’s very exciting, but I really think the transformative work of the lab is around this notion that psychedelics might be the master key for unlocking critical periods.

LEAH: Gül has long been fascinated by the interaction between drugs and consciousness, but she got her start when psychedelic research was still pretty taboo. It wasn’t until about ten years ago, with the publication of the octopus genome, that she found a path to studying the relationship between neurotransmitters, drugs, and social behavior.

LEAH: You saw the publication of that octopus genome and you thought that—that’s my entry point. Why?

GÜL: Now, octopuses and humans are separated from each other by over 650 million years ago. What that means is that, since we had a last common ancestor with octopuses, dinosaurs have come and gone, right? So it’s a really long time ago. And we’re much more closely related to a sea urchin, say, than we are to an octopus, which, you know, I think surprises a lot of people. But the, the insight there is that even though they are separated by all this evolutionary history, even though their brains look nothing like each other, right—like a mammalian brain has a cortex, it has a subcortical area, limbic system, it has things like the amygdala and the nucleus accumbens, and the default mode network—brain regions that people were talking about as being important for the effects of psychedelics. And instead an octopus doesn’t have any of those brain regions. Its brain looks more like a slug’s brain than it does like our brain. It’s a sort of massively parallel distributed neural network that has as many neurons outside of the central brain as inside the central brain, right? It’s just organized totally differently. And yet, when you give them MDMA, it produces the same prosocial effects in octopuses as it does in mammals. 

LEAH: Ok, so what does that mean, the fact that octopuses and humans can get high on the same stuff?

GÜL: What it really points to is that the similarity at the molecular level is what accounts for these behavioral differences, and that once the molecules are in place, they can use any sort of anatomical toolset to instantiate that behavior. And all that anatomy and circuit mapping is sort of an accident of evolutionary history rather than the sort of the core, true mechanism.

LEAH: So in other words, it’s not the fact that we have this particular brain region that allows us to be social in a particular way but just that our neurons and structures interact with chemicals in the same way as any other organism with those would?

GÜL: Yeah, and that those brain regions, they are necessary, and they may even be sufficient, but they’re only one instantiation. In other words, a different animal might have a different toolkit of brain parts and still be able to build that same social behavior out of those molecules. I think that’s why so many people were blown away by this experiment, because it really challenged this underlying assumption that in order to build complex behaviors, in order to do really interesting things, you needed a cortex and you needed extra layers of cortex and you needed essentially a mammalian type template. And that just seems to be wrong.

LEAH: Octopuses are intelligent, are revered, maybe more than your average invertebrate or other non-human, non-mammalian species. So you chose a fairly intelligent species, and you’re looking at psychedelics…I’m curious if that was challenging to get the support to actually bring this study to life?

GÜL: I want to tread carefully here because the truth is that I think that there’s a lot of hype around octopuses that gives people the wrong impression. Like, there are movies on streaming services that try and suggest that they’re like these cuddly animals that are just swimming around looking for a guy going through a divorce to give him a hug and save his life. And it’s just not true. So that movie is that beautiful fiction. Octopuses are viciously asocial. They are top predators in their habitat. They are in some ways, the type of—some people have made a lot about the fact that they have this theory of mind-like behavior, which some people believe is required for consciousness. But octopuses are sort of strange in that, although in mammals we’ve always assumed the theory of mind evolved because of the selection pressures of social living, in octopuses, it seems to be derived from the selection pressures imposed by hunting behaviors. And so it’s a cognitive empathy, not an emotional empathy. And it turns out that those two types of processes are controlled by different subtypes of neurons and neural circuits. And cognitive empathy is sort of what psychopaths are really good at—it’s what you need to play poker. And so I like to sort of, a little bit tone down the anthropomorphized notion of what makes an octopus special by reminding people that in many ways they should be thought of as very effective hunters that are using this theory of mind strategy to manipulate their environment to get an advantage in taking down a shrimp if that’s what they’re hunting.

LEAH: So then getting back to the experiment, what happens when you give a very antisocial, very effective killer MDMA?

GÜL: Well, so normally, the species that we were looking at in that experiment was octopus Octopus bimaculoides—based on the, just a rough back of the envelope calculation based on neuron number, they’re probably something between a dog and a cat in terms of intelligence. Octopus bimaculoides, like almost all of the 300 or so known species of octopus, is aggressively asocial. So if you put them in another tank with another animal, they will attack and kill them. You know, some species of octopus are a little less aggressively asocial, so they’ll tolerate another animal, but that’s not really social, that’s just social tolerance, which is different than a true social behavior. 

Before MDMA, they were, as expected, avoiding the part of the tank that had the other octopus in it. And after MDMA, they spent significantly—a greater percentage of their time in the side of the tank that had the other octopus in it. 

We also observed that as soon as they got to the MDMA dose that is in the rough ballpark of what is effective in humans, they started doing behaviors that were relaxing their posture, they seemed to sort of reach their arms over the other octopus’s flowerpot and kind of, like, draped their arms all over it. One octopus spent a significant amount of time playing with the little airstone that we had lowered into the tank to aerate it. Another one was doing sort of backflips over the barrier between the different chambers. So they seemed to be—just to anthropomorphize—sort of dancing and playing. And so, we can’t really say that much about those behaviors until we do a more rigorous sort of quantification, but just anecdotally, it did seem like they had a pretty robust behavioral response to the to the drug that was similar, at least on the face of it to what it looks like in humans.

LEAH: I just want to pause and apologize for crushing any romanticized ideas about octopuses as sweet cuddly creatures desperate for human love…and also acknowledge that that was a LOT of octopus talk for an episode about the human brain. But I promise it’s all related. Because after Gül published her research about octopuses, she started to wonder how MDMA might actually serve a therapeutic purpose, by manipulating the brain and reopening a precious window of time for learning new social behaviors. This window, also known as a critical period, is something that scientists have been fascinated with for nearly a century but has remained shrouded in mystery. So to start… what even is a critical period?

GÜL: A critical period is a window of time when the brain is extremely sensitive to its environment and can form lasting long lasting memories. And so, you know, people have known about critical periods since 1935, when Conrad Lorenz first described it, you know, we’ve studied them in plasticity, language learning, touch motor learning. All kinds of different brain functions seem to be constrained by learning that is, you know, restricted to these, these periods of time, usually during development. And we discovered a new one, and that new one was this critical period for social reward learning, which we think is basically why you know, teenagers are so much more susceptible to peer pressure, why when you move to a new country, you might feel a little bit socially awkward because you didn’t learn the social rules of that culture, you learned the social rules of your own culture and, and you’re not able to pick them up as easily anymore because that window of time is closed. 

And so when we first started working on this critical period, we focused on MDMA—and this is the 2019 Nature paper—we focused on MDMA because it had these prosocial effects, these acute prosocial effects that we had discovered in the octopus, but others had shown in rats and mice as well, and humans as a matter of fact. And so we thought that this prosocial effect was the reason why MDMA was able to reopen this critical period for social learning. But in that paper, one of the first insights that we had that maybe that view was wrong, came from the fact that if we gave MDMA in a social context, then it reopened the social critical period, but if we gave MDMA in an isolated context, it did not.

LEAH: In other words, it wasn’t just the ecstasy alone that seemed to trigger a social response, but the combination of that with a social environment. So that cliche about set and setting? Turns out the hippies were onto something.

GÜL: The clinicians have noticed this as well, like you can’t take MDMA, and go to a rave and expect to cure your PTSD, you really need to pair that MDMA with the right context, in the case of PTSD, sort of an inner directed trip, with a focus on kind of unlocking the set of habits and behaviors that you have developed around protecting yourself during that traumatic event that were, you know, once adaptive, but are no longer adaptive, now that that traumatic event is over. But it also sort of put in our head like, Well, maybe if it’s not true that you need this prosocial effect of MDMA, to unlock critical periods, maybe other psychedelics which are not, you know, sort of acutely prosocial in the way that MDMA is, right? Like, nobody’s doing a 30 person cuddle puddle on LSD. People are staring at a chair, and like, looking at the molecules floating in and out of space, right? We wanted to know, is this ability to reopen critical periods, something that generalizes across psychedelics, whether they have this acute prosocial effect or not? And amazingly, it does. So it doesn’t matter whether it’s ketamine, Ibogaine, LSD, psilocybin—they all reopen the critical period for social reward learning. 

LEAH: Fascinating. Okay, so we’re able to use psychedelics to reopen these critical periods. Do we understand what’s happening on a physiological level?

GÜL: So we’re just at the beginning of unlocking that we have some beginnings of the mechanism. Neuroscientists have been obsessed with critical periods for almost 100 years. You know, there have been three Nobel Prizes, 7,000 papers looking at the mechanisms underlying critical periods, and that’s because neuroscientists have had this intuition for a long time, that the reason that we’re so crummy at curing diseases of the brain is because by the time we intervene, the relevant critical period has closed. And so we’ve had this intuition that if we could find a master key for unlocking them, that we could treat all kinds of other diseases of the brain. And so in that journey, in looking for those mechanisms, three main classes of mechanism have emerged. 

LEAH: I won’t get too deep into the weeds here, but suffice it to say that Gül and her team focused on two mechanisms. First, the extracellular matrix, which she describes as “the glue between the neurons and the glia” and which plays a role in locking learning and memory into place as people mature into adulthood. The second is “metaplasticity,” which is like how much you can manipulate synaptic plasticity. Or, in my crude language, the degree of re-spongification you can do to a brain.

GÜL: And actually, what we found is that psychedelics seem to restore metaplasticity, like in a juvenile brain. And then the other major mechanism is that it seems to be, although we’re still working on the details, that the psychedelics seem to break down this extracellular matrix. 

LEAH: And what did that look like in—it was mice that you were studying, right? 

GÜL: So normally oxytocin plasticity is pretty easy to induce—it’s robust in juveniles. But as the animals get older, you basically can’t induce it anymore. But what psychedelics do is they bring it back. So in adults, suddenly oxytocin is able to induce plasticity again. It was interesting, because, you know, there were some people who were saying things like, “Oh, psychedelics are ‘psychoplastogens,’” which is a term that I hate, because it turns out that there are lots of drugs that induce plasticity directly. So most drugs of abuse like heroin, cocaine, alcohol, nicotine, these are all robust psychoactive drugs that induce plasticity, so they are more deserving of the of the name psychoplastogen than psychedelics are because it turns out that psychedelics don’t really, in adult brain tissue, they don’t induce plasticity by themselves, they instead restore the ability of other stimuli to induce plasticity. And this matters because, you know, most psychedelic drugs, their abuse liability is very low, especially compared to heroin and cocaine and other drugs of abuse.

And so, you know, it’s really important to kind of be able to differentiate these different mechanisms, because even though there’s some mechanistic overlap between the notion of a critical period and the notion of plasticity, you know, the drugs of abuse are really the ones that are engaging in this hyperplasticity, whereas psychedelics are really seeming to induce more of this metaplasticity. Being able to differentiate those two things, you know, it’s going to come down to drugs that are being sought as useful therapeutics for curing drug addiction versus drugs that are actually addictive drugs themselves, right? 

LEAH: The effect that, like, heroin or cocaine is having is not—it seems like what you’re saying is, it’s not inducing a similar kind of opening of the critical period.

GÜL: Right. So cocaine does not reopen the critical period. Psychedelics do. Drugs of abuse, when you take them, you know, you’re almost instantaneously learning that cocaine tastes good here, it tastes good there, it tastes good whether I’m hungry, whether I’m thirsty, whether I’m tired, it’s just good, right? And that, that ability to sort of, almost instantaneously learn the reward value of that drug is, is, you know, what we think of when we think of hyperplasticity, so you’re inducing a memory rather than changing the ability to create new memories.

LEAH: So that seems to lead really nicely into the idea of psychedelic therapeutics, where they can be used within a curated context to learn or unlearn or relearn something in specific. Can you talk to me a little bit about what the applications are, and what the kind of the set and setting required for that to work?

GÜL: Right now we are in, in the middle of what I would call a Tesla versus Edison kind of debate about this. And, really, psychedelics are challenging roughly 50 years worth of dogma around how to treat neuropsychiatric disease, right? So for the last 50 or so years, we’ve been operating under the assumption that, you know, if you have depression, it’s because you have a biochemical imbalance in serotonin and all we have to do to fix your depression is to fix that imbalance. And so we give drugs like Prozac, which are selective serotonin reuptake inhibitors, which in theory are increasing the amount of serotonin in the synapse and fixing that imbalance right. And similarly, the working model on addiction is, if you’re addicted, your imbalance is in dopamine, if you’re in pain, your imbalance is in opioids. So basically this biochemical imbalance model is the pervasive model. 

Unfortunately, it doesn’t work that well. I think that there were a handful of cases of severe genetic causes of depression, that it seems to help people. But by and large, I think people are frustrated by the fact that, you know, these drugs are sort of medicalizing people for life, they’re blunting their ability to have the normal range of emotional responses to their world. And in terms of addiction they’re mostly a total abject failure. And then you’ve got the psychedelics, right? And so the psychedelics are coming in. And unlike some of these other approaches, what the psychedelics seem to be doing is saying, look, if you give it in the right context, if people have like a big epiphany and understand the source of their trauma, their heroin addiction, their depression, then what you’re getting is a sort of transformation, a cognitive flexibility that allows people to reformulate those painful events and create new habits that are more adaptive to the current circumstances. And that context that you give them in seems to really matter. And the best evidence that we have that context matters is that if we compare the clinical trials—which were published in 2021 and 2023 and funded by the MAPS PBC, now Lykos—that those clinical trials of MDMA-assisted psychotherapy for PTSD showed a nearly doubling of the effectiveness compared to psychotherapy alone, right? In contrast, if you look at the clinical trials for psilocybin for depression that were funded by Compass Pathways, another company, that clinical trial, there, they said, you know, “forget that therapy, what we really care about, we’re going to treat psilocybin like it’s just a next generation SSRI.” And when we do that, psilocybin basically was no different than SSRIs. And in fact, that clinical trial is considered a failure because in order to get psilocybin approved as a new therapy, it has to do better than existing therapies, right? What this has kind of done to the field is say, “Okay, we got the biochemical imbalance model, which is the one that we’ve been working off of, for the last 50 years. And now, maybe we need to rethink that and think of it more as a learning model, that is not correcting a biochemical imbalance but allowing people to learn from their environment, again, in a new way.” 

LEAH: It seems that if we’re, if we’re reopening these critical periods, and allowing kind of more plasticity and learning again, that we’re also opening ourselves up to learning negative things. I’m curious how powerful you think this might be, how much we may be capable of learning within that metaplastic period, that critical period, that could be both positive for us or negative. What is the extent of that?

GÜL: With this insight about, you know, critical periods, I think that as you, as you suggest, really, it’s a number of things all at once. So one, it’s, wow, this is a, you know, we can use this a lot more than we thought we could. So, we’re very interested in and looking at motor learning after stroke. I can imagine also for learning languages, people who had had cochlear implants who want to learn to speak after their implants there’s a lot of positive things. I think it also speaks to a little bit of a missed opportunity, since we’re mostly all the clinical trials to date have focused on the drug itself and not on the weeks afterwards, where the critical period seems to stay open. And the duration of how long that critical period stays open is proportional to the duration of the trip, of the acute subjective effects of the psychedelic. So I think that tells us that all these drug companies out there who are trying to engineer out the trip might actually be engineering out the effective part of the drug—this critical period reopening. 

LEAH: This is an important point. Although it’s tempting to create a version of LSD or shrooms that has the mind-opening effects without the full psychedelic experience—something companies like Delix Therapeutics are actively working on right now—it turns out that whatever’s creating that hallucinogenic trip might be a necessary part of the therapeutic process.

GÜL: And then on the sort of negative side of things. I mean, we already have anecdotal evidence from the drug use in the 60s, right? These drugs, if they’re reopening critical periods, it certainly explains why it was that someone like Charles Manson, who you could think of as a very bad context a psychopath context, is taking these hippies feeding them a bunch of LSD, and then sort of indoctrinating them into his cult for weeks on end, and then turning people who were hippies into, you know, murderers so that they could achieve helter skelter and save the world, according to Charles Manson, right? And so I think this is both the opportunity and the danger. And I think, because of this mechanistic insight, we really need to be rethinking some of the sort of laxness we’ve taken towards, “oh, they’re miracle drugs, they’ll cure everything.” When really, they’re really very powerful medicines that are doing something pretty profound to the brain, and that we need to use them with care. 

LEAH: It’s making me think about how a little bit in a slightly different way about the dangers of psychedelics. For people who use psychedelics recreationally, I think one of the dangers that sometimes we talk about is hurting our brains, or doing something dangerous, or making bad decisions, whatever jumping off of a—I don’t know—jumping off of a car. But it seems like there’s another potential danger, which is taking psychedelics going out to a party or a music festival or something like that, and having an experience that, during this kind of more mentally plastic, malleable state, having an extremely positive or potentially extremely negative experience that could that we could kind of absorb really deeply. I’m curious if that’s true.

GÜL: The 2023 paper that we published last summer, what we showed is that, for drugs like MDMA and psilocybin, the critical period stays open for about two weeks after the trip wears off, right? And so ibogaine is more than a month, LSD, it’s like three weeks, right. And these are mouse times. So in humans, it’s at least that, probably more. And so you stay in this vulnerable state for a really long time, and our prediction would be that yes, indeed, during that vulnerable time, just like we don’t let children watch, you know, certain types of violent films, why we protect them against certain types of experiences, because we don’t want to overwhelm them while they are in this vulnerable state of susceptibility and receptivity, right? We want to provide them with a safe, nurturing environment, right? I think, basically, when we’re taking psychedelics, this is what we’re doing to people. We’re restoring them to that childlike state of vulnerability. And yes, I do think that if you’re, let’s say, you’re in an abusive relationship, and you take psychedelics to, you know, have some insight into your abuse and your trauma, and then after the trip is over, you just go back to your abuser and continue to be abused, you’re potentially making the effects of that trauma, that much worse, right? 

That is definitely why—think that just like after a heart attack, your heart tissue is much more vulnerable to what’s called reperfusion injury. I think that we should sort of start to think about psychedelics in this way.

LEAH: And it feels like it’s happening really fast. And it just, you know, it makes me wonder where we’re going and what will come of it.

GÜL: Yeah, I mean, it does feel like it’s happening fast, although not really that fast. I mean, I started working on this ten years ago, and, you know, and I’ve been aware of them for, you know, 30 years, since I first started studying neuroscience. The way that I think of it, I’ve heard some companies say, “Oh, well, you know, the way the solution is to democratize these medicines by getting rid of the psychedelic side effects, side effects, and then, you know, engineering that out and then making these pills, just like we give out SSRIs.” And I would just say that SSRIs are not totally benign. I have a friend who studies emotion, and, you know, she said pain, emotional pain is an adaptive signal to change something in your environment. And so to think of SSRIs as blunting your ability to respond adaptively to painful things in your environment like that is, is probably a mistake, right? You would never in a million years say to a stroke patient, “Oh, we cleaned out your blood clot. But, you know, physical therapy, that’s just pie in the sky, that’s too expensive, not available to you. Sorry, no physical therapy for you.” That’s ludicrous.

LEAH: I was thinking about the comparison with physical therapy. My mom is a physical therapist. And she’s always trying to get people to start with physical therapy and see how their bodies can learn how to heal themselves, rather than just having this kind of intervention. So I was thinking about that, that kind of potential parallel there, I don’t know how far it extends—the idea of kind of retraining ourselves instead of just replacing a part or chemically rebalancing something.

GÜL: Yeah, I mean, there are certainly cases, right, where, you know, it doesn’t make a lot of sense to do the physical therapy without removing a blood clot first, right, without removing the arterial clot in your heart, right? Like, it just doesn’t make sense to give the one without the other. And I actually think that’s true for psychedelics as well. So, we’re working on right now looking at how we might use these drugs in different cases. And, you know, we are very focused on stroke, motor learning after stroke, because after you have a stroke, there’s this window of time, for about two months after the stroke where you can learn a lot, you can retrain, but then it closes, and no amount of extra physical therapy is going to change your clinical outcome. And so, we are hopeful that we can reopen this critical period with psychedelics and that we can pair psychedelics with that physical therapy and get more learning and memory—and more restoration of motor function. But we don’t think that we should just give psychedelics and tell people to go on home. We think that we really do want to pair it with that therapy.

I also don’t think that it will work, for example, to just give the psychedelics and expect it, by themselves, you know restore the biochemical imbalance in things like autism and that there, we’re gonna want to do the correction of whatever underlying—if it’s a genetic cause of autism, like we study—underlying biochemical imbalance that’s caused by the genetic mutation, and then pair that with the psychedelic. The analogy I like to use is that critical periods probably the classic example of critical periods is that if you’re born with cataracts in both eyes, and you don’t have them removed by the time you’re about five years old, then even if you physically remove them, because the relevant critical period has closed, you will not be able to restore vision, right? Even though the physical impediment to light has been removed, the brain can’t rewire itself, so you will never see again. And so the dream there is that you could give psychedelics and you could reopen. But again, in somebody who has bilateral cataracts if you don’t—if you give psychedelics, but then you don’t remove the cataracts, you still haven’t solved the problem. You really have to pair this intervention that corrects the underlying problem with the intervention that enables relearning rewiring, plasticity, degradation of the extracellular matrix, all of these things, to really make that work together.

LEAH: So lastly, I’m curious for you, what, what you feel are the most exciting kind of questions that you’re trying to answer now. Or perhaps the most exciting applications of the research that you’re doing.

GÜL: The stroke project is something that really has my rapt attention because there’s so many people who’ve had a stroke—roughly 500,000 people a year who are not able to recover full function. And that’s just in the United States, right? That’s a lot of people who are, who are sort of suffering and there’s really nothing that we can offer them. So that is one place that I’m really focusing a lot of my energy on trying to test this idea that we can reopen the critical period and help those patients out. 

Sort of the next next thing after that is to really go back to first principles, trying to understand, why do we have critical periods? Why do they close? And why do we have ready-made mechanisms for reopening them? And for me, being able to ask these sort of high level, big questions, having an evolutionarily distant species, like an octopus to compare solutions to, really offers a unique insight. Do octopuses have critical periods? We don’t know. Maybe they don’t. They’re able to regenerate their arms after they lose them, so maybe it doesn’t make sense to close down their ability to learn from new motor programs later in life because they’re having to regrow arms. Or maybe they do, but they don’t use the same mechanisms. So we’ve been focused on extracellular matrix and metaplasticity, but there are other ideas out there about what makes octopuses, or cephalopods in general, sort of so behaviorally flexible, that have to do with unique ways that they process RNA and DNA and enables them to learn a lot of behavioral repertoire, in possibly a totally new way that we haven’t been thinking about when we thought about critical periods. So for me, being able to look at critical periods and use the psychedelics as tools for understanding these broad principles of, why do they exist, why did they close, and why can we reopen them, is sort of the next frontier.

LEAH: Is the answering why, just purely out of this kind of pure scientific curiosity? Or is there a reason for wanting to know the why?

GÜL: I mean, you’re asking me a “why” question about why!

LEAH: I know. Well, you brought up metaplasticity so…

GÜL: For me, science is an epistemology. It’s a method for asking those “why” questions about the world. And for me, every single thing that I say in science is provisional, and it’s a working model until somebody else says, “Aha! But what about octopuses?” Or what about whatever? That, you know, forces me to challenge, that challenge is my model and says, “Oh, this model used to work. But now we have this one other piece of information. And now it doesn’t quite work, let’s restructure it in a way that can incorporate this new information.” And so it’s this constant process of why why why why, why, why. 

The thing is that I think that all scientists, just on some level, have that story of when they were a kid, and they just got fascinated and started running down a rabbit hole of, you know, why why, why, why, why, and haven’t stopped running. Right? And I do think that that sort of ability to stay in that mode of running down a dream or wandering aimlessly and just following something without having a specific purpose more just a creative curiosity, “why” type of approach is, is kind of what it’s like to be a child. And for scientists that can hang on to that with their scientific questions it sort of yeah, getting to spend your whole adult life, still tapping into that childlike joy and wonder for the universe. 

LEAH: Well, thank you so much. I think that’s a really good place to leave off. I’m so grateful for your time, this has been fascinating.

GÜL: Thank you very much for having me.

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LEAH: This is The Edge, brought to you by California magazine and the Cal Alumni Association. I’m Leah Worthington. This episode was produced by Coby McDonald, with support from Pat Joseph and Nathalia Alcantara. Special thanks to Gül Dölen. Original music by Mogli Maureal. Additional music from Blue Dot Sessions.

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