Gül Dölen — Psychedelic Science and Radical Healing

30:13And I want to talk about the cautions also with this. And that the brain in that critical period, that open state is as the brain of a child is vulnerable and malleable. Yeah. And also that neuroplasticity, you know, I've been known to say when I first heard neuroscientists, because neuroplasticity, this is not a, this is a new knowledge, right? And I remember 20 years ago talking to people. It was kind of this new discovery. It was thrilling, right? To think, because when I grew up and we grew up in the 20th century, you learned that at some point the brain stopped developing. Like you're 16 or 18 or 25 and you're not really going to learn anything new or be anyone new.

30:53And that is out the window, right? But you also, that neuroplasticity also can go both ways. Right. So yeah, this gets thrown around a lot and especially the chemists are pushing this idea that psychedelics are inducing plasticity. And I ask people to really exercise caution around using that word because not all plasticity is good plasticity. We know that almost every drug of abuse, cocaine, heroin, fentanyl, alcohol, nicotine, they all induce massive amounts of plasticity. And this plasticity is hyperplasticity. And we think it's sort of the mechanism that enables those addictive drives to get locked in.

31:38And so going back to the language analogy, you know, you've taken a pill and instead of being able to, so with cocaine, for example, the language you learn is, I love cocaine. I love it here. I love it there. I love it everywhere. Right. And you just learn that one thing a lot. Right. And so that gets locked in and that gets encoded as hyperplasticity. In contrast, what psychedelics seem to be doing is not hyperplasticity. Instead, what they seem to be doing is enabling a change so that the same stimulus is able to induce plasticity more easily. And that is called metaplasticity, the plasticity of plasticity.

32:22And this is important because, you know, when we start really diving into the mechanism, and who we want to, you know, give psychedelics to and who we don't want to give psychedelics to. I think, you know, these opposing types of mechanisms, it makes it make sense that metaplasticity is going to enable some flexibility around that super well-learned heroin addiction. But for example, we have some evidence to suggest that people with autism, part of the pathogenesis of the disease is that they have a failure to close critical periods properly. And so we want to be extra careful in people with autism, schizophrenia, which has some genetic overlap with autism in giving these medicines.

33:07And there's a profound awareness and responsibility, I think, in the field also that we are partaking of in part with the plant medicines, especially something like ayahuasca of medicines as they are known in those places, that they are rooted in place and traditions and peoples. I think one of the interesting things for me about, you know, being at the Denver Conference or in this world, there's this, there is, and I'm sure we got to this as Westerners, but there is a reverence for the elders, the cultures that have tended these, known about this healing and used it ceremonially. but there's an, I want you to hear what you have to say about that, but it felt to me refreshing to see that.

33:57Again, I don't know, I'm sure that wasn't there at the beginning when we were, you know, I don't think Timothy Leary cared about where anything came from, but there's also this interesting study about how important the setting is and about the Bruce Alexander work. Okay, so let me just go back to the notion about, you know, respecting indigenous use and traditions and not trying to co-opt their traditions. And I guess I'm of two minds of this. One is that, of course, we want to be respectful of these traditions. But at the same time, you know, when I first started working on this, I got a lot of pushback.

34:34Like, why do we need to understand the mechanism? We know from, you know, hundreds, if not thousands of years of, you know, indigenous use that these medicines are powerful and they work. And we have all this underground therapy work suggesting that, you know, they're effective. We don't need to know the mechanism. We just need to demonstrate it to the FDA and get approval. And as a neuroscientist who studies mechanism, I hated that idea. I was very angry at that sort of notion. And I, you know, my explanation was, listen, we can't just pluck something from another culture and expect to use it the way that we understand disease, the way that we understand, you know, illness, the way that we understand healing without putting into that mechanistic context of our own.

35:20The other thing that I heard recently, which I loved, is for the plant medicines, surely we have borrowed from other cultures, but MDMA and LSD and ketamine and PCP are synthetic compounds that we are the knowledge keepers of. This culture invented them and this medicinal tradition and this chemical tradition invented and we are the stewards of it. And so it is our responsibility to understand how they work in our medicinal context, in our neuroscience framework. And otherwise, we're going to possibly do great damage or miss big opportunities for what else we might be able to use them for in understanding the way that we conceptualize the brain for our types of disease.

36:11To be good stewards, to be good elders, right? To be good ancestors, as Carl Sagan said. And also, we have to acknowledge, and I think this is a hard thing for people to talk about in this field, because the healing, the magnitude of the healing is so astonishing and beautiful. And, you know, they're good for PTSD and addiction and perhaps Parkinson's and strokes, and I think are not great. There's no cure for narcissism, right? And a narcissist, you know, Charles Manson gave LSD to his followers and there are some billionaires we might mention who famously remain narcissistic after using a lot of ketamine.

36:52Yeah. And by the way, also, meditators can be great narcissists too. That's right. But that, because these substances are so powerful, that's. Well, so what I would say is, you know, sort of thinking about it in our framework, just let's talk about narcissism in particular. at least when I went to medical school, the working sort of understanding of narcissism is that, you know, narcissism is totally normal and required when you are three to four years old. You need to be a narcissist in order to get your parents to give you what you want and your grandmother to give you the lollipop that you want, right?

37:29You need to live in that world where everything revolves around you because humans are altricial species. We cannot survive without care. So that's appropriate. If you get injured early or you don't overcome that stage of development, you can get stuck in that narcissistic pattern well into adulthood. Now think about what I'm saying about what we're doing with psychedelics. We are reopening critical periods and returning people to that childlike state of early development. We are inviting people essentially to become, you know, more narcissistic in their worldview. view. We are asking them to be more flexible in their worldview.

38:11We're returning people to a state when they believed in things, right? Like very few adults believe in Santa Claus, I hope. I'm not ruining it for anybody here.

38:24Exactly. Yeah, I actually, just funny sidebar, I said this to a friend of mine's teenage daughter, and she laughed it off. And then later she told her mom, Ghoul was joking, right? Like, Santa's real. So I'm always a little careful. I don't want to make assumptions. But anyway, we're returning people to this stage of sort of flexible belief systems where they accept a looser, let's say, rule set for causality. And we have to be careful as we understand what these psychedelics are doing to give people the right healing context so that they don't, you know, they don't lose track of it. And it's also another reason that I'm worried about trying to treat psychedelics like their next generation SSRIs, right?

39:14So ketamine therapy is a good example. Since when it first got approved, there have been now a lot of concern raised over people having to go back every week, taking it for, you know, sometimes years at a time, developing some more of these personality disorders, and also developing abuse liability around ketamine, right? We say the abuse liability is low for MDMA if we're giving it three times in a clinical setting. But if we're being forced to give them every two or three weeks, the situation could be very different. And we just haven't collected that kind of data. And then the point you made about Charles Manson I think is also an important one.

39:57We are very amazed by psychedelics and what they can do. but I believe that psychedelics are like any learning. Depending on what you provide, that's what gets learned. There's no valence to it. It's not good or it's not bad. It's just neutral. And so if you are trying to overcome PTSD and you get exposed to a good therapist, you protect yourself after you had the MDMA, you don't go back into a home where you're still being abused, those are all good outcomes. But if you take these psychedelics and spend time with a psychopath or a narcissist or an abusive person, you could be inducing a kind of lasting trauma that is going to get locked in while you're still in this vulnerable, sensitive state.

40:46And so this is another classic example of how understanding the mechanism can teach us a lot about how to use these medicines, even in a therapeutic setting, appropriately. Okay. So I'm going to open this up for questions for about 15 minutes. And then at the end of that, we'll come back up here and finish. And I haven't, we haven't talked about the octopus. So if anybody is really interested in that, you can ask that question. There's a hand right here and right here too. Yeah. That last comment you made made me really want to ask this question I've been thinking about the whole time. There's no Santa Claus.

41:24That's what you were going to ask. It sounds like the training of the therapists who guide people through this is so vital, more vital than just even general therapists. And how would Will does, beyond the drugs getting regulated, how would that be regulated? because it sounds like that would be like a whole other ball of wax is part A. Part B, from like a system standpoint, it also sounds like it's a very difficult medical intervention to scale because of how highly intense the intervention is. So those are my two questions. Okay, those are great questions. And I think they are very much coming from the state of things right now and the way that psychiatric illness has been treated by the sort of pharmaceutical industry, right?

42:43We've come to accept this as a limitation that, you know, we're going to have this huge burden and it's really hard. But if you go to, let's say, neurology, which is, you know, where we're next focusing our attention, nobody would ever say, you know, the interventional radiologist has to do this crazy long surgery to remove your blood clot that caused you to have this stroke. But I'm sorry, occupational therapy is just too expensive. You go on home. That would never happen, right? So in neurology, we have a totally different paradigm for understanding the importance of the learning combined with the intervention.

43:27And it's not a problem in neurology. Nobody says in neurology, how are we ever going to pay for this intensive intervention and this intensive therapy? How are we ever going to train enough occupational therapies to give people this medicine? So I'm hopeful that if we can demonstrate our theory, especially in the stroke trial that we are starting hopefully within the next month, we can help establish this idea, this framework for understanding how psychedelics are working in neurology where this is already accepted and slowly bring psychiatry and psychological illnesses over to that way of thinking.

44:08Now, the first part of your question is also important. This is a little bit of a debate right now. We don't know that there has to be a specific kind of psychotherapy that requires a specific kind of intervention. There are a lot of different therapies that seem to work. And there have been review articles written about this by psychiatrists who emphasize that the most important thing is that you provide a framework for the patient to understand their healing. in the therapeutic setting. So whether you use cognitive behavioral therapy or Freudian analysis doesn't seem to matter much as long as you provide people with a framework for understanding the transformation.

44:51So I think there's a lot more research that needs to be done to understand exactly how that's happening. And I think that we can't get lost or scared of this challenge because it's potentially very exciting, right, to try and figure this out with something that actually works? You know, it's striking at these gatherings of scientists and practitioners and activists and funders. For example, there's a young woman named Juliana who, she's somebody who, brilliant, became addicted to opioids, spent time in prison. Her life was saved. You know, she did Ibogaine treatment in Mexico, and she never wanted opioids again.

45:34and at all of these conferences she's on stage saying like her whole life's mission now is is that the quality of the training has to be so high and so she's out there like there are these networks of training being being created because there's this understanding of that right yeah yeah but you're the brilliant scientist that can answer a question that the last panel i asked couldn't answer. It was on AI and education. And my fear, of course, a lot of it as a writer, et cetera, we struck on this, was that the person on the panel said his child of three was using AI. In the critical period that you're talking about, when is the brain forming and learning how to learn and using AI would stop that process?

46:24Yeah, I don't think AI will stop that process. I think what a person who is getting a lot of learning through AI at age three is getting essentially a degenerate sort of limited social interaction. So human beings are incredibly social. You know, I used to have, my lab studies social behaviors, and I used to have to harp on about this and provide data about mortality rates and lonely people. But I think we all learned that lesson in pandemic. I don't have to belabor the point now. We are incredibly social. It matters to us that we get, like, we don't learn as well if we're learning from even on Zoom, even on computer monitors, because it's degenerate social information.

47:09We don't have the olfactory cues. We don't have the touch cues. We don't have, you know, the ability to move through the social environment, right? And so I think that it's already, we already know that all of these technologies that were sold to us with the promise of people are going to be less lonely because they can check on their friends on Facebook. That's just going to, and that made things worse, right? Because, you know, when you put something up on Facebook or Instagram or whatever, I I don't have social media, but, you know, I am aware of these things. You are providing essentially a very glossed over version of what's going on in your life.

47:49You're not allowing the other person to smell your fear and to know your pain. And so rather than it being an opportunity to develop empathic skills and reciprocity and helping, you're learning competitive fear, anxiety, right? And so I think that these technologies that are being sold to us, AI companions and, you know, they're going to help with, you know, the health care crisis and helping with elderly, I think that they are nowhere near, you know, what a normal social interaction is like. And on the other hand, the reason that we have critical periods is that we're adapting to whatever environment we're in.

48:31So Alison Gopnik, who is a famous child developmental psychologist, actually, in my department at Berkeley. And she has written several books on child development and all of the fears that we all have over, you know, new technologies. And she says, you know, every generation wrings their hands over the new technologies. And she gives this great example of, you know, how there was this new technology that Plato was very afraid of because, you know, paper was going to make it so that people weren't going to be able to memorize epic poems anymore. Right. And so he was right. He was right. And yet how many people are that worried about not being able to recite the Odyssey?

49:19Like not that many. So it's I think, you know, the reason that we have critical periods is because the environment that we're born into might be very different than what our parents had. And maybe the reason that we have, you know, multiple cultures using these psychedelics is that we live a long time and the world changes in our lifetime. and to be able to reopen and learn and maybe take an AI class may be the reason that we're, I'm not, generally speaking, very optimistic about AI, but, you know, I'm middle-aged now, and so I'm allowed to be a little skeptical of the new technologies. Why don't we take a few questions, and then, you know, we can just see what, here's one up here, and then I'm sure there's one back I'm not looking at.

50:10I'll start. Okay, you start. I have a question for you. You're talking about clinical use of psychedelics. What are your thoughts on microdosing and using psychedelics in a non-clinical situation? So we have looked at this, and microdoses do not reopen the critical period. And I can't 100 % say whether or not that is of psilocybin. You know, whatever it's doing is just below our detection threshold. I should also say that microdosing mechanisms can be very different depending on psychedelics. So, for example, people develop very quick tolerance on LSD and psilocybin microdosing because those receptors get internalized.

50:55On the other hand, ibogaine, it seems that you don't develop tolerance to microdoses of ibogaine in the same way because it gets stored in the fat. So, you know, there might be differences here. All of the clinical studies trying to look at microdosing suggest that it's mostly placebo effects at this point. That being said, I have nothing against macrodoses being used for optimization. and you know I do think that there's mechanistic overlap for example between psychedelic induced mystical states and mystical states that have been used by religious practices like you know meditation and going and living in a cave for a month and you know sound baths and these other deprivation techniques because we know that deprivation in this way can also reopen critical periods.

51:50And so I do think that there's some restorative power in being able to do this in a controlled way for personal growth. Okay. Yeah. First, thank you so much for your work. For me, this is quite personal. I have Parkinson's and I have several loved ones who are in treatment now for depression with ketamine. Two-part question. One is, can you talk a little bit about how the mechanism for Parkinson's might work, what the timeline might be, what intervention might be used? And then secondly, given the short time duration of the critical period for ketamine, how might one in treatment optimize their strategies to make that work?

52:30Yeah. I mean, so I have to say I'm a little bit, I think the Parkinson's data is still very much equivocal. There are some data that suggests that it's really good for the depression and the psychiatric part of Parkinson's, it's pretty clear that it's not actually reversing the death of the dopaminergic neurons in the substantia nigra. And it's not clear that even if there's some motor recovery, that that would have anything to do with the critical period mechanism I'm describing, right? So just to be clear, the critical period mechanism accounts for, I think, a lot of what we're seeing with psychedelics, but not everything.

53:13So the headache, there's a lot of increasingly good evidence that psychedelics given once or twice can rid somebody of cluster headaches permanently. And these are, you know, suicide headaches, really, really bad headaches. And I think that that's a direct action of the psychedelic on the blood vessels and doesn't necessarily have anything to do with this critical period mechanism. Some people have proposed GDNF or BDNF, which are nerve growth factors. I think I recently went to a conference which suggests that that's unlikely to be the case. And I just urge people to be cautious about these kinds of growth factor type explanations because, you know, BDNF is brain-derived nerve growth factor.

54:01Implicating BDNF in some pathological or patho, you know, or curative mechanism is like saying the brain is involved because basically everything involves BDNF. This conversation is causing BDNF to be released in your bodies, right? Like it's implicated in addiction and it just doesn't have the explanatory power that I would require. So I think the jury is still out on Parkinson's. With ketamine, again, I think that the way that people are showing improved durability with ketamine is to pair it with therapy, right? So if you give ketamine and you don't give therapy, at two weeks out, you know, your effects look about the same.

54:47But if you give ketamine plus therapy and you compare out a year later, that group is doing much better and they have this persistent effect compared to the people that are just getting ketamine by themselves. And also I think that rates of success for treatment, what we call treatment-resistant depression, which SSRIs don't work, is quite high with that kind of extended ketamine treatment. Yeah, I mean, the data, so the ketamine clinics are sort of collecting this data, and they're getting mass amounts of data, but they're still slow to publish because they want to really do a good job of looking all the way out.

55:26So I'm sorry I don't have better news on that, but that's where we're at. Okay, one more question. I'm going to take it here. Thank you so much. My question is about actually just the journey to more social and cultural acceptance of this work. Obviously, there's many, much work to do to do more research, to understand the efficacy. What else do you think needs to happen to actually change the cultural narrative? Well, I mean, I think some of it is time. I do think that we want to give people the opportunity to learn about it. But also, you know, I think you brought up a great point about Ibogaine.

56:03So the reason that Ibogaine is getting so much traction right now is because people are excited about the idea that it's not recreationally used, right? And so conservative states like Texas, you know, are just devoting a huge amount of funding. They just got a bill approved to approve$50 million in research funding for Ibogaine research in Texas. And this is because the conservatives understood that if they can kind of pitch this as a dangerous, difficult treatment, a medicine that people aren't using, you know, recreationally, it was much easier to convince conservative governments. because I think a lot of the conservative governments are worried that this is, you know, this push to talk about the medical efficacy of psychedelics is sort of being used in the same way as the sort of thin edge of the wedge that happened in cannabis.

57:06And I think that there's a lot of concern in conservative states that that's what's happening with psychedelics. So Ibogaine is sort of well positioned to allay those fears. But I also am nervous about, you know, the rah, rah, rah, because I am very enthusiastic about psychedelics. I think they're doing this incredible thing. But I think if we overdo it, if we oversell this idea, first of all, there's going to be a huge amount of disappointment. Second, we're going to give the wrong impression to people that, you know, this is a miracle pill. And then when it becomes sort of less criminalized, people are going to take it and assume that it's totally safe and they can do whatever.

57:50And, you know, there are cases of people who have overused, who have, you know, tried to do this work on their own without, you know, proper therapy and support who've ended up committing suicide because they just couldn't handle all the trauma that they brought up in doing this work solo. So I want to be measured in the way that I'm enthusiastic about it. And if that means that it takes a little bit longer to get this approved, then fine, because I really, really, really don't want to set us up for the next fentanyl face plant, right? Right. Okay. Yeah. And so this kind of leads into something.

58:31One thing I want to talk about is the counterintuitive kind of parallel universe of support that is forming for this. So last week in Denver at this, I don't know, there are probably 8 ,000 people there, the MAPS conference, Science of Psychedelics, Rick Perry of Texas spoke. He's, yeah, he's behind getting the$50 million for Ibogaine research in Texas. He's part of something called Ibogaine for America, or America for Ibogaine, together with this visionary Appalachian activist who's, you know, been surrounded by opioid addiction and sees this as transformative. And they are going to try to get every state to match in millions of dollars.

59:15I moderated a panel with former Senator Kyrsten Cinema and Tim Ryan. So she's in Arizona, Ohio. Senator Bergstrom, who's a former military general, a Republican, also who has seen the transformative effect on veterans. So there was this bizarre, I mean, it felt bizarre that psychedelics was making this bipartisan, not just, not just dialogue, but like this shared passion for making something happen and actually for making healing happen. Also, I thought, you know, the cross-generational, like there's young energy and there are the elders and there's a real regard for like the elder scientists, for example, and the elder activists.

59:56I don't know. Does that strike you in this world? I felt like if people could just see this was happening, it would kind of give you hope just that it's possible. Yeah, no, it's really exciting. And I know where that enthusiasm is coming from. I mean, I went to medical school and I never did a residency because I just felt like all we were doing all day long was taking down people's traumas, taking down people's injuries, and not really being able to provide them with any real help. And then I went down to this clinic in Mexico and, you know, I talked to dozens of people who, you know, had a gun in their mouth yesterday.

1:00:29And then three days later, they're giving everybody hugs and, you know, crying for the first time in 40 years and really letting their guard down in these incredible ways. and I sort of became a transformation junkie. And that part of me that went to medical school came back alive and I was excited to get to spend time around people who were having these big transformations. So it's not surprising to me that this is bipartisan. I think if you've been exposed to it and you see it, it is very moving. Yeah. So you have a core value of curiosity. and maybe that is a prerequisite for being a scientist or being a good scientist.

1:01:12I read another interview who said you love the down the rabbit hole experience. And here's something you said. I think part of the reason psychedelics are so able to enchant people is because they bring back that wondrous curiosity, that joyous let me just follow this rabbit hole feeling and it's wonderful. I wonder how doing this science kind of shapes the way you move through the world. Yeah. Well, you know, I think starting with, you know, my first experiences of awe at the natural world with, you know, seeing these sea urchins at the bottom of the sea with my grandmother, the zoologist in Turkey, all the way up until now, I've always come back to that as the reason that I do science, right?

1:02:01It's not just about psychedelics, it's science in general. And that is kind of the reason that we did the octopus experiment. At the time, I was struggling to get funding. We had this incredible discovery, which I knew was going to change the world about critical periods. And nobody would fund me. I had private foundation money, but the NIH was like, no, psychedelics will never be used for therapy. You're dreaming. Go study oxytocin. And I was like, intranasal oxytocin doesn't cross the blood-brain barrier. Why would I study that? That's terrible. And so I, you know, I was very frustrated. And I had, you know, people like Roland Griffiths, who's, you know, was an elder for me and a mentor, an informal mentor for me saying, oh, just, you know.

1:02:51At Johns Hopkins. Yeah, Johns Hopkins. Just, you know, rejigger your application and make it sound like you're studying the bad effects of psychedelics and they'll give you the money. And I said, no, if we're right about this, I want to get credit, you know, I want to get credit for having this idea, you know, 10 years ago. And so I just wasn't getting funding. And I was getting to the point where we were going to have to close down the lab because I just couldn't pay for people. And so kind of as a last ditch thing, I was like, well, you know, I got a little bit of money left. Let's do this octopus thing.

1:03:22And I was already kind of down the rabbit hole on octopuses anyway when a collaborator of mine at Woods Hole called and said, you know, we have seven octopuses. Do you have any experiment that you want to do on them? And I was like, yeah, ship them down. So he FedExed them down. He got on a plane. He came the next day. And we took, like, baseline measurements of what they're like, you know, in the tank. And this is an especially combative antisocial species of octopus. Yeah, so octopuses, even if you've seen my octopus teacher, don't believe it. They are not friendly. They are not cuddly. They are vicious predators and very asocial.

1:04:03And so if you put two of them in the tank together, they will normally kill each other. But when we gave them MDMA, they did not. So they spent significantly more time around the other octopus. and this was a huge surprise to us because, you know, we diverged from octopuses over 650 million years ago. They don't have any of the brain regions that we think of as being related to psychedelic activities. So they don't have a cortex. They don't have a default mode network. They don't have an amygdala or a nucleus accumbens. And yet at the molecular level, they're similar enough that the binding pocket for serotonin that MDMA binds to is conserved.

1:04:45And so they're able to have this effect. And what it suggests is that serotonin has been acting as a molecule that encodes social behaviors for a very long time, and that all of these brain areas and this anatomy is just sort of secondary, an accident of evolutionary history. And I got to tell you, this experiment kind of knocked me off my seat for a while because, you know, I'm somebody who does circuit mapping. I do a lot of, you know, track tracing between different brain regions to figure out the circuitry. And this was really saying, no, that's not really the mechanism that you think it is.

1:05:26And so I'm always, I always go back to that. The way you discover the really big things is not by doing the careful next experiment. It's by asking, I wonder what would happen if, right? and taking those big risks because you're just curious and you're just following the joy. And so I think that's true for all of my best discoveries have always been that way. And, you know, that includes from when I was a child to right up until this day. Cool. Thank you so much for what you're doing and for this conversation.

1:06:19Gull Dolan leads the Dolan Lab at UC Berkeley, where she is a professor and the Bob and Renee Parsons endowed chair in the Department of Neuroscience and the Department of Psychology at the Berkeley Center for the Science of Psychedelics and the Helen Wills Neuroscience Institute. She also maintains an adjunct professorship in neuroscience and neurology at the Johns Hopkins University School of Medicine. You can read more at her website at dolanlab.org. Special thanks this week to Tricia Johnson, Matt Windholtz, Ava Hartman, and Emily Talco.

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