The Joy of Why - Can Psychedelics Improve Mental Health?

Episode Date: June 6, 2024

During traumatic periods and their aftermath, our brains can fall into habitual ways of thinking that may be helpful in the short run but become maladaptive years later. For the brain to read...just to new situations later in life, it needs to be restored to the malleable state it was in when the habits first formed. That is exactly what Gül Dölen, a neuroscientist and psychiatric researcher at the University of California, Berkeley, is working toward in her lab. What is her surprising tool? Psychedelics.  In this episode, Dölen shares with co-host Janna Levin the surprising potential of psychedelics to change the lives of those grappling with addiction, depression and post-traumatic stress.

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Starting point is 00:00:00 Hello, I'm Brian Cox. I'm Robin Ince, and this is the Infinite Monkey Cage trailer for our brand new series. We've got mummies, we've got magic, we've got asteroids. Mummies, magic and asteroids. What's the link? That it was an asteroid that magically went over the world that led to Imhotep the mummy coming back to life? That's correct. I thought it would be weird, scientific as ever. But the most important thing to know is that we are going to deal with the biggest scientific question we finally ask.
Starting point is 00:00:25 What is better, cats or dogs? Listen wherever you get your podcasts. Welcome to the Joy of Why. This is Jana Levin. On June 4th, an advisory panel for the Federal Drug Administration recommended against approving the use of the psychedelic drug MDMA as a treatment for post-traumatic stress disorder. Various concerns, some about safety, overshadowed the demonstrable value of the drug in the opinion of the panel. The path to approval for drug therapies is notoriously fraught with profound complexities, a high bar on proof in clinical trials, the medical injunction to do no harm, as well
Starting point is 00:01:07 as social and political nuances. But what's the fundamental neuroscience behind the news story? Why are so many psychiatric researchers enthusiastic about the promise of psychedelics? We happened to take on this subject a few weeks ago with neuroscientist Gould Dolan. Here is that episode. New drug leads can come from practically anywhere. Penicillin's discovery was spurred from mold spores that accidentally landed in a petri dish. Cancer treatments can be dredged from the bottom of the sea,
Starting point is 00:01:48 and synthetic antibodies can now be engineered from scratch. But there's a class of drugs that mainstream medicine has generally overlooked that could prove life-changing for many people facing addiction, depression, post-traumatic stress, if scientists embrace the potential power of psychedelics. I'm Jana Levin, and this is The Joy of Why, a podcast from Quantum Magazine, where I take turns with my co-host, Steve Strogatz, exploring some of the most exciting research in math and science today.
Starting point is 00:02:32 most exciting research in math and science today. Here to take us on a trip, though a very scientific one, mind you, into the latest research on psychedelics is Gould Dolan, professor and Parsons Endowed Chair of Psychology, Psychedelics, and Ne and neuroscience at the University of California, Berkeley. Gould holds an MD and PhD from Brown University and MIT and completed her postdoc at Stanford University. Her research interrogates the neural circuitry and biological mechanisms underlying behavior with a focus on the causes of and potential treatments for what Gould calls diseases of the social brain. Gould, thanks so much for joining us. Thank you so much for having me. It's a real pleasure. Now, your lab recently published a truly fascinating paper in the journal Nature
Starting point is 00:03:15 that suggests psychedelics could be valuable in treating neuropsychiatric diseases. And I want to get into the details of this research, but first I think it's important that we just ask the basics, such as what are psychedelics and how do you define them, possibly differently than some of your peers? Yeah. So psychedelics are a broad class of drugs that, generally speaking, are defined as inducing an altered state of consciousness. And this altered state of consciousness is so different from your everyday walking around kind of consciousness that people feel like they have an epiphany, they're experiencing the world in a totally different way.
Starting point is 00:03:58 And typically, this involves heightened sensory systems, heightened feelings, heightened smells, heightened emotions. And they're just radically different from your everyday experiences. Now, that's a pretty experiential definition. So there isn't a definition that's rooted in the actual compounds, for instance, or the mechanisms that they exploit to operate? So this is a little bit of an area of debate. The traditional view has been that psychedelics include compounds from all kinds of different drug classes, all kinds of different receptor binding, all kinds of subtle differences in the tone or the subjective quality of the psychedelic experience. tone or the subjective quality of the psychedelic experience. So hallucinogenic psychedelics tend to be in the tryptamine class that also bind to the serotonin 2A receptor, but there are also
Starting point is 00:04:54 psychedelics like MDMA, which bind to the serotonin transporter, and they are not really inducing hallucinations, but more what people have called empathogenic responses. Then there are psychedelics like ketamine and PCP, which bind to yet another kind of receptor, and they seem to induce dissociative type of psychedelic trips. And then there's the real weirdos like Ibogaine, which we don't even know which receptor they're really acting through. And they induce a totally different kind of trip, which people have classified as onirogenic. It's been a little bit of a debate because the chemists who have really been focused on the serotonin 2A receptor and the hallucinogenic subset of psychedelics really want to try and narrow
Starting point is 00:05:45 the definition around that one mechanism. And I think our research really challenges that view. And we've discovered five new properties of these compounds that are overlapping and violate the boundary of the serotonin 2A receptor as a classifier. boundary of the serotonin 2A receptor as a classifier. And this term onirogenic is about a dream state. Is that right? And that's somehow disambiguated from these ideas of dissociative. Yeah. So people who talk about the onirogenic state in Ibogaine will talk about wandering around as if in a dream. Some people will talk about seeing their life as a series of snapshots playing backwards in time. All of these descriptions are people's attempt to describe the ineffable, the experience being so alien that it's hard to put words to it. If they sound kind of floofy and not particularly precise,
Starting point is 00:06:46 that's part of the experience. People are reporting on something that they find difficult to even bring up in words. So we're talking about things that people here in Western cultures have experimented with, but of course, in cultures all over the world, there's a rich history rooted in spiritualism and myth-making and healing. Now, you're a very serious biological researcher and acclaimed scientist. What leads you from this kind of canonical scientist Western mind to get into the sphere of psychedelic research? I think especially now that psychedelics have become acceptable as
Starting point is 00:07:27 research topics, you might find the number of neuroscientists who have always been interested in psychedelics to be larger than you might expect. It's the dream of a serious neuroscientist to be able to get these big psychological terms, consciousness, ego, down to a single molecule or a single methyl group. I had already had that sort of insight about psychedelics and consciousness when I was in college. I went to Duke and I had designed my own major. It was comparative perspectives on the mind. And I had this idea that if we're going to ask those big questions, we're going to need some kind of breakthrough that's going to allow us to correlate the molecular mechanism to these bigger psychological phenomenon. And the first time I had this insight that this is the way forward was when I saw the
Starting point is 00:08:17 serotonin molecule right next to the LSD molecule. And the similarity between them really convinced me that when people are having these altered states of consciousness on psychedelics, what they're really experiencing is one molecule binding to another molecule. And that to me was profound because it said everything that we think of as consciousness, everything that we think of as spirituality, everything that we think of as ego, everything that we think of as vision is just molecules. But at that time, around 1997, 98, studying psychedelics was not really considered serious. It was a fringe topic. And so I put it on the back burner.
Starting point is 00:09:00 And I really didn't go back to it until I started my own lab about 10 years ago at Johns Hopkins. Now, your work on psychedelics eventually led you to the insight that, among other things, the drugs seem to affect what behavioral biologists call critical periods in brain development. I'd love to hear your brief explanation for our audience on what a critical period is and why it's so important. Yeah. So critical periods are a phenomenon that was described in 1935 by Conrad Lorenz. And the first critical period he described was imprinting behavior in snow geese, where
Starting point is 00:09:40 right after hatching, the baby birds will form a long-lasting attachment to whatever is moving around in their environment. And typically, this would be their mother. But if their mother isn't there, if it's another animal, if it's a crazy scientist, then they'll form that attachment to that other moving object. And that 48 hours during which they are incredibly sensitive to anything moving around in their environment and they're able to form this long-lasting learned attachment is what Conrad Lorenz calls the critical period. Since then, we've discovered literally dozens of other critical periods. Probably most people will be familiar with the critical period for language. So it's
Starting point is 00:10:23 much easier to learn a language when you're a kid. If you try and learn a second language as an adult, you're always going to have an accent. It's really hard to learn. And that's because there's a critical period for language learning. And as an adult, you're just no longer in that window anymore. Now, why is it valuable that psychedelics reopen critical periods in adulthood? I think neuroscientists have had the insight for almost 100 years that the ability to reopen critical periods would radically because there just isn't enough space in the genome to encode every single behavior as a gene. And so instead, what's encoded is the ability to learn from your environment. And so most of our behavior is learned behavior.
Starting point is 00:11:16 And it has to be learned at the right time in the right order and paying attention to the right stimuli. And that's what the critical periods are. They're just the ability to learn. So this ability to learn from your environment is really what we think is responsible for the intense behavioral complexity of our behaviors that we're able to exist in. And it's the reason why you can have Turkish parents, for example, in my case, but be fluent in English if you were born and raised in the United States, right? It's whatever environment you're in, you adapt accordingly. As opposed to having Turkish genetically coded.
Starting point is 00:11:56 Right, exactly. And passed down genetically. Exactly. That would be somewhat inconvenient, right? But what that also means is those critical periods close, and we think they close because it's really hard to spend your life in that open state. I don't know about you. Being a teenager was hard for me. I found it to be very stressful to constantly care what the mean girls thought of me and whether I was wearing the right exact shade of acid wash jeans. And it's just emotionally draining to constantly be learning and aware and sensitive to your environment. And so as we get older, we tend to do things by habit.
Starting point is 00:12:34 We simplify the problems around us by just doing things by rote memorization and just proceeding efficiently with our habits. proceeding efficiently with our habits. And so what neuroscientists have appreciated for a long time is that when we have a disease of the brain, when we have an injury to the brain, we are terrible at being able to cure those diseases of the brain because by the time we intervene, the relevant critical period has already closed. So since we're talking about mental health, let's use the example of PTSD. If you had an injury or a traumatic event that happened when you were a child, and then that critical period relevant to the PTSD is closed, then the therapy that we do later on in life is minimally effective in its ability to
Starting point is 00:13:27 change the memories around that trauma. Fascinating. A hundred years of psychoanalysis, right? More, more than that. And people start to roll around to the idea that without some medical or biological assistance, psychoanalysis alone, at least, might not move the needle. Right. I think that especially with psychiatric illness, we have a tendency to think of it as all feelings and not really talk about the brain so much. But I just want to give a classic example of how reopening critical periods is so important for the brain. There's a critical period for vision and kids who were born with cataracts in both eyes, if they don't have those cataracts removed by say age five, then even if you remove them, even though the physical barrier to light
Starting point is 00:14:20 getting to the brain has been removed, those people will be blind forever because the brain is not able to make the necessary rearrangements to the visual circuitry to interpret it and receive that information. So that's because there's a critical period. And if we could reopen that critical period, then you could remove the cataracts later on in life. And so what we're imagining is going on with psychedelic-assisted psychotherapy based on our results is that the psychotherapy is the removing of the cataracts, right?
Starting point is 00:14:54 It's the intervention. It's the thing that matters. But if the intervention is going to have any impact on the brain, then the brain needs to be restored to that malleable state where it can adjust to the new conditions. Fascinating. Now, you're actually studying the biological opening and closing of the critical period in a lab setting. And I'm curious, what are the techniques you need to exploit to be able to do that? We took three approaches to understanding the critical period.
Starting point is 00:15:26 So first we had to define the critical period. And in this case, we defined it using a behavioral assay. Then we used electrophysiology to find a neural correlate of that behavioral change. And then we used molecular biology and RNA sequencing to identify a molecular correlate of that change that corresponds to the critical period opening. And so we took those three approaches because we knew that we wanted to understand not just the behavioral change that happens, but also get down to the electrical signature and the molecular signature so that we could compare our critical period to other critical periods that people had described previously. And you did a study, I believe it was 2019, using some of these methods where you specifically
Starting point is 00:16:22 looked at MDMA, sometimes referred to as ecstasy in colloquial terms, and you showed it was able to open a critical period. Can you tell me a little bit more about that study? Yeah. So when we started that study, we really weren't thinking that psychedelics were the master key for opening critical periods. We were focused on a critical period that was all about peer social reward learning. So very similar to the Conrad Lorenz critical period, but instead of attachment to mom, it was attachment to peers in the social group. So when we did the 2019 study, we were really focused on MDMA being special and different from other psychedelics because it has this uniquely pro-social quality, right? So we knew from studies in humans and from Alexander Shulgin's work that MDMA makes people
Starting point is 00:17:13 want to hug each other. The 60-person cuddle puddles at raves. It's just very special and unique in making people want to reach out and be social. And so in that study, what we were able to show is that if we gave MDMA and then we waited for 48 hours, what we were able to do is restore the ability to learn from your social environment in adults back to the levels that we had seen in juveniles. And we thought at the time that this could account for some of the most important features of the human clinical trials of MDMA-assisted psychotherapy for PTSD, namely that patients were talking about how on MDMA and afterwards, they felt like they opened up their ability to trust people, trust themselves, love themselves, form this therapeutic alliance with the psychotherapist.
Starting point is 00:18:07 And we thought it was just all about the social. One of the really important features of that paper was we were able to demonstrate that the context really mattered. If we gave MDMA in a social context, then it reopened the social critical period. But if we gave it in an isolation context, it did not open the social critical period. And actually, that experiment was the first clue that we might be wrong about the whole social part of this thing, right? That the social might just be a red herring, and that the context is what was driving which critical period was being open, not the sort of pro-social properties of MDMA per se. So if in your youth, when the
Starting point is 00:18:54 critical periods are naturally open, you have a traumatic experience and you learn to distrust people and then it closes in your whole life, You're in this loop. Here's an opportunity to reopen that critical period and learn a different association. It's very interesting. People say things like very few psychological problems are defects of understanding. Actually, there's something biologically paralyzed is what you're describing. Yeah. The way that I'm thinking about it now is that really in psychedelics and psychiatry, there is a Tesla versus Edison kind of debate happening between the biochemical imbalance model and the learning model, right? And so SSRIs and 40 years of big pharma has been really operating under the biochemical imbalance
Starting point is 00:19:46 model of neuropsychiatric disease that when you're depressed, it's just because you have an imbalance in serotonin and you give a pill and it just restores that imbalance. And then you just take the pill to keep your serotonin balanced and that's it, right? And what we're finding with the psychedelics and with this critical period idea, it's learning. And these things that people learned when they were traumatized were adaptive in the moment, right? It saved them in the moment. It allowed them to survive the traumatic event, but that learned pattern of behavior is no longer adaptive as they get older. And they need to adjust and adapt to their new circumstances and start to behave the way that they should if there isn't an immediate threat to their lives.
Starting point is 00:20:36 What psychedelics are showing is that actually you can give these drugs and if you pair them with psychotherapy, then you can create a change in the brain and the mind of the person that is durable and that only requires one, two, maybe three doses of the drug, and that once that change has happened because of whatever the drug is doing, the patient maintains that cured state for very long periods of time. And so I think this learning model is very powerful and is a challenge to the way that we've been operating and seeing neuropsychiatric disease. That's beautifully expressed. And I know that more recently, your lab has expanded to show that a variety of psychedelics, not just MDMA, can open this
Starting point is 00:21:27 critical period. Now, do these compounds achieve the same kind of downstream effect in the same ways neurochemically, biologically? Yeah. So first of all, we did find that we were wrong in the 2019 paper when we concluded that it was all about how MDMA is social and that's why it's able to open this social critical period. In the paper that was published this summer, the 2023 paper, we found that all of the psychedelics, whether they have this pro-social property or not, are able to reopen this critical period. social property or not are able to reopen this critical period. And this told us right off the bat that they have some shared mechanism that is enabling critical period reopening. And we wanted
Starting point is 00:22:13 to know what is that shared mechanism? LSD and psilocybin, their effects, both hallucinogenic and possibly other effects were being mediated by the serotonin 2A receptor, which was a favorite molecule for a bunch of reasons historically. But when we tested it, what we found is that the serotonin 2A receptor binding is important for some, but not all psychedelics. So it was a mechanism, but it wasn't the universal mechanism. And so we were on the hunt for that universal mechanism. And that's why we turned to the RNA sequencing studies and to look at the transcriptional profiles, because we noticed that the psychedelics were having these effects
Starting point is 00:22:57 that were lasting anywhere from 48 hours to a month after the trip had gone away. And so we knew that whatever change was happening at the cellular level that could be this common mechanism that goes across psychedelics, regardless of which receptor they're binding to, had to be something that was slow acting or encoded in a slower way. And so for us, transcription and translation of the DNA and RNA was an obvious candidate. So that's what we looked at. And when we did that analysis, we found if we didn't do the right control experiment, so if we just said drugs versus saline, then the signal we got was like, the brain is involved,
Starting point is 00:23:41 the brain is active. But when we controlled and we said, no, we want to know what the psychedelics are doing, but that cocaine isn't doing. Because cocaine is a different type of drug. It does cause a lot of the same kinds of plasticity effects that people have been trying to use as the explanation for what's happening with psychedelics. And yet it doesn't have the therapeutic properties of psychedelics. It's very different in terms of its abuse liability. Cocaine is a highly
Starting point is 00:24:10 addictive drug, and most psychedelics are not addictive. And so there's a number of important differences. So in our transcriptional profiling study, we really wanted to differentiate what are the psychedelics doing to synapses and to the brain that cocaine is not doing. And so when we use that exclusion criteria, then we came up with a list of genes that were being altered by psychedelics that were very interesting. Roughly 20% of them were genes that either encode components or regulators of the extracellular matrix, which was huge for us. And so what is the extracellular matrix? Yeah, so the extracellular matrix is essentially, you can think of it as the grout between the
Starting point is 00:24:57 synapses. It's the thing that's holding the synapses together. It's regulating the flow of molecules from one synapse to another. It's regulating how easily they can move around, how easily they can change shape, how easily they can insert and take out receptors. So it's regulating all kinds of stuff from the outside. And one of the reasons that we got so excited about this is that laying down of the extracellular matrix is a last step as critical periods close down. So once you got your memories, and once you want them to be stable and not very flexible, and you don't want to forget what your grandma's face looks like,
Starting point is 00:25:36 you lay down the extracellular matrix and it locks the memories into place. And so it was interesting to us that our transcriptional profiling data suggested that what the psychedelics seem to be doing is breaking up that extracellular matrix, possibly degrading it, removing it, enabling that flexibility. And our working model is that when it enables that flexibility, it enables metaplasticity to happen. And that's what enables these big changes in learning and memory. That's quite incredible. You can actually see it as a cellular level, what it means to open a critical period.
Starting point is 00:26:12 Yeah. We still have a long way to go to be able to say, okay, we reopened it and we saw that this molecule degraded, but I'm building on essentially a hundred years worth of mechanistic studies. Neuroscientists are obsessed with critical periods. There's something like 7,000 papers if you search critical period plus mechanism. We really have focused a lot on it. And there's a lot of evidence around this extracellular matrix idea. But what's interesting is that most of the extracellular matrix studies have been in the cortex. And they've been focused on critical periods for
Starting point is 00:26:45 vision and touch and hearing. And it was amazing to us that even though we were looking at this critical period around feelings and social and not in the cortex, in the reward center of the brain, we came up with the same types of molecules that was extraordinary to us and really leads us towards this idea that these drugs might be master keys for unlocking lots of critical periods. We'll be right back. Welcome back. You talked about PTSD and depression and what you've called diseases of the social brain. But you have also thought about this in terms of what may be genetically induced disorders like autism and how using psychedelics to open a critical period could help learn social cues that people with autism didn't learn in their youth. Is that still a promising avenue for research? Yeah, it's definitely where my heart is. But I just want to say that we should exercise some caution about how we think about autism, because some of the work that I did as a PhD student really suggested that this one type of autism,
Starting point is 00:28:11 Fragile X, which is the first identified most common cause of autism even now, is actually a problem with closing critical periods. And so my PhD work was the basis of a clinical trial for a drug that was essentially attempting to restore the biochemical imbalance for this genetic cause of autism by manipulating this receptor, the metabotropic glutamate receptor, MGLUAR. And those clinical trials, even though there was dozens of papers in preclinical studies in animals suggesting that this was a promising approach for treating autism, in human trials, that approach failed. And when it failed, I think a lot of the clinicians were like, that's because mice aren't humans, and we should have never gotten excited based on mouse studies to begin with.
Starting point is 00:28:55 But I actually took a very different view because I noticed that one of the major differences between the mouse studies and the human studies is that every single one of the mouse studies on which this idea was built was carried out very early in development. Whereas the human clinical trials, they intervened in adulthood. And so we hadn't discovered the social critical period at that time, but basically my working model on why those trials failed is that by the time we got around to intervening, the social critical period had failed. But the psychedelics could potentially be used as an adjunct to restore the ability to learn from the social environment once that biochemical imbalance has been corrected. And so that's how I'm imagining it. But before we jump to clinical
Starting point is 00:29:43 trials and start giving psychedelics, which we think are opening critical periods to patients whose critical periods didn't close properly in the first place, I think we want to do these studies in animals first and really get a handle on how safe they are for patients. Are there still a lot of social sigmas or operational barriers due to government restrictions, for instance, or limitations on what grants would be awarded in terms of pursuing psychedelic research. No, I think that era has come to a close.
Starting point is 00:30:16 When I started my lab 10 years ago, I remember applying for NIH grants and the program officers would just scoff at me. They would say, this is ridiculous. You're never going to see psychedelics in clinical practice. So why are you bothering trying to work on this? You should just work on oxytocin. And I was like, I think if we're right about this, it's a really big deal. It's something that neuroscience has been looking for a long time and I want to get credit for having had this idea 10 years ago, right? And so I was stubborn about it. And it took me 17 tries to try and get my first R01. And it was
Starting point is 00:30:52 brutal. And I almost quit several times, but I was stubborn and I saw the potential and I just didn't want to let it go. Now, I think it's almost the opposite problem. Like everybody is so excited about psychedelics. Every single neuroscientist who ever thought these are the key for understanding the big questions in neuroscience went home and applied for a DEA license and wants to work on psychedelics. And now I think the NIH is being inundated
Starting point is 00:31:18 with psychedelics grants. And I recently heard that the director of the NIMH said, I can't spend 70% of the budget on psychedelics. Like, come on, guys. So has this changed this newfound freedom to explore what used to be shunned practices? Has that allowed for a vision of what future of treatment might be like? I don't really see, for instance, when I go to my insurance policy that I can file a claim for psychedelic treatment. I think that's coming sooner than you might realize. I think that the FDA has to approve it
Starting point is 00:31:58 and then all of the insurance companies billing stuff, that stuff has to be worked out. But I would say that within five years or so, that'll be the case. I do think we still have a lot of work to do. So for example, as much as I've been telling you this story as if the biochemical imbalance versus the learning theory of psychedelics, the learning theory has won and nobody believes the biochemical imbalance theory, that's not true. In fact, there are a lot of chemists, especially in a lot of drug companies who are very invested in the idea that we want to engineer out the psychedelic side effects and turn these drugs into next generation SSRIs. And the way that they're selling that idea is to say, oh, we want to democratize
Starting point is 00:32:44 these. It just takes too long to go to a therapist for eight hours and have this long trip. We want something where we can just give a pill and they can go home and that'll make it easier access to people. And so they are really pushing hard on that. And there's a lot of money behind that. And there's a lot of historical precedent around taking that approach. I still think that there's a lot of opportunity to improve our interventions and our outcomes by focusing on the learning model. And if we're right about this critical period idea of what psychedelics are doing, then we need to be expanding out and thinking about all kinds of other diseases of the brain,
Starting point is 00:33:26 be expanding out and thinking about all kinds of other diseases of the brain, including things like stroke, neurological diseases that also have a learning period. And if we can do that, I think the benefit to the neuropsychiatric space will be a roadmap for understanding neuropsychiatric disease the way that we understand, say, cardiovascular disease. Now, where is your research headed? What on the scientific horizon looks really exciting for you? Our most important next step is to really test this idea that they are the master keys and that we can unlock lots of critical periods and that we can switch which critical period gets unlocked by switching the context. The next follow-up on that is how does the neuron know it's in the right context? How mechanistically does the brain know it's in the right context?
Starting point is 00:34:17 And how can we modify that and how can we enable switching between contexts so that we can get better at identifying the right memories to go after. We have some ideas based on what we know about learning and memory rules and coincidence detection. We have some candidates that we're looking at. So that's the next thing. And then we also had done the MDMA study in octopuses to show that this is an evolutionarily ancient property of this drug
Starting point is 00:34:45 and that it conserved across species that are separated from each other by 650 million years of evolution. We're still very much interested in the octopus because octopuses are so evolutionarily distant from us. Typically in neuroscience, what has been the tradition is that if you want to understand the human brain, you go for the brain that is either a human brain or something as closely related to the human brain as we can. And so people have studied monkeys to try and understand how the human brain functions. But there's this other idea out there, which actually was pioneered by J.Z. Young, that in order to understand how to build complex behavior from molecules, synapses, and circuits, you really should look for an animal that is maximally different from the human brain, but yet capable of doing those complex behaviors. And so he identified the octopus as the best example of that, where their brains are so different from ours. They look much more like a slug brain, and yet they're
Starting point is 00:35:51 capable of doing some pretty remarkable cognitive tasks. And so if we can understand the rules by comparing maximally different species, that'll give us great insight into what really matters for building these complex functions. And so I would very much like to use the octopus, try and figure out, do they have critical periods? Do they close? If they close, can they be reopened with psychedelics? And then what are the mechanisms that they're using? And we already have some hints that they may be using some of the same mechanisms, but they also have remarkable, extraordinarily different mechanisms for enabling this biological behavioral diversity in their repertoire of behaviors. Now, I have to ask, does an octopus on MDMA want to cuddle?
Starting point is 00:36:41 Yes, it does. Honestly, I didn't think it was going to work because whatever you might have seen on television, octopuses are viciously asocial and normally they will kill each other if you put them in a tank together. I just thought this is never going to work, but I also knew that they will suspend that vicious asociality when they're mating, and that all of their closely related cephalopod species are social. So it seemed to me that they might have the neural circuitry for encoding sociality, and that normally they just turn it off for whatever evolutionary adaptive reason, and that maybe MDMA could release that closure. And so that's what we did. Amazing.
Starting point is 00:37:28 Here at Joy of Why, we like to ask our guests the closing question. What aspect of your research brings you joy? For me, it's that little bit of heart racing that happens when you feel like you're on the precipice of something that doesn't make any sense at all. And you just go over and you're like, oh, no, it's not at all how I thought it was going to be. And that little bit of awe and fear that comes when you're just at the edge of discovering something big is my favorite part of doing this type of work. We've been speaking with the wonderful Ghul Dolan of UC Berkeley.
Starting point is 00:38:13 Ghul, it's been an absolute pleasure. Thank you very much. Thanks for joining us. The Joy of Why is a podcast from Quantum Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests, or other editorial decisions in this podcast or in Quantum Magazine. The Joy of Why is produced by PRX Productions. The production team is Caitlin Folds, Livia Brock, Genevieve Sponsler, and Merit Jacob. The executive producer of PRX Productions is Jocelyn Gonzalez.
Starting point is 00:39:05 Morgan Church and Edwin Ochoa provide additional assistance. From Quantum Magazine, John Rennie and Thomas Lin provided editorial guidance with support from Matt Karlstrom, Samuel Velasco, Nona Griffin, Arlene Santana, and Madison Goldberg. Our theme music is from APM Music. Julian Lin came up with the podcast name. The episode art is by Peter Greenwood, and our logo is by Jackie King and Christina Armitage. Special thanks to the Columbia Journalism School and Burt Odom-Reed at the Cornell Broadcast Studios. I'm your host,
Starting point is 00:39:47 Janna Levin. If you have any questions or comments for us, please email us at quanta at simonsfoundation.org. Thanks for listening. If you're enjoying The Joy of Why, and you're not already subscribed, hit the subscribe or follow button where you're listening. You can also leave a review for the show. It helps people find this podcast. From PRX.

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