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Speaker 1: Hi, I'm Ethan Nadelman, and this is Psychoactive, a production

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Speaker 1: of I Heart Radio and Protozoa Pictures. Psychoactive is the

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Speaker 1: show where we talk about all things drugs. But any

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Speaker 1: of views expressed here do not represent those of I

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Speaker 1: Heart Media, Protozoa Pictures, or their executives and employees. Indeed, heed,

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Speaker 1: as an inveterate contrarian, I can tell you they may

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Speaker 1: not even represent my own. And nothing contained in this

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Speaker 1: show should be used as medical advice or encouragement to

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Speaker 1: use any type of drug. Hello, Psychoactive listeners. So today

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Speaker 1: we're gonna venture into a territory which I rarely or

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Speaker 1: ever enter into, which is the neuroscience of drugs. You know,

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Speaker 1: I'm I'm always drawn to the history, the culture, the politics,

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Speaker 1: what have you, the therapeutic side, but it's important to

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Speaker 1: try to get a sense of why some drugs work

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Speaker 1: the way they do, and in this case, we're going

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Speaker 1: to focus on why m D M A and psychedelics

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Speaker 1: seem to have this remarkable therapeutic potential, which is kind

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Speaker 1: of sort of what's behind this psychedelic renaissance. The person

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Speaker 1: I've asked to join me today to talk about This

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Speaker 1: is Professor goul Dolin. She's in the Department of Neuroscience

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Speaker 1: at Johns Hopkins Glula Medicine. She's been doing research on

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Speaker 1: psycholics in recent years, but she's got a much longer

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Speaker 1: background going to doing research on oxytocin and try to

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Speaker 1: understand autism better. She got her m d and her

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Speaker 1: PhD at Brown and m I T. She did a

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Speaker 1: post stock training at Stanford. She's been publishing important articles

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Speaker 1: for a good fifteen years, but has really started to

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Speaker 1: generate some incredible excitement in recent years because of a

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Speaker 1: few studies that she's done that seemed to provide some

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Speaker 1: new insights into how and why M D m A,

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Speaker 1: into some extent, psychedelics work the way they do. One

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Speaker 1: of them involves octopuses and another is studies done on mice,

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Speaker 1: but with important implications for understanding why m D m

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Speaker 1: A works the way it does and other psychedelics with

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Speaker 1: human beings. So cool, Thanks ever so much for joining

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Speaker 1: me on Psychoactive. Thank you very much for having me.

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Speaker 1: So let me just start off the first most basic question.

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Speaker 1: We now have these studies and by the way'm gonna

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Speaker 1: sometimes say M D M A and psychedelics. Sometimes I'll

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Speaker 1: say m d M A and other psychedelics, as m

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Speaker 1: d M A isn't quite a psychedelic. So if I

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Speaker 1: go back and forth, just I hope our listeners will

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Speaker 1: give me a little of forgiveness there. But but the

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Speaker 1: first questions, we know there's been studies, you know, you

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Speaker 1: do studies on animals at the beginning to show the

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Speaker 1: safety of a drug, to make sure that M D

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Speaker 1: M A or something is not toxic. But just the

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Speaker 1: very basic question, if we already have a good sense

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Speaker 1: that these drugs are having an impact on humans, say

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Speaker 1: in a therapeutic context and therapeutic value, why even bother

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Speaker 1: with studies and other animals. Yeah, that's a great question,

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Speaker 1: and it's actually something I've debated a little bit with

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Speaker 1: people who are very invested in, you know, pursuing the

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Speaker 1: clinical trials. They cost a lot more money, So why

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Speaker 1: why do we need the mechanism? And the reason is

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Speaker 1: is because you know, while many of these drugs have

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Speaker 1: been used in traditional healing practices for years and years

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Speaker 1: and years centuries, we are using them differently. Necessarily, we're

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Speaker 1: using them differently because we are embedding these practices in

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Speaker 1: a different culture, and we are trying to treat people

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Speaker 1: who are raised in a different culture. And so if

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Speaker 1: we're going to try and adapt them for use the

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Speaker 1: way that we want to use them, we really need

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Speaker 1: to have a strong basis and understanding what they're doing,

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Speaker 1: why they're working, so that we can use them appropriately,

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Speaker 1: so that we don't inadvertently cause harm when we're trying

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Speaker 1: to apply them in new ways, so that we understand

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Speaker 1: both the limit patitions, the constraints, and the opportunities that

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Speaker 1: work in our context. And I will just back up

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Speaker 1: and say one more thing, which is that I think

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Speaker 1: that because of the way science gets reported in our

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Speaker 1: newspapers and then the lay press, you know, there's this

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Speaker 1: impression that we understand a lot of things from doing

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Speaker 1: studies in humans exclusively, but almost all of the mechanisms

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Speaker 1: that we understand we understand because we've been able to

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Speaker 1: do very basic studies in animal models. Right. So, you

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Speaker 1: know you mentioned my interest in oxytocin. Almost everything we

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Speaker 1: know about oxytocin and its involvement and regulating love, and

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Speaker 1: its involvement at regulating neurotransmitters and the connections between neurons

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Speaker 1: and how signals get transmitted between those brain cells. All

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Speaker 1: of those studies were done in animals, and then we

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Speaker 1: extrapolated from those two humans based on similarity. These that

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Speaker 1: we know exists between mice and human brains. Oxytocin. That's

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Speaker 1: the drug that's kind of known as the love drug

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Speaker 1: or the hug drug, the one that gets released when

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Speaker 1: the mother nurses her baby or when people make love

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Speaker 1: or things like that. That's right, that's right. And the

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Speaker 1: other drugs that everybody talks about is serotonin, the neurochemical

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Speaker 1: that people have implicated in mood and depression. And that

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Speaker 1: all of these drugs like Prozac that are selective serotonin

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Speaker 1: reuptake inhibitors or s s r e s. These molecules,

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Speaker 1: everything we know about them, we know about them because

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Speaker 1: of animal studies that we've been extrapolated to humans. I see.

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Speaker 1: So now, when we think about animal studies, typically, you know,

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Speaker 1: we think about mice or rats, or maybe you might

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Speaker 1: think about things like you know, primates, apes and orangutangs

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Speaker 1: or or maybe even dolphins. You know, things that are

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Speaker 1: known for high intelligence and are sort of closer to us.

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Speaker 1: But you decided to work with octopuses and to administer

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Speaker 1: NDMA to octopus is why. Yeah. So basically, I mean,

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Speaker 1: I think it's a very strong tradition in science to

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Speaker 1: try and understand human emotion and cognition and disease by

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Speaker 1: focusing on the closest relative that we can do these

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Speaker 1: kinds of experiments in, and then that way we presume

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Speaker 1: that we will be able to understand some sort of rules,

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Speaker 1: and because they're closely related, it's easier to make that extrapolation.

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Speaker 1: But the approach that we decided to take was one

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Speaker 1: that had kind of been in the scientific literature for

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Speaker 1: a while. It was actually proposed by Jay z Young,

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Speaker 1: who's really important physiologist and ethologists in neuroscience and behavioral

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Speaker 1: studies of animals, and he said, what you really want

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Speaker 1: to do is to go for the animal that is

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Speaker 1: evolutionarily most distant from us, so most different, separated by

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Speaker 1: as much evolutionary time as you can, who also exhibits

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Speaker 1: some of the complex behaviors that we do you and

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Speaker 1: that by comparing those maximally different brains to each other,

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Speaker 1: then you can sort of overlook or look past all

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Speaker 1: the extraneous historical accidents of evolution and figure out the

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Speaker 1: rules for how to build complexity and so we decided

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Speaker 1: that we wanted to understand how seratonin, this neuro transmitter

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Speaker 1: that I mentioned, has been implicated in almost every function

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Speaker 1: you can think of, including mood and feeding and temperature regulation,

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Speaker 1: and we wanted to know how old is its role

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Speaker 1: in regulating social behaviors and can we deduce any of

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Speaker 1: those rules by looking at an octopus? And so basically,

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Speaker 1: I mean, if I understand it, so, an octopus is

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Speaker 1: quite radically different than human beings. They don't have the

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Speaker 1: same kind of brain. All the things that the parts

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Speaker 1: of the brain are supposedly light up when you do mbma,

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Speaker 1: they don't even have that. So the common element is

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Speaker 1: that they have these serotonin transporters. Is that the key

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Speaker 1: thing that makes it relevant here. Yeah, So that was

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Speaker 1: actually the idea we were testing. Their brains don't look

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Speaker 1: anything like our brains. Their brains actually look much more

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Speaker 1: like a snail's brain because they are mollusks and they

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Speaker 1: don't have the same sort of organization of centralizing all

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Speaker 1: the brain functions into one but they have a central brain,

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Speaker 1: but they also have distributed brains controlling each of their arms.

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Speaker 1: And so in the absence of all of the brain

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Speaker 1: regions that we think of as being important for social

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Speaker 1: behaviors or cognition. That they were able to respond to

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Speaker 1: the m d M A in pretty similar ways to

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Speaker 1: the ways that mice and rats and humans respond to

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Speaker 1: m d M A. In other words, when we measured

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Speaker 1: their pro social behavior, their desire to spend time in

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Speaker 1: the chamber that had the other octopus in it increased

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Speaker 1: after we gave them m d M A. That told

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Speaker 1: us that all of the anatomical things that were used

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Speaker 1: to attributing the functions of these drugs too really are

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Speaker 1: sort of extraneous detail, and that they're accidents of the

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Speaker 1: evolutionary history of that animal, and that the thing that

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Speaker 1: really matters for encoding this social function of serotonin is

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Speaker 1: at the level of molecules and specifically the proteins that

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Speaker 1: encode the serotonin transporter which m d M A binds to,

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Speaker 1: and that just by having that, it's enough to override

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Speaker 1: the normal behavior that we see in octopuses, which is,

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Speaker 1: you know, they're not social. In fact, if you put

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Speaker 1: two octopuses in it, this species in particular, if you

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Speaker 1: put them in a tank together, they will kill each other.

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Speaker 1: And so M D M A has this very powerful

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Speaker 1: ability to override that and make them desire social interaction

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Speaker 1: and spend more time with the other animals. I have

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Speaker 1: to tell you what I mean. Until like a couple

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Speaker 1: of days ago, when I started prepping for our conversation,

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Speaker 1: almost everything I knew about octopus this was from seeing

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Speaker 1: that Academy Award winning documentary by the South African fellow

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Speaker 1: Craig Foster, My Octopus Teacher, which I loved. It talks

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Speaker 1: about the sort of wariness in a social ability of octopus,

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Speaker 1: but obviously there's this bonding that goes on there between them.

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Speaker 1: Although some people said, maybe we're just anthropomorphizing, you know,

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Speaker 1: attributing to the octopus human characteristics and behavior more than

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Speaker 1: its appropriate, but it was I don't know. I mean,

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Speaker 1: as I'm reading your study, I just kept thinking about that.

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Speaker 1: Have you seen that film? I have. I have seen it.

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Speaker 1: It was beautifully shot film. But I agree with the

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Speaker 1: concern that we're anthropomorphizing. And I'll just put it out

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Speaker 1: there that Aristotle actually thought that octopuses were the stupidest animal,

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Speaker 1: and that was because back in his time, you know,

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Speaker 1: there were abundant in the sea and they were sort

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Speaker 1: of easy to catch. Because all you had to do

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Speaker 1: is put a rod in front of them, and they would,

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Speaker 1: out of this intense sense of curiosity, reach out and

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Speaker 1: grab the rod, and then you just pull the rod

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Speaker 1: up and the octopus would come with it. So, you know,

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Speaker 1: people have been studying octopuses for thousands of years, and

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Speaker 1: depending on your perspective, whether you consider them an easy

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Speaker 1: to catch food source or whether you are making netslix

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Speaker 1: documentary about them, the tendency to anthropomorphized can lead you

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Speaker 1: to very different conclusions about what they're capable of. And

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Speaker 1: so one thing I would say is that even though

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Speaker 1: we characterize them as being a social most of the time,

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Speaker 1: in fact, they do suspend that a sociality during brief

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Speaker 1: times that are important for their behavior. So the species

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Speaker 1: that we were studying in the M. D m A

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Speaker 1: paper was octopus by maculoids, or the California two spot octopus,

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Speaker 1: and that octopus will suspend this sort of aggressive stance

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Speaker 1: that they take to other members of their species when

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Speaker 1: they are mating. We know that they must have the

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Speaker 1: circuitry for social behavior somewhere in their brains, and that,

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Speaker 1: for whatever reason that we haven't really understood, evolutionary selection

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Speaker 1: pressures have made it so that it's more beneficial to

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Speaker 1: whatever strategy they're using to mostly be a social and

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Speaker 1: turn off that sociality except when they're going to be mating. Yeah. Yeah,

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Speaker 1: I was reading about octopus before talking with you. I

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Speaker 1: mean I saw that not all octopuses are a social

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Speaker 1: I think you just pointed out, like there's something called

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Speaker 1: a larger Pacific strike octopus, which is a little more social.

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Speaker 1: So the element of there being a bit of loaners, right,

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Speaker 1: was kind of relevant to the research because you're looking

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Speaker 1: at the sociability associated with m d m A. That's right. Well,

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Speaker 1: I mean, honestly, we didn't know what was going to happen.

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Speaker 1: We started the experiment thinking, you know, maybe what's going

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Speaker 1: to happen is is that sarahtonin is old or the

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Speaker 1: transmitter and the transporter is there. But when we give

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Speaker 1: the m d M A, it's just going to induce

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Speaker 1: sort of a hyperactive behavior or something similar to what

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Speaker 1: emphetamines might do to the brain of a mammal. Because

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Speaker 1: it's in the amphetamine class and saratonin, we didn't know

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Speaker 1: if this pro social function was as old as some

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Speaker 1: of its other functions, and we didn't know if it

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Speaker 1: could bind to it, if it was going to also

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Speaker 1: bind to other transporters and do other things. So we

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Speaker 1: wanted to start with this social because that was the

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Speaker 1: question that we were interested in, but also octopuses because

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Speaker 1: they're so a social When we just did the baseline

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Speaker 1: measurements of how much time they spend in the social

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Speaker 1: chamber versus the chamber that had a little toy object

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Speaker 1: in it, they spent almost all of their time in

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Speaker 1: the toy object chamber, which was maximally distant from the

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Speaker 1: other octopus. And so that made a really nice baseline measurement.

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Speaker 1: And so when we gave them m D M A

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Speaker 1: and the behavior shifted hundred and eighty degrees and now

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Speaker 1: they spent most of their time in the social chamber.

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Speaker 1: We didn't need very many animals to be able to

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Speaker 1: statistically draw the conclusion that, you know, the M D

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Speaker 1: M A had this effect on changing their social behavior.

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Speaker 1: So cool. When it comes to administering in the email

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Speaker 1: of the drugs to the mice or other animal, how

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Speaker 1: do you do it is an injection or another means?

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Speaker 1: And how do you figure out the right dosing levels

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Speaker 1: and what's comparable too levels and humans. Yeah, So with

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Speaker 1: the mices sort of straightforward. We just give them an

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Speaker 1: injection what we call an I P injection interpretornal injection,

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Speaker 1: and we're just injecting it directly into their abdomen. And

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Speaker 1: because most of these psychedelics are very leoad brain barrier permeable,

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Speaker 1: it gets into the brain. And we test the doses

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Speaker 1: to make sure that we start with the human dose

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Speaker 1: and adjust it for weight, and we just kind of

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Speaker 1: tietrate until we see the effect, and remarkably, the effects

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Speaker 1: seem to be pretty close. The dose that we would

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Speaker 1: use in a human is usually within ten times of

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Speaker 1: what we see in a mouse, tentimes more ten times

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Speaker 1: less or the same, and so that was reassuring. That

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Speaker 1: can change because mouth metabolism is very fast, so we

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Speaker 1: have to be careful about that, so we want to

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Speaker 1: test it every time. The trickier one was definitely the

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Speaker 1: octo us because we didn't know how to deliver it.

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Speaker 1: The octopus is a secreature and so the way that

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Speaker 1: it receives drugs normally, the equivalent would be if we

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Speaker 1: put it in the water is on their gills and

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Speaker 1: it's sort of washing over their gills and getting into

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Speaker 1: the blood directly from the gills, and so putting m

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Speaker 1: d M A and the water might be something like

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Speaker 1: figuring out a way of making aerosolized m d M

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Speaker 1: A and putting somebody in a hot box with aerosolized

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Speaker 1: m d M A for thirty minutes. So we really

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Speaker 1: weren't sure, but we decided to go ahead and try

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Speaker 1: it anyway. And this is true with all experiments that

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Speaker 1: we do an octopus, we never want to just assume

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Speaker 1: that it's the same because their physiology is so different.

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Speaker 1: They don't have a liver. They have something between a

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Speaker 1: liver and a pancreas. Those cells have some of the

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Speaker 1: features of both. It's not clear that they have a

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Speaker 1: blood brain barrier. They don't even metabolize oxygen in the

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Speaker 1: same way that we do. So we had to test

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Speaker 1: it and we just titrated. We start high and then

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Speaker 1: work our way backwards until we got to the right dose.

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Speaker 1: Uh huh, Yeah, so cool. When you're testing animals given psychedelics,

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Speaker 1: is it getting the permission from the university or from

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Speaker 1: the funding agencies is any different than giving animals other

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Speaker 1: types of drugs. Yeah, we have to go through all

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Speaker 1: of the regulatory requirements for being approved for giving Schedule

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Speaker 1: one medicines, and so that's a regulatory process that we

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Speaker 1: have to do, but both the federal and the state

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Speaker 1: level took us about a year to get all of

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Speaker 1: those licenses approved. And then once we get the licenses,

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Speaker 1: then we have to go back to our Animal Care

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Speaker 1: and Use Committee and work with them back and forth

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Speaker 1: to make sure that we have done all the appropriate

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Speaker 1: safeguarding measurements and that we're really making sure that we

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Speaker 1: are doing these experiments in the safest and least stressful

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Speaker 1: way for the animals. The octopus is sort of a

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Speaker 1: unique situation because currently in the United States, octopuses are

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Speaker 1: have the same regulatory requirements as all other invertebrates, so

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Speaker 1: flies and worms and cockroaches and all the invertebrates, right,

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Speaker 1: but we are sensitive to the fact that octopus is

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Speaker 1: their behavioral repertoire is much more complex, and we certainly

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Speaker 1: don't agree with Aristotle that they're the dumbest animals. So

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Speaker 1: we have taken care to apply all the same standards

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Speaker 1: that we use for mouth studies for the octopus to

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Speaker 1: make sure that we're treating them in a way that

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Speaker 1: respects their intelligence and their ability to feel pain and

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Speaker 1: take care of them. We'll be talking more after we

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Speaker 1: hear this add You know, the thing I was wondering

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Speaker 1: in reading about your study was that I thought back

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Speaker 1: to the famous rat park studies that Bruce Alexander did

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Speaker 1: with I think it was mice and cocaine. This is

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Speaker 1: back in the seventies, I think, and this is the

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Speaker 1: famous experiment where, you know, everybody knows the basic studies

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Speaker 1: of you put mice or monkeys in a cage and

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Speaker 1: you make available to them cocaine or a kind of

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Speaker 1: saline solution, alternative placebo thing. Many of them will just

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Speaker 1: keep injecting or consuming the cocaine until they die. But

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Speaker 1: what Bruce Alexander showed was that when you did the

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Speaker 1: same experiment with animals that were in a kind of

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Speaker 1: wildlike environment, in fact, they either had no interest in

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Speaker 1: the cocaine, or if they did show any interest, they

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Speaker 1: used it in a sort of moderation. It didn't fundamentally

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Speaker 1: affect their lives. And it was all about the importance

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Speaker 1: of setting, especially in terms of determining how people consume drugs,

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Speaker 1: why they get into problematic relationships, all this sort of

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Speaker 1: thing I wondered, if you've been doing this study and

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Speaker 1: somehow been able to do it with octopus who were

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Speaker 1: in the wild where they have to have a greater fear,

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Speaker 1: presumably about predators, do you think you would have had

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Speaker 1: a different Well, it's a good question, and it's definitely

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Speaker 1: something that we have thought a lot about. I mean,

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Speaker 1: the rat part experiment. When I first started my lab

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Speaker 1: back in two thousand fourteen, that study had a big

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Speaker 1: effect on me because what it really made me realize

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Speaker 1: is that when we started doing a lot of studies

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Speaker 1: in rats, especially, but mice also, for a number of

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Speaker 1: practical technical reasons, it was easier to keep isolation housing them.

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Speaker 1: But rats and mice are both social animals, and so

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Speaker 1: a lot of the conclusions we drew from some of

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Speaker 1: those early drug addiction studies were probably wrong because we

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Speaker 1: were essentially studying animals who were enduring sort of social isolation, stress,

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Speaker 1: and maybe more depressed, maybe more vulnerable to their drug

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Speaker 1: environment because they weren't getting all of the social support

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Speaker 1: that would be normal for their environment. Octopuses are sort

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Speaker 1: of different than that. So octopus is in the wild

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Speaker 1: or a social they prefer not to be living with

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Speaker 1: other animals, except for as you mentioned, the larger Pacific

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Speaker 1: striped octopus or LPSO, seems to be the only decidedly

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Speaker 1: social octopus. But for the most part, octopuses prefer to

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Speaker 1: live a socially. We had to design the experiment taking

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Speaker 1: that into consideration because we certainly didn't want to put

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Speaker 1: them into a stressful situation by essentially allowing them to

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Speaker 1: attack each other, which is why we kept the other

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Speaker 1: octopus underneath the flower pots, so that maybe they showed

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Speaker 1: aggressive postures but couldn't actually hurt each other, and taking

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Speaker 1: that into consideration, also didn't use a different essay that

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Speaker 1: we use in mice that requires them to live together overnight,

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Speaker 1: because we knew that they were a social So we

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Speaker 1: always have to take those kinds of how do they

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Speaker 1: live in the wild into consideration when we're trying to

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Speaker 1: design experiments and not accidentally retesting the stress effects of

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Speaker 1: living in a way that they are not ethologically suited

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Speaker 1: to live when we do the experiment right, because presumably

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Speaker 1: though a sociability was an evolutionary thing that developed, right

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Speaker 1: in terms of their survival, the ones that survive are

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Speaker 1: the ones that are smarter, and maybe the ones that

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Speaker 1: are more a social I mean, you know, one thing

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Speaker 1: that I find to be fascinating and kind of what

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Speaker 1: keeps drawing me back to wanting to do more studies

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Speaker 1: than octopus is that all of the other cephalopods are social. Right,

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Speaker 1: So nautilus has a shell, that's true, But squid and

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Speaker 1: cuttlefish don't have an external shell either, and yet they

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Speaker 1: are very social. And so there's something separate about octopus.

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Speaker 1: Is maybe that because they're hunting for fish and they've

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Speaker 1: taken on predatory behaviors that are similar to other top predators,

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Speaker 1: and that they for some reason it's not advantageous to

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Speaker 1: do pack hunting. We don't really know. And so this

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Speaker 1: is why I'm so fascinated by the larger Pacific striped octopus,

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Speaker 1: because somehow something is different, and that species of the

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Speaker 1: three d or so known species of octopus is the

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Speaker 1: one that has evolved the social pattern of living. And

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Speaker 1: it would be I think fascinating to know what was

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Speaker 1: the selection pressure that pushed them to that type of

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Speaker 1: living that's so different from all the rest. But presumably

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Speaker 1: be harder to discern the impact of M D M

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Speaker 1: A among creatures that have a higher level of sociability. Well, so,

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Speaker 1: I mean that's actually a pretty good segue to talk

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Speaker 1: about what m d m A does in mice right there.

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Speaker 1: So basically we knew that m d m A already

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Speaker 1: had acute pro social effects in mice and in humans,

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Speaker 1: and some of the work that supported that actually was

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Speaker 1: from behavioral tests that are very similar to the one

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Speaker 1: that we did in octopuses. So I'm just putting the

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Speaker 1: animals in a large arena that's divided into three rooms

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Speaker 1: and just measuring how much time they spend in each

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Speaker 1: of the three rooms, one of which has an other

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Speaker 1: social animal and one of them that doesn't. And that

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Speaker 1: was sort of looking at what happens when you're given

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Speaker 1: the drug and the animal is experiencing the acute effects

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Speaker 1: of the drugs. So the altered state of consciousness plus

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Speaker 1: this Recreational users of m d m A are known for,

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Speaker 1: you know, cuddle puddles and lots of pro social hugging

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Speaker 1: and wanting to be close to other people, right, and

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Speaker 1: we see that same behavior in mice and in octopuses.

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Speaker 1: But we were in my lab already studying another phenomenon.

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Speaker 1: We were interested in the developmental regulation of social behaviors,

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Speaker 1: because we know that a person's way of being social

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Speaker 1: changes over their lifetime. Right, So, teenagers are famously they

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Speaker 1: love to hang out with each other, they have, you know,

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Speaker 1: three hundred friends. They're always on the phone. They just

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Speaker 1: can't get enough of social interaction. But as you get older,

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Speaker 1: you kind of you like to be social, but jeez,

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Speaker 1: you know, sometimes you need some quality alone time to

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Speaker 1: gather your thoughts and replenish your social resources, if you will.

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Speaker 1: And so that change across development suggested to us that

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Speaker 1: there must be something like a critical period for social behaviors,

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Speaker 1: and we thought it was important to try and understand

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Speaker 1: the neural mechanisms of that, because those changes in the

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Speaker 1: way that we learn from our social environment probably have

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Speaker 1: a big impact on things like peer pressure and also

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Speaker 1: probably impact Why it is that when you have a

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Speaker 1: social injury when you're very young, it has a much

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Speaker 1: more devastating long term consequence than if you have a

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Speaker 1: social injury when you're old. Why we do things like

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Speaker 1: we safeguard children, why we make sure that they're not

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Speaker 1: exposed to violent television content, and why we sort of

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Speaker 1: monitor to make sure that they are not receiving damaging

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Speaker 1: information when social information when they're young. And so what

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Speaker 1: my live set out to do is to use a

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Speaker 1: different essay. So now we're not just measuring acute effects

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Speaker 1: of social interactions. We're using an assay called social conditioned

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Speaker 1: place preference, which is just animals being put in a

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Speaker 1: chamber and we just have two types of betting on

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Speaker 1: the floor, and we just take a baseline measurement just

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Speaker 1: to make sure that they don't have some pre existing

432
00:25:17,880 --> 00:25:20,520
Speaker 1: bias for one of the two types of betting. We

433
00:25:20,680 --> 00:25:22,760
Speaker 1: just let them run around for thirty minutes on the

434
00:25:22,760 --> 00:25:25,119
Speaker 1: two types of betting, measure how much time they spend

435
00:25:25,119 --> 00:25:27,760
Speaker 1: on each, and then we put them in a new

436
00:25:27,880 --> 00:25:30,080
Speaker 1: chamber with one of the two types of betting, and

437
00:25:30,119 --> 00:25:32,960
Speaker 1: this time they're paying for twenty four hours with their

438
00:25:32,960 --> 00:25:36,439
Speaker 1: social group members. And then we put them for twenty

439
00:25:36,440 --> 00:25:38,800
Speaker 1: four hours on the other type of betting, this time

440
00:25:38,840 --> 00:25:42,120
Speaker 1: by themselves. And then we take another measurement, asking how

441
00:25:42,160 --> 00:25:45,080
Speaker 1: much time do they now after they formed this association

442
00:25:45,200 --> 00:25:48,920
Speaker 1: between the betting and the social environment, how much time

443
00:25:48,920 --> 00:25:51,160
Speaker 1: do they spend in each of those two types of bettings.

444
00:25:51,240 --> 00:25:54,040
Speaker 1: And by doing that, what we've discovered and other people

445
00:25:54,080 --> 00:25:57,760
Speaker 1: have shown as well, is that mice, especially juvenile mice,

446
00:25:57,960 --> 00:26:02,879
Speaker 1: will form a long lasting wrong positive association between the

447
00:26:02,920 --> 00:26:07,359
Speaker 1: betting and a social environment, and a negative association to

448
00:26:07,880 --> 00:26:13,000
Speaker 1: the betting associated with being by themselves and that ability

449
00:26:13,040 --> 00:26:17,159
Speaker 1: to learn from their social environment or the rewarding nature

450
00:26:17,240 --> 00:26:20,680
Speaker 1: of that social environment. What we discovered is is that

451
00:26:21,119 --> 00:26:24,440
Speaker 1: as the animals get older, that goes away, and that

452
00:26:24,680 --> 00:26:28,520
Speaker 1: attenuation or that diminishment of the ability to learn from

453
00:26:28,560 --> 00:26:32,720
Speaker 1: the social environment we describe as a critical period for

454
00:26:32,920 --> 00:26:36,640
Speaker 1: social reward learning and critical period. I mean, when I've

455
00:26:36,680 --> 00:26:39,400
Speaker 1: heard you talk about this, it is connected to sort

456
00:26:39,400 --> 00:26:42,720
Speaker 1: of that notion of imprinting when certain types of birds,

457
00:26:42,920 --> 00:26:45,480
Speaker 1: maybe migratory birds or birds that leave the mother very

458
00:26:45,480 --> 00:26:48,880
Speaker 1: early hatch, that they attached to the first thing that

459
00:26:48,920 --> 00:26:51,240
Speaker 1: they encounter, whether it could be a human being, it

460
00:26:51,280 --> 00:26:54,120
Speaker 1: could be another animal, it could even be another inanimate object.

461
00:26:54,240 --> 00:26:56,720
Speaker 1: Is that the kind of sort of simplistic notion of

462
00:26:56,720 --> 00:27:00,600
Speaker 1: the critical period that's relevant here? Absolutely? In fact, that

463
00:27:00,800 --> 00:27:06,439
Speaker 1: imprinting behavior and snow geese was the first behavior that

464
00:27:06,560 --> 00:27:10,640
Speaker 1: Conrad Lorenz back in nineteen thirty five described and coined

465
00:27:10,680 --> 00:27:13,800
Speaker 1: the phrase critical period to describe, and what he was

466
00:27:13,880 --> 00:27:17,760
Speaker 1: referring to is that long lasting attachment that you're describing

467
00:27:18,040 --> 00:27:21,640
Speaker 1: that happens, but only within the first forty eight hours

468
00:27:21,680 --> 00:27:26,280
Speaker 1: after hatching. After that, they don't form that long lasting attachment.

469
00:27:26,359 --> 00:27:30,280
Speaker 1: That whatever's in their environment that they've attached to ceases

470
00:27:30,359 --> 00:27:33,119
Speaker 1: to be relevant in the same way and ceases to

471
00:27:33,200 --> 00:27:36,960
Speaker 1: be a salient signal that allows them to form a

472
00:27:37,000 --> 00:27:40,680
Speaker 1: long lasting attachment. And so that window of time where

473
00:27:41,240 --> 00:27:44,320
Speaker 1: the animal is much more sensitive to their environment and

474
00:27:44,440 --> 00:27:48,200
Speaker 1: able to form these long lasting memories. Conrad Lorenz called

475
00:27:48,200 --> 00:27:51,359
Speaker 1: a critical period, and he did that in nineteen thirty five,

476
00:27:51,560 --> 00:27:54,639
Speaker 1: but since then there have been lots and lots of

477
00:27:54,640 --> 00:27:57,480
Speaker 1: critical periods that have been described. I think most people

478
00:27:57,520 --> 00:28:00,439
Speaker 1: are familiar in their own lives with the critical period

479
00:28:00,520 --> 00:28:03,320
Speaker 1: for language learning. So if you've ever tried to learn

480
00:28:03,320 --> 00:28:06,480
Speaker 1: a language later on in life, it's much harder to learn.

481
00:28:06,600 --> 00:28:09,000
Speaker 1: You have to practice, you have to study. You will

482
00:28:09,040 --> 00:28:11,320
Speaker 1: always have an accent when you speak it. You won't

483
00:28:11,359 --> 00:28:14,719
Speaker 1: speak it with the same sort of fluidity and ease

484
00:28:14,880 --> 00:28:18,280
Speaker 1: as you did your native language. My sister seems to

485
00:28:18,280 --> 00:28:20,880
Speaker 1: be the exception to this rule because she doesn't seem

486
00:28:20,880 --> 00:28:23,719
Speaker 1: to have a critical period for languages. She speaks like

487
00:28:24,080 --> 00:28:26,640
Speaker 1: five or six fluently in a couple more just as

488
00:28:26,720 --> 00:28:30,120
Speaker 1: needed basis. But for most people, you know, the language

489
00:28:30,160 --> 00:28:32,040
Speaker 1: that you learned as a child is the one that

490
00:28:32,119 --> 00:28:34,440
Speaker 1: you know and the one that you speak fluidly without

491
00:28:34,520 --> 00:28:37,680
Speaker 1: an accent, and anything else later on is much harder

492
00:28:37,760 --> 00:28:41,760
Speaker 1: and not as fluid, And so that is reflecting the

493
00:28:41,800 --> 00:28:44,720
Speaker 1: fact that there's a critical period for language learning. But

494
00:28:44,760 --> 00:28:46,880
Speaker 1: there are other critical periods as well. So there are

495
00:28:46,880 --> 00:28:51,520
Speaker 1: critical periods for organizing the visual system, for organizing the

496
00:28:51,680 --> 00:28:55,400
Speaker 1: touch system, and probably clinically, the one that we are

497
00:28:55,600 --> 00:28:58,360
Speaker 1: sort of most fascinated by and will follow up with

498
00:28:58,600 --> 00:29:02,400
Speaker 1: is that there's a critical period for recovering motor function

499
00:29:02,600 --> 00:29:04,920
Speaker 1: after you have a stroke. So right after you have

500
00:29:04,960 --> 00:29:07,960
Speaker 1: a stroke, you have this short window of time six

501
00:29:08,000 --> 00:29:11,400
Speaker 1: weeks seems to be this sort of sweet spot where

502
00:29:11,600 --> 00:29:14,239
Speaker 1: if you do intensive physical therapy, that's where you're going

503
00:29:14,240 --> 00:29:17,800
Speaker 1: to get the most recovery. But after that window is closed,

504
00:29:18,120 --> 00:29:20,280
Speaker 1: you know you're not going to get much more motor

505
00:29:20,360 --> 00:29:24,480
Speaker 1: recovery after that window is closed. So now your focus

506
00:29:24,560 --> 00:29:28,840
Speaker 1: was on social reward learning aspects of critical period. So

507
00:29:29,000 --> 00:29:31,360
Speaker 1: is that a relatively newer concept or also one that

508
00:29:31,400 --> 00:29:34,440
Speaker 1: goes back a while. No, So we discovered the social

509
00:29:34,480 --> 00:29:37,520
Speaker 1: reward learning critical period. And we were able to discover

510
00:29:37,600 --> 00:29:40,280
Speaker 1: it because we were able to do this in animal studies,

511
00:29:40,320 --> 00:29:43,080
Speaker 1: so we were able to look at fifteen different ages,

512
00:29:43,240 --> 00:29:45,400
Speaker 1: we were able to look at both sexes. It was

513
00:29:45,480 --> 00:29:49,800
Speaker 1: hundreds and hundreds of mice and really characterized the developmental timeline.

514
00:29:50,320 --> 00:29:53,760
Speaker 1: But that being said, you know, people who do human

515
00:29:53,880 --> 00:29:57,640
Speaker 1: cognition studies and child development studies had already sort of

516
00:29:57,680 --> 00:30:00,440
Speaker 1: had an inkling that something like this must have exists

517
00:30:00,640 --> 00:30:03,640
Speaker 1: just by doing comparisons between two different ages and the

518
00:30:03,680 --> 00:30:07,240
Speaker 1: ways that children process social information. There was an idea

519
00:30:07,320 --> 00:30:10,960
Speaker 1: out there that it might exist, but it wasn't formally

520
00:30:11,080 --> 00:30:14,200
Speaker 1: demonstrated until we we showed it in mice. I see,

521
00:30:14,320 --> 00:30:16,120
Speaker 1: and when you're administering the n D m A to

522
00:30:16,160 --> 00:30:18,800
Speaker 1: the mice, does it make a difference whether these mice

523
00:30:19,000 --> 00:30:23,920
Speaker 1: are the equivalent of juveniles or adolescents or adults. Yeah,

524
00:30:24,000 --> 00:30:28,880
Speaker 1: So when we were trying to characterize the behavioral critical period,

525
00:30:29,120 --> 00:30:32,120
Speaker 1: we also did some studies to try and understand what

526
00:30:32,280 --> 00:30:38,479
Speaker 1: are the cellular and synaptic mechanisms underlying that establishment and

527
00:30:38,560 --> 00:30:41,560
Speaker 1: constraining of that learning and memory to this window. And

528
00:30:41,600 --> 00:30:45,200
Speaker 1: we had implicated oxytocin that we talked about before in

529
00:30:45,240 --> 00:30:47,760
Speaker 1: that process, and we thought, well, we want to be

530
00:30:47,800 --> 00:30:52,760
Speaker 1: able to reopen this critical period because neuroscientists, pretty much

531
00:30:52,840 --> 00:30:56,000
Speaker 1: since we first knew about critical periods, had had the

532
00:30:56,080 --> 00:31:00,240
Speaker 1: intuition that the ability to reopen critical periods is going

533
00:31:00,280 --> 00:31:04,640
Speaker 1: to be immensely powerful as a therapeutic. But oxytocin doesn't

534
00:31:04,680 --> 00:31:07,000
Speaker 1: cross the blood brain barriers. So you might have heard

535
00:31:07,160 --> 00:31:11,200
Speaker 1: in the lay press people talking about intronasal oxytocin, but honestly,

536
00:31:11,240 --> 00:31:13,680
Speaker 1: that just doesn't really worked out. Well, it doesn't get

537
00:31:13,720 --> 00:31:17,240
Speaker 1: into the brain. Whatever affects people are reporting of intronasal

538
00:31:17,320 --> 00:31:21,240
Speaker 1: oxytocin are probably indirect effects on the brain and affects

539
00:31:21,240 --> 00:31:24,080
Speaker 1: that that oxytocin is having in the body, not in

540
00:31:24,120 --> 00:31:27,000
Speaker 1: the brain. And so we thought, well, gosh, you know,

541
00:31:27,160 --> 00:31:30,160
Speaker 1: is there some other way that we might be able

542
00:31:30,240 --> 00:31:34,959
Speaker 1: to trigger this reopening of the critical period. And we

543
00:31:35,040 --> 00:31:37,760
Speaker 1: knew that m d M A had these pro social

544
00:31:37,800 --> 00:31:40,560
Speaker 1: effects and m d M A there was some anecdotal

545
00:31:40,600 --> 00:31:43,960
Speaker 1: evidence that it might also be triggering oxytocin release in

546
00:31:44,240 --> 00:31:47,320
Speaker 1: the central nervous system. And so what we did is

547
00:31:47,600 --> 00:31:50,880
Speaker 1: unlike the octopus experiments and other experiments that had been

548
00:31:50,920 --> 00:31:53,400
Speaker 1: done before we gave the m d M A in

549
00:31:53,480 --> 00:31:56,640
Speaker 1: adult animals. So remember, at the adult age, the critical

550
00:31:56,640 --> 00:31:59,040
Speaker 1: period is closed. So we gave the m d M

551
00:31:59,040 --> 00:32:01,040
Speaker 1: A and then we just way did for forty eight

552
00:32:01,040 --> 00:32:03,200
Speaker 1: hours for all of the acute m d M A

553
00:32:03,280 --> 00:32:06,760
Speaker 1: to wash out of the system, and then we measured

554
00:32:06,800 --> 00:32:10,840
Speaker 1: social reward learning again in the adult animals. And what

555
00:32:10,920 --> 00:32:13,880
Speaker 1: we found is is that forty eight hours after we

556
00:32:13,920 --> 00:32:17,560
Speaker 1: gave the m d m A, that juvenile ability, that

557
00:32:17,680 --> 00:32:20,640
Speaker 1: ability to learn from the social environment, came back in

558
00:32:20,680 --> 00:32:26,000
Speaker 1: the adults. And that restoration of the juvenile behavior in adulthood,

559
00:32:26,200 --> 00:32:29,160
Speaker 1: we thought was very strong evidence that what we've done

560
00:32:29,240 --> 00:32:32,760
Speaker 1: is reopened this critical period. And then at the same time,

561
00:32:32,800 --> 00:32:36,400
Speaker 1: if we gave m d m A to the juvenile animals,

562
00:32:37,160 --> 00:32:41,040
Speaker 1: we had no impact on the magnitude of social reward learning.

563
00:32:41,080 --> 00:32:43,520
Speaker 1: So it wasn't just that the adult animals are sort

564
00:32:43,560 --> 00:32:48,680
Speaker 1: of satiated and that we just drained the emotional bucket

565
00:32:48,720 --> 00:32:51,440
Speaker 1: and made them thirsty for social again, because if that

566
00:32:51,600 --> 00:32:54,440
Speaker 1: was the case, then we would have expected that depriving

567
00:32:54,480 --> 00:32:59,040
Speaker 1: the animals and juveniles would also restore an increased level

568
00:32:59,080 --> 00:33:02,719
Speaker 1: of social reward learning and it didn't. And so taken together,

569
00:33:02,760 --> 00:33:05,840
Speaker 1: those two things really convinced us that what we're looking

570
00:33:05,880 --> 00:33:09,360
Speaker 1: at is a reopening of a critical period, not some

571
00:33:09,440 --> 00:33:13,080
Speaker 1: sort of satiation with sociality. Right. And you saw this

572
00:33:13,160 --> 00:33:17,200
Speaker 1: reopening though in the adult mice that were in social situations,

573
00:33:17,240 --> 00:33:20,160
Speaker 1: but not the ones that had been isolated, right. So

574
00:33:20,320 --> 00:33:24,360
Speaker 1: that is a really interesting component of this study which

575
00:33:24,400 --> 00:33:28,120
Speaker 1: I think lends further support to the idea that critical

576
00:33:28,200 --> 00:33:33,320
Speaker 1: period reopening is what really accounts for the incredible therapeutic

577
00:33:33,360 --> 00:33:36,360
Speaker 1: effects that we're seeing with these drugs. So one of

578
00:33:36,360 --> 00:33:38,840
Speaker 1: the things that I think probably your audience will be

579
00:33:38,880 --> 00:33:43,800
Speaker 1: familiar with is that psychedelics in particular have this feature

580
00:33:43,960 --> 00:33:47,960
Speaker 1: of being set and setting dependent. Right, So if you're

581
00:33:48,000 --> 00:33:51,520
Speaker 1: around people that you feel comfortable with or giving off

582
00:33:51,560 --> 00:33:53,480
Speaker 1: good vibes, if you will, then the M d m

583
00:33:53,480 --> 00:33:56,440
Speaker 1: A experience can be very different than if you're feeling

584
00:33:56,480 --> 00:34:01,640
Speaker 1: threatened or anxious or not safe. And that phenomenology of

585
00:34:01,680 --> 00:34:05,520
Speaker 1: the set and setting dependence of psychedelic drugs also translates

586
00:34:05,600 --> 00:34:08,839
Speaker 1: to the therapeutic effects, right. So you can't just take

587
00:34:09,000 --> 00:34:10,920
Speaker 1: M d M A and go to a rave and

588
00:34:10,960 --> 00:34:13,640
Speaker 1: expect that your PTSD is going to be cured, you

589
00:34:13,719 --> 00:34:16,520
Speaker 1: really want to pair the m d M A with

590
00:34:16,600 --> 00:34:21,359
Speaker 1: the context of psychoanalysis to look at the trauma that

591
00:34:21,440 --> 00:34:24,719
Speaker 1: you're trying to deal with, and then rewriting those memories

592
00:34:24,719 --> 00:34:27,840
Speaker 1: around the trauma during the trip. And we think actually

593
00:34:27,880 --> 00:34:31,799
Speaker 1: afterwards as well, and this context dependence or you know,

594
00:34:31,840 --> 00:34:34,440
Speaker 1: the set and setting, but we call it context dependence

595
00:34:34,600 --> 00:34:39,520
Speaker 1: of psychedelics effects we think are different than for example,

596
00:34:39,920 --> 00:34:43,600
Speaker 1: m d M A has like a mild social anxiolytic property.

597
00:34:43,719 --> 00:34:48,279
Speaker 1: Psilocybin and LSD and ketamine have anti depressive properties, but

598
00:34:48,360 --> 00:34:52,320
Speaker 1: those antidepressive and anxiolytic properties of the drugs don't seem

599
00:34:52,360 --> 00:34:55,400
Speaker 1: to be context dependent, right, And so these drugs do

600
00:34:55,440 --> 00:34:57,560
Speaker 1: a lot of different things in the brain. Some of

601
00:34:57,600 --> 00:34:59,880
Speaker 1: the properties are context dependent and some of them are

602
00:34:59,880 --> 00:35:03,759
Speaker 1: in not. And we think that the exciting possibility is

603
00:35:03,800 --> 00:35:06,520
Speaker 1: that the remarkable sort of this is going to be

604
00:35:06,600 --> 00:35:10,480
Speaker 1: a cure for neuro psychiatric disease. Part of these drugs

605
00:35:10,640 --> 00:35:13,600
Speaker 1: comes from that context dependence, and so we were really

606
00:35:13,640 --> 00:35:17,279
Speaker 1: excited that unlike other studies which had looked at the

607
00:35:17,320 --> 00:35:21,040
Speaker 1: antidepressive properties of the anxiolytic properties and shown that these

608
00:35:21,080 --> 00:35:25,680
Speaker 1: were not context dependent. Critical period reopening is context dependent.

609
00:35:25,800 --> 00:35:29,120
Speaker 1: So you can only reopen the social critical period if

610
00:35:29,160 --> 00:35:31,839
Speaker 1: you give M d M A in the social context.

611
00:35:32,160 --> 00:35:34,759
Speaker 1: And we think that the social part of that is

612
00:35:34,800 --> 00:35:37,560
Speaker 1: a little bit of a We have more evidence now

613
00:35:37,640 --> 00:35:40,480
Speaker 1: suggesting that that's a little bit of a red herring,

614
00:35:40,640 --> 00:35:45,319
Speaker 1: because we are excited about the possibility that psychedelics are

615
00:35:45,560 --> 00:35:49,280
Speaker 1: the master key for unlocking critical periods across the brain,

616
00:35:49,480 --> 00:35:53,080
Speaker 1: sort of writ large and if that's true, then we

617
00:35:53,160 --> 00:35:56,960
Speaker 1: would expect that the dependence on the social context is

618
00:35:57,000 --> 00:35:59,520
Speaker 1: true because we're trying to open a social critical period.

619
00:35:59,800 --> 00:36:02,000
Speaker 1: But if we were trying to open a visual critical

620
00:36:02,040 --> 00:36:06,320
Speaker 1: period or a motor learning critical period, then visual experience

621
00:36:06,400 --> 00:36:09,799
Speaker 1: or motor experience during the acute phase of the psychedelic

622
00:36:09,840 --> 00:36:13,160
Speaker 1: would be the important context, not social. And now, when

623
00:36:13,160 --> 00:36:15,360
Speaker 1: you found that what you were finding with M d

624
00:36:15,520 --> 00:36:18,720
Speaker 1: M A was also true with the variety of psychedelics,

625
00:36:18,800 --> 00:36:21,279
Speaker 1: was that surprising to you. Yeah, So that work isn't

626
00:36:21,320 --> 00:36:24,759
Speaker 1: published yet, but I'm happy to briefly mention it. We

627
00:36:25,080 --> 00:36:28,640
Speaker 1: basically did those experiments as a control. I was fairly

628
00:36:28,640 --> 00:36:31,000
Speaker 1: certain that the reason that M D M A was

629
00:36:31,040 --> 00:36:34,600
Speaker 1: having this remarkable ability to reopen the critical period was

630
00:36:34,719 --> 00:36:38,040
Speaker 1: because but so pro social in quality, right, It's acute

631
00:36:38,040 --> 00:36:41,360
Speaker 1: subjective effects are really pro social. But you know, nobody's

632
00:36:41,400 --> 00:36:44,080
Speaker 1: taking LSD and doing a cuddle puddle. In fact, most

633
00:36:44,080 --> 00:36:45,960
Speaker 1: people need to kind of especially if they're having an

634
00:36:46,000 --> 00:36:49,120
Speaker 1: inner directed trip. You know, they need quiet and maybe

635
00:36:49,120 --> 00:36:51,360
Speaker 1: one or two other people, but they're not cuddling the

636
00:36:51,400 --> 00:36:53,480
Speaker 1: way they are with M D M A. And so

637
00:36:53,680 --> 00:36:58,600
Speaker 1: we were really surprised when LSD and psilocybin and ketamine

638
00:36:58,640 --> 00:37:02,160
Speaker 1: and I began all also reopened this critical period. And

639
00:37:02,239 --> 00:37:04,960
Speaker 1: what that suggested immediately to us, and this is what

640
00:37:05,000 --> 00:37:08,719
Speaker 1: we're following up in the subsequent studies, is that the

641
00:37:09,080 --> 00:37:14,520
Speaker 1: acute subjective character of psychedelics really isn't the thing. So

642
00:37:14,600 --> 00:37:18,080
Speaker 1: the thing that makes them all similar is their ability

643
00:37:18,120 --> 00:37:21,120
Speaker 1: to open the critical period. And in fact that the

644
00:37:21,120 --> 00:37:23,479
Speaker 1: thing that they share in common, and which is why

645
00:37:23,520 --> 00:37:26,319
Speaker 1: I call all of them psychedelics, is that they all

646
00:37:26,440 --> 00:37:29,680
Speaker 1: induce an altered state of consciousness. Right, And it's hard

647
00:37:29,719 --> 00:37:33,000
Speaker 1: to define exactly what that means that altered state of consciousness,

648
00:37:33,040 --> 00:37:37,279
Speaker 1: but all of the psychedelics, whether they're dissociative, hallucinogetic, and

649
00:37:37,440 --> 00:37:41,400
Speaker 1: pathogenic or own irogenic. They all have that property of

650
00:37:41,400 --> 00:37:45,120
Speaker 1: inducing that altered state of consciousness, and so our recent

651
00:37:45,200 --> 00:37:49,560
Speaker 1: studies really suggest that maybe what it feels like to

652
00:37:49,640 --> 00:37:52,239
Speaker 1: be in an altered state of consciousness is just what

653
00:37:52,360 --> 00:37:55,520
Speaker 1: it feels like to open critical period. But now you're

654
00:37:55,560 --> 00:37:58,680
Speaker 1: probably using that phrase altered state of consciousness in an

655
00:37:58,680 --> 00:38:02,480
Speaker 1: hour sense because given the name of this podcast, right, psychoactive,

656
00:38:02,560 --> 00:38:05,399
Speaker 1: which essentially implies altered state of consciousness, And we think

657
00:38:05,400 --> 00:38:09,200
Speaker 1: about that applying really to almost all psychoactive substances, So

658
00:38:09,440 --> 00:38:13,520
Speaker 1: not just the psychedelics, but cocaine or opioids, or for

659
00:38:13,600 --> 00:38:17,160
Speaker 1: that matter, it could be caffeine or nicotine or you know,

660
00:38:17,160 --> 00:38:20,879
Speaker 1: any range of others insufficient doses. So what about those

661
00:38:20,920 --> 00:38:24,120
Speaker 1: other substances, I mean, they are altering consciousness, Is it

662
00:38:24,239 --> 00:38:26,440
Speaker 1: just that they're altering it in a different way or

663
00:38:26,520 --> 00:38:29,680
Speaker 1: different degree. Yeah, So I guess I would quibble with

664
00:38:29,719 --> 00:38:34,040
Speaker 1: the idea that they're all altering consciousness. They're all altering

665
00:38:34,600 --> 00:38:37,000
Speaker 1: brain function, I guess. And so I guess it sort

666
00:38:37,000 --> 00:38:40,000
Speaker 1: of depends on how broadly you want to define consciousness.

667
00:38:40,080 --> 00:38:42,080
Speaker 1: If you want to define it really broadly and you

668
00:38:42,080 --> 00:38:44,759
Speaker 1: want to say consciousness is just in the sense of

669
00:38:45,120 --> 00:38:49,880
Speaker 1: conscious versus unconscious. Then every anesthetic is also a psycho

670
00:38:50,280 --> 00:38:53,520
Speaker 1: well psychoactive. But when people say the altered state of

671
00:38:53,520 --> 00:38:56,920
Speaker 1: consciousness induced by psychedelics, I think they're referring to a

672
00:38:57,040 --> 00:39:00,760
Speaker 1: very narrow sense of what it means to be conscious. Again,

673
00:39:00,800 --> 00:39:02,600
Speaker 1: it's a little bit hard to define. I mean, I

674
00:39:02,600 --> 00:39:05,440
Speaker 1: feel like philosophers have written whole books about what is

675
00:39:05,520 --> 00:39:08,239
Speaker 1: the interesting sense of the word consciousness, and so I

676
00:39:08,320 --> 00:39:10,919
Speaker 1: don't really want to spend too much time on that.

677
00:39:11,000 --> 00:39:14,640
Speaker 1: But what I will say is is that the shared

678
00:39:14,680 --> 00:39:19,560
Speaker 1: ability of psychedelics to alter the sense of consciousness that's

679
00:39:19,680 --> 00:39:23,840
Speaker 1: different from other psychoactive drugs like cocaine and nicotine and

680
00:39:23,880 --> 00:39:27,839
Speaker 1: alcohol and even marijuana, seems to be related to their

681
00:39:27,880 --> 00:39:32,200
Speaker 1: therapeutic effects, right, Because it's not like people are curing

682
00:39:32,280 --> 00:39:35,240
Speaker 1: drug addiction with cocaine. It's not like people are curing

683
00:39:35,320 --> 00:39:41,600
Speaker 1: PTSD with cocaine, right. In fact, cocaine's psychotropic or psychoactive

684
00:39:41,680 --> 00:39:45,440
Speaker 1: effects are more likely to leave do abuse and addiction

685
00:39:45,560 --> 00:39:49,880
Speaker 1: like behaviors. They incidentally take a reward and make it

686
00:39:50,040 --> 00:39:53,920
Speaker 1: context independent, and they're really what I would call drugs

687
00:39:53,920 --> 00:39:59,160
Speaker 1: that induce Cocaine in particular, induce hyper plasticity, And so

688
00:39:59,400 --> 00:40:02,360
Speaker 1: by plastic see, what I mean is is that synapses

689
00:40:02,560 --> 00:40:05,359
Speaker 1: in the brain, which are the connections between neurons and

690
00:40:05,400 --> 00:40:08,920
Speaker 1: how they communicate with each other, the weights that are

691
00:40:08,960 --> 00:40:12,960
Speaker 1: assigned to each of those synapses change as you encode memories.

692
00:40:13,239 --> 00:40:17,560
Speaker 1: And we think that that plasticity of the synaptic weights

693
00:40:17,680 --> 00:40:21,480
Speaker 1: is what's responsible for encoding memories. And what cocaine seems

694
00:40:21,520 --> 00:40:25,520
Speaker 1: to do is massively increase the number of synapses and

695
00:40:25,640 --> 00:40:29,759
Speaker 1: dendritic sprouting and create a whole bunch of extra memories

696
00:40:29,880 --> 00:40:35,920
Speaker 1: that are around using cocaine, enjoying cocaine, associating every positive

697
00:40:36,000 --> 00:40:38,960
Speaker 1: feeling you've ever had with cocaine, and that sort of

698
00:40:39,040 --> 00:40:44,759
Speaker 1: hyperplastic response is very different from what we see with psychedelics. Well,

699
00:40:44,840 --> 00:40:46,279
Speaker 1: let me ask you this school, I mean, because let

700
00:40:46,280 --> 00:40:48,200
Speaker 1: me just throw in two other drugs here that kind

701
00:40:48,200 --> 00:40:50,759
Speaker 1: of fall in between. I mean, obviously m D M

702
00:40:50,800 --> 00:40:54,000
Speaker 1: A is amphetamine based, and so one question is what

703
00:40:54,120 --> 00:40:56,560
Speaker 1: about other types of amphetamine. They share some things in

704
00:40:56,600 --> 00:40:59,160
Speaker 1: common with cocaine, some things in common with M D

705
00:40:59,320 --> 00:41:02,080
Speaker 1: M A. Of the other one is what about th HC,

706
00:41:02,560 --> 00:41:05,160
Speaker 1: which kind of falls in between the kind of altered.

707
00:41:05,239 --> 00:41:07,560
Speaker 1: In fact, many people say it does create altered state

708
00:41:07,600 --> 00:41:11,520
Speaker 1: of consciousness in ways that sometimes can resemble the psychedelics.

709
00:41:11,520 --> 00:41:14,359
Speaker 1: So what about those two Amphetamine and t HC. Yeah,

710
00:41:14,400 --> 00:41:17,799
Speaker 1: so we haven't actually tested either one directly, but I

711
00:41:17,920 --> 00:41:21,400
Speaker 1: suspect that emphetamine is going to look very much like cocaine,

712
00:41:21,480 --> 00:41:24,280
Speaker 1: which you know, cocaine does not reopen the critical period,

713
00:41:24,320 --> 00:41:28,360
Speaker 1: but it does induce these addiction like behaviors and addiction

714
00:41:28,440 --> 00:41:32,839
Speaker 1: like changes in synapsis. Th HC is definitely a strange one,

715
00:41:32,920 --> 00:41:35,839
Speaker 1: and it's an in between case, and we really don't know.

716
00:41:36,080 --> 00:41:38,960
Speaker 1: And one of the things about TAHC that I've always

717
00:41:39,000 --> 00:41:42,080
Speaker 1: been sort of fascinated about is that it seems to

718
00:41:42,120 --> 00:41:45,680
Speaker 1: be a great imitator. So if you've, you know, mostly

719
00:41:45,800 --> 00:41:50,200
Speaker 1: been intoxicated with alcohol and then you start doing th HC,

720
00:41:50,560 --> 00:41:53,600
Speaker 1: you know you're high, your teach the highest sort of mellow.

721
00:41:53,840 --> 00:41:57,080
Speaker 1: But after you do t HC, after you've tried any

722
00:41:57,120 --> 00:41:59,920
Speaker 1: of the psychedelics, then suddenly it can take on a

723
00:42:00,040 --> 00:42:03,400
Speaker 1: sort of psychedelic character. And I don't have any clue

724
00:42:03,400 --> 00:42:05,840
Speaker 1: about what that's about. The reason that we sort of

725
00:42:05,960 --> 00:42:10,160
Speaker 1: didn't focus on THHC in our experiments is that t HC,

726
00:42:10,600 --> 00:42:14,120
Speaker 1: especially at very high doses seems to induce a certain

727
00:42:14,120 --> 00:42:16,880
Speaker 1: amount of paranoia in people, and we actually think we

728
00:42:16,960 --> 00:42:19,960
Speaker 1: have a hypothesis about why that is. But you'll have

729
00:42:20,000 --> 00:42:22,879
Speaker 1: to invite me again for a different podcast to talk

730
00:42:22,920 --> 00:42:26,040
Speaker 1: about that one. Okay, well, so let's just talk about

731
00:42:26,080 --> 00:42:28,239
Speaker 1: some of the other implications of the study. So you

732
00:42:28,320 --> 00:42:30,520
Speaker 1: find that you know it's working, and obviously you know

733
00:42:30,680 --> 00:42:31,920
Speaker 1: m d m A, you know, and is sort of

734
00:42:31,920 --> 00:42:36,279
Speaker 1: a pathogen heartwarming, cuddly whereas we think about the psychedelics,

735
00:42:36,280 --> 00:42:38,480
Speaker 1: and sometimes I guess one of the theories is that

736
00:42:38,560 --> 00:42:42,520
Speaker 1: the intensity of the sort of spiritual or mystical experience

737
00:42:42,640 --> 00:42:46,120
Speaker 1: is part of what is associated with their efficacy. But

738
00:42:46,600 --> 00:42:48,800
Speaker 1: one of the other things that I saw you pointing

739
00:42:48,800 --> 00:42:51,000
Speaker 1: out is that, you know, we've typically at least I've

740
00:42:51,000 --> 00:42:52,759
Speaker 1: typically thought about you do m d m A just

741
00:42:52,760 --> 00:42:55,520
Speaker 1: psycholics and you have a psychotherapeutic you work with the

742
00:42:55,520 --> 00:42:59,920
Speaker 1: therapist immediately thereafter. But you're pointing out that this critical

743
00:43:00,080 --> 00:43:03,919
Speaker 1: period that gets opened, it's not just for a few

744
00:43:03,960 --> 00:43:07,120
Speaker 1: hours or something. It can be quite a bit longer,

745
00:43:07,560 --> 00:43:10,560
Speaker 1: and that the longer the drug experience last, maybe the

746
00:43:10,640 --> 00:43:14,400
Speaker 1: longer the critical period last. And so just talk about

747
00:43:14,440 --> 00:43:17,040
Speaker 1: that and the implications of that. Yeah, So I mean

748
00:43:17,120 --> 00:43:19,880
Speaker 1: I mentioned that we were beginning to have some evidence

749
00:43:20,000 --> 00:43:23,160
Speaker 1: that what it feels like to be in this psychedelic

750
00:43:23,280 --> 00:43:26,319
Speaker 1: altered state of consciousness is just what it feels like

751
00:43:26,520 --> 00:43:30,279
Speaker 1: to reopen critical periods. And part of the evidence we

752
00:43:30,360 --> 00:43:34,239
Speaker 1: have for that is this proportionality between how long the

753
00:43:34,280 --> 00:43:38,319
Speaker 1: acute subjective effects of psychedelics last and how long the

754
00:43:38,360 --> 00:43:42,640
Speaker 1: critical period stays open after the psychedelic acute effects have

755
00:43:42,760 --> 00:43:46,200
Speaker 1: worn off. And so just to compare the different drugs,

756
00:43:46,239 --> 00:43:50,120
Speaker 1: so ketamine, you know, most people's acute effects of ketamine

757
00:43:50,200 --> 00:43:54,040
Speaker 1: lass anywhere from thirty minutes to maximum sort of two hours,

758
00:43:54,320 --> 00:43:57,319
Speaker 1: whereas people who take LSD, you know, it's eight to

759
00:43:57,400 --> 00:44:01,520
Speaker 1: ten hours is the typical acute subjective effects last, Whereas

760
00:44:01,560 --> 00:44:05,160
Speaker 1: I began lasts for a really long time. So between

761
00:44:05,200 --> 00:44:09,240
Speaker 1: thirty six and seventy two hour long acute subjective effects

762
00:44:09,239 --> 00:44:11,600
Speaker 1: of I be game. And just like that, what we

763
00:44:11,680 --> 00:44:14,719
Speaker 1: see is that ted amine keeps the critical period open

764
00:44:14,800 --> 00:44:18,040
Speaker 1: for forty eight hours. Psilocybin and m D m A

765
00:44:18,200 --> 00:44:20,520
Speaker 1: seem to keep it open for about two weeks after

766
00:44:20,640 --> 00:44:23,640
Speaker 1: we give the drug LSD for three weeks, and I began,

767
00:44:23,800 --> 00:44:25,839
Speaker 1: you know, we haven't found the outer limit of it,

768
00:44:25,880 --> 00:44:28,560
Speaker 1: but at least a month after we give I BEGANN

769
00:44:28,640 --> 00:44:32,279
Speaker 1: the critical period stays open. And so that has I

770
00:44:32,320 --> 00:44:37,600
Speaker 1: think three really important implications. One is that, as I said,

771
00:44:37,640 --> 00:44:41,040
Speaker 1: it sort of lends further support to the idea that

772
00:44:41,080 --> 00:44:44,960
Speaker 1: critical period reopening is the thing that makes this class

773
00:44:44,960 --> 00:44:48,680
Speaker 1: of drugs a single drug class, the shared property across

774
00:44:48,920 --> 00:44:51,719
Speaker 1: the drugs. The second one is that I think when

775
00:44:51,719 --> 00:44:56,839
Speaker 1: we're designing clinical trials for using these drugs to cure PTSD,

776
00:44:57,280 --> 00:45:00,440
Speaker 1: we're gonna band to be really really careful about out

777
00:45:00,440 --> 00:45:04,120
Speaker 1: making sure that we offer enough support to people after

778
00:45:04,239 --> 00:45:07,719
Speaker 1: the acute subjective effects have worn off, because what's two

779
00:45:07,760 --> 00:45:10,200
Speaker 1: weeks in a mouth could be two months in a

780
00:45:10,320 --> 00:45:13,080
Speaker 1: human right, And what we think this is analogous to

781
00:45:13,320 --> 00:45:16,960
Speaker 1: is putting a person back into this sort of vulnerable

782
00:45:17,080 --> 00:45:20,279
Speaker 1: and sensitive state, just like a child. And so we

783
00:45:20,320 --> 00:45:23,440
Speaker 1: want to offer support to those people. And you know,

784
00:45:23,480 --> 00:45:26,560
Speaker 1: I would very much like to get funding to run

785
00:45:26,560 --> 00:45:30,720
Speaker 1: a clinical trial that looks at the difference between people

786
00:45:30,760 --> 00:45:33,359
Speaker 1: who were given sort of standard of care the way

787
00:45:33,360 --> 00:45:37,000
Speaker 1: the FDA wanted the trials to be designed, and another

788
00:45:37,080 --> 00:45:39,480
Speaker 1: group where instead of just going home and writing in

789
00:45:39,480 --> 00:45:42,320
Speaker 1: your journal and calling into the therapist for the weeks

790
00:45:42,360 --> 00:45:45,400
Speaker 1: after you get to go to something like a retreat

791
00:45:45,680 --> 00:45:49,920
Speaker 1: and you are given the sort of space and support

792
00:45:50,080 --> 00:45:53,520
Speaker 1: and therapy that you need to continue to integrate those

793
00:45:53,600 --> 00:45:56,919
Speaker 1: memories and those traumatic habits that you've developed from your

794
00:45:57,040 --> 00:46:00,720
Speaker 1: being traumatized, that you reintegrate them in to your new

795
00:46:00,760 --> 00:46:04,759
Speaker 1: personality habits and traits and your new world in that

796
00:46:04,880 --> 00:46:08,360
Speaker 1: sort of safe space. So that's the second implication, and

797
00:46:08,400 --> 00:46:10,920
Speaker 1: then the third implication, and this sort of touches on

798
00:46:11,000 --> 00:46:14,360
Speaker 1: what you mentioned about Roland Griffith's studies about the depth

799
00:46:14,360 --> 00:46:17,239
Speaker 1: of the mexical experience. I think that what this is

800
00:46:17,320 --> 00:46:20,600
Speaker 1: telling us is that there are a lot of enthusiasm

801
00:46:20,719 --> 00:46:24,560
Speaker 1: right now, especially from the business world, to rush to

802
00:46:24,680 --> 00:46:30,000
Speaker 1: develop psychedelics that don't have any kind of psychedelic side

803
00:46:30,040 --> 00:46:34,239
Speaker 1: effects if you will so engineer out the mystical experience

804
00:46:34,320 --> 00:46:38,680
Speaker 1: the big trip right and I suspect that those efforts

805
00:46:38,719 --> 00:46:43,759
Speaker 1: will all take miracle drugs like LSD and psilocybin and

806
00:46:43,880 --> 00:46:47,160
Speaker 1: I beginning, which have these very profound ability to change

807
00:46:47,480 --> 00:46:52,600
Speaker 1: memories and potentially cure things like heroin addiction and essentially

808
00:46:52,719 --> 00:46:55,239
Speaker 1: engineer them back down to being something like an S

809
00:46:55,239 --> 00:46:57,319
Speaker 1: s R I, because I think if you get rid

810
00:46:57,400 --> 00:47:01,200
Speaker 1: of that long experience, you're going to interfere with the

811
00:47:01,280 --> 00:47:05,120
Speaker 1: mechanism that is reopening critical periods. So when you're talking

812
00:47:05,160 --> 00:47:08,040
Speaker 1: about this extended length of the critical period, it's not

813
00:47:08,120 --> 00:47:11,760
Speaker 1: just about being cautious about how therapists deal with that period,

814
00:47:11,840 --> 00:47:14,279
Speaker 1: being aware that it's not just about the hours and

815
00:47:14,360 --> 00:47:17,120
Speaker 1: days afterwards, but you're also talking that there's actually this

816
00:47:17,320 --> 00:47:20,600
Speaker 1: bonus that maybe people didn't realize, that there's this extended

817
00:47:20,719 --> 00:47:24,320
Speaker 1: period of time in which the insights can be almost

818
00:47:24,320 --> 00:47:28,759
Speaker 1: harvested and developed even more more thoroughly, more deeply, absolutely, absolutely,

819
00:47:28,760 --> 00:47:32,000
Speaker 1: and in fact I think that this is why for

820
00:47:32,200 --> 00:47:38,080
Speaker 1: really really entrenched memories and really hardcore addictions like heroin addiction,

821
00:47:38,480 --> 00:47:42,400
Speaker 1: the big sort of anecdotal stories that we hear about

822
00:47:42,680 --> 00:47:47,440
Speaker 1: recovery from heroin addiction are all coming from iby game, right,

823
00:47:47,600 --> 00:47:51,879
Speaker 1: not from ketamine or psilocybin, right, Because those memories are

824
00:47:51,920 --> 00:47:55,960
Speaker 1: really entrenched into the fabric or the whole sort of

825
00:47:56,080 --> 00:48:00,440
Speaker 1: network of memories and habits and patterns and personality traits

826
00:48:00,440 --> 00:48:03,480
Speaker 1: that a humans developed over their lifetime, and to undo

827
00:48:03,600 --> 00:48:07,240
Speaker 1: them you probably need to have the critical periods stay

828
00:48:07,280 --> 00:48:10,640
Speaker 1: open for a long time so that you can say, Okay, oh,

829
00:48:10,640 --> 00:48:12,680
Speaker 1: I'm going to the park, and normally I would have

830
00:48:12,719 --> 00:48:15,040
Speaker 1: a heroin craving here, but you know what, I don't

831
00:48:15,040 --> 00:48:18,400
Speaker 1: need that anymore, you know, rewriting those memories around the

832
00:48:18,480 --> 00:48:24,799
Speaker 1: whole whole circuit of memories that surround that very entrenched addiction. Now,

833
00:48:24,840 --> 00:48:28,400
Speaker 1: are there implications on me, for example, about say, multi dosing,

834
00:48:28,520 --> 00:48:31,680
Speaker 1: like giving ketamine five or six days in a row,

835
00:48:32,000 --> 00:48:35,759
Speaker 1: or administering multiple doses of d M A or psilocybi

836
00:48:35,800 --> 00:48:39,360
Speaker 1: els D over a period of days or weeks. Anything

837
00:48:39,400 --> 00:48:41,800
Speaker 1: you can say about that stuff, we see added benefits,

838
00:48:41,880 --> 00:48:46,160
Speaker 1: reduced benefits. Yeah. So, honestly, when we first started these experiments,

839
00:48:46,280 --> 00:48:49,520
Speaker 1: I basically have the intuition that, you know, the longer

840
00:48:49,560 --> 00:48:52,279
Speaker 1: you can keep it open, the better, and that that

841
00:48:52,360 --> 00:48:55,680
Speaker 1: would help you to have the most access to those

842
00:48:55,960 --> 00:48:59,280
Speaker 1: sort of calcified memories, if you will. But I'm beginning

843
00:48:59,280 --> 00:49:03,400
Speaker 1: to think that actually there probably is an opportunity to

844
00:49:03,440 --> 00:49:06,840
Speaker 1: stabber them, especially because you sort of hinted at this

845
00:49:06,960 --> 00:49:11,000
Speaker 1: and the question. Especially the serotonin psychedelics seem to have

846
00:49:11,200 --> 00:49:16,839
Speaker 1: this property of causing desensitization or tolerance very quickly. So

847
00:49:16,960 --> 00:49:20,360
Speaker 1: people who do micro dosing of psilocybin, you know, not

848
00:49:20,520 --> 00:49:22,920
Speaker 1: everybody has the same experience, but a lot of people

849
00:49:22,920 --> 00:49:26,720
Speaker 1: will report that very quickly the effects of the drug

850
00:49:26,960 --> 00:49:30,040
Speaker 1: seems to attenuate, right. And so what we have also

851
00:49:30,200 --> 00:49:33,360
Speaker 1: discovered is that we've kind of a little bit taken

852
00:49:33,400 --> 00:49:37,240
Speaker 1: down the primacy of the serotonin to a receptor, because

853
00:49:37,440 --> 00:49:41,839
Speaker 1: while psilocybin and LSD obviously really you know, we have

854
00:49:41,960 --> 00:49:44,640
Speaker 1: to activate the serotonin too a receptor in order to

855
00:49:44,680 --> 00:49:48,120
Speaker 1: get these critical period reopening, ketamine m D M A

856
00:49:48,280 --> 00:49:51,480
Speaker 1: and I began don't care about the serotonin receptor. In fact,

857
00:49:51,800 --> 00:49:54,760
Speaker 1: there's evidence that ketamine is working through a different receptor

858
00:49:54,800 --> 00:49:57,320
Speaker 1: called an m D A. I began is probably working

859
00:49:57,360 --> 00:50:00,319
Speaker 1: through the cappa opioid receptor m D M A. It's

860
00:50:00,360 --> 00:50:03,960
Speaker 1: not clear it's causing a release of serotonin, and it's

861
00:50:04,000 --> 00:50:07,920
Speaker 1: probably binding to all fourteen of the serotonin receptors, not

862
00:50:08,080 --> 00:50:11,800
Speaker 1: just to A. And it doesn't require to A to reopen.

863
00:50:12,040 --> 00:50:15,640
Speaker 1: And so it might be that, you know, to stagger

864
00:50:15,880 --> 00:50:19,880
Speaker 1: not only drugs that have different durations of critical period.

865
00:50:19,960 --> 00:50:22,280
Speaker 1: So for example, if you want to on ramp somebody

866
00:50:22,320 --> 00:50:26,600
Speaker 1: who's had a very very serious horrible, maybe complex PTSD

867
00:50:27,120 --> 00:50:30,440
Speaker 1: and facing the traumatic memories all at once is too

868
00:50:30,560 --> 00:50:33,040
Speaker 1: much for them, So maybe we want to start gently

869
00:50:33,120 --> 00:50:35,759
Speaker 1: with them with some I'm just making this up, but

870
00:50:35,920 --> 00:50:38,960
Speaker 1: this is what our newer data is starting to suggest

871
00:50:39,040 --> 00:50:42,479
Speaker 1: that we want to start looking at the possibility of

872
00:50:42,560 --> 00:50:46,719
Speaker 1: combining maybe some short acting, some micro doses, some ketamines

873
00:50:46,840 --> 00:50:50,160
Speaker 1: early on, just to loosen things up, and then as

874
00:50:50,200 --> 00:50:53,480
Speaker 1: the patient gets more comfortable, kind of do the longer

875
00:50:53,560 --> 00:50:56,719
Speaker 1: trips that go deeper and then sort of stagger on

876
00:50:56,760 --> 00:50:59,040
Speaker 1: top of that the big, big trip at the end.

877
00:50:59,280 --> 00:51:03,280
Speaker 1: And that could potentially allow us to mix and match

878
00:51:03,440 --> 00:51:06,799
Speaker 1: so that we can do the most work over a

879
00:51:06,800 --> 00:51:09,520
Speaker 1: long period of time, but also give people breaks and

880
00:51:09,560 --> 00:51:12,879
Speaker 1: also give people an opportunity to wait in if they're

881
00:51:12,920 --> 00:51:15,040
Speaker 1: not ready to be kind of thrown out the deep

882
00:51:15,160 --> 00:51:19,560
Speaker 1: end of the pool. Let's take a break here and

883
00:51:19,600 --> 00:51:34,880
Speaker 1: go to an ad. Is there a limited number of

884
00:51:34,920 --> 00:51:37,320
Speaker 1: times that one could use m d m A or

885
00:51:37,360 --> 00:51:40,360
Speaker 1: these other drugs in order to open up this critical period?

886
00:51:40,440 --> 00:51:44,080
Speaker 1: You know, listeners of this podcast, numerous episodes, I've expressed

887
00:51:44,080 --> 00:51:46,759
Speaker 1: my great sadness that m d m A, which was

888
00:51:46,800 --> 00:51:48,680
Speaker 1: such a wonderful drug in my life when I was

889
00:51:48,719 --> 00:51:51,400
Speaker 1: in my thirties and forties and mostly using it with

890
00:51:51,440 --> 00:51:53,959
Speaker 1: my romantic partner or with a close set of friends

891
00:51:54,000 --> 00:51:55,719
Speaker 1: only a couple of times in a rage setting. Just

892
00:51:55,760 --> 00:51:57,799
Speaker 1: doesn't really seem to work for me much in the

893
00:51:57,840 --> 00:52:00,759
Speaker 1: last and fifteen years, And I'm wondering, is there only

894
00:52:00,880 --> 00:52:03,560
Speaker 1: so many times you can use and the mail the

895
00:52:03,560 --> 00:52:06,120
Speaker 1: others to open that critical period. I mean, we don't

896
00:52:06,160 --> 00:52:08,920
Speaker 1: really have hard data on that. What I will say

897
00:52:09,200 --> 00:52:12,560
Speaker 1: is that I have an idea that there's gonna be

898
00:52:12,760 --> 00:52:17,080
Speaker 1: interactions between them. So for example, there's one clinical study

899
00:52:17,120 --> 00:52:20,680
Speaker 1: in humans that shows that if you don't take people

900
00:52:20,719 --> 00:52:23,600
Speaker 1: off their S s R I medications so they're Prozac

901
00:52:23,719 --> 00:52:25,759
Speaker 1: or any of the drugs in that class, then the

902
00:52:25,880 --> 00:52:28,560
Speaker 1: M d M A stops working. And that sort of

903
00:52:28,600 --> 00:52:31,759
Speaker 1: makes sense because if the idea is that when you're

904
00:52:31,800 --> 00:52:35,080
Speaker 1: blocking the serotone and transporter, M d M A actually

905
00:52:35,080 --> 00:52:37,040
Speaker 1: has to sit in the same bonding pocket. So if

906
00:52:37,200 --> 00:52:39,839
Speaker 1: the prozac is in there blocking it away, then it's

907
00:52:39,880 --> 00:52:43,280
Speaker 1: possible that that interferes with M d m AS ability

908
00:52:43,320 --> 00:52:45,439
Speaker 1: to get into that same pocket and cause the same

909
00:52:45,480 --> 00:52:49,160
Speaker 1: remarkable consequences. But what's more than that is is that

910
00:52:49,200 --> 00:52:53,040
Speaker 1: there's some older literature suggesting not with s s RRI,

911
00:52:53,360 --> 00:52:57,520
Speaker 1: but with older generation antidepressants like tricyclicant and m a

912
00:52:57,600 --> 00:53:01,200
Speaker 1: O wise that what is happening. The reason that there's

913
00:53:01,239 --> 00:53:04,480
Speaker 1: this delay between when you start taking the antidepressant and

914
00:53:04,520 --> 00:53:06,880
Speaker 1: when you start to feel the effect is that the

915
00:53:06,920 --> 00:53:09,920
Speaker 1: real effect of the drug might not be increasing the

916
00:53:09,960 --> 00:53:14,200
Speaker 1: amount of serotonin that's available in the synapse itself, but

917
00:53:14,360 --> 00:53:18,120
Speaker 1: that by increasing the basil levels loading around the neuron

918
00:53:18,239 --> 00:53:22,640
Speaker 1: serotonin that triggers in the cells that are normally receiving

919
00:53:22,640 --> 00:53:26,480
Speaker 1: the serotonin signal to pull in some of those serotonin

920
00:53:26,560 --> 00:53:30,040
Speaker 1: receptors and sort of downregulate the number of receptors that

921
00:53:30,080 --> 00:53:32,719
Speaker 1: are in the membrane. So sort of like if you've

922
00:53:32,719 --> 00:53:36,280
Speaker 1: got a bunch of microphones out into an arena and

923
00:53:36,520 --> 00:53:38,960
Speaker 1: everybody in the arena is screaming, maybe you pull a

924
00:53:38,960 --> 00:53:41,160
Speaker 1: couple of those microphones in so that it's not so

925
00:53:41,320 --> 00:53:44,760
Speaker 1: loud anymore. So that's kind of one early idea about

926
00:53:44,840 --> 00:53:50,799
Speaker 1: how antidepressive drugs were working, and there is some suggestion

927
00:53:51,000 --> 00:53:55,200
Speaker 1: that this could also be happening for LSD and psilocybin

928
00:53:55,320 --> 00:53:59,000
Speaker 1: as well. So I could potentially formulate at least a

929
00:53:59,080 --> 00:54:02,440
Speaker 1: hypothesis about why m d M A might stop working

930
00:54:02,480 --> 00:54:05,960
Speaker 1: if you're also doing a lot of other psychedelics and

931
00:54:06,280 --> 00:54:10,240
Speaker 1: or taking prozac or any of these other antidepressive drugs,

932
00:54:10,280 --> 00:54:14,279
Speaker 1: because they're sort of including each other's mechanism, Which is

933
00:54:14,320 --> 00:54:16,799
Speaker 1: why I think it will be useful to develop an

934
00:54:16,920 --> 00:54:20,279
Speaker 1: arsenal of drugs that are doing this with lots of

935
00:54:20,280 --> 00:54:23,320
Speaker 1: different receptors. Right, So maybe I begin it's going to

936
00:54:23,440 --> 00:54:26,880
Speaker 1: help for somebody who has already kind of maximally tuned

937
00:54:27,040 --> 00:54:31,359
Speaker 1: the serotonin receptors. So is it a matter that does

938
00:54:31,400 --> 00:54:33,560
Speaker 1: not one developed? I mean, even like I think in

939
00:54:33,600 --> 00:54:35,680
Speaker 1: my case, I never did the antidepressants, and I have

940
00:54:35,800 --> 00:54:38,480
Speaker 1: not been. I've been an occasional user of the psychoelics

941
00:54:38,480 --> 00:54:41,560
Speaker 1: and DMA for decades, but never a frequent user. I mean,

942
00:54:41,719 --> 00:54:44,320
Speaker 1: is there an element in which one does develop a tolerance?

943
00:54:44,640 --> 00:54:47,120
Speaker 1: Just going back to that issue, if one's using this

944
00:54:47,200 --> 00:54:50,239
Speaker 1: drug in the psychotherapy, right in the proper setting, in

945
00:54:50,360 --> 00:54:53,200
Speaker 1: order to open up this critical period and deal with

946
00:54:53,239 --> 00:54:57,200
Speaker 1: the past traumas PTSD or I was talking about psilocybin

947
00:54:57,200 --> 00:54:59,719
Speaker 1: and depression or whatever it might be, and you make

948
00:54:59,800 --> 00:55:03,319
Speaker 1: so progress. But I mean, obviously we sometimes see there's

949
00:55:03,320 --> 00:55:06,640
Speaker 1: some research suggesting that when you do this, a one

950
00:55:06,680 --> 00:55:10,080
Speaker 1: off can provide a real cure, right, not just a palliative,

951
00:55:10,120 --> 00:55:13,520
Speaker 1: but a cure. Can there be value in our possibilities

952
00:55:13,560 --> 00:55:16,760
Speaker 1: in terms of doing this two times, five times, ten times,

953
00:55:16,800 --> 00:55:20,239
Speaker 1: twenty times, or is it kind of gonna peek out,

954
00:55:20,360 --> 00:55:22,759
Speaker 1: like if it doesn't take the first time to do it,

955
00:55:22,880 --> 00:55:25,959
Speaker 1: the second time, I got to do something else. Yeah, So,

956
00:55:26,080 --> 00:55:29,239
Speaker 1: I mean there are already trials where I think in

957
00:55:29,280 --> 00:55:33,160
Speaker 1: Europe MAPS is running some trials for complex PTSD doing

958
00:55:33,239 --> 00:55:36,200
Speaker 1: sort of multiple rounds of m d m A. But again,

959
00:55:36,360 --> 00:55:39,279
Speaker 1: because of this issue of tolerance, again, it's going to

960
00:55:39,360 --> 00:55:43,440
Speaker 1: be really important to understand the mechanism because it's probably

961
00:55:43,480 --> 00:55:45,640
Speaker 1: going to be the case that we're going to need

962
00:55:45,719 --> 00:55:49,279
Speaker 1: to fine tune the dosing regiment so that we're not

963
00:55:49,360 --> 00:55:53,120
Speaker 1: giving new m d M A before the critical period

964
00:55:53,200 --> 00:55:56,120
Speaker 1: that we open is already closed back up again, so

965
00:55:56,200 --> 00:56:00,120
Speaker 1: that we can sort of maximally extend the amount of

966
00:56:00,200 --> 00:56:04,480
Speaker 1: time that the person can do the psychotherapy work without

967
00:56:04,600 --> 00:56:09,080
Speaker 1: running into tolerance issues from staggering them too close to

968
00:56:09,080 --> 00:56:12,440
Speaker 1: each other. But again, also this is going to be

969
00:56:12,480 --> 00:56:16,239
Speaker 1: a case for trying to understand the mechanism, because one

970
00:56:16,280 --> 00:56:18,960
Speaker 1: of the next follow up questions that my lab is

971
00:56:19,000 --> 00:56:22,719
Speaker 1: really pursuing is, Okay, you know, we know that they're

972
00:56:22,719 --> 00:56:26,279
Speaker 1: all working at different receptors. We have some hint that

973
00:56:26,480 --> 00:56:29,640
Speaker 1: the next step, which is the biochemical signaling that comes

974
00:56:29,680 --> 00:56:32,440
Speaker 1: after that, is also not the same for all of

975
00:56:32,440 --> 00:56:35,560
Speaker 1: the different drugs. And so what's the next, next next step,

976
00:56:35,600 --> 00:56:38,920
Speaker 1: what's the thing, what's the last final common denominator that

977
00:56:39,080 --> 00:56:42,719
Speaker 1: brings all of these psychedelics into the realm of being

978
00:56:42,719 --> 00:56:46,600
Speaker 1: able to be these master keys for critical period reopening

979
00:56:46,840 --> 00:56:51,920
Speaker 1: and can we target that directly without melting the brain

980
00:56:52,120 --> 00:56:55,440
Speaker 1: or causing seizures or causing a person to lose all

981
00:56:55,480 --> 00:56:58,040
Speaker 1: of their memories. As we get a better handle on

982
00:56:58,120 --> 00:57:02,359
Speaker 1: how these things are working, we can start to do

983
00:57:02,400 --> 00:57:05,040
Speaker 1: a better job of designing trials with the drugs that

984
00:57:05,120 --> 00:57:09,360
Speaker 1: we have, but then also learning from those mechanisms to

985
00:57:09,520 --> 00:57:13,120
Speaker 1: know what are the limitations and what are the other

986
00:57:13,200 --> 00:57:18,680
Speaker 1: things downstream that we could potentially boost to stop for example,

987
00:57:18,720 --> 00:57:22,480
Speaker 1: of tolerance or maybe reverse if the tolerance doesn't end

988
00:57:22,560 --> 00:57:25,000
Speaker 1: up being part of the mechanism for how the drugs

989
00:57:25,040 --> 00:57:28,720
Speaker 1: are curing. And I think that the tolerance issue really

990
00:57:28,840 --> 00:57:32,120
Speaker 1: is probably going to be more relevant to the non

991
00:57:32,200 --> 00:57:36,960
Speaker 1: context dependent anti depressive properties of these drugs, which are

992
00:57:37,000 --> 00:57:40,080
Speaker 1: going to be separate from critical period opening. And I

993
00:57:40,160 --> 00:57:44,240
Speaker 1: think that critical period reopening is going to end up

994
00:57:44,320 --> 00:57:51,080
Speaker 1: being the explanation for these cures, whereas the anti depressive

995
00:57:51,120 --> 00:57:53,880
Speaker 1: properties are going to be more about the palliatives. And

996
00:57:53,920 --> 00:57:56,120
Speaker 1: we can already see that a little bit in the

997
00:57:56,160 --> 00:57:59,640
Speaker 1: clinical trial. So if we compare the way that the

998
00:58:00,040 --> 00:58:04,640
Speaker 1: New England Journal of Medicine psilocybin versus SSRRI for depression

999
00:58:04,720 --> 00:58:08,800
Speaker 1: trial went, you know, basically they used the psilocybin the

1000
00:58:08,880 --> 00:58:13,040
Speaker 1: same way that we give prozac, right, and so they

1001
00:58:13,040 --> 00:58:16,480
Speaker 1: were given the drug monitored for you know, bad side effects,

1002
00:58:16,480 --> 00:58:19,600
Speaker 1: but psychotherapy wasn't you know, a big component of it.

1003
00:58:19,720 --> 00:58:22,920
Speaker 1: And what they saw is is that the effects of

1004
00:58:23,360 --> 00:58:27,520
Speaker 1: um psilocybin on depression were very similar to s s RI,

1005
00:58:27,800 --> 00:58:32,320
Speaker 1: not worse, but not dramatically better either. Whereas the MAPS

1006
00:58:32,400 --> 00:58:36,200
Speaker 1: trial that was published in Nature Medicine last year, that one,

1007
00:58:36,280 --> 00:58:39,960
Speaker 1: you know, the the whole approach was this is an

1008
00:58:40,000 --> 00:58:46,040
Speaker 1: adjunct therapy and the context is psychotherapy. And in that case,

1009
00:58:46,320 --> 00:58:52,000
Speaker 1: even though we still have issues around controls and direct comparisons,

1010
00:58:52,280 --> 00:58:57,800
Speaker 1: the ability to cure the PTSD compared to ss RISE

1011
00:58:57,920 --> 00:59:01,680
Speaker 1: or compared to just psychotherapy RAP alone seems to be

1012
00:59:01,720 --> 00:59:07,240
Speaker 1: remarkably improved. So cool. At your lab at John's Hawkins,

1013
00:59:07,360 --> 00:59:11,960
Speaker 1: you have a project called FATHOM p h A t

1014
00:59:12,560 --> 00:59:17,280
Speaker 1: H O M. So what does that stand for and

1015
00:59:17,400 --> 00:59:19,280
Speaker 1: what's it about? What are you trying to accomplish there

1016
00:59:19,320 --> 00:59:22,080
Speaker 1: beyond what the research you've described so far. Yeah, so

1017
00:59:22,120 --> 00:59:27,640
Speaker 1: that stands for psychedelic healing adjunct therapy harnessing opened malleability.

1018
00:59:27,640 --> 00:59:30,720
Speaker 1: That came up with that in a dream, and I

1019
00:59:30,800 --> 00:59:33,720
Speaker 1: loved it because I love this idea that when people

1020
00:59:33,760 --> 00:59:36,640
Speaker 1: have really great m d m A experiences, they call

1021
00:59:36,680 --> 00:59:40,720
Speaker 1: it oceanic boundlessness. And I love the FATHOM as like

1022
00:59:40,760 --> 00:59:44,520
Speaker 1: a metaphor for that oceanic boundlessness. And basically, we're taking

1023
00:59:44,560 --> 00:59:48,919
Speaker 1: the unfathomable, which is cures for some of these brain diseases,

1024
00:59:49,120 --> 00:59:52,040
Speaker 1: and making them fathomable again. You know, that's sort of

1025
00:59:52,080 --> 00:59:55,520
Speaker 1: the dream that we are hoping. So the FATHOM project

1026
00:59:55,640 --> 01:00:00,840
Speaker 1: is really just our intuition that based on the fact

1027
01:00:00,840 --> 01:00:03,840
Speaker 1: that all of the psychedelics, whether they're empathogenic or not,

1028
01:00:04,120 --> 01:00:07,240
Speaker 1: or reopening the critical period, that these are the master

1029
01:00:07,400 --> 01:00:11,120
Speaker 1: keys for unlocking all critical periods. And that that's true,

1030
01:00:11,680 --> 01:00:15,560
Speaker 1: then the number of brain disorders and even probably non

1031
01:00:15,600 --> 01:00:19,080
Speaker 1: brain disorders. So I have an idea about curing allergy

1032
01:00:19,360 --> 01:00:24,400
Speaker 1: and curing stutter and curing stroke would be remarkably increased

1033
01:00:24,480 --> 01:00:27,440
Speaker 1: if it's true that these are the master key for

1034
01:00:27,560 --> 01:00:30,920
Speaker 1: unlocking critical periods that neuroscientists have been looking for for

1035
01:00:30,960 --> 01:00:34,800
Speaker 1: almost a hundred years. And the project is really everything

1036
01:00:34,960 --> 01:00:38,560
Speaker 1: from the basic research that we are doing to try

1037
01:00:38,600 --> 01:00:41,919
Speaker 1: and convince ourselves that they are in fact the master key,

1038
01:00:42,000 --> 01:00:45,080
Speaker 1: all the way up to human clinical trials for stroke

1039
01:00:45,200 --> 01:00:48,680
Speaker 1: that we are getting we're revving up to do and

1040
01:00:48,800 --> 01:00:52,920
Speaker 1: potentially in the future looking at what other ways that

1041
01:00:53,000 --> 01:00:56,680
Speaker 1: we can understand the brain using psychedelics. So with stroke,

1042
01:00:56,760 --> 01:00:59,120
Speaker 1: for example, obviously with m D m. A was talking

1043
01:00:59,120 --> 01:01:03,400
Speaker 1: about psychotherapypy with strokes once talking about physical therapy and

1044
01:01:03,440 --> 01:01:06,600
Speaker 1: reopening that critical period. And do you imagine that somebody

1045
01:01:06,680 --> 01:01:09,600
Speaker 1: is subject to a stroke and gets partially paralyzed, that

1046
01:01:09,720 --> 01:01:12,600
Speaker 1: they would be able to go through these sessions. I mean,

1047
01:01:12,680 --> 01:01:15,200
Speaker 1: maybe not just one, but to do them two, three

1048
01:01:15,240 --> 01:01:17,240
Speaker 1: or four times a year to keep returning to that

1049
01:01:17,320 --> 01:01:20,880
Speaker 1: critical period with a physical therapist and delving more deeply

1050
01:01:20,920 --> 01:01:25,000
Speaker 1: into it. Absolutely, So that's the dream. Basically, what we

1051
01:01:25,120 --> 01:01:27,760
Speaker 1: think is is that most people who have a stroke

1052
01:01:27,880 --> 01:01:31,200
Speaker 1: now get some physical therapy, but it's not the sort

1053
01:01:31,200 --> 01:01:35,640
Speaker 1: of intensive motor practice that they need to get full recovery.

1054
01:01:35,960 --> 01:01:40,720
Speaker 1: And so most people get partial recovery. They compensate, you know,

1055
01:01:40,800 --> 01:01:43,960
Speaker 1: they learn how to button their pants with the other hands,

1056
01:01:44,040 --> 01:01:47,000
Speaker 1: They learn how to use their whole hand instead of

1057
01:01:47,040 --> 01:01:50,280
Speaker 1: their fingers to manipulate objects. But you know, what we

1058
01:01:50,360 --> 01:01:55,080
Speaker 1: want is full recovery of normal levels of motion. But

1059
01:01:55,280 --> 01:01:58,120
Speaker 1: this is just for motors strokes, but you know, all strokes.

1060
01:01:58,240 --> 01:02:01,960
Speaker 1: And the ideas is that if we can pair the

1061
01:02:02,080 --> 01:02:05,200
Speaker 1: psychedelic and the way we're imagining it right now is

1062
01:02:05,280 --> 01:02:07,640
Speaker 1: is that the optimal way to pair it is not

1063
01:02:07,840 --> 01:02:11,560
Speaker 1: to pair it to practicing the specific motion that you

1064
01:02:11,600 --> 01:02:14,080
Speaker 1: are trying to get back, so like reaching for your

1065
01:02:14,120 --> 01:02:17,400
Speaker 1: cup or something, but that we should pair it with

1066
01:02:17,480 --> 01:02:21,480
Speaker 1: some sort of video game so that you are taking

1067
01:02:21,520 --> 01:02:24,560
Speaker 1: full advantage of the fact that psychedelics seem to put

1068
01:02:24,600 --> 01:02:29,640
Speaker 1: people into this mode of play like behavior, or non

1069
01:02:29,720 --> 01:02:33,800
Speaker 1: goal directed behavior, and that practicing motor in that sort

1070
01:02:33,840 --> 01:02:38,680
Speaker 1: of non goal directed manner paired with psychedelics should maximally

1071
01:02:38,840 --> 01:02:43,040
Speaker 1: restore the old ways of learning motor behaviors that you

1072
01:02:43,080 --> 01:02:44,720
Speaker 1: had from when you were a child, and that that

1073
01:02:44,880 --> 01:02:49,080
Speaker 1: will help restore more function after the stroke critical period

1074
01:02:49,080 --> 01:02:52,480
Speaker 1: has closed. And could you imagine virtual reality types of

1075
01:02:52,520 --> 01:02:55,320
Speaker 1: machinery also playing a role in his stuff. Yeah. So

1076
01:02:55,360 --> 01:02:59,760
Speaker 1: our collaborators on this project are Steve Zeiler and John Krakauer,

1077
01:03:00,040 --> 01:03:03,600
Speaker 1: and they have been developing not exactly virtual reality, but

1078
01:03:03,680 --> 01:03:07,720
Speaker 1: a video game that they can manipulate. The patient manipulates

1079
01:03:07,760 --> 01:03:10,520
Speaker 1: their arm and a dolphin on the screen kind of

1080
01:03:10,560 --> 01:03:15,440
Speaker 1: swims around. And we love that interactive video game aspect

1081
01:03:15,560 --> 01:03:18,680
Speaker 1: of it that they could play while they were on

1082
01:03:18,720 --> 01:03:21,800
Speaker 1: psychedelics and for several days after the acute effects have

1083
01:03:21,840 --> 01:03:24,760
Speaker 1: worn off, continue to practice with that to kind of

1084
01:03:24,800 --> 01:03:27,280
Speaker 1: trigger the right kinds of mine. So that's exactly the

1085
01:03:27,440 --> 01:03:30,720
Speaker 1: idea that we are pursuing. Fascinating. I mean, I read

1086
01:03:30,760 --> 01:03:33,200
Speaker 1: that you know, years ago your interests and maybe still

1087
01:03:33,240 --> 01:03:35,760
Speaker 1: you had a strong interest in autism, and I guess

1088
01:03:35,760 --> 01:03:38,040
Speaker 1: with autism there was for quite a while, maybe still

1089
01:03:38,160 --> 01:03:40,880
Speaker 1: the notion that it's grounded in some sort of chemical imbalance.

1090
01:03:41,000 --> 01:03:43,520
Speaker 1: But how do you see this work relating to autism

1091
01:03:43,560 --> 01:03:47,040
Speaker 1: and trying to help people with it. Yeah, So when

1092
01:03:47,080 --> 01:03:49,960
Speaker 1: I was a graduate student, you know, my thesis was

1093
01:03:50,200 --> 01:03:53,760
Speaker 1: something called the M blu R Theory of fragilects and Autism,

1094
01:03:53,760 --> 01:03:57,640
Speaker 1: and it was basically testing this idea that what causes

1095
01:03:58,040 --> 01:04:01,600
Speaker 1: most of the impairments that we see in fragile X,

1096
01:04:01,600 --> 01:04:05,440
Speaker 1: which is a subtype of autism, are really an imbalance

1097
01:04:05,640 --> 01:04:09,480
Speaker 1: of this signaling that happens through another type of receptor

1098
01:04:09,520 --> 01:04:13,120
Speaker 1: called the m gluar and the protein that's missing in

1099
01:04:13,040 --> 01:04:16,200
Speaker 1: in fragile x. And we were very excited. We know,

1100
01:04:16,280 --> 01:04:19,080
Speaker 1: we did all these studies in animals and then we

1101
01:04:19,080 --> 01:04:21,400
Speaker 1: were able to show that if we turned down the

1102
01:04:21,880 --> 01:04:25,680
Speaker 1: m glure signaling, then we could restore normal function in

1103
01:04:25,720 --> 01:04:28,480
Speaker 1: a bunch of different domains in mice. And we did

1104
01:04:28,520 --> 01:04:31,800
Speaker 1: those studies and then twenty six other pre clinical labs

1105
01:04:32,240 --> 01:04:35,880
Speaker 1: replicated those findings, and all of the big drug companies

1106
01:04:35,920 --> 01:04:38,720
Speaker 1: got so excited. They were like, this is it. We've

1107
01:04:38,760 --> 01:04:41,960
Speaker 1: got the mechanism. Hundreds of millions of dollars were invested

1108
01:04:42,000 --> 01:04:46,640
Speaker 1: in clinical trials, and to the disappointment of the whole field,

1109
01:04:46,800 --> 01:04:51,800
Speaker 1: those clinical trials did not show clinically relevant improvements in

1110
01:04:52,000 --> 01:04:54,800
Speaker 1: human patients with autism. And I think that some of

1111
01:04:54,840 --> 01:04:59,000
Speaker 1: the people after those trials sort of dismissed them and said, well,

1112
01:04:59,040 --> 01:05:01,000
Speaker 1: you know, a mouse isn't human, and that's why they

1113
01:05:01,000 --> 01:05:04,640
Speaker 1: didn't work. But the authors themselves of the clinical trial

1114
01:05:04,720 --> 01:05:07,960
Speaker 1: studies wrote a follow up paper sort of discussing, you know,

1115
01:05:08,040 --> 01:05:10,959
Speaker 1: what they thought might have happened and what might be

1116
01:05:11,240 --> 01:05:13,760
Speaker 1: some future directions. And one of the things that they

1117
01:05:13,960 --> 01:05:17,760
Speaker 1: mentioned is is that all of the pre clinical studies,

1118
01:05:17,800 --> 01:05:21,760
Speaker 1: all of the mouth studies, were done very early in development,

1119
01:05:21,880 --> 01:05:25,840
Speaker 1: So either from genesis in the case of genetic manipulations

1120
01:05:25,960 --> 01:05:30,640
Speaker 1: or even just the pharmacological manipulations, all happened in juvenile

1121
01:05:30,720 --> 01:05:35,240
Speaker 1: animals before a critical period for social reward learning would

1122
01:05:35,280 --> 01:05:38,560
Speaker 1: be closed. And granted, these studies were done before we

1123
01:05:38,600 --> 01:05:41,080
Speaker 1: had discovered this critical period. So I'm not you know,

1124
01:05:41,120 --> 01:05:44,200
Speaker 1: pointing fingers or anything, but to me, that's very interesting

1125
01:05:44,240 --> 01:05:47,120
Speaker 1: because what it suggests is this that maybe what we

1126
01:05:47,160 --> 01:05:50,120
Speaker 1: need to do with autism is go back and test

1127
01:05:50,200 --> 01:05:55,040
Speaker 1: that biochemical imbalanced idea, but in this time, instead of

1128
01:05:55,120 --> 01:05:59,080
Speaker 1: giving the drug by itself, we pair it with reopening

1129
01:05:59,080 --> 01:06:02,640
Speaker 1: of the social critical period, and under those conditions of

1130
01:06:03,040 --> 01:06:07,160
Speaker 1: restoring the imbalance in the open state of the critical

1131
01:06:07,240 --> 01:06:11,520
Speaker 1: period will allow patients to learn from their social environment

1132
01:06:11,560 --> 01:06:14,880
Speaker 1: in the way that they missed out on early in development. Wow,

1133
01:06:15,000 --> 01:06:17,040
Speaker 1: So do you actually have a study underway of trying

1134
01:06:17,080 --> 01:06:19,320
Speaker 1: to look at opening up the critical period with people

1135
01:06:19,320 --> 01:06:23,479
Speaker 1: with autism. We are starting in animals because I want

1136
01:06:23,480 --> 01:06:26,720
Speaker 1: to move carefully on this because one of the things

1137
01:06:26,760 --> 01:06:30,440
Speaker 1: that we know about autism is that the autistic mice

1138
01:06:30,520 --> 01:06:34,200
Speaker 1: do seem to have there's some indication that their critical

1139
01:06:34,280 --> 01:06:38,560
Speaker 1: periods don't close normally and that they have hyper plasticity.

1140
01:06:38,600 --> 01:06:42,400
Speaker 1: Before we'd be willing to jump into human clinical trials

1141
01:06:42,440 --> 01:06:44,960
Speaker 1: for that, I would want to make sure that a

1142
01:06:45,160 --> 01:06:48,160
Speaker 1: it works in mice, but also that it's safe, right,

1143
01:06:48,240 --> 01:06:52,240
Speaker 1: because especially with schizophrenia and autism, there's been a lot

1144
01:06:52,280 --> 01:06:56,680
Speaker 1: of very well justified hesitation to jump in with psychedelics

1145
01:06:56,720 --> 01:07:00,840
Speaker 1: in case there's overlap between what causes tis UM and

1146
01:07:00,960 --> 01:07:04,400
Speaker 1: the same mechanisms that the psychedelics are triggering. But I

1147
01:07:04,440 --> 01:07:07,840
Speaker 1: also want to just say that while this sounds like

1148
01:07:07,920 --> 01:07:12,280
Speaker 1: I'm making one big rosy blanket, I also just wanna

1149
01:07:12,640 --> 01:07:16,600
Speaker 1: caution that these are very powerful drugs, right. They have

1150
01:07:16,880 --> 01:07:20,800
Speaker 1: incredible potential. But if we don't understand how long they're

1151
01:07:20,880 --> 01:07:24,480
Speaker 1: lasting and what the impacts of the context are on

1152
01:07:24,520 --> 01:07:27,600
Speaker 1: our ability to change things. Then I think they can

1153
01:07:27,600 --> 01:07:31,640
Speaker 1: be dangerous and used for ill by bad actors as well.

1154
01:07:31,800 --> 01:07:34,760
Speaker 1: I'm sure you've heard this analogy before. But of course

1155
01:07:34,880 --> 01:07:38,160
Speaker 1: we know that Charles Manson was giving members of his

1156
01:07:38,280 --> 01:07:43,200
Speaker 1: group LSD and indoctrinating them into his family. And this

1157
01:07:43,320 --> 01:07:46,800
Speaker 1: is not surprising to me as I think about how

1158
01:07:46,840 --> 01:07:51,480
Speaker 1: easy it is to manipulate children, how important it is

1159
01:07:51,520 --> 01:07:55,320
Speaker 1: to safeguard children from being exposed to certain kinds of things,

1160
01:07:55,320 --> 01:07:59,320
Speaker 1: and if we're really returning people to this childlike state

1161
01:07:59,320 --> 01:08:01,640
Speaker 1: of vulnerable city, we also want to make sure that

1162
01:08:01,680 --> 01:08:05,520
Speaker 1: we protect ourselves from exposing ourselves to the wrong kinds

1163
01:08:05,560 --> 01:08:08,800
Speaker 1: of people. Yeah, yeah, no, I mean that definitely makes sense.

1164
01:08:08,840 --> 01:08:11,400
Speaker 1: I think you're exactly right in terms of the negative

1165
01:08:11,480 --> 01:08:14,560
Speaker 1: possibilities in terms of cults and all this sort of stuff.

1166
01:08:14,640 --> 01:08:17,960
Speaker 1: So gl I typically ask my guess how and why

1167
01:08:18,000 --> 01:08:20,439
Speaker 1: they got into this line of work, And I've read

1168
01:08:20,479 --> 01:08:22,519
Speaker 1: that you know, you come both your parents were doctors,

1169
01:08:22,520 --> 01:08:25,640
Speaker 1: and you come from a family full of doctors and scientists.

1170
01:08:25,640 --> 01:08:28,160
Speaker 1: But what can you share with us about your own

1171
01:08:28,400 --> 01:08:32,080
Speaker 1: use of psychedelics and how it may have impacted the

1172
01:08:32,080 --> 01:08:34,840
Speaker 1: ways you think about the research you're doing. Now. Yeah,

1173
01:08:35,000 --> 01:08:37,639
Speaker 1: as a scientist, I'm a little bit hesitant to talk

1174
01:08:37,680 --> 01:08:40,040
Speaker 1: about any of this kind of thing, but I will

1175
01:08:40,120 --> 01:08:42,679
Speaker 1: just say that I think you would find that a

1176
01:08:42,760 --> 01:08:47,040
Speaker 1: larger percentage of neuroscientists than you might imagine first became

1177
01:08:47,160 --> 01:08:51,559
Speaker 1: interested in studying the brain because of psychedelics. And so

1178
01:08:51,640 --> 01:08:54,400
Speaker 1: I can tell you that my interest in this subject

1179
01:08:54,479 --> 01:08:57,320
Speaker 1: really started with a class that I took in college.

1180
01:08:57,520 --> 01:09:00,599
Speaker 1: My professor was Cynthia Kon, and she taught this class

1181
01:09:00,640 --> 01:09:03,720
Speaker 1: called Drugs, Brain, and Behavior. And about half of the

1182
01:09:03,760 --> 01:09:06,280
Speaker 1: class where you know, psychonauts who just wanted to know

1183
01:09:06,360 --> 01:09:08,880
Speaker 1: what they were putting in their bodies, and the other

1184
01:09:08,920 --> 01:09:12,400
Speaker 1: half were sort of eager beaver medical students who wanted

1185
01:09:12,439 --> 01:09:15,880
Speaker 1: to get, you know, a leg up on pharmacology. And

1186
01:09:16,040 --> 01:09:20,280
Speaker 1: when I saw the serotonin molecule picture right next to

1187
01:09:20,320 --> 01:09:24,880
Speaker 1: the LSD molecule, I had sort of an epiphany that

1188
01:09:25,120 --> 01:09:27,280
Speaker 1: this was going to be the way that we were

1189
01:09:27,320 --> 01:09:32,000
Speaker 1: going to be able to answer the hard problems of neuroscience.

1190
01:09:32,120 --> 01:09:35,000
Speaker 1: What is consciousness? How is it that we know the world,

1191
01:09:35,400 --> 01:09:38,840
Speaker 1: what exists in the world? The sort of metaphysical problems

1192
01:09:38,880 --> 01:09:42,880
Speaker 1: that I think most neuroscientists start out with and eventually

1193
01:09:42,960 --> 01:09:45,679
Speaker 1: give up on because they realized that they're very hard

1194
01:09:45,760 --> 01:09:47,559
Speaker 1: and we're never going to be able to have sort

1195
01:09:47,560 --> 01:09:51,000
Speaker 1: of mechanistic detail on them. In that moment, in that class,

1196
01:09:51,080 --> 01:09:54,639
Speaker 1: I had the idea that psychedelics would really be the

1197
01:09:54,680 --> 01:09:59,519
Speaker 1: tool to help us answer those big questions. And I

1198
01:09:59,600 --> 01:10:03,240
Speaker 1: continue you to feel that, although I'm really excited that

1199
01:10:03,520 --> 01:10:05,600
Speaker 1: now seems to be the time to be able to

1200
01:10:05,680 --> 01:10:08,800
Speaker 1: do it, because I think when I was in undergrad

1201
01:10:09,120 --> 01:10:11,200
Speaker 1: we were still very much in the middle of the

1202
01:10:11,240 --> 01:10:13,880
Speaker 1: war on drugs, and I mean, obviously your listeners don't

1203
01:10:13,920 --> 01:10:17,160
Speaker 1: know a lot about that, but this shift that we've seen,

1204
01:10:17,280 --> 01:10:19,920
Speaker 1: even in the last three or four years, it's not

1205
01:10:20,040 --> 01:10:23,040
Speaker 1: complete yet. I mean, I'm still struggling to get funding

1206
01:10:23,160 --> 01:10:26,559
Speaker 1: from the nih for this kind of research because even

1207
01:10:26,600 --> 01:10:30,320
Speaker 1: though the higher ups are saying, yes, we're interested, there's

1208
01:10:30,439 --> 01:10:32,919
Speaker 1: still a lot of minds that need to be changed

1209
01:10:32,960 --> 01:10:36,440
Speaker 1: to see their potential. But for me, beyond the clinical

1210
01:10:36,920 --> 01:10:42,040
Speaker 1: aspects of it, I really am still incredibly motivated by

1211
01:10:42,240 --> 01:10:46,680
Speaker 1: the opportunity I see to use these as tools for

1212
01:10:46,800 --> 01:10:52,160
Speaker 1: discovering answers to the big questions like consciousness, right, And

1213
01:10:52,200 --> 01:10:55,160
Speaker 1: when it comes to your reticence about talking about whether

1214
01:10:55,320 --> 01:10:56,920
Speaker 1: or how what you might have done, it is part

1215
01:10:56,920 --> 01:11:00,000
Speaker 1: of that about needing government funding, or part of about

1216
01:11:00,120 --> 01:11:03,000
Speaker 1: fear about the climate shifting, or part of it that

1217
01:11:03,080 --> 01:11:06,120
Speaker 1: you're not yet a senior professor with a big chair

1218
01:11:06,280 --> 01:11:08,479
Speaker 1: and all this sort of stuff. What holds you back

1219
01:11:08,520 --> 01:11:10,280
Speaker 1: in that? I mean, I think it's a little bit

1220
01:11:10,280 --> 01:11:13,840
Speaker 1: of all of those things. But also people often tend

1221
01:11:13,960 --> 01:11:16,360
Speaker 1: to think of science as a metaphysics, you know, a

1222
01:11:16,439 --> 01:11:19,599
Speaker 1: certain this is what's in the world, right, And I

1223
01:11:19,640 --> 01:11:21,760
Speaker 1: don't think of science that way. I think science is

1224
01:11:21,800 --> 01:11:25,479
Speaker 1: an epistemology. In other words, science is how do we

1225
01:11:26,280 --> 01:11:29,120
Speaker 1: learn the world? What are the methods we use for

1226
01:11:29,240 --> 01:11:32,880
Speaker 1: discovering what is and isn't in the world. And there

1227
01:11:33,000 --> 01:11:37,280
Speaker 1: is an older scientific tradition where it was acceptable to

1228
01:11:37,479 --> 01:11:41,280
Speaker 1: know the world through direct personal experience. I mean, there

1229
01:11:41,320 --> 01:11:44,479
Speaker 1: have been Nobel Prizes one for that kind of and

1230
01:11:44,600 --> 01:11:49,000
Speaker 1: equals one science, right, but especially in neuroscience, that is

1231
01:11:49,479 --> 01:11:54,280
Speaker 1: not something that is necessarily thought to be good science.

1232
01:11:54,479 --> 01:11:58,400
Speaker 1: And especially this might be true with psychedelics because they

1233
01:11:58,439 --> 01:12:02,280
Speaker 1: do have this no edic property of you know, when

1234
01:12:02,320 --> 01:12:04,880
Speaker 1: you take them. You have this sense that like, oh okay,

1235
01:12:04,920 --> 01:12:07,679
Speaker 1: now I really really know, like everything I knew before

1236
01:12:08,320 --> 01:12:10,719
Speaker 1: is not as true as what I know now because

1237
01:12:10,720 --> 01:12:13,679
Speaker 1: of the psychedelics. And I think this leads some people

1238
01:12:13,720 --> 01:12:17,360
Speaker 1: to narcissism in science. I think it has the potential

1239
01:12:17,520 --> 01:12:22,639
Speaker 1: to lead to sort of confirmation bias and um So,

1240
01:12:22,760 --> 01:12:25,000
Speaker 1: you know, at least in my own research, I have

1241
01:12:25,200 --> 01:12:31,240
Speaker 1: been very very um careful and nervous to over extropically

1242
01:12:31,640 --> 01:12:37,360
Speaker 1: personal experiences to the research because I think, especially with psychedelics,

1243
01:12:37,439 --> 01:12:40,800
Speaker 1: confirmation bias is a real problem. I can't say that

1244
01:12:40,840 --> 01:12:46,440
Speaker 1: I've fully succeeded in that because you know, but nevertheless

1245
01:12:46,520 --> 01:12:49,360
Speaker 1: it's something I worry about. Well, well, I've just learned

1246
01:12:49,400 --> 01:12:52,880
Speaker 1: so much from our conversation as well as preparing for

1247
01:12:52,880 --> 01:12:56,240
Speaker 1: our conversation. Thanks so much for joining me on Psychoactive.

1248
01:12:56,280 --> 01:12:58,360
Speaker 1: I think it's only a matter of short time before

1249
01:12:58,360 --> 01:13:00,080
Speaker 1: you're gonna be another one of those big shot some

1250
01:13:00,200 --> 01:13:02,840
Speaker 1: psycholic studies with your own chair, and you already have

1251
01:13:02,880 --> 01:13:05,839
Speaker 1: your huge program. You're already making quite a name for yourself.

1252
01:13:05,920 --> 01:13:09,160
Speaker 1: But this is fascinating. I really am curious to see

1253
01:13:09,360 --> 01:13:13,160
Speaker 1: where your research goes into other areas. So thanks so

1254
01:13:13,240 --> 01:13:16,479
Speaker 1: much for joining me on Psychoactive. My pleasure and thank

1255
01:13:16,520 --> 01:13:20,960
Speaker 1: you very much for having me. If you're enjoying Psychoactive,

1256
01:13:21,360 --> 01:13:23,840
Speaker 1: please tell your friends about it, or you can write

1257
01:13:23,920 --> 01:13:26,400
Speaker 1: us a review at Apple Podcasts or wherever you get

1258
01:13:26,439 --> 01:13:29,559
Speaker 1: your podcasts. We love to hear from our listeners. If

1259
01:13:29,600 --> 01:13:32,519
Speaker 1: you'd like to share your own stories, comments and ideas,

1260
01:13:32,640 --> 01:13:35,719
Speaker 1: then leave us a message at one eight three three

1261
01:13:36,280 --> 01:13:42,400
Speaker 1: seven seven nine sixty that's eight three three psycho zero,

1262
01:13:42,760 --> 01:13:46,200
Speaker 1: or you can email us at Psychoactive at protozoa dot com,

1263
01:13:46,520 --> 01:13:49,680
Speaker 1: or find me on Twitter at Ethan Natalman. You can

1264
01:13:49,680 --> 01:13:53,880
Speaker 1: also find contact information in our show notes. Psychoactive is

1265
01:13:53,920 --> 01:13:57,439
Speaker 1: a production of I Heart Radio and Protozoa Pictures. It's

1266
01:13:57,479 --> 01:14:01,520
Speaker 1: hosted by me Ethan Nadelman. It's produced by Noam Osband

1267
01:14:01,600 --> 01:14:05,960
Speaker 1: and Josh Stain. The executive producers are Dylan Golden, Ari Handel,

1268
01:14:06,120 --> 01:14:10,320
Speaker 1: Elizabeth Geesus and Darren Aronofsky from Protozoa Pictures, Alex Williams

1269
01:14:10,360 --> 01:14:13,040
Speaker 1: and Matt Frederick from My Heart Radio and me Ethan

1270
01:14:13,240 --> 01:14:17,799
Speaker 1: edelmid Our music is by Ari Blucien and Especial Thanks

1271
01:14:17,880 --> 01:14:21,639
Speaker 1: to a Brio, s f Bianca Grimshaw and Robert BB.

1272
01:14:32,560 --> 01:14:37,080
Speaker 1: Next week I'll be talking with Plaul Armentano, Normal's longtime

1273
01:14:37,280 --> 01:14:42,640
Speaker 1: deputy director about marijuana and driving. If we didn't have

1274
01:14:42,800 --> 01:14:46,280
Speaker 1: that linear correlation, we wouldn't have per SE levels for alcohol.

1275
01:14:46,320 --> 01:14:48,639
Speaker 1: In fact, per SE levels for alcohol only date back

1276
01:14:48,680 --> 01:14:51,760
Speaker 1: about forty or fifty years. The reason we don't have

1277
01:14:51,960 --> 01:14:56,720
Speaker 1: these levels for cannabis or opioids or a number of

1278
01:14:56,800 --> 01:15:00,880
Speaker 1: other drugs that we don't impact driving performance is because

1279
01:15:00,920 --> 01:15:05,800
Speaker 1: there is no linear correlation. Subscribe to Cycoactive now see it,

1280
01:15:05,800 --> 01:15:06,320
Speaker 1: don't miss it.