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How Do Psychedelics Work? · What's Your Problem?

• 0:15
  Speaker 1: Pushkin. Let's talk about psychedelics. It's been a few years
• 0:24
  Speaker 1: since the FDA approved the use of ketamine to treat
• 0:27
  Speaker 1: depression in certain patients. Later this year, the FDA may
• 0:31
  Speaker 1: also approve the use of MDMA in combination with therapy
• 0:35
  Speaker 1: to treat PTSD post traumatic stress disorder, and researchers around
• 0:41
  Speaker 1: the world are studying other powerful psychedelics like psilocybin, ibogaine,
• 0:46
  Speaker 1: and LSD. It's been clear for a long time that
• 0:49
  Speaker 1: these are very powerful drugs, and it's becoming clear that
• 0:53
  Speaker 1: these drugs may be particularly helpful in certain contexts. But
• 0:58
  Speaker 1: still less clear is a very big, very important question,
• 1:03
  Speaker 1: how exactly do psychedelics work. I'm Jacob Goldstein and this
• 1:13
  Speaker 1: is What's Your Problem, the show where I talk to
• 1:15
  Speaker 1: people who are trying to make technological progress. My guest
• 1:19
  Speaker 1: today is goul Dolan. She's a professor of psychology and
• 1:22
  Speaker 1: neuroscience at the University of California at Berkeley. Goule's problem
• 1:27
  Speaker 1: is summed up in a phrase from a paper that
• 1:30
  Speaker 1: she co authored last year in the journal Nature. She's
• 1:34
  Speaker 1: trying to identify quote, a common neurobiological mechanism that can
• 1:39
  Speaker 1: account for the shared therapeutic effects of psychedelics. In other words,
• 1:45
  Speaker 1: why do all these very different drugs seem to have
• 1:48
  Speaker 1: similar powerful effects on the brain. Goole has a theory
• 1:52
  Speaker 1: about this, about why all these different drugs seem to
• 1:55
  Speaker 1: have similar effects, and if she's right, it could mean
• 1:59
  Speaker 1: that psychedelics used in the right context, may be useful
• 2:02
  Speaker 1: beyond mental illness. Goul thinks, among other things, psychedelics may
• 2:07
  Speaker 1: be able to help patients recod from strokes. We started
• 2:11
  Speaker 1: the conversation talking about the origin of Ghul's quest to
• 2:14
  Speaker 1: understand how psychedelics work.
• 2:19
  Speaker 2: About ten years ago when I started my lab, you know,
• 2:22
  Speaker 2: there were starting to be some hints that psychedelics were
• 2:25
  Speaker 2: having these remarkable effects in you know, all kinds of
• 2:28
  Speaker 2: diseases that didn't seem terribly connected to each other, right,
• 2:32
  Speaker 2: so addiction and depression and PTSD, and you know, the
• 2:36
  Speaker 2: people who study those diseases each have their way of
• 2:39
  Speaker 2: studying them and modeling them in animals, and they're they're
• 2:43
  Speaker 2: siloed into different spaces. And yet we were starting to
• 2:47
  Speaker 2: hear hints that, you know, it didn't matter which psychedelic
• 2:51
  Speaker 2: they were kind of interchangeably showing some promise in all
• 2:55
  Speaker 2: of these different areas that seem unconnected to each other.
• 2:58
  Speaker 2: I mean not just in terms of what behavioral essays
• 3:01
  Speaker 2: we use, but even sort of what brain regions might
• 3:04
  Speaker 2: be important. Right, Like, the depression people were focused on
• 3:07
  Speaker 2: the hippi campus and the frontal cortex.
• 3:10
  Speaker 3: The PTSD people.
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  Speaker 2: Were focused on the amygdala, the you know, the addiction
• 3:15
  Speaker 2: people were focused on the nucleus, thecumbents, and they were
• 3:18
  Speaker 2: just sort of all over the place, and yet there
• 3:20
  Speaker 2: seemed to be this overlap. But when we then discovered
• 3:25
  Speaker 2: that all of the psychedelics seemed to be doing the
• 3:27
  Speaker 2: same thing, it sort of began to settle in that
• 3:31
  Speaker 2: this explanation that we came up with could account for
• 3:35
  Speaker 2: why all of these diseases that look so different from
• 3:38
  Speaker 2: each other could be responding to psychedelics in a therapeutic way.
• 3:43
  Speaker 1: So should we start the explanation with talking about critical periods?
• 3:48
  Speaker 1: Is that a reasonable place to start. Let's start with
• 3:50
  Speaker 1: critical periods. What's the critical period?
• 3:52
  Speaker 3: Right?
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  Speaker 2: So, critical periods are something that you know, neuroscientists have
• 3:56
  Speaker 2: known about for almost one hundred years. They were first
• 3:59
  Speaker 2: described in nineteen thirty five by Conrad Lorenz, who was
• 4:03
  Speaker 2: describing and imprinting behavior in baby geese, So basically, forty
• 4:09
  Speaker 2: eight hours after they hatch from their eggs, they will
• 4:12
  Speaker 2: imprint onto anything that is moving around in their immediate environment.
• 4:17
  Speaker 2: So typically this would be their mother, but you know,
• 4:20
  Speaker 2: if there's a crazy scientist around, it might be to
• 4:22
  Speaker 2: the crazy scientist.
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  Speaker 1: And there are photos of the baby geese following him
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  Speaker 1: around right in fact, as if he were a mamma goose.
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  Speaker 4: Yeah, exactly.
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  Speaker 2: And so but that window of time where they're so
• 4:34
  Speaker 2: sensitive to their environment and they form these lasting attachments
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  Speaker 2: only lasts about forty eight hours, and then afterwards they don't.
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  Speaker 2: They're not sensitive to their environment in the same way.
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  Speaker 2: They're not learning from their environment in the same way.
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  Speaker 2: And that window of time Conrad Lorenz called it the
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  Speaker 2: critical period. And since that time we've discovered literally dozens
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  Speaker 2: of other critical periods. So there are critical periods for
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  Speaker 2: rewiring the visual system, critical periods for touch, critical periods
• 5:01
  Speaker 2: for movement, critical periods for language. Language is probably the
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  Speaker 2: one that most people are familiar with. If they try
• 5:08
  Speaker 2: to learn enough their language when they were older, it's
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  Speaker 2: much harder and you always have an accent compared to
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  Speaker 2: the language you learn as a child, and so neuroscientists
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  Speaker 2: have known about these critical periods for a long time,
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  Speaker 2: and we've had this idea that maybe the reason that
• 5:25
  Speaker 2: we're so bad at curing diseases of the brain, neuropsychiatric
• 5:29
  Speaker 2: illnesses and neurological diseases, is because by the time we
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  Speaker 2: get around to correcting whatever is the underlying problem, the
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  Speaker 2: relevant critical period.
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  Speaker 3: Has already closed.
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  Speaker 2: And so the classic example of this is if you
• 5:44
  Speaker 2: are born with bilateral cataracts in your eyes and you
• 5:47
  Speaker 2: don't have them removed by the time you're aged five
• 5:50
  Speaker 2: or so, then you will be blind forever because even
• 5:53
  Speaker 2: if you remove the cataracts, wants the ability of the
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  Speaker 2: visual part of the brain to adapt to the corrected
• 6:01
  Speaker 2: visual environment. Once the critical period has closed, it can't
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  Speaker 2: adapt again, and so even though the impediment is removed,
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  Speaker 2: the brain can respond to it, and so you're blind forever.
• 6:12
  Speaker 2: And so we have been looking, probably for the last
• 6:15
  Speaker 2: one hundred years or so for ways to reopen critical periods,
• 6:19
  Speaker 2: with the idea that if we could reopen them, we
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  Speaker 2: could potentially cure or do a better job of correcting
• 6:27
  Speaker 2: some of these impairments later in life.
• 6:29
  Speaker 1: So in this Nature paper, that you published last year.
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  Speaker 1: You write, it's tempting to speculate that the altered state
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  Speaker 1: of consciousness shared by all psychedelics reflects the subjective experience
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  Speaker 1: of reopening critical periods. Let me say, first of all,
• 6:47
  Speaker 1: I like, it's tempting to speculate. It's like, you're not
• 6:50
  Speaker 1: even speculating.
• 6:51
  Speaker 5: It's more speculative than speculating, right, Like, we're not going
• 6:54
  Speaker 5: to speculate, but we're tempted to speculate. So and I
• 6:58
  Speaker 5: appreciate that, right, Like, this is clearly speculative, it's based
• 7:01
  Speaker 5: on research and mice. But why are you tempted to
• 7:04
  Speaker 5: speculate that psychedelics may reopen critical periods in the brain?
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  Speaker 3: Right?
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  Speaker 2: So, the reason that we're tempted to speculate this is because,
• 7:16
  Speaker 2: you know, one of the other things that brings together
• 7:19
  Speaker 2: psychedelics as a group of drugs is that they all
• 7:23
  Speaker 2: induced this altered state of consciousness. So we discovered a
• 7:26
  Speaker 2: critical period in twenty nineteen for Social rewards learning. It
• 7:30
  Speaker 2: was a brand new critical period. Although you know, there
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  Speaker 2: was a lot of literature from human studies suggesting that
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  Speaker 2: such a critical period should exist, but it just took
• 7:40
  Speaker 2: doing it. In nine hundred mice to be able to
• 7:43
  Speaker 2: formally demonstrate it. So we did that. We showed that
• 7:46
  Speaker 2: there's this social critical period, and originally we showed that
• 7:50
  Speaker 2: MDMA was able to reopen this critical period. And we
• 7:53
  Speaker 2: thought because MDMA is characterized by having this pro social
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  Speaker 2: property that makes it different from the other psychedelics in that,
• 8:02
  Speaker 2: you know, it's altered state of consciousness, plus you know,
• 8:06
  Speaker 2: cuddle puddles and empathy, right, and so we thought it's
• 8:09
  Speaker 2: because of that pro social property of MDMA that it's
• 8:13
  Speaker 2: able to open this social critical period. But then when
• 8:17
  Speaker 2: we figured out that well LSD and I began and KETYMI,
• 8:21
  Speaker 2: none of which are like particularly pro social, nobody's you know,
• 8:25
  Speaker 2: doing a thirty person cuddle puddle on I begin right,
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  Speaker 2: even though they don't have this pro social property, they
• 8:31
  Speaker 2: are all also able.
• 8:32
  Speaker 3: To open this critical period.
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  Speaker 2: And so that was our first hint that maybe the
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  Speaker 2: common property is between psychedelics that accounts for this altered
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  Speaker 2: state of consciousness that they all induce is the common
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  Speaker 2: property of inducing critical period reopening.
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  Speaker 1: And so specifically, can you just talk a little bit
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  Speaker 1: more about the specific critical period in mice that you're
• 8:59
  Speaker 1: looking at here, right?
• 9:01
  Speaker 2: So, we're measuring something called social condition place preference, which
• 9:05
  Speaker 2: is just an assay to measure the ability of the
• 9:10
  Speaker 2: mice to learn from their social environments. And so that
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  Speaker 2: ability changes over time, and as they get older, they
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  Speaker 2: stop learning from their social environment. And so this developmental
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  Speaker 2: change relates to why we think teenagers are so much
• 9:25
  Speaker 2: more susceptible to peer pressure than adults. We think it
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  Speaker 2: relates to why you're so much more sensitive to learning
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  Speaker 2: the rules of your culture when you're young, so you know,
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  Speaker 2: you learn what's polite.
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  Speaker 1: So it's basically the idea is that there's a critical
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  Speaker 1: there is some set of critical periods for learning social
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  Speaker 1: behavior from language to norms, and that that those clothes
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  Speaker 1: over the course of childhood and adolescents.
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  Speaker 3: That's right, that's right.
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  Speaker 2: And we think that that critical period, like other critical
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  Speaker 2: periods like language, you know, is curtailed as you get
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  Speaker 2: older because basically it's sort of expensive energe to always
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  Speaker 2: be having to learn from your social environment.
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  Speaker 3: You know, I like to.
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  Speaker 2: Think back on my teenage years and you know, mostly
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  Speaker 2: I'm relieved that they're over, because you know, it was
• 10:21
  Speaker 2: time consuming and energetically exhausting to you know, have to
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  Speaker 2: care about the exact right shade of acid washed genes
• 10:29
  Speaker 2: that the cool kids are wearing.
• 10:30
  Speaker 1: Right, and now you wear whatever acid wash genes you want, right,
• 10:34
  Speaker 1: that's right.
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  Speaker 4: I wear mom jeans that are acid washed.
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  Speaker 1: And so then you find that when you give psychedelics
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  Speaker 1: to an old mouse, they're able to the.
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  Speaker 2: Learning that they were doing in juvenile in their juvenile
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  Speaker 2: period return, so they're able to learn again like a juvenile.
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  Speaker 1: Have you tested this theory on other critical periods in
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  Speaker 1: mice or on other animals?
• 11:01
  Speaker 2: Yeah, So basically, as soon as we got this this result,
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  Speaker 2: I reached out to every single person that I know
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  Speaker 2: who works on critics periods, and I was like, do
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  Speaker 2: you have a critical period that you want to try
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  Speaker 2: and reopen? Because I think we might have accidentally stumbled
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  Speaker 2: on the master key for unlocking critical periods, and so
• 11:20
  Speaker 2: we're working on it. We definitely have some collaborations going.
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  Speaker 2: But in the meantime between sort of when we first
• 11:27
  Speaker 2: have this twenty nineteen paper and then this summer, there
• 11:30
  Speaker 2: have been some hints that other critical periods are being
• 11:35
  Speaker 2: reopened by say ketamine. There are two papers showing that ketamine,
• 11:40
  Speaker 2: if given back to back to back to back can
• 11:43
  Speaker 2: reopen the critical period for ocular dominance plasticity, which is
• 11:47
  Speaker 2: this visual critical period that we've learned so much about
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  Speaker 2: the mechanisms about. So that's a first hint, and we
• 11:54
  Speaker 2: are working feverishly to see if we can reopen other
• 11:59
  Speaker 2: critical periods like motor learning for stroke. We're doing that
• 12:03
  Speaker 2: in both mice and in humans. We're working on some
• 12:06
  Speaker 2: language critical periods in collaboration with some of the labs.
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  Speaker 2: So you know, the jury is still out, but there's
• 12:13
  Speaker 2: some other reasons to make us think that we're on
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  Speaker 2: the right track with this idea about the master key.
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  Speaker 1: When you say master key in this context, in this context,
• 12:23
  Speaker 1: exactly what do you mean?
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  Speaker 2: So I guess what I mean is is that when
• 12:28
  Speaker 2: I was a graduate student, we were a little bit
• 12:30
  Speaker 2: in a debate with another lab that was proposing that
• 12:34
  Speaker 2: there would be some drug or manipulation that you could
• 12:38
  Speaker 2: do that could reopen all critical periods, and that you
• 12:43
  Speaker 2: could just give that drug and it would it would
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  Speaker 2: it would be the master key, right and for unlocking
• 12:50
  Speaker 2: all of these critical periods. And at the time, I
• 12:53
  Speaker 2: remember being really skeptical of that idea, and I thought, well,
• 12:58
  Speaker 2: anything that can do that to the brain is either
• 13:01
  Speaker 2: going to induce amnesia, cause seizure, or disrupt the structural
• 13:07
  Speaker 2: integrity of the brain. And I thought that because of
• 13:11
  Speaker 2: what we knew about, you know, basically the mechanisms that
• 13:14
  Speaker 2: constrain critical periods to these windows of time, like like.
• 13:19
  Speaker 1: You couldn't work without breaking the brain. The only way
• 13:22
  Speaker 1: to reopen the critical period is the master key is
• 13:24
  Speaker 1: like a sledgehammer that's just gonna totally break everything. So
• 13:27
  Speaker 1: why even bother.
• 13:29
  Speaker 2: Right, And I you know, I called it the Melti
• 13:31
  Speaker 2: brain problem, right, And so then when we when we
• 13:34
  Speaker 2: started getting these results for the psychedelics, I was, I
• 13:39
  Speaker 2: started thinking, well, how come we're not running into the
• 13:42
  Speaker 2: Melty brain problem? And I think, and this is at
• 13:46
  Speaker 2: this point still speculative, and we're we're actively pursuing this
• 13:50
  Speaker 2: line of research. So I don't want to overstate the case.
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  Speaker 2: But my hunch is that the way that we are
• 13:56
  Speaker 2: able to circumvent, or the way that psychedelics specifically are circumventing,
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  Speaker 2: the Melty brain problem is that they are context specific.
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  Speaker 2: So it's not that psychdelics are causing reopening of all
• 14:12
  Speaker 2: critical periods everywhere in the brain all at the same time.
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  Speaker 2: It seems to be that they are not you know,
• 14:21
  Speaker 2: destroying or melting the brain, because they're only making available
• 14:26
  Speaker 2: for modification the subset of synapses, circuits, memories, and grams
• 14:34
  Speaker 2: that are have been recently activated, and that is why
• 14:38
  Speaker 2: they have this constraint of being context dependent.
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  Speaker 1: So this is this is why your thesis is they
• 14:45
  Speaker 1: will psychedels will be helpful when paired with interventions like therapy,
• 14:51
  Speaker 1: but not by themselves.
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  Speaker 4: Well, this is.
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  Speaker 2: This is the explanation we have for why the psychedelics
• 15:00
  Speaker 2: aren't breaking the the brain rather than I mean, basically,
• 15:06
  Speaker 2: the clinical data is driving this idea that in fact
• 15:11
  Speaker 2: the context matters, right.
• 15:12
  Speaker 1: But it's a potential mechanistic explanation for that.
• 15:15
  Speaker 2: Clinical well that feature, that's right, it's a mechanistic explanation
• 15:19
  Speaker 2: for a clinical description, which you know, I don't think
• 15:22
  Speaker 2: is going to be the case for every single application
• 15:24
  Speaker 2: that psychedelics might be used for. So, for example, I
• 15:27
  Speaker 2: think the critical period idea nicely explains why MDMA assisted
• 15:32
  Speaker 2: psychotherapy works. If we're able to demonstrate that we can
• 15:37
  Speaker 2: correct motor impairments following stroke with psychedelics paired with physical therapy,
• 15:44
  Speaker 2: then that'll be a nice other explanation.
• 15:47
  Speaker 1: That's a huge idea. You've just dropped in the middle
• 15:50
  Speaker 1: of a list, by the.
• 15:52
  Speaker 2: Way, right, So, by the way, that's also quite quite speculative.
• 16:00
  Speaker 1: After the break, how gool plans to test this hypothesis
• 16:04
  Speaker 1: that psychedelics may help patients recovering from strokes. Let's just
• 16:19
  Speaker 1: talk about how we get from this sort of you know,
• 16:23
  Speaker 1: seems like psychedelics reopen one critical period in mice to like,
• 16:29
  Speaker 1: can this idea be helpful in humans?
• 16:31
  Speaker 4: Right?
• 16:33
  Speaker 1: You must know the aphorism mice lie and primates exaggerate.
• 16:36
  Speaker 1: I was thinking of that one.
• 16:39
  Speaker 2: I mean, I think that a little bit of why
• 16:42
  Speaker 2: it's so hard to translate this stuff from mouse studies
• 16:46
  Speaker 2: to human studies so far is that mostly what they've
• 16:50
  Speaker 2: been used for is non psychiatric disease, and so it's
• 16:54
  Speaker 2: really sort of impossible to measure or to recapitulate all
• 17:00
  Speaker 2: of the features of a psychiatric disease.
• 17:03
  Speaker 3: In a mouse. Right, Like if.
• 17:04
  Speaker 2: PTSD is mostly in humans and females is caused by
• 17:09
  Speaker 2: you can't really model rape in a mouse, right, And
• 17:12
  Speaker 2: so there are all these other features of the illness
• 17:15
  Speaker 2: that you know, you can try and approximate by fear learning,
• 17:18
  Speaker 2: but you're not really going to capture the salient elements.
• 17:22
  Speaker 2: And so this is kind of why I think an
• 17:26
  Speaker 2: important test case of this idea of the master key
• 17:30
  Speaker 2: is to switch away from neuropsychiatric disease and move into
• 17:34
  Speaker 2: neurological disease, because then you know, we can explicitly test
• 17:40
  Speaker 2: this learning model. Right if we switch to a neurological
• 17:43
  Speaker 2: disease like stroke, and we're able to show that if
• 17:47
  Speaker 2: we give psychedelics and pair it with physical therapy, we
• 17:51
  Speaker 2: are able to restore motor learning. But if we give
• 17:55
  Speaker 2: psychedelics and then just send them on home without any
• 17:59
  Speaker 2: additional physical therapy, then nothing really is going to happen.
• 18:02
  Speaker 2: That I think would be an explicit test of this
• 18:05
  Speaker 2: idea that what the mechanism at work here is about
• 18:09
  Speaker 2: learning and memory rather than a magic bill that corrects
• 18:12
  Speaker 2: an underlying biochemical imbalance.
• 18:15
  Speaker 1: Well, yes, I mean that's the side of it, addressing
• 18:17
  Speaker 1: this debate that you're involved in, but also going on
• 18:21
  Speaker 1: there presumably if you're able to do this test in
• 18:23
  Speaker 1: stroke patients, is if psychedelics plus physical therapy after a
• 18:29
  Speaker 1: stroke leads to better recovery than physical therapy alone. That's great.
• 18:33
  Speaker 1: I mean, I don't even care about the mechanism at
• 18:35
  Speaker 1: that point, right, Like, is somebody going to do a
• 18:38
  Speaker 1: phase one safety trial soon? Like is somebody going to
• 18:42
  Speaker 1: give stroke patients psychedelics?
• 18:44
  Speaker 4: We are, we are working on it.
• 18:46
  Speaker 2: Right after this call, I have a meeting to try
• 18:48
  Speaker 2: and secure funding to make that happen. So we are
• 18:52
  Speaker 2: on it, and we are actually doing it in parallel
• 18:54
  Speaker 2: with mouth studies for mechanism. And you know, I understand
• 18:58
  Speaker 2: why people are so much more jazzed about you know
• 19:01
  Speaker 2: the clinical outcomes and you know the real world impacts
• 19:04
  Speaker 2: of these things. But I have to say, I think
• 19:08
  Speaker 2: mechanism should not be underestimated as an important way of
• 19:12
  Speaker 2: understanding this, because we never would have even come up
• 19:14
  Speaker 2: with this idea of thinking about stroke if we hadn't
• 19:18
  Speaker 2: thought of the mechanism. Right, So, if we the mechanism
• 19:21
  Speaker 2: is what is leading us to speculate, if this mechanism
• 19:26
  Speaker 2: is true, then these other diseases should respond in this
• 19:30
  Speaker 2: predictable way.
• 19:31
  Speaker 1: There was a better way I could have framed that,
• 19:34
  Speaker 1: And I apologize. I mean, what I really mean is, yes,
• 19:37
  Speaker 1: it's it's useful and big to learn the mechanism. But
• 19:40
  Speaker 1: like helping stroke patients get better is also a huge deal.
• 19:45
  Speaker 1: Would perhaps be diplomatic way to say that.
• 19:48
  Speaker 2: I mean, I don't mind the undiplomatic way, because that's
• 19:51
  Speaker 2: I've been dealing with this right from the beginning.
• 19:53
  Speaker 4: Right.
• 19:53
  Speaker 2: So, the first time I presented this critical period idea
• 19:57
  Speaker 2: at a meeting, it was in Portugal, and you know,
• 19:59
  Speaker 2: the room was full of people who were already doing
• 20:03
  Speaker 2: clinical trials for psilocybin for depression and MDMA for PTSD,
• 20:09
  Speaker 2: and they were already very much invested in the idea
• 20:11
  Speaker 2: that it was going to work based on some underground
• 20:14
  Speaker 2: therapists results and anecdotal reports, some of their you know,
• 20:19
  Speaker 2: pilot studies, and they were like, why do we need mechanism?
• 20:22
  Speaker 4: Who cares?
• 20:23
  Speaker 2: We know it's going to work, and going backwards to
• 20:26
  Speaker 2: look in mice seems silly.
• 20:27
  Speaker 4: We know it's going to work. It's just the way
• 20:29
  Speaker 4: to die.
• 20:30
  Speaker 2: And I said at that time it was like, mechanism matters,
• 20:33
  Speaker 2: and there are going to be a million different ways
• 20:35
  Speaker 2: that we might fail if we don't understand exactly how
• 20:38
  Speaker 2: these drugs are working. And basically that prediction ended up
• 20:42
  Speaker 2: being true because the two people who were represented in
• 20:45
  Speaker 2: that room were on the one side, the people arguing for,
• 20:49
  Speaker 2: you know, let's just use psilocybin like a next generation SSRI,
• 20:53
  Speaker 2: and their trial failed. And then the other half of
• 20:55
  Speaker 2: the room where people who were saying, no, we need
• 20:57
  Speaker 2: to pair it with psychotherapy, and their trial was successful.
• 21:01
  Speaker 2: And our mechanism, we think explains the difference between them.
• 21:06
  Speaker 1: Is there an animal model you can use is to
• 21:09
  Speaker 1: test your hypothesis that in stroke patients psychedelics plus physical
• 21:16
  Speaker 1: therapy would work better than physical therapy alone.
• 21:20
  Speaker 2: Yes, So basically, one of the people I reached out
• 21:22
  Speaker 2: to when you know, we first got this critical period
• 21:25
  Speaker 2: result for all of the psychedelics. We're two neurologists at
• 21:30
  Speaker 2: John Hopkins, so Steve Zeiler and John Krackauer, and Steve
• 21:34
  Speaker 2: Zyler especially had been working on developing a mouse model
• 21:39
  Speaker 2: of stroke. And what he has shown is that just
• 21:43
  Speaker 2: like in human patients with stroke, right after the stroke,
• 21:47
  Speaker 2: there is a critical period that gets reopened and some
• 21:50
  Speaker 2: amount of physical therapy is able to restore function, but
• 21:55
  Speaker 2: that that is time limited. So in my you know,
• 21:58
  Speaker 2: within seven days after the stroke, they're no longer able
• 22:01
  Speaker 2: to learn. In humans that's a little bit longer. So
• 22:04
  Speaker 2: you know, in humans. After your stroke, you're able to
• 22:07
  Speaker 2: benefit from therap physical therapy for about two months. At
• 22:10
  Speaker 2: about three months it goes away, and that window of time,
• 22:15
  Speaker 2: you know, it's closure. And people have thought about, well,
• 22:18
  Speaker 2: you know, nobody has dreamed big that we might be
• 22:20
  Speaker 2: able to reopen it. But people have tried to do
• 22:23
  Speaker 2: other manipulations that might keep it open longer, you know,
• 22:26
  Speaker 2: by enriching the environment, by you know, giving them SSRIs,
• 22:30
  Speaker 2: and none of those things have worked.
• 22:32
  Speaker 1: It's the injury of the stroke itself is inducing the
• 22:36
  Speaker 1: brain to reopen the critical period that has been closed
• 22:39
  Speaker 1: since childhood, and that allows people to whatever, try and
• 22:43
  Speaker 1: relearn language, try and relearn motor skills whatever they have
• 22:46
  Speaker 1: lost in the stroke. Obviously not always successfully.
• 22:50
  Speaker 3: That's right.
• 22:50
  Speaker 2: And basically until this this psychedelic idea came around, the
• 22:54
  Speaker 2: most effective way to reopen the critical period for motor
• 22:58
  Speaker 2: learning after stroke was to give another stroke, which is
• 23:01
  Speaker 2: not you know, very therapeutically viable, right Like, nobody wants
• 23:05
  Speaker 2: to hear their stroke with another stroke. So this idea
• 23:10
  Speaker 2: is testable and we are in parallel testing it in
• 23:14
  Speaker 2: collaboration with the Xylor lab. This is not a social
• 23:17
  Speaker 2: critical period this is a motor critical period. So let's
• 23:20
  Speaker 2: test the idea that in this context what matters is
• 23:24
  Speaker 2: the motor learning or the practicing a motor task, not
• 23:27
  Speaker 2: the social And so we're testing that and combining with
• 23:31
  Speaker 2: different psychedelics, but we're comparing all of those different conditions
• 23:34
  Speaker 2: to test this idea in mice, and then in parallel,
• 23:37
  Speaker 2: we will do the study to look at you know,
• 23:40
  Speaker 2: trying to reopen in humans.
• 23:43
  Speaker 1: And so the mouse study is underway now, and you're
• 23:45
  Speaker 1: trying to get funding for the human study, that's right.
• 23:49
  Speaker 1: And then once you have the money, then you go
• 23:51
  Speaker 1: to the institutional review board and say can we do this?
• 23:55
  Speaker 2: Yeah, you know, everything's queued up and wow, you know,
• 23:58
  Speaker 2: everything is basically ready to go.
• 24:01
  Speaker 4: We just need the money.
• 24:03
  Speaker 1: So non trivial, but it's a lot probably surmountable.
• 24:08
  Speaker 4: Yeah, yeah, I mean it's a lot of money.
• 24:10
  Speaker 2: We're asking for a million dollars to run, you know,
• 24:13
  Speaker 2: a safety trial and about twenty people. And then if
• 24:16
  Speaker 2: that phase one trial goes well. The way the trial
• 24:19
  Speaker 2: is designed is that it will allow us to collect
• 24:22
  Speaker 2: just a little bit of in addition to how well
• 24:25
  Speaker 2: this patient population, right, because these are older people who
• 24:28
  Speaker 2: have other medical issues, so we just want to be
• 24:32
  Speaker 2: double sure that you know, these drugs are safe in
• 24:34
  Speaker 2: this population. But the way we've designed the trial is
• 24:38
  Speaker 2: it'll give us some hints about efficacy, so we'll test,
• 24:41
  Speaker 2: you know, a little bit of you know, their ability
• 24:43
  Speaker 2: to recover motor function. And the most important thing about
• 24:46
  Speaker 2: the human trial and the way that I the reason
• 24:48
  Speaker 2: that I paired up with Steve and John is because
• 24:51
  Speaker 2: they have actually developed a sort of gamified virtual reality
• 24:56
  Speaker 2: context for delivering this physical therapy. It's a virtual reality
• 25:01
  Speaker 2: kind of room, and the cameras track the person's body
• 25:05
  Speaker 2: position in space, and as they move their arm around,
• 25:09
  Speaker 2: a dolphin on a screen moves around, and it's sort
• 25:12
  Speaker 2: of a fun way to get people to practice moving.
• 25:16
  Speaker 2: But it's also a little bit more play like, which
• 25:19
  Speaker 2: is more the way that we learn during our childhood.
• 25:23
  Speaker 2: So there's this shift in the way we learn between
• 25:26
  Speaker 2: childhood and adulthood from exploratory learning to sort of goal
• 25:32
  Speaker 2: directed exploitatory learning, and so we want to kind of
• 25:36
  Speaker 2: mimic that as much as possible, to make it fun
• 25:39
  Speaker 2: and to make it not be goal directed.
• 25:42
  Speaker 1: They're already doing that sort of psychedelic adjacent sounding thing
• 25:48
  Speaker 1: where your arm is a dolphin and you're playing. They're
• 25:51
  Speaker 1: doing that without psychedelics, and you're like, let's definitely add
• 25:53
  Speaker 1: some psychedelics to that. I mean, is that not to
• 25:55
  Speaker 1: be glib about it, but they're already doing that without psychedelics.
• 25:58
  Speaker 4: That's right.
• 25:59
  Speaker 2: So they have developed that whole paradigm to test the
• 26:04
  Speaker 2: efficacy of that sort of gamified environment compare to standard
• 26:09
  Speaker 2: of care, because standard of care is really mostly just
• 26:14
  Speaker 2: teaching patients how to say the other hand, to zip
• 26:18
  Speaker 2: their zipper and brush their hand. It's really compensatory, not
• 26:22
  Speaker 2: trying to bring back the lost motor function. And so
• 26:27
  Speaker 2: they've done head to head studies of the virtual reality
• 26:31
  Speaker 2: game version versus standard of care during that open state,
• 26:36
  Speaker 2: of the normal open state of the critical beers, so
• 26:38
  Speaker 2: right after the stroke. They've shown that there's better outcomes
• 26:43
  Speaker 2: if they use this gamified version. And so now we're saying, okay,
• 26:47
  Speaker 2: let's take all those people who didn't get the optimal
• 26:51
  Speaker 2: therapy right after their stroke, people who had a stroke
• 26:54
  Speaker 2: a year ago, and go back and see if we
• 26:56
  Speaker 2: can reopen this critical period and then give them what
• 27:00
  Speaker 2: we think is the better therapy in terms of this
• 27:03
  Speaker 2: virtual reality.
• 27:08
  Speaker 1: We'll be back in a minute with the lightning round. Okay,
• 27:21
  Speaker 1: let's finish with the lightning round.
• 27:24
  Speaker 4: Okay.
• 27:25
  Speaker 1: What's your biggest professional disagreement with your mother.
• 27:30
  Speaker 4: Whether psychedelics can cure allergies?
• 27:34
  Speaker 1: Go on.
• 27:35
  Speaker 2: Okay, Well, so my mother is an allergy and immunologist clinician.
• 27:41
  Speaker 2: She's retired now, but you know, I've told her this
• 27:45
  Speaker 2: crazy idea that we had about psychedelics and she was like, no,
• 27:49
  Speaker 2: that's not how it works. And the idea is based
• 27:52
  Speaker 2: on the fact that, you know, there's some evidence to
• 27:54
  Speaker 2: support the notion that allergy happens because you know, the
• 27:58
  Speaker 2: immune system, the part of the immune system that's normally
• 28:01
  Speaker 2: supposed to fight off parasitic infections, is being underutilized by
• 28:07
  Speaker 2: our modern diets, which are put more parasite free than
• 28:11
  Speaker 2: our evolutionary history, and so it's sort of left jobless
• 28:16
  Speaker 2: and it's looking for a job. And my idea is that, well,
• 28:19
  Speaker 2: maybe the brain is assigning the job and saying that
• 28:22
  Speaker 2: dog barked at you, that's scary, that's the threat to
• 28:25
  Speaker 2: go after that immune system, and that if that's a
• 28:29
  Speaker 2: learned association that the brain decided that it could unlearn
• 28:33
  Speaker 2: it too.
• 28:34
  Speaker 3: By reopening this critical period.
• 28:35
  Speaker 4: It's totally speculative.
• 28:36
  Speaker 2: I have to say, like, I don't believe it enough
• 28:39
  Speaker 2: where I'm like out, you know, doing psychedelics and snuggling
• 28:42
  Speaker 2: up to a horse.
• 28:43
  Speaker 4: I would love to cure my horse allergies. But I don't.
• 28:46
  Speaker 4: I don't believe it enough to go for it.
• 28:48
  Speaker 3: I think it's a testable hypothesis that we should study.
• 28:51
  Speaker 1: And your and your mom believes it even less than
• 28:53
  Speaker 1: you do.
• 28:54
  Speaker 4: That's right.
• 28:55
  Speaker 1: Yes, what's your favorite portrayal of a psychedelics of a
• 29:01
  Speaker 1: psychedelic experience in you know, in whatever, in a book,
• 29:04
  Speaker 1: in a movie, in music.
• 29:07
  Speaker 2: I really still have a soft spot in my heart
• 29:12
  Speaker 2: for the Huxley description of him staring at a chair,
• 29:16
  Speaker 2: because you know, as a scientist, I have to say
• 29:19
  Speaker 2: that one really resonates. Like I'm not a religious person,
• 29:23
  Speaker 2: mystical experiences, that stuff doesn't really resonate with me. But
• 29:27
  Speaker 2: he's staring at a chair and sort of being mesmerized
• 29:31
  Speaker 2: by the you know, asymptotic distribution of chair molecules the
• 29:35
  Speaker 2: further away you get from the chair, and then the
• 29:38
  Speaker 2: Huxley molecules the further and then you know, the two
• 29:41
  Speaker 2: of them sitting on each other and suddenly they're inert
• 29:44
  Speaker 2: they're intermixed, and Huxley is the chair.
• 29:47
  Speaker 4: I mean that that resonates.
• 29:48
  Speaker 1: But have you ever taken psychedelics for work?
• 29:54
  Speaker 4: I don't know.
• 29:55
  Speaker 2: Yeah, I don't really want to talk about that or
• 29:58
  Speaker 2: answer that question.
• 30:00
  Speaker 1: Mine totally reasonable. Do you have any advice for people
• 30:04
  Speaker 1: who are considering taking psychedelics recreationally.
• 30:08
  Speaker 2: Yeah, it would say that, you know, these are powerful
• 30:10
  Speaker 2: medicines and that we should honor and respect their power,
• 30:15
  Speaker 2: and that they're doing something. If we're right, they're doing
• 30:18
  Speaker 2: something very big to the brain, and that this transformation
• 30:24
  Speaker 2: should not be taken lightly. And you know, I would
• 30:27
  Speaker 2: also emphasize that our studies suggest that once you reopen
• 30:31
  Speaker 2: these critical periods, especially with psilocybin, MDMA and LSD, they
• 30:36
  Speaker 2: stay open for several weeks after the acute effects of
• 30:40
  Speaker 2: the drug wear off, and so you're gonna be in
• 30:43
  Speaker 2: a in a sort of vulnerable state that's reminiscent of childhood.
• 30:48
  Speaker 2: And I would say be very very cautious about who
• 30:51
  Speaker 2: you expose yourself to during that period. You know, if
• 30:55
  Speaker 2: you're in a traumatic relationship, it's probably a good idea
• 30:59
  Speaker 2: to stay away from your traumatizer for a couple of
• 31:01
  Speaker 2: weeks after you've taken the drug, you know. I think
• 31:05
  Speaker 2: that we can learn a lot from the history of
• 31:08
  Speaker 2: these drugs.
• 31:10
  Speaker 3: You know.
• 31:10
  Speaker 2: Charles Manson is a good example of somebody who gave
• 31:14
  Speaker 2: psychedelics to people and then used it to, you know,
• 31:18
  Speaker 2: when they were in this vulnerable state, which presumably lasted
• 31:21
  Speaker 2: for a long time, to indoctrinate them into his way
• 31:25
  Speaker 2: of thinking, and turned a bunch of hippies into killers
• 31:28
  Speaker 2: who were going to, you know, induce helter skelter to
• 31:31
  Speaker 2: save the world. This is the sort of awesome power
• 31:36
  Speaker 2: of these drugs that we need to be very mindful
• 31:39
  Speaker 2: of and not treat them like little toys.
• 31:43
  Speaker 1: Anything else, anything else we should talk about. I know
• 31:45
  Speaker 1: you've got to go. I don't want to keep you,
• 31:47
  Speaker 1: but if there's anything else you want to say.
• 31:49
  Speaker 2: Please, I think we covered a lot, super fun. Thank
• 31:53
  Speaker 2: you so much, any.
• 31:56
  Speaker 4: Thanks one million dollars.
• 32:06
  Speaker 1: Gool Dolan is a professor of psychology and science at
• 32:10
  Speaker 1: UC Berkeley. Today's show was produced by Gabriel Hunter Cheng.
• 32:14
  Speaker 1: It was edited by Lyddy Jean Kott and engineered by
• 32:18
  Speaker 1: Sarah Bruguier. You can email us at problem at Pushkin
• 32:21
  Speaker 1: dot Fm. I'm Jacob Goldstein and we'll be back next
• 32:25
  Speaker 1: week with another episode of What's Your Problem.