WEBVTT - How Do Psychedelics Work? 0:00:15.356 --> 0:00:24.036 Pushkin. Let's talk about psychedelics. It's been a few years 0:00:24.116 --> 0:00:27.076 since the FDA approved the use of ketamine to treat 0:00:27.116 --> 0:00:31.516 depression in certain patients. Later this year, the FDA may 0:00:31.596 --> 0:00:35.236 also approve the use of MDMA in combination with therapy 0:00:35.716 --> 0:00:40.996 to treat PTSD post traumatic stress disorder, and researchers around 0:00:41.036 --> 0:00:45.996 the world are studying other powerful psychedelics like psilocybin, ibogaine, 0:00:46.156 --> 0:00:49.596 and LSD. It's been clear for a long time that 0:00:49.636 --> 0:00:53.356 these are very powerful drugs, and it's becoming clear that 0:00:53.396 --> 0:00:57.916 these drugs may be particularly helpful in certain contexts. But 0:00:58.356 --> 0:01:02.236 still less clear is a very big, very important question, 0:01:03.236 --> 0:01:13.116 how exactly do psychedelics work. I'm Jacob Goldstein and this 0:01:13.196 --> 0:01:15.276 is What's Your Problem, the show where I talk to 0:01:15.316 --> 0:01:19.116 people who are trying to make technological progress. My guest 0:01:19.156 --> 0:01:22.716 today is goul Dolan. She's a professor of psychology and 0:01:22.836 --> 0:01:27.196 neuroscience at the University of California at Berkeley. Goule's problem 0:01:27.516 --> 0:01:30.476 is summed up in a phrase from a paper that 0:01:30.556 --> 0:01:34.196 she co authored last year in the journal Nature. She's 0:01:34.236 --> 0:01:39.876 trying to identify quote, a common neurobiological mechanism that can 0:01:39.916 --> 0:01:44.956 account for the shared therapeutic effects of psychedelics. In other words, 0:01:45.276 --> 0:01:48.076 why do all these very different drugs seem to have 0:01:48.156 --> 0:01:52.276 similar powerful effects on the brain. Goole has a theory 0:01:52.316 --> 0:01:55.276 about this, about why all these different drugs seem to 0:01:55.276 --> 0:01:59.236 have similar effects, and if she's right, it could mean 0:01:59.396 --> 0:02:02.756 that psychedelics used in the right context, may be useful 0:02:02.916 --> 0:02:07.356 beyond mental illness. Goul thinks, among other things, psychedelics may 0:02:07.396 --> 0:02:11.596 be able to help patients recod from strokes. We started 0:02:11.596 --> 0:02:14.556 the conversation talking about the origin of Ghul's quest to 0:02:14.676 --> 0:02:16.556 understand how psychedelics work. 0:02:19.156 --> 0:02:22.316 About ten years ago when I started my lab, you know, 0:02:22.396 --> 0:02:25.596 there were starting to be some hints that psychedelics were 0:02:25.596 --> 0:02:28.916 having these remarkable effects in you know, all kinds of 0:02:28.956 --> 0:02:32.036 diseases that didn't seem terribly connected to each other, right, 0:02:32.116 --> 0:02:36.916 so addiction and depression and PTSD, and you know, the 0:02:36.956 --> 0:02:39.876 people who study those diseases each have their way of 0:02:39.916 --> 0:02:43.756 studying them and modeling them in animals, and they're they're 0:02:43.796 --> 0:02:47.036 siloed into different spaces. And yet we were starting to 0:02:47.116 --> 0:02:51.476 hear hints that, you know, it didn't matter which psychedelic 0:02:51.556 --> 0:02:55.076 they were kind of interchangeably showing some promise in all 0:02:55.116 --> 0:02:58.836 of these different areas that seem unconnected to each other. 0:02:58.916 --> 0:03:01.996 I mean not just in terms of what behavioral essays 0:03:01.996 --> 0:03:04.236 we use, but even sort of what brain regions might 0:03:04.236 --> 0:03:07.956 be important. Right, Like, the depression people were focused on 0:03:07.996 --> 0:03:10.156 the hippi campus and the frontal cortex. 0:03:10.276 --> 0:03:11.836 The PTSD people. 0:03:11.676 --> 0:03:15.956 Were focused on the amygdala, the you know, the addiction 0:03:15.996 --> 0:03:18.236 people were focused on the nucleus, thecumbents, and they were 0:03:18.236 --> 0:03:20.516 just sort of all over the place, and yet there 0:03:20.516 --> 0:03:24.956 seemed to be this overlap. But when we then discovered 0:03:25.036 --> 0:03:27.196 that all of the psychedelics seemed to be doing the 0:03:27.316 --> 0:03:31.076 same thing, it sort of began to settle in that 0:03:31.676 --> 0:03:35.276 this explanation that we came up with could account for 0:03:35.836 --> 0:03:38.436 why all of these diseases that look so different from 0:03:38.436 --> 0:03:43.436 each other could be responding to psychedelics in a therapeutic way. 0:03:43.996 --> 0:03:48.596 So should we start the explanation with talking about critical periods? 0:03:48.676 --> 0:03:50.876 Is that a reasonable place to start. Let's start with 0:03:50.876 --> 0:03:52.396 critical periods. What's the critical period? 0:03:52.956 --> 0:03:53.156 Right? 0:03:53.196 --> 0:03:56.796 So, critical periods are something that you know, neuroscientists have 0:03:56.996 --> 0:03:59.716 known about for almost one hundred years. They were first 0:03:59.756 --> 0:04:03.916 described in nineteen thirty five by Conrad Lorenz, who was 0:04:03.996 --> 0:04:09.916 describing and imprinting behavior in baby geese, So basically, forty 0:04:09.916 --> 0:04:12.636 eight hours after they hatch from their eggs, they will 0:04:12.996 --> 0:04:17.116 imprint onto anything that is moving around in their immediate environment. 0:04:17.236 --> 0:04:20.076 So typically this would be their mother, but you know, 0:04:20.076 --> 0:04:22.356 if there's a crazy scientist around, it might be to 0:04:22.436 --> 0:04:23.436 the crazy scientist. 0:04:23.596 --> 0:04:27.036 And there are photos of the baby geese following him 0:04:27.036 --> 0:04:29.836 around right in fact, as if he were a mamma goose. 0:04:29.916 --> 0:04:31.396 Yeah, exactly. 0:04:31.476 --> 0:04:34.156 And so but that window of time where they're so 0:04:34.356 --> 0:04:37.636 sensitive to their environment and they form these lasting attachments 0:04:38.036 --> 0:04:41.036 only lasts about forty eight hours, and then afterwards they don't. 0:04:41.236 --> 0:04:43.356 They're not sensitive to their environment in the same way. 0:04:43.556 --> 0:04:45.676 They're not learning from their environment in the same way. 0:04:45.716 --> 0:04:48.836 And that window of time Conrad Lorenz called it the 0:04:48.836 --> 0:04:53.716 critical period. And since that time we've discovered literally dozens 0:04:53.756 --> 0:04:56.836 of other critical periods. So there are critical periods for 0:04:56.956 --> 0:05:01.596 rewiring the visual system, critical periods for touch, critical periods 0:05:01.636 --> 0:05:05.596 for movement, critical periods for language. Language is probably the 0:05:05.596 --> 0:05:07.996 one that most people are familiar with. If they try 0:05:08.036 --> 0:05:11.356 to learn enough their language when they were older, it's 0:05:11.436 --> 0:05:13.916 much harder and you always have an accent compared to 0:05:13.956 --> 0:05:17.796 the language you learn as a child, and so neuroscientists 0:05:17.836 --> 0:05:20.756 have known about these critical periods for a long time, 0:05:21.436 --> 0:05:25.396 and we've had this idea that maybe the reason that 0:05:25.476 --> 0:05:29.516 we're so bad at curing diseases of the brain, neuropsychiatric 0:05:29.556 --> 0:05:33.436 illnesses and neurological diseases, is because by the time we 0:05:33.516 --> 0:05:38.516 get around to correcting whatever is the underlying problem, the 0:05:38.636 --> 0:05:40.316 relevant critical period. 0:05:39.996 --> 0:05:40.996 Has already closed. 0:05:41.436 --> 0:05:44.396 And so the classic example of this is if you 0:05:44.516 --> 0:05:47.796 are born with bilateral cataracts in your eyes and you 0:05:47.876 --> 0:05:50.596 don't have them removed by the time you're aged five 0:05:50.716 --> 0:05:53.916 or so, then you will be blind forever because even 0:05:53.996 --> 0:05:57.196 if you remove the cataracts, wants the ability of the 0:05:57.316 --> 0:06:01.116 visual part of the brain to adapt to the corrected 0:06:01.236 --> 0:06:04.756 visual environment. Once the critical period has closed, it can't 0:06:04.796 --> 0:06:07.996 adapt again, and so even though the impediment is removed, 0:06:08.476 --> 0:06:11.276 the brain can respond to it, and so you're blind forever. 0:06:12.596 --> 0:06:15.916 And so we have been looking, probably for the last 0:06:15.916 --> 0:06:19.716 one hundred years or so for ways to reopen critical periods, 0:06:19.716 --> 0:06:22.756 with the idea that if we could reopen them, we 0:06:22.836 --> 0:06:27.036 could potentially cure or do a better job of correcting 0:06:27.036 --> 0:06:29.036 some of these impairments later in life. 0:06:29.556 --> 0:06:32.916 So in this Nature paper, that you published last year. 0:06:33.396 --> 0:06:38.436 You write, it's tempting to speculate that the altered state 0:06:38.716 --> 0:06:43.796 of consciousness shared by all psychedelics reflects the subjective experience 0:06:43.956 --> 0:06:47.476 of reopening critical periods. Let me say, first of all, 0:06:47.516 --> 0:06:50.156 I like, it's tempting to speculate. It's like, you're not 0:06:50.236 --> 0:06:51.156 even speculating. 0:06:51.196 --> 0:06:54.436 It's more speculative than speculating, right, Like, we're not going 0:06:54.516 --> 0:06:58.596 to speculate, but we're tempted to speculate. So and I 0:06:58.636 --> 0:07:01.236 appreciate that, right, Like, this is clearly speculative, it's based 0:07:01.276 --> 0:07:04.316 on research and mice. But why are you tempted to 0:07:04.356 --> 0:07:09.116 speculate that psychedelics may reopen critical periods in the brain? 0:07:09.996 --> 0:07:10.196 Right? 0:07:10.516 --> 0:07:14.996 So, the reason that we're tempted to speculate this is because, 0:07:16.196 --> 0:07:19.356 you know, one of the other things that brings together 0:07:19.396 --> 0:07:23.236 psychedelics as a group of drugs is that they all 0:07:23.276 --> 0:07:26.556 induced this altered state of consciousness. So we discovered a 0:07:26.556 --> 0:07:30.756 critical period in twenty nineteen for Social rewards learning. It 0:07:30.796 --> 0:07:33.596 was a brand new critical period. Although you know, there 0:07:33.676 --> 0:07:37.556 was a lot of literature from human studies suggesting that 0:07:37.596 --> 0:07:40.876 such a critical period should exist, but it just took 0:07:40.996 --> 0:07:43.156 doing it. In nine hundred mice to be able to 0:07:43.156 --> 0:07:46.396 formally demonstrate it. So we did that. We showed that 0:07:46.436 --> 0:07:49.956 there's this social critical period, and originally we showed that 0:07:50.156 --> 0:07:53.196 MDMA was able to reopen this critical period. And we 0:07:53.276 --> 0:07:58.716 thought because MDMA is characterized by having this pro social 0:07:58.836 --> 0:08:02.396 property that makes it different from the other psychedelics in that, 0:08:02.796 --> 0:08:06.156 you know, it's altered state of consciousness, plus you know, 0:08:06.236 --> 0:08:09.956 cuddle puddles and empathy, right, and so we thought it's 0:08:09.996 --> 0:08:13.516 because of that pro social property of MDMA that it's 0:08:13.556 --> 0:08:17.156 able to open this social critical period. But then when 0:08:17.156 --> 0:08:21.556 we figured out that well LSD and I began and KETYMI, 0:08:21.676 --> 0:08:24.996 none of which are like particularly pro social, nobody's you know, 0:08:25.076 --> 0:08:27.876 doing a thirty person cuddle puddle on I begin right, 0:08:28.716 --> 0:08:31.316 even though they don't have this pro social property, they 0:08:31.316 --> 0:08:33.116 are all also able. 0:08:32.836 --> 0:08:34.676 To open this critical period. 0:08:34.716 --> 0:08:38.116 And so that was our first hint that maybe the 0:08:38.756 --> 0:08:45.516 common property is between psychedelics that accounts for this altered 0:08:45.556 --> 0:08:48.716 state of consciousness that they all induce is the common 0:08:48.756 --> 0:08:51.996 property of inducing critical period reopening. 0:08:52.316 --> 0:08:56.036 And so specifically, can you just talk a little bit 0:08:56.036 --> 0:08:59.596 more about the specific critical period in mice that you're 0:08:59.636 --> 0:09:01.556 looking at here, right? 0:09:01.596 --> 0:09:05.916 So, we're measuring something called social condition place preference, which 0:09:05.956 --> 0:09:09.956 is just an assay to measure the ability of the 0:09:10.036 --> 0:09:13.956 mice to learn from their social environments. And so that 0:09:14.276 --> 0:09:18.036 ability changes over time, and as they get older, they 0:09:18.036 --> 0:09:21.956 stop learning from their social environment. And so this developmental 0:09:22.036 --> 0:09:25.276 change relates to why we think teenagers are so much 0:09:25.316 --> 0:09:28.596 more susceptible to peer pressure than adults. We think it 0:09:28.636 --> 0:09:32.196 relates to why you're so much more sensitive to learning 0:09:32.316 --> 0:09:35.596 the rules of your culture when you're young, so you know, 0:09:35.716 --> 0:09:36.956 you learn what's polite. 0:09:37.396 --> 0:09:40.156 So it's basically the idea is that there's a critical 0:09:40.316 --> 0:09:44.236 there is some set of critical periods for learning social 0:09:44.516 --> 0:09:50.476 behavior from language to norms, and that that those clothes 0:09:50.676 --> 0:09:53.516 over the course of childhood and adolescents. 0:09:53.796 --> 0:09:54.596 That's right, that's right. 0:09:55.516 --> 0:10:00.196 And we think that that critical period, like other critical 0:10:00.236 --> 0:10:04.236 periods like language, you know, is curtailed as you get 0:10:04.276 --> 0:10:10.636 older because basically it's sort of expensive energe to always 0:10:10.676 --> 0:10:13.316 be having to learn from your social environment. 0:10:13.476 --> 0:10:14.436 You know, I like to. 0:10:15.876 --> 0:10:18.716 Think back on my teenage years and you know, mostly 0:10:18.716 --> 0:10:21.716 I'm relieved that they're over, because you know, it was 0:10:21.996 --> 0:10:26.836 time consuming and energetically exhausting to you know, have to 0:10:26.876 --> 0:10:29.636 care about the exact right shade of acid washed genes 0:10:29.676 --> 0:10:30.796 that the cool kids are wearing. 0:10:30.876 --> 0:10:33.956 Right, and now you wear whatever acid wash genes you want, right, 0:10:34.076 --> 0:10:34.596 that's right. 0:10:34.716 --> 0:10:37.396 I wear mom jeans that are acid washed. 0:10:39.636 --> 0:10:43.556 And so then you find that when you give psychedelics 0:10:43.596 --> 0:10:46.996 to an old mouse, they're able to the. 0:10:47.036 --> 0:10:51.076 Learning that they were doing in juvenile in their juvenile 0:10:51.116 --> 0:10:54.676 period return, so they're able to learn again like a juvenile. 0:10:55.396 --> 0:10:59.036 Have you tested this theory on other critical periods in 0:10:59.116 --> 0:11:01.116 mice or on other animals? 0:11:01.596 --> 0:11:05.316 Yeah, So basically, as soon as we got this this result, 0:11:05.516 --> 0:11:07.956 I reached out to every single person that I know 0:11:08.156 --> 0:11:10.236 who works on critics periods, and I was like, do 0:11:10.236 --> 0:11:13.436 you have a critical period that you want to try 0:11:13.436 --> 0:11:16.396 and reopen? Because I think we might have accidentally stumbled 0:11:16.396 --> 0:11:20.076 on the master key for unlocking critical periods, and so 0:11:20.196 --> 0:11:23.836 we're working on it. We definitely have some collaborations going. 0:11:24.476 --> 0:11:27.476 But in the meantime between sort of when we first 0:11:27.556 --> 0:11:30.876 have this twenty nineteen paper and then this summer, there 0:11:30.916 --> 0:11:35.916 have been some hints that other critical periods are being 0:11:35.956 --> 0:11:40.756 reopened by say ketamine. There are two papers showing that ketamine, 0:11:40.796 --> 0:11:43.196 if given back to back to back to back can 0:11:43.236 --> 0:11:47.156 reopen the critical period for ocular dominance plasticity, which is 0:11:47.196 --> 0:11:51.076 this visual critical period that we've learned so much about 0:11:51.076 --> 0:11:54.796 the mechanisms about. So that's a first hint, and we 0:11:54.836 --> 0:11:59.156 are working feverishly to see if we can reopen other 0:11:59.236 --> 0:12:02.996 critical periods like motor learning for stroke. We're doing that 0:12:03.036 --> 0:12:06.436 in both mice and in humans. We're working on some 0:12:06.556 --> 0:12:09.836 language critical periods in collaboration with some of the labs. 0:12:09.956 --> 0:12:13.636 So you know, the jury is still out, but there's 0:12:13.676 --> 0:12:15.956 some other reasons to make us think that we're on 0:12:16.036 --> 0:12:19.436 the right track with this idea about the master key. 0:12:20.036 --> 0:12:23.396 When you say master key in this context, in this context, 0:12:23.396 --> 0:12:24.316 exactly what do you mean? 0:12:25.316 --> 0:12:28.036 So I guess what I mean is is that when 0:12:28.076 --> 0:12:30.796 I was a graduate student, we were a little bit 0:12:30.796 --> 0:12:34.356 in a debate with another lab that was proposing that 0:12:34.396 --> 0:12:38.596 there would be some drug or manipulation that you could 0:12:38.596 --> 0:12:43.356 do that could reopen all critical periods, and that you 0:12:43.436 --> 0:12:47.916 could just give that drug and it would it would 0:12:48.516 --> 0:12:50.916 it would be the master key, right and for unlocking 0:12:50.956 --> 0:12:53.796 all of these critical periods. And at the time, I 0:12:53.876 --> 0:12:58.516 remember being really skeptical of that idea, and I thought, well, 0:12:58.556 --> 0:13:01.636 anything that can do that to the brain is either 0:13:01.756 --> 0:13:07.516 going to induce amnesia, cause seizure, or disrupt the structural 0:13:07.996 --> 0:13:11.196 integrity of the brain. And I thought that because of 0:13:11.236 --> 0:13:14.556 what we knew about, you know, basically the mechanisms that 0:13:14.676 --> 0:13:19.356 constrain critical periods to these windows of time, like like. 0:13:19.276 --> 0:13:22.036 You couldn't work without breaking the brain. The only way 0:13:22.116 --> 0:13:24.756 to reopen the critical period is the master key is 0:13:24.796 --> 0:13:27.676 like a sledgehammer that's just gonna totally break everything. So 0:13:27.756 --> 0:13:28.716 why even bother. 0:13:29.196 --> 0:13:31.396 Right, And I you know, I called it the Melti 0:13:31.436 --> 0:13:34.316 brain problem, right, And so then when we when we 0:13:34.396 --> 0:13:39.676 started getting these results for the psychedelics, I was, I 0:13:39.716 --> 0:13:42.436 started thinking, well, how come we're not running into the 0:13:42.436 --> 0:13:46.276 Melty brain problem? And I think, and this is at 0:13:46.276 --> 0:13:50.716 this point still speculative, and we're we're actively pursuing this 0:13:50.836 --> 0:13:53.556 line of research. So I don't want to overstate the case. 0:13:53.876 --> 0:13:56.876 But my hunch is that the way that we are 0:13:56.916 --> 0:14:01.476 able to circumvent, or the way that psychedelics specifically are circumventing, 0:14:01.916 --> 0:14:06.756 the Melty brain problem is that they are context specific. 0:14:07.236 --> 0:14:12.636 So it's not that psychdelics are causing reopening of all 0:14:12.676 --> 0:14:16.676 critical periods everywhere in the brain all at the same time. 0:14:17.076 --> 0:14:21.556 It seems to be that they are not you know, 0:14:21.636 --> 0:14:26.276 destroying or melting the brain, because they're only making available 0:14:26.476 --> 0:14:34.436 for modification the subset of synapses, circuits, memories, and grams 0:14:34.596 --> 0:14:38.316 that are have been recently activated, and that is why 0:14:38.636 --> 0:14:41.436 they have this constraint of being context dependent. 0:14:42.316 --> 0:14:45.476 So this is this is why your thesis is they 0:14:45.556 --> 0:14:51.076 will psychedels will be helpful when paired with interventions like therapy, 0:14:51.516 --> 0:14:53.316 but not by themselves. 0:14:53.756 --> 0:14:54.756 Well, this is. 0:14:56.436 --> 0:15:00.596 This is the explanation we have for why the psychedelics 0:15:00.596 --> 0:15:06.236 aren't breaking the the brain rather than I mean, basically, 0:15:06.276 --> 0:15:11.276 the clinical data is driving this idea that in fact 0:15:11.396 --> 0:15:13.076 the context matters, right. 0:15:12.996 --> 0:15:15.996 But it's a potential mechanistic explanation for that. 0:15:15.996 --> 0:15:19.076 Clinical well that feature, that's right, it's a mechanistic explanation 0:15:19.116 --> 0:15:22.276 for a clinical description, which you know, I don't think 0:15:22.436 --> 0:15:24.716 is going to be the case for every single application 0:15:24.796 --> 0:15:27.676 that psychedelics might be used for. So, for example, I 0:15:27.716 --> 0:15:32.796 think the critical period idea nicely explains why MDMA assisted 0:15:32.836 --> 0:15:37.596 psychotherapy works. If we're able to demonstrate that we can 0:15:37.716 --> 0:15:44.916 correct motor impairments following stroke with psychedelics paired with physical therapy, 0:15:44.956 --> 0:15:47.036 then that'll be a nice other explanation. 0:15:47.676 --> 0:15:50.796 That's a huge idea. You've just dropped in the middle 0:15:50.836 --> 0:15:52.236 of a list, by the. 0:15:52.196 --> 0:15:55.996 Way, right, So, by the way, that's also quite quite speculative. 0:16:00.756 --> 0:16:04.316 After the break, how gool plans to test this hypothesis 0:16:04.716 --> 0:16:19.436 that psychedelics may help patients recovering from strokes. Let's just 0:16:19.556 --> 0:16:22.556 talk about how we get from this sort of you know, 0:16:23.596 --> 0:16:28.716 seems like psychedelics reopen one critical period in mice to like, 0:16:29.836 --> 0:16:31.796 can this idea be helpful in humans? 0:16:31.916 --> 0:16:32.076 Right? 0:16:33.836 --> 0:16:36.756 You must know the aphorism mice lie and primates exaggerate. 0:16:36.836 --> 0:16:38.196 I was thinking of that one. 0:16:39.716 --> 0:16:42.116 I mean, I think that a little bit of why 0:16:42.156 --> 0:16:46.436 it's so hard to translate this stuff from mouse studies 0:16:46.436 --> 0:16:50.356 to human studies so far is that mostly what they've 0:16:50.356 --> 0:16:54.636 been used for is non psychiatric disease, and so it's 0:16:54.716 --> 0:17:00.636 really sort of impossible to measure or to recapitulate all 0:17:00.636 --> 0:17:03.476 of the features of a psychiatric disease. 0:17:03.116 --> 0:17:05.036 In a mouse. Right, Like if. 0:17:04.956 --> 0:17:08.956 PTSD is mostly in humans and females is caused by 0:17:09.396 --> 0:17:12.396 you can't really model rape in a mouse, right, And 0:17:12.436 --> 0:17:15.676 so there are all these other features of the illness 0:17:15.836 --> 0:17:18.956 that you know, you can try and approximate by fear learning, 0:17:18.996 --> 0:17:21.956 but you're not really going to capture the salient elements. 0:17:22.196 --> 0:17:26.036 And so this is kind of why I think an 0:17:26.036 --> 0:17:29.796 important test case of this idea of the master key 0:17:30.356 --> 0:17:34.756 is to switch away from neuropsychiatric disease and move into 0:17:34.836 --> 0:17:40.276 neurological disease, because then you know, we can explicitly test 0:17:40.356 --> 0:17:43.716 this learning model. Right if we switch to a neurological 0:17:43.756 --> 0:17:47.876 disease like stroke, and we're able to show that if 0:17:47.916 --> 0:17:51.156 we give psychedelics and pair it with physical therapy, we 0:17:51.196 --> 0:17:55.756 are able to restore motor learning. But if we give 0:17:55.756 --> 0:17:59.196 psychedelics and then just send them on home without any 0:17:59.196 --> 0:18:02.356 additional physical therapy, then nothing really is going to happen. 0:18:02.876 --> 0:18:05.276 That I think would be an explicit test of this 0:18:05.436 --> 0:18:09.596 idea that what the mechanism at work here is about 0:18:09.676 --> 0:18:12.796 learning and memory rather than a magic bill that corrects 0:18:12.796 --> 0:18:14.636 an underlying biochemical imbalance. 0:18:15.236 --> 0:18:17.356 Well, yes, I mean that's the side of it, addressing 0:18:17.676 --> 0:18:21.716 this debate that you're involved in, but also going on 0:18:21.796 --> 0:18:23.876 there presumably if you're able to do this test in 0:18:23.916 --> 0:18:29.276 stroke patients, is if psychedelics plus physical therapy after a 0:18:29.316 --> 0:18:33.836 stroke leads to better recovery than physical therapy alone. That's great. 0:18:33.916 --> 0:18:35.796 I mean, I don't even care about the mechanism at 0:18:35.836 --> 0:18:38.316 that point, right, Like, is somebody going to do a 0:18:38.356 --> 0:18:42.156 phase one safety trial soon? Like is somebody going to 0:18:42.156 --> 0:18:43.836 give stroke patients psychedelics? 0:18:44.516 --> 0:18:45.796 We are, we are working on it. 0:18:46.116 --> 0:18:48.196 Right after this call, I have a meeting to try 0:18:48.236 --> 0:18:52.076 and secure funding to make that happen. So we are 0:18:52.076 --> 0:18:54.316 on it, and we are actually doing it in parallel 0:18:54.396 --> 0:18:58.116 with mouth studies for mechanism. And you know, I understand 0:18:58.196 --> 0:19:01.036 why people are so much more jazzed about you know 0:19:01.116 --> 0:19:04.876 the clinical outcomes and you know the real world impacts 0:19:04.876 --> 0:19:07.796 of these things. But I have to say, I think 0:19:08.276 --> 0:19:12.236 mechanism should not be underestimated as an important way of 0:19:12.356 --> 0:19:14.876 understanding this, because we never would have even come up 0:19:14.916 --> 0:19:18.436 with this idea of thinking about stroke if we hadn't 0:19:18.476 --> 0:19:21.716 thought of the mechanism. Right, So, if we the mechanism 0:19:21.996 --> 0:19:26.276 is what is leading us to speculate, if this mechanism 0:19:26.396 --> 0:19:30.076 is true, then these other diseases should respond in this 0:19:30.276 --> 0:19:31.236 predictable way. 0:19:31.636 --> 0:19:33.796 There was a better way I could have framed that, 0:19:34.756 --> 0:19:37.636 And I apologize. I mean, what I really mean is, yes, 0:19:37.716 --> 0:19:40.796 it's it's useful and big to learn the mechanism. But 0:19:40.996 --> 0:19:44.916 like helping stroke patients get better is also a huge deal. 0:19:45.196 --> 0:19:48.356 Would perhaps be diplomatic way to say that. 0:19:48.716 --> 0:19:51.676 I mean, I don't mind the undiplomatic way, because that's 0:19:51.796 --> 0:19:53.556 I've been dealing with this right from the beginning. 0:19:53.636 --> 0:19:53.796 Right. 0:19:53.836 --> 0:19:57.116 So, the first time I presented this critical period idea 0:19:57.156 --> 0:19:59.716 at a meeting, it was in Portugal, and you know, 0:19:59.756 --> 0:20:03.196 the room was full of people who were already doing 0:20:03.756 --> 0:20:08.876 clinical trials for psilocybin for depression and MDMA for PTSD, 0:20:09.156 --> 0:20:11.836 and they were already very much invested in the idea 0:20:11.916 --> 0:20:14.596 that it was going to work based on some underground 0:20:14.676 --> 0:20:18.876 therapists results and anecdotal reports, some of their you know, 0:20:19.516 --> 0:20:22.596 pilot studies, and they were like, why do we need mechanism? 0:20:22.636 --> 0:20:23.156 Who cares? 0:20:23.236 --> 0:20:25.916 We know it's going to work, and going backwards to 0:20:26.036 --> 0:20:27.396 look in mice seems silly. 0:20:27.476 --> 0:20:29.116 We know it's going to work. It's just the way 0:20:29.196 --> 0:20:29.556 to die. 0:20:30.036 --> 0:20:32.956 And I said at that time it was like, mechanism matters, 0:20:33.036 --> 0:20:35.276 and there are going to be a million different ways 0:20:35.276 --> 0:20:38.716 that we might fail if we don't understand exactly how 0:20:38.756 --> 0:20:42.396 these drugs are working. And basically that prediction ended up 0:20:42.436 --> 0:20:45.196 being true because the two people who were represented in 0:20:45.276 --> 0:20:48.796 that room were on the one side, the people arguing for, 0:20:49.196 --> 0:20:52.636 you know, let's just use psilocybin like a next generation SSRI, 0:20:53.196 --> 0:20:55.836 and their trial failed. And then the other half of 0:20:55.876 --> 0:20:57.876 the room where people who were saying, no, we need 0:20:57.916 --> 0:21:01.636 to pair it with psychotherapy, and their trial was successful. 0:21:01.676 --> 0:21:05.396 And our mechanism, we think explains the difference between them. 0:21:06.396 --> 0:21:09.596 Is there an animal model you can use is to 0:21:09.756 --> 0:21:16.356 test your hypothesis that in stroke patients psychedelics plus physical 0:21:16.356 --> 0:21:19.356 therapy would work better than physical therapy alone. 0:21:20.116 --> 0:21:22.556 Yes, So basically, one of the people I reached out 0:21:22.596 --> 0:21:25.636 to when you know, we first got this critical period 0:21:25.756 --> 0:21:30.236 result for all of the psychedelics. We're two neurologists at 0:21:30.316 --> 0:21:34.236 John Hopkins, so Steve Zeiler and John Krackauer, and Steve 0:21:34.276 --> 0:21:39.076 Zyler especially had been working on developing a mouse model 0:21:39.236 --> 0:21:43.596 of stroke. And what he has shown is that just 0:21:43.716 --> 0:21:46.676 like in human patients with stroke, right after the stroke, 0:21:47.156 --> 0:21:50.716 there is a critical period that gets reopened and some 0:21:50.836 --> 0:21:55.036 amount of physical therapy is able to restore function, but 0:21:55.196 --> 0:21:58.516 that that is time limited. So in my you know, 0:21:58.716 --> 0:22:01.676 within seven days after the stroke, they're no longer able 0:22:01.716 --> 0:22:04.436 to learn. In humans that's a little bit longer. So 0:22:04.996 --> 0:22:07.276 you know, in humans. After your stroke, you're able to 0:22:07.436 --> 0:22:10.796 benefit from therap physical therapy for about two months. At 0:22:10.836 --> 0:22:14.836 about three months it goes away, and that window of time, 0:22:15.396 --> 0:22:18.276 you know, it's closure. And people have thought about, well, 0:22:18.436 --> 0:22:20.596 you know, nobody has dreamed big that we might be 0:22:20.596 --> 0:22:23.436 able to reopen it. But people have tried to do 0:22:23.556 --> 0:22:26.836 other manipulations that might keep it open longer, you know, 0:22:26.916 --> 0:22:30.716 by enriching the environment, by you know, giving them SSRIs, 0:22:30.956 --> 0:22:32.276 and none of those things have worked. 0:22:32.796 --> 0:22:36.436 It's the injury of the stroke itself is inducing the 0:22:36.476 --> 0:22:39.636 brain to reopen the critical period that has been closed 0:22:39.636 --> 0:22:43.676 since childhood, and that allows people to whatever, try and 0:22:43.716 --> 0:22:46.836 relearn language, try and relearn motor skills whatever they have 0:22:46.996 --> 0:22:50.156 lost in the stroke. Obviously not always successfully. 0:22:50.076 --> 0:22:50.556 That's right. 0:22:50.596 --> 0:22:54.916 And basically until this this psychedelic idea came around, the 0:22:54.956 --> 0:22:58.276 most effective way to reopen the critical period for motor 0:22:58.356 --> 0:23:01.796 learning after stroke was to give another stroke, which is 0:23:01.836 --> 0:23:05.556 not you know, very therapeutically viable, right Like, nobody wants 0:23:05.596 --> 0:23:09.956 to hear their stroke with another stroke. So this idea 0:23:10.196 --> 0:23:14.196 is testable and we are in parallel testing it in 0:23:14.276 --> 0:23:17.436 collaboration with the Xylor lab. This is not a social 0:23:17.476 --> 0:23:20.516 critical period this is a motor critical period. So let's 0:23:20.556 --> 0:23:24.116 test the idea that in this context what matters is 0:23:24.236 --> 0:23:27.516 the motor learning or the practicing a motor task, not 0:23:27.716 --> 0:23:30.996 the social And so we're testing that and combining with 0:23:31.036 --> 0:23:34.796 different psychedelics, but we're comparing all of those different conditions 0:23:34.836 --> 0:23:37.756 to test this idea in mice, and then in parallel, 0:23:37.756 --> 0:23:40.196 we will do the study to look at you know, 0:23:40.316 --> 0:23:42.276 trying to reopen in humans. 0:23:43.156 --> 0:23:45.796 And so the mouse study is underway now, and you're 0:23:45.796 --> 0:23:48.636 trying to get funding for the human study, that's right. 0:23:49.716 --> 0:23:51.556 And then once you have the money, then you go 0:23:51.676 --> 0:23:54.236 to the institutional review board and say can we do this? 0:23:55.356 --> 0:23:58.636 Yeah, you know, everything's queued up and wow, you know, 0:23:58.716 --> 0:24:01.156