Gul Dolen on Why Giving MDMA & Psychedelics to Octopuses and Mice Is Important

use any type of drug. Hello, Psychoactive listeners. So today we're gonna venture into a territory which I rarely or ever enter into, which is the neuroscience of drugs. You know, I'm I'm always drawn to the history, the culture, the politics, what have you, the therapeutic side, but it's important to try to get a sense of why some drugs work the way they do, and in this case, we're going to focus on why m D M A and psychedelics seem to have this remarkable therapeutic potential, which is kind

of sort of what's behind this psychedelic renaissance. The person I've asked to join me today to talk about This is Professor goul Dolin. She's in the Department of Neuroscience at Johns Hopkins Glula Medicine. She's been doing research on psycholics in recent years, but she's got a much longer background going to doing research on oxytocin and try to understand autism better. She got her m d and her PhD at Brown and m I T. She did a

post stock training at Stanford. She's been publishing important articles for a good fifteen years, but has really started to generate some incredible excitement in recent years because of a few studies that she's done that seemed to provide some new insights into how and why M D m A,

into some extent, psychedelics work the way they do. One of them involves octopuses and another is studies done on mice, but with important implications for understanding why m D m A works the way it does and other psychedelics with human beings. So cool, Thanks ever so much for joining me on Psychoactive. Thank you very much for having me. So let me just start off the first most basic question. We now have these studies and by the way'm gonna

sometimes say M D M A and psychedelics. Sometimes I'll say m d M A and other psychedelics, as m d M A isn't quite a psychedelic. So if I go back and forth, just I hope our listeners will give me a little of forgiveness there. But but the first questions, we know there's been studies, you know, you do studies on animals at the beginning to show the safety of a drug, to make sure that M D

M A or something is not toxic. But just the very basic question, if we already have a good sense that these drugs are having an impact on humans, say in a therapeutic context and therapeutic value, why even bother with studies and other animals. Yeah, that's a great question, and it's actually something I've debated a little bit with people who are very invested in, you know, pursuing the clinical trials. They cost a lot more money, So why

why do we need the mechanism? And the reason is is because you know, while many of these drugs have been used in traditional healing practices for years and years and years centuries, we are using them differently. Necessarily, we're using them differently because we are embedding these practices in a different culture, and we are trying to treat people

who are raised in a different culture. And so if we're going to try and adapt them for use the way that we want to use them, we really need to have a strong basis and understanding what they're doing, why they're working, so that we can use them appropriately, so that we don't inadvertently cause harm when we're trying to apply them in new ways, so that we understand both the limit patitions, the constraints, and the opportunities that

work in our context. And I will just back up and say one more thing, which is that I think that because of the way science gets reported in our newspapers and then the lay press, you know, there's this impression that we understand a lot of things from doing studies in humans exclusively, but almost all of the mechanisms that we understand we understand because we've been able to do very basic studies in animal models. Right. So, you

know you mentioned my interest in oxytocin. Almost everything we know about oxytocin and its involvement and regulating love, and its involvement at regulating neurotransmitters and the connections between neurons and how signals get transmitted between those brain cells. All of those studies were done in animals, and then we extrapolated from those two humans based on similarity. These that

we know exists between mice and human brains. Oxytocin. That's the drug that's kind of known as the love drug or the hug drug, the one that gets released when the mother nurses her baby or when people make love or things like that. That's right, that's right. And the other drugs that everybody talks about is serotonin, the neurochemical

that people have implicated in mood and depression. And that all of these drugs like Prozac that are selective serotonin reuptake inhibitors or s s r e s. These molecules, everything we know about them, we know about them because of animal studies that we've been extrapolated to humans. I see. So now, when we think about animal studies, typically, you know, we think about mice or rats, or maybe you might think about things like you know, primates, apes and orangutangs

or or maybe even dolphins. You know, things that are known for high intelligence and are sort of closer to us. But you decided to work with octopuses and to administer

NDMA to octopus is why. Yeah. So basically, I mean, I think it's a very strong tradition in science to try and understand human emotion and cognition and disease by focusing on the closest relative that we can do these kinds of experiments in, and then that way we presume that we will be able to understand some sort of rules, and because they're closely related, it's easier to make that extrapolation.

But the approach that we decided to take was one that had kind of been in the scientific literature for

a while. It was actually proposed by Jay z Young, who's really important physiologist and ethologists in neuroscience and behavioral studies of animals, and he said, what you really want to do is to go for the animal that is evolutionarily most distant from us, so most different, separated by as much evolutionary time as you can, who also exhibits some of the complex behaviors that we do you and that by comparing those maximally different brains to each other,

then you can sort of overlook or look past all the extraneous historical accidents of evolution and figure out the rules for how to build complexity and so we decided that we wanted to understand how seratonin, this neuro transmitter that I mentioned, has been implicated in almost every function you can think of, including mood and feeding and temperature regulation, and we wanted to know how old is its role in regulating social behaviors and can we deduce any of

those rules by looking at an octopus? And so basically, I mean, if I understand it, so, an octopus is quite radically different than human beings. They don't have the same kind of brain. All the things that the parts of the brain are supposedly light up when you do mbma, they don't even have that. So the common element is that they have these serotonin transporters. Is that the key thing that makes it relevant here. Yeah, So that was actually the idea we were testing. Their brains don't look

anything like our brains. Their brains actually look much more like a snail's brain because they are mollusks and they don't have the same sort of organization of centralizing all the brain functions into one but they have a central brain, but they also have distributed brains controlling each of their arms. And so in the absence of all of the brain regions that we think of as being important for social

behaviors or cognition. That they were able to respond to the m d M A in pretty similar ways to the ways that mice and rats and humans respond to m d M A. In other words, when we measured their pro social behavior, their desire to spend time in the chamber that had the other octopus in it increased after we gave them m d M A. That told us that all of the anatomical things that were used to attributing the functions of these drugs too really are

sort of extraneous detail, and that they're accidents of the evolutionary history of that animal, and that the thing that really matters for encoding this social function of serotonin is at the level of molecules and specifically the proteins that encode the serotonin transporter which m d M A binds to, and that just by having that, it's enough to override the normal behavior that we see in octopuses, which is,

you know, they're not social. In fact, if you put two octopuses in it, this species in particular, if you put them in a tank together, they will kill each other. And so M D M A has this very powerful ability to override that and make them desire social interaction and spend more time with the other animals. I have

to tell you what I mean. Until like a couple of days ago, when I started prepping for our conversation, almost everything I knew about octopus this was from seeing that Academy Award winning documentary by the South African fellow Craig Foster, My Octopus Teacher, which I loved. It talks about the sort of wariness in a social ability of octopus, but obviously there's this bonding that goes on there between them.

Although some people said, maybe we're just anthropomorphizing, you know, attributing to the octopus human characteristics and behavior more than its appropriate, but it was I don't know. I mean, as I'm reading your study, I just kept thinking about that. Have you seen that film? I have. I have seen it. It was beautifully shot film. But I agree with the

concern that we're anthropomorphizing. And I'll just put it out there that Aristotle actually thought that octopuses were the stupidest animal, and that was because back in his time, you know, there were abundant in the sea and they were sort of easy to catch. Because all you had to do is put a rod in front of them, and they would, out of this intense sense of curiosity, reach out and grab the rod, and then you just pull the rod

up and the octopus would come with it. So, you know, people have been studying octopuses for thousands of years, and depending on your perspective, whether you consider them an easy to catch food source or whether you are making netslix documentary about them, the tendency to anthropomorphized can lead you

to very different conclusions about what they're capable of. And so one thing I would say is that even though we characterize them as being a social most of the time, in fact, they do suspend that a sociality during brief

times that are important for their behavior. So the species that we were studying in the M. D m A paper was octopus by maculoids, or the California two spot octopus, and that octopus will suspend this sort of aggressive stance that they take to other members of their species when

they are mating. We know that they must have the circuitry for social behavior somewhere in their brains, and that, for whatever reason that we haven't really understood, evolutionary selection pressures have made it so that it's more beneficial to whatever strategy they're using to mostly be a social and turn off that sociality except when they're going to be mating. Yeah. Yeah,

I was reading about octopus before talking with you. I mean I saw that not all octopuses are a social I think you just pointed out, like there's something called a larger Pacific strike octopus, which is a little more social. So the element of there being a bit of loaners, right, was kind of relevant to the research because you're looking at the sociability associated with m d m A. That's right. Well, I mean, honestly, we didn't know what was going to happen.

We started the experiment thinking, you know, maybe what's going to happen is is that sarahtonin is old or the transmitter and the transporter is there. But when we give the m d M A, it's just going to induce sort of a hyperactive behavior or something similar to what

emphetamines might do to the brain of a mammal. Because it's in the amphetamine class and saratonin, we didn't know if this pro social function was as old as some of its other functions, and we didn't know if it could bind to it, if it was going to also

bind to other transporters and do other things. So we wanted to start with this social because that was the question that we were interested in, but also octopuses because they're so a social When we just did the baseline measurements of how much time they spend in the social chamber versus the chamber that had a little toy object in it, they spent almost all of their time in the toy object chamber, which was maximally distant from the

other octopus. And so that made a really nice baseline measurement. And so when we gave them m D M A and the behavior shifted hundred and eighty degrees and now they spent most of their time in the social chamber. We didn't need very many animals to be able to statistically draw the conclusion that, you know, the M D M A had this effect on changing their social behavior.

So cool. When it comes to administering in the email of the drugs to the mice or other animal, how do you do it is an injection or another means? And how do you figure out the right dosing levels and what's comparable too levels and humans. Yeah, So with the mices sort of straightforward. We just give them an injection what we call an I P injection interpretornal injection,

and we're just injecting it directly into their abdomen. And because most of these psychedelics are very leoad brain barrier permeable, it gets into the brain. And we test the doses to make sure that we start with the human dose and adjust it for weight, and we just kind of tietrate until we see the effect, and remarkably, the effects seem to be pretty close. The dose that we would use in a human is usually within ten times of what we see in a mouse, tentimes more ten times

less or the same, and so that was reassuring. That can change because mouth metabolism is very fast, so we have to be careful about that, so we want to test it every time. The trickier one was definitely the octo us because we didn't know how to deliver it.

The octopus is a secreature and so the way that it receives drugs normally, the equivalent would be if we put it in the water is on their gills and it's sort of washing over their gills and getting into the blood directly from the gills, and so putting m d M A and the water might be something like figuring out a way of making aerosolized m d M A and putting somebody in a hot box with aerosolized m d M A for thirty minutes. So we really weren't sure, but we decided to go ahead and try

it anyway. And this is true with all experiments that we do an octopus, we never want to just assume that it's the same because their physiology is so different. They don't have a liver. They have something between a liver and a pancreas. Those cells have some of the features of both. It's not clear that they have a blood brain barrier. They don't even metabolize oxygen in the same way that we do. So we had to test

it and we just titrated. We start high and then work our way backwards until we got to the right dose. Uh huh, Yeah, so cool. When you're testing animals given psychedelics, is it getting the permission from the university or from the funding agencies is any different than giving animals other

types of drugs. Yeah, we have to go through all of the regulatory requirements for being approved for giving Schedule one medicines, and so that's a regulatory process that we have to do, but both the federal and the state level took us about a year to get all of

those licenses approved. And then once we get the licenses, then we have to go back to our Animal Care and Use Committee and work with them back and forth to make sure that we have done all the appropriate safeguarding measurements and that we're really making sure that we are doing these experiments in the safest and least stressful

way for the animals. The octopus is sort of a unique situation because currently in the United States, octopuses are have the same regulatory requirements as all other invertebrates, so flies and worms and cockroaches and all the invertebrates, right, but we are sensitive to the fact that octopus is their behavioral repertoire is much more complex, and we certainly

don't agree with Aristotle that they're the dumbest animals. So we have taken care to apply all the same standards that we use for mouth studies for the octopus to make sure that we're treating them in a way that respects their intelligence and their ability to feel pain and take care of them. We'll be talking more after we hear this add You know, the thing I was wondering in reading about your study was that I thought back to the famous rat park studies that Bruce Alexander did

with I think it was mice and cocaine. This is back in the seventies, I think, and this is the famous experiment where, you know, everybody knows the basic studies of you put mice or monkeys in a cage and you make available to them cocaine or a kind of saline solution, alternative placebo thing. Many of them will just

keep injecting or consuming the cocaine until they die. But what Bruce Alexander showed was that when you did the same experiment with animals that were in a kind of wildlike environment, in fact, they either had no interest in the cocaine, or if they did show any interest, they used it in a sort of moderation. It didn't fundamentally

affect their lives. And it was all about the importance of setting, especially in terms of determining how people consume drugs, why they get into problematic relationships, all this sort of thing I wondered, if you've been doing this study and somehow been able to do it with octopus who were in the wild where they have to have a greater fear, presumably about predators, do you think you would have had a different Well, it's a good question, and it's definitely

something that we have thought a lot about. I mean, the rat part experiment. When I first started my lab back in two thousand fourteen, that study had a big effect on me because what it really made me realize is that when we started doing a lot of studies in rats, especially, but mice also, for a number of practical technical reasons, it was easier to keep isolation housing them.

But rats and mice are both social animals, and so a lot of the conclusions we drew from some of those early drug addiction studies were probably wrong because we were essentially studying animals who were enduring sort of social isolation, stress, and maybe more depressed, maybe more vulnerable to their drug environment because they weren't getting all of the social support that would be normal for their environment. Octopuses are sort

of different than that. So octopus is in the wild or a social they prefer not to be living with other animals, except for as you mentioned, the larger Pacific striped octopus or LPSO, seems to be the only decidedly social octopus. But for the most part, octopuses prefer to

live a socially. We had to design the experiment taking that into consideration because we certainly didn't want to put them into a stressful situation by essentially allowing them to attack each other, which is why we kept the other octopus underneath the flower pots, so that maybe they showed aggressive postures but couldn't actually hurt each other, and taking that into consideration, also didn't use a different essay that we use in mice that requires them to live together overnight,

because we knew that they were a social So we always have to take those kinds of how do they live in the wild into consideration when we're trying to design experiments and not accidentally retesting the stress effects of living in a way that they are not ethologically suited to live when we do the experiment right, because presumably though a sociability was an evolutionary thing that developed, right in terms of their survival, the ones that survive are

the ones that are smarter, and maybe the ones that are more a social I mean, you know, one thing that I find to be fascinating and kind of what keeps drawing me back to wanting to do more studies than octopus is that all of the other cephalopods are social. Right, So nautilus has a shell, that's true, But squid and cuttlefish don't have an external shell either, and yet they are very social. And so there's something separate about octopus.

Is maybe that because they're hunting for fish and they've taken on predatory behaviors that are similar to other top predators, and that they for some reason it's not advantageous to do pack hunting. We don't really know. And so this is why I'm so fascinated by the larger Pacific striped octopus, because somehow something is different, and that species of the three d or so known species of octopus is the

one that has evolved the social pattern of living. And it would be I think fascinating to know what was the selection pressure that pushed them to that type of living that's so different from all the rest. But presumably be harder to discern the impact of M D M A among creatures that have a higher level of sociability. Well, so, I mean that's actually a pretty good segue to talk about what m d m A does in mice right there.

So basically we knew that m d m A already had acute pro social effects in mice and in humans, and some of the work that supported that actually was from behavioral tests that are very similar to the one that we did in octopuses. So I'm just putting the animals in a large arena that's divided into three rooms and just measuring how much time they spend in each of the three rooms, one of which has an other

social animal and one of them that doesn't. And that was sort of looking at what happens when you're given the drug and the animal is experiencing the acute effects of the drugs. So the altered state of consciousness plus this Recreational users of m d m A are known for, you know, cuddle puddles and lots of pro social hugging and wanting to be close to other people, right, and we see that same behavior in mice and in octopuses. But we were in my lab already studying another phenomenon.

We were interested in the developmental regulation of social behaviors, because we know that a person's way of being social changes over their lifetime. Right, So, teenagers are famously they love to hang out with each other, they have, you know, three hundred friends. They're always on the phone. They just

can't get enough of social interaction. But as you get older, you kind of you like to be social, but jeez, you know, sometimes you need some quality alone time to gather your thoughts and replenish your social resources, if you will.

And so that change across development suggested to us that there must be something like a critical period for social behaviors, and we thought it was important to try and understand the neural mechanisms of that, because those changes in the way that we learn from our social environment probably have a big impact on things like peer pressure and also probably impact Why it is that when you have a social injury when you're very young, it has a much

more devastating long term consequence than if you have a social injury when you're old. Why we do things like we safeguard children, why we make sure that they're not exposed to violent television content, and why we sort of monitor to make sure that they are not receiving damaging information when social information when they're young. And so what my live set out to do is to use a different essay. So now we're not just measuring acute effects

of social interactions. We're using an assay called social conditioned place preference, which is just animals being put in a chamber and we just have two types of betting on the floor, and we just take a baseline measurement just to make sure that they don't have some pre existing

bias for one of the two types of betting. We just let them run around for thirty minutes on the two types of betting, measure how much time they spend on each, and then we put them in a new chamber with one of the two types of betting, and this time they're paying for twenty four hours with their social group members. And then we put them for twenty four hours on the other type of betting, this time

by themselves. And then we take another measurement, asking how much time do they now after they formed this association between the betting and the social environment, how much time do they spend in each of those two types of bettings.

And by doing that, what we've discovered and other people have shown as well, is that mice, especially juvenile mice, will form a long lasting wrong positive association between the betting and a social environment, and a negative association to the betting associated with being by themselves and that ability to learn from their social environment or the rewarding nature

of that social environment. What we discovered is is that as the animals get older, that goes away, and that attenuation or that diminishment of the ability to learn from the social environment we describe as a critical period for

social reward learning and critical period. I mean, when I've heard you talk about this, it is connected to sort of that notion of imprinting when certain types of birds, maybe migratory birds or birds that leave the mother very early hatch, that they attached to the first thing that they encounter, whether it could be a human being, it could be another animal, it could even be another inanimate object. Is that the kind of sort of simplistic notion of

the critical period that's relevant here? Absolutely? In fact, that imprinting behavior and snow geese was the first behavior that Conrad Lorenz back in nineteen thirty five described and coined the phrase critical period to describe, and what he was referring to is that long lasting attachment that you're describing that happens, but only within the first forty eight hours after hatching. After that, they don't form that long lasting attachment.

That whatever's in their environment that they've attached to ceases to be relevant in the same way and ceases to be a salient signal that allows them to form a long lasting attachment. And so that window of time where the animal is much more sensitive to their environment and able to form these long lasting memories. Conrad Lorenz called a critical period, and he did that in nineteen thirty five, but since then there have been lots and lots of

critical periods that have been described. I think most people are familiar in their own lives with the critical period for language learning. So if you've ever tried to learn a language later on in life, it's much harder to learn. You have to practice, you have to study. You will always have an accent when you speak it. You won't speak it with the same sort of fluidity and ease as you did your native language. My sister seems to be the exception to this rule because she doesn't seem

to have a critical period for languages. She speaks like five or six fluently in a couple more just as needed basis. But for most people, you know, the language that you learned as a child is the one that you know and the one that you speak fluidly without an accent, and anything else later on is much harder and not as fluid, And so that is reflecting the fact that there's a critical period for language learning. But

there are other critical periods as well. So there are critical periods for organizing the visual system, for organizing the touch system, and probably clinically, the one that we are sort of most fascinated by and will follow up with is that there's a critical period for recovering motor function

after you have a stroke. So right after you have a stroke, you have this short window of time six weeks seems to be this sort of sweet spot where if you do intensive physical therapy, that's where you're going to get the most recovery. But after that window is closed, you know you're not going to get much more motor recovery after that window is closed. So now your focus was on social reward learning aspects of critical period. So is that a relatively newer concept or also one that

goes back a while. No, So we discovered the social reward learning critical period. And we were able to discover it because we were able to do this in animal studies, so we were able to look at fifteen different ages, we were able to look at both sexes. It was hundreds and hundreds of mice and really characterized the developmental timeline.

But that being said, you know, people who do human cognition studies and child development studies had already sort of had an inkling that something like this must have exists just by doing comparisons between two different ages and the ways that children process social information. There was an idea out there that it might exist, but it wasn't formally

demonstrated until we we showed it in mice. I see, and when you're administering the n D m A to the mice, does it make a difference whether these mice are the equivalent of juveniles or adolescents or adults. Yeah, So when we were trying to characterize the behavioral critical period, we also did some studies to try and understand what are the cellular and synaptic mechanisms underlying that establishment and

constraining of that learning and memory to this window. And we had implicated oxytocin that we talked about before in that process, and we thought, well, we want to be able to reopen this critical period because neuroscientists, pretty much since we first knew about critical periods, had had the intuition that the ability to reopen critical periods is going to be immensely powerful as a therapeutic. But oxytocin doesn't

cross the blood brain barriers. So you might have heard in the lay press people talking about intronasal oxytocin, but honestly, that just doesn't really worked out. Well, it doesn't get into the brain. Whatever affects people are reporting of intronasal oxytocin are probably indirect effects on the brain and affects that that oxytocin is having in the body, not in the brain. And so we thought, well, gosh, you know, is there some other way that we might be able

to trigger this reopening of the critical period. And we knew that m d M A had these pro social effects and m d M A there was some anecdotal evidence that it might also be triggering oxytocin release in the central nervous system. And so what we did is unlike the octopus experiments and other experiments that had been done before we gave the m d M A in adult animals. So remember, at the adult age, the critical

period is closed. So we gave the m d M A and then we just way did for forty eight hours for all of the acute m d M A to wash out of the system, and then we measured social reward learning again in the adult animals. And what we found is is that forty eight hours after we gave the m d m A, that juvenile ability, that ability to learn from the social environment, came back in

the adults. And that restoration of the juvenile behavior in adulthood, we thought was very strong evidence that what we've done is reopened this critical period. And then at the same time, if we gave m d m A to the juvenile animals, we had no impact on the magnitude of social reward learning.

So it wasn't just that the adult animals are sort of satiated and that we just drained the emotional bucket and made them thirsty for social again, because if that was the case, then we would have expected that depriving the animals and juveniles would also restore an increased level of social reward learning and it didn't. And so taken together, those two things really convinced us that what we're looking at is a reopening of a critical period, not some

sort of satiation with sociality. Right. And you saw this reopening though in the adult mice that were in social situations, but not the ones that had been isolated, right. So that is a really interesting component of this study which I think lends further support to the idea that critical period reopening is what really accounts for the incredible therapeutic

effects that we're seeing with these drugs. So one of the things that I think probably your audience will be familiar with is that psychedelics in particular have this feature of being set and setting dependent. Right, So if you're around people that you feel comfortable with or giving off good vibes, if you will, then the M d m A experience can be very different than if you're feeling

threatened or anxious or not safe. And that phenomenology of the set and setting dependence of psychedelic drugs also translates to the therapeutic effects, right. So you can't just take M d M A and go to a rave and expect that your PTSD is going to be cured, you really want to pair the m d M A with the context of psychoanalysis to look at the trauma that you're trying to deal with, and then rewriting those memories

around the trauma during the trip. And we think actually afterwards as well, and this context dependence or you know, the set and setting, but we call it context dependence of psychedelics effects we think are different than for example, m d M A has like a mild social anxiolytic property. Psilocybin and LSD and ketamine have anti depressive properties, but those antidepressive and anxiolytic properties of the drugs don't seem to be context dependent, right, And so these drugs do

a lot of different things in the brain. Some of the properties are context dependent and some of them are in not. And we think that the exciting possibility is that the remarkable sort of this is going to be a cure for neuro psychiatric disease. Part of these drugs comes from that context dependence, and so we were really excited that unlike other studies which had looked at the antidepressive properties of the anxiolytic properties and shown that these

were not context dependent. Critical period reopening is context dependent. So you can only reopen the social critical period if you give M d M A in the social context.

And we think that the social part of that is a little bit of a We have more evidence now suggesting that that's a little bit of a red herring, because we are excited about the possibility that psychedelics are the master key for unlocking critical periods across the brain, sort of writ large and if that's true, then we would expect that the dependence on the social context is true because we're trying to open a social critical period.

But if we were trying to open a visual critical period or a motor learning critical period, then visual experience or motor experience during the acute phase of the psychedelic would be the important context, not social. And now, when you found that what you were finding with M d M A was also true with the variety of psychedelics, was that surprising to you. Yeah, So that work isn't published yet, but I'm happy to briefly mention it. We

basically did those experiments as a control. I was fairly certain that the reason that M D M A was having this remarkable ability to reopen the critical period was because but so pro social in quality, right, It's acute subjective effects are really pro social. But you know, nobody's taking LSD and doing a cuddle puddle. In fact, most people need to kind of especially if they're having an

inner directed trip. You know, they need quiet and maybe one or two other people, but they're not cuddling the way they are with M D M A. And so we were really surprised when LSD and psilocybin and ketamine and I began all also reopened this critical period. And what that suggested immediately to us, and this is what we're following up in the subsequent studies, is that the

acute subjective character of psychedelics really isn't the thing. So the thing that makes them all similar is their ability to open the critical period. And in fact that the thing that they share in common, and which is why I call all of them psychedelics, is that they all induce an altered state of consciousness. Right, And it's hard to define exactly what that means that altered state of consciousness, but all of the psychedelics, whether they're dissociative, hallucinogetic, and

pathogenic or own irogenic. They all have that property of inducing that altered state of consciousness, and so our recent studies really suggest that maybe what it feels like to be in an altered state of consciousness is just what

it feels like to open critical period. But now you're probably using that phrase altered state of consciousness in an hour sense because given the name of this podcast, right, psychoactive, which essentially implies altered state of consciousness, And we think about that applying really to almost all psychoactive substances, So not just the psychedelics, but cocaine or opioids, or for that matter, it could be caffeine or nicotine or you know,

any range of others insufficient doses. So what about those other substances, I mean, they are altering consciousness, Is it just that they're altering it in a different way or different degree. Yeah, So I guess I would quibble with the idea that they're all altering consciousness. They're all altering brain function, I guess. And so I guess it sort of depends on how broadly you want to define consciousness.

If you want to define it really broadly and you want to say consciousness is just in the sense of conscious versus unconscious. Then every anesthetic is also a psycho well psychoactive. But when people say the altered state of consciousness induced by psychedelics, I think they're referring to a very narrow sense of what it means to be conscious. Again,

it's a little bit hard to define. I mean, I feel like philosophers have written whole books about what is the interesting sense of the word consciousness, and so I don't really want to spend too much time on that.

But what I will say is is that the shared ability of psychedelics to alter the sense of consciousness that's different from other psychoactive drugs like cocaine and nicotine and alcohol and even marijuana, seems to be related to their therapeutic effects, right, Because it's not like people are curing drug addiction with cocaine. It's not like people are curing PTSD with cocaine, right. In fact, cocaine's psychotropic or psychoactive effects are more likely to leave do abuse and addiction

like behaviors. They incidentally take a reward and make it context independent, and they're really what I would call drugs that induce Cocaine in particular, induce hyper plasticity, And so by plastic see, what I mean is is that synapses in the brain, which are the connections between neurons and how they communicate with each other, the weights that are assigned to each of those synapses change as you encode memories. And we think that that plasticity of the synaptic weights

is what's responsible for encoding memories. And what cocaine seems to do is massively increase the number of synapses and dendritic sprouting and create a whole bunch of extra memories that are around using cocaine, enjoying cocaine, associating every positive feeling you've ever had with cocaine, and that sort of hyperplastic response is very different from what we see with psychedelics. Well, let me ask you this school, I mean, because let me just throw in two other drugs here that kind

of fall in between. I mean, obviously m D M A is amphetamine based, and so one question is what about other types of amphetamine. They share some things in common with cocaine, some things in common with M D M A. Of the other one is what about th HC, which kind of falls in between the kind of altered. In fact, many people say it does create altered state of consciousness in ways that sometimes can resemble the psychedelics.

So what about those two Amphetamine and t HC. Yeah, so we haven't actually tested either one directly, but I suspect that emphetamine is going to look very much like cocaine, which you know, cocaine does not reopen the critical period, but it does induce these addiction like behaviors and addiction like changes in synapsis. Th HC is definitely a strange one, and it's an in between case, and we really don't know.

And one of the things about TAHC that I've always been sort of fascinated about is that it seems to be a great imitator. So if you've, you know, mostly been intoxicated with alcohol and then you start doing th HC, you know you're high, your teach the highest sort of mellow. But after you do t HC, after you've tried any of the psychedelics, then suddenly it can take on a sort of psychedelic character. And I don't have any clue

about what that's about. The reason that we sort of didn't focus on THHC in our experiments is that t HC, especially at very high doses seems to induce a certain amount of paranoia in people, and we actually think we have a hypothesis about why that is. But you'll have to invite me again for a different podcast to talk about that one. Okay, well, so let's just talk about

some of the other implications of the study. So you find that you know it's working, and obviously you know m d m A, you know, and is sort of a pathogen heartwarming, cuddly whereas we think about the psychedelics, and sometimes I guess one of the theories is that the intensity of the sort of spiritual or mystical experience

is part of what is associated with their efficacy. But one of the other things that I saw you pointing out is that, you know, we've typically at least I've typically thought about you do m d m A just psycholics and you have a psychotherapeutic you work with the therapist immediately thereafter. But you're pointing out that this critical period that gets opened, it's not just for a few hours or something. It can be quite a bit longer, and that the longer the drug experience last, maybe the

longer the critical period last. And so just talk about that and the implications of that. Yeah, So I mean I mentioned that we were beginning to have some evidence that what it feels like to be in this psychedelic altered state of consciousness is just what it feels like

to reopen critical periods. And part of the evidence we have for that is this proportionality between how long the acute subjective effects of psychedelics last and how long the critical period stays open after the psychedelic acute effects have

worn off. And so just to compare the different drugs, so ketamine, you know, most people's acute effects of ketamine lass anywhere from thirty minutes to maximum sort of two hours, whereas people who take LSD, you know, it's eight to ten hours is the typical acute subjective effects last, Whereas I began lasts for a really long time. So between thirty six and seventy two hour long acute subjective effects

of I be game. And just like that, what we see is that ted amine keeps the critical period open for forty eight hours. Psilocybin and m D m A seem to keep it open for about two weeks after we give the drug LSD for three weeks, and I began, you know, we haven't found the outer limit of it, but at least a month after we give I BEGANN the critical period stays open. And so that has I

think three really important implications. One is that, as I said, it sort of lends further support to the idea that critical period reopening is the thing that makes this class of drugs a single drug class, the shared property across

the drugs. The second one is that I think when we're designing clinical trials for using these drugs to cure PTSD, we're gonna band to be really really careful about out making sure that we offer enough support to people after the acute subjective effects have worn off, because what's two weeks in a mouth could be two months in a human right, And what we think this is analogous to is putting a person back into this sort of vulnerable and sensitive state, just like a child. And so we

want to offer support to those people. And you know, I would very much like to get funding to run a clinical trial that looks at the difference between people who were given sort of standard of care the way the FDA wanted the trials to be designed, and another group where instead of just going home and writing in your journal and calling into the therapist for the weeks after you get to go to something like a retreat and you are given the sort of space and support

and therapy that you need to continue to integrate those memories and those traumatic habits that you've developed from your being traumatized, that you reintegrate them in to your new personality habits and traits and your new world in that sort of safe space. So that's the second implication, and then the third implication, and this sort of touches on what you mentioned about Roland Griffith's studies about the depth

of the mexical experience. I think that what this is telling us is that there are a lot of enthusiasm right now, especially from the business world, to rush to develop psychedelics that don't have any kind of psychedelic side effects if you will so engineer out the mystical experience the big trip right and I suspect that those efforts will all take miracle drugs like LSD and psilocybin and I beginning, which have these very profound ability to change

memories and potentially cure things like heroin addiction and essentially engineer them back down to being something like an S s R I, because I think if you get rid of that long experience, you're going to interfere with the

mechanism that is reopening critical periods. So when you're talking about this extended length of the critical period, it's not just about being cautious about how therapists deal with that period, being aware that it's not just about the hours and days afterwards, but you're also talking that there's actually this bonus that maybe people didn't realize, that there's this extended period of time in which the insights can be almost

harvested and developed even more more thoroughly, more deeply, absolutely, absolutely, and in fact I think that this is why for really really entrenched memories and really hardcore addictions like heroin addiction, the big sort of anecdotal stories that we hear about recovery from heroin addiction are all coming from iby game, right, not from ketamine or psilocybin, right, Because those memories are really entrenched into the fabric or the whole sort of

network of memories and habits and patterns and personality traits that a humans developed over their lifetime, and to undo them you probably need to have the critical periods stay open for a long time so that you can say, Okay, oh, I'm going to the park, and normally I would have a heroin craving here, but you know what, I don't need that anymore, you know, rewriting those memories around the

whole whole circuit of memories that surround that very entrenched addiction. Now, are there implications on me, for example, about say, multi dosing, like giving ketamine five or six days in a row, or administering multiple doses of d M A or psilocybi els D over a period of days or weeks. Anything you can say about that stuff, we see added benefits,

reduced benefits. Yeah. So, honestly, when we first started these experiments, I basically have the intuition that, you know, the longer you can keep it open, the better, and that that would help you to have the most access to those sort of calcified memories, if you will. But I'm beginning to think that actually there probably is an opportunity to stabber them, especially because you sort of hinted at this and the question. Especially the serotonin psychedelics seem to have

this property of causing desensitization or tolerance very quickly. So people who do micro dosing of psilocybin, you know, not everybody has the same experience, but a lot of people will report that very quickly the effects of the drug

seems to attenuate, right. And so what we have also discovered is that we've kind of a little bit taken down the primacy of the serotonin to a receptor, because while psilocybin and LSD obviously really you know, we have to activate the serotonin too a receptor in order to get these critical period reopening, ketamine m D M A

and I began don't care about the serotonin receptor. In fact, there's evidence that ketamine is working through a different receptor called an m D A. I began is probably working through the cappa opioid receptor m D M A. It's not clear it's causing a release of serotonin, and it's probably binding to all fourteen of the serotonin receptors, not just to A. And it doesn't require to A to reopen.

And so it might be that, you know, to stagger not only drugs that have different durations of critical period.

So for example, if you want to on ramp somebody who's had a very very serious horrible, maybe complex PTSD and facing the traumatic memories all at once is too much for them, So maybe we want to start gently with them with some I'm just making this up, but this is what our newer data is starting to suggest that we want to start looking at the possibility of combining maybe some short acting, some micro doses, some ketamines early on, just to loosen things up, and then as

the patient gets more comfortable, kind of do the longer trips that go deeper and then sort of stagger on top of that the big, big trip at the end. And that could potentially allow us to mix and match so that we can do the most work over a long period of time, but also give people breaks and also give people an opportunity to wait in if they're not ready to be kind of thrown out the deep end of the pool. Let's take a break here and

go to an ad. Is there a limited number of times that one could use m d m A or these other drugs in order to open up this critical period? You know, listeners of this podcast, numerous episodes, I've expressed my great sadness that m d m A, which was such a wonderful drug in my life when I was in my thirties and forties and mostly using it with my romantic partner or with a close set of friends

only a couple of times in a rage setting. Just doesn't really seem to work for me much in the last and fifteen years, And I'm wondering, is there only so many times you can use and the mail the others to open that critical period. I mean, we don't really have hard data on that. What I will say is that I have an idea that there's gonna be

interactions between them. So for example, there's one clinical study in humans that shows that if you don't take people off their S s R I medications so they're Prozac or any of the drugs in that class, then the M d M A stops working. And that sort of makes sense because if the idea is that when you're blocking the serotone and transporter, M d M A actually

has to sit in the same bonding pocket. So if the prozac is in there blocking it away, then it's possible that that interferes with M d m AS ability to get into that same pocket and cause the same remarkable consequences. But what's more than that is is that there's some older literature suggesting not with s s RRI, but with older generation antidepressants like tricyclicant and m a

O wise that what is happening. The reason that there's this delay between when you start taking the antidepressant and when you start to feel the effect is that the real effect of the drug might not be increasing the amount of serotonin that's available in the synapse itself, but that by increasing the basil levels loading around the neuron serotonin that triggers in the cells that are normally receiving the serotonin signal to pull in some of those serotonin

receptors and sort of downregulate the number of receptors that are in the membrane. So sort of like if you've got a bunch of microphones out into an arena and everybody in the arena is screaming, maybe you pull a couple of those microphones in so that it's not so loud anymore. So that's kind of one early idea about how antidepressive drugs were working, and there is some suggestion that this could also be happening for LSD and psilocybin

as well. So I could potentially formulate at least a hypothesis about why m d M A might stop working if you're also doing a lot of other psychedelics and or taking prozac or any of these other antidepressive drugs, because they're sort of including each other's mechanism, Which is why I think it will be useful to develop an arsenal of drugs that are doing this with lots of different receptors. Right, So maybe I begin it's going to help for somebody who has already kind of maximally tuned

the serotonin receptors. So is it a matter that does not one developed? I mean, even like I think in my case, I never did the antidepressants, and I have not been. I've been an occasional user of the psychoelics and DMA for decades, but never a frequent user. I mean, is there an element in which one does develop a tolerance?

Just going back to that issue, if one's using this drug in the psychotherapy, right in the proper setting, in order to open up this critical period and deal with the past traumas PTSD or I was talking about psilocybin and depression or whatever it might be, and you make so progress. But I mean, obviously we sometimes see there's some research suggesting that when you do this, a one off can provide a real cure, right, not just a palliative,

but a cure. Can there be value in our possibilities in terms of doing this two times, five times, ten times, twenty times, or is it kind of gonna peek out, like if it doesn't take the first time to do it,

the second time, I got to do something else. Yeah, So, I mean there are already trials where I think in Europe MAPS is running some trials for complex PTSD doing sort of multiple rounds of m d m A. But again, because of this issue of tolerance, again, it's going to be really important to understand the mechanism because it's probably going to be the case that we're going to need to fine tune the dosing regiment so that we're not giving new m d M A before the critical period

that we open is already closed back up again, so that we can sort of maximally extend the amount of time that the person can do the psychotherapy work without running into tolerance issues from staggering them too close to each other. But again, also this is going to be a case for trying to understand the mechanism, because one of the next follow up questions that my lab is really pursuing is, Okay, you know, we know that they're

all working at different receptors. We have some hint that the next step, which is the biochemical signaling that comes after that, is also not the same for all of

the different drugs. And so what's the next, next next step, what's the thing, what's the last final common denominator that brings all of these psychedelics into the realm of being able to be these master keys for critical period reopening and can we target that directly without melting the brain or causing seizures or causing a person to lose all

of their memories. As we get a better handle on how these things are working, we can start to do a better job of designing trials with the drugs that we have, but then also learning from those mechanisms to know what are the limitations and what are the other things downstream that we could potentially boost to stop for example, of tolerance or maybe reverse if the tolerance doesn't end up being part of the mechanism for how the drugs

are curing. And I think that the tolerance issue really is probably going to be more relevant to the non context dependent anti depressive properties of these drugs, which are going to be separate from critical period opening. And I think that critical period reopening is going to end up being the explanation for these cures, whereas the anti depressive properties are going to be more about the palliatives. And we can already see that a little bit in the

clinical trial. So if we compare the way that the New England Journal of Medicine psilocybin versus SSRRI for depression trial went, you know, basically they used the psilocybin the same way that we give prozac, right, and so they were given the drug monitored for you know, bad side effects, but psychotherapy wasn't you know, a big component of it. And what they saw is is that the effects of um psilocybin on depression were very similar to s s RI,

not worse, but not dramatically better either. Whereas the MAPS trial that was published in Nature Medicine last year, that one, you know, the the whole approach was this is an adjunct therapy and the context is psychotherapy. And in that case, even though we still have issues around controls and direct comparisons, the ability to cure the PTSD compared to ss RISE or compared to just psychotherapy RAP alone seems to be

remarkably improved. So cool. At your lab at John's Hawkins, you have a project called FATHOM p h A t H O M. So what does that stand for and what's it about? What are you trying to accomplish there beyond what the research you've described so far. Yeah, so that stands for psychedelic healing adjunct therapy harnessing opened malleability. That came up with that in a dream, and I loved it because I love this idea that when people have really great m d m A experiences, they call

it oceanic boundlessness. And I love the FATHOM as like a metaphor for that oceanic boundlessness. And basically, we're taking the unfathomable, which is cures for some of these brain diseases, and making them fathomable again. You know, that's sort of the dream that we are hoping. So the FATHOM project is really just our intuition that based on the fact that all of the psychedelics, whether they're empathogenic or not, or reopening the critical period, that these are the master

keys for unlocking all critical periods. And that that's true, then the number of brain disorders and even probably non brain disorders. So I have an idea about curing allergy and curing stutter and curing stroke would be remarkably increased if it's true that these are the master key for unlocking critical periods that neuroscientists have been looking for for

almost a hundred years. And the project is really everything from the basic research that we are doing to try and convince ourselves that they are in fact the master key, all the way up to human clinical trials for stroke that we are getting we're revving up to do and potentially in the future looking at what other ways that

we can understand the brain using psychedelics. So with stroke, for example, obviously with m D m. A was talking about psychotherapypy with strokes once talking about physical therapy and reopening that critical period. And do you imagine that somebody is subject to a stroke and gets partially paralyzed, that

they would be able to go through these sessions. I mean, maybe not just one, but to do them two, three or four times a year to keep returning to that critical period with a physical therapist and delving more deeply into it. Absolutely, So that's the dream. Basically, what we think is is that most people who have a stroke now get some physical therapy, but it's not the sort of intensive motor practice that they need to get full recovery.

And so most people get partial recovery. They compensate, you know, they learn how to button their pants with the other hands, They learn how to use their whole hand instead of their fingers to manipulate objects. But you know, what we want is full recovery of normal levels of motion. But this is just for motors strokes, but you know, all strokes.

And the ideas is that if we can pair the psychedelic and the way we're imagining it right now is is that the optimal way to pair it is not to pair it to practicing the specific motion that you are trying to get back, so like reaching for your cup or something, but that we should pair it with some sort of video game so that you are taking full advantage of the fact that psychedelics seem to put people into this mode of play like behavior, or non

goal directed behavior, and that practicing motor in that sort of non goal directed manner paired with psychedelics should maximally restore the old ways of learning motor behaviors that you had from when you were a child, and that that will help restore more function after the stroke critical period has closed. And could you imagine virtual reality types of

machinery also playing a role in his stuff. Yeah. So our collaborators on this project are Steve Zeiler and John Krakauer, and they have been developing not exactly virtual reality, but a video game that they can manipulate. The patient manipulates their arm and a dolphin on the screen kind of

swims around. And we love that interactive video game aspect of it that they could play while they were on psychedelics and for several days after the acute effects have worn off, continue to practice with that to kind of trigger the right kinds of mine. So that's exactly the

idea that we are pursuing. Fascinating. I mean, I read that you know, years ago your interests and maybe still you had a strong interest in autism, and I guess with autism there was for quite a while, maybe still the notion that it's grounded in some sort of chemical imbalance. But how do you see this work relating to autism

and trying to help people with it. Yeah, So when I was a graduate student, you know, my thesis was something called the M blu R Theory of fragilects and Autism, and it was basically testing this idea that what causes most of the impairments that we see in fragile X, which is a subtype of autism, are really an imbalance of this signaling that happens through another type of receptor called the m gluar and the protein that's missing in

in fragile x. And we were very excited. We know, we did all these studies in animals and then we were able to show that if we turned down the m glure signaling, then we could restore normal function in a bunch of different domains in mice. And we did those studies and then twenty six other pre clinical labs replicated those findings, and all of the big drug companies got so excited. They were like, this is it. We've

got the mechanism. Hundreds of millions of dollars were invested in clinical trials, and to the disappointment of the whole field, those clinical trials did not show clinically relevant improvements in human patients with autism. And I think that some of the people after those trials sort of dismissed them and said, well, you know, a mouse isn't human, and that's why they

didn't work. But the authors themselves of the clinical trial studies wrote a follow up paper sort of discussing, you know, what they thought might have happened and what might be

some future directions. And one of the things that they mentioned is is that all of the pre clinical studies, all of the mouth studies, were done very early in development, So either from genesis in the case of genetic manipulations or even just the pharmacological manipulations, all happened in juvenile animals before a critical period for social reward learning would be closed. And granted, these studies were done before we

had discovered this critical period. So I'm not you know, pointing fingers or anything, but to me, that's very interesting because what it suggests is this that maybe what we need to do with autism is go back and test that biochemical imbalanced idea, but in this time, instead of giving the drug by itself, we pair it with reopening of the social critical period, and under those conditions of restoring the imbalance in the open state of the critical

period will allow patients to learn from their social environment in the way that they missed out on early in development. Wow, So do you actually have a study underway of trying to look at opening up the critical period with people

with autism. We are starting in animals because I want to move carefully on this because one of the things that we know about autism is that the autistic mice do seem to have there's some indication that their critical periods don't close normally and that they have hyper plasticity.

Before we'd be willing to jump into human clinical trials for that, I would want to make sure that a it works in mice, but also that it's safe, right, because especially with schizophrenia and autism, there's been a lot of very well justified hesitation to jump in with psychedelics in case there's overlap between what causes tis UM and

the same mechanisms that the psychedelics are triggering. But I also want to just say that while this sounds like I'm making one big rosy blanket, I also just wanna caution that these are very powerful drugs, right. They have incredible potential. But if we don't understand how long they're lasting and what the impacts of the context are on our ability to change things. Then I think they can be dangerous and used for ill by bad actors as well.

I'm sure you've heard this analogy before. But of course we know that Charles Manson was giving members of his

group LSD and indoctrinating them into his family. And this is not surprising to me as I think about how easy it is to manipulate children, how important it is to safeguard children from being exposed to certain kinds of things, and if we're really returning people to this childlike state of vulnerable city, we also want to make sure that we protect ourselves from exposing ourselves to the wrong kinds of people. Yeah, yeah, no, I mean that definitely makes sense.

I think you're exactly right in terms of the negative possibilities in terms of cults and all this sort of stuff. So gl I typically ask my guess how and why they got into this line of work, And I've read that you know, you come both your parents were doctors, and you come from a family full of doctors and scientists. But what can you share with us about your own use of psychedelics and how it may have impacted the

ways you think about the research you're doing. Now. Yeah, as a scientist, I'm a little bit hesitant to talk about any of this kind of thing, but I will just say that I think you would find that a larger percentage of neuroscientists than you might imagine first became interested in studying the brain because of psychedelics. And so I can tell you that my interest in this subject really started with a class that I took in college. My professor was Cynthia Kon, and she taught this class

called Drugs, Brain, and Behavior. And about half of the class where you know, psychonauts who just wanted to know what they were putting in their bodies, and the other half were sort of eager beaver medical students who wanted to get, you know, a leg up on pharmacology. And when I saw the serotonin molecule picture right next to the LSD molecule, I had sort of an epiphany that this was going to be the way that we were going to be able to answer the hard problems of neuroscience.

What is consciousness? How is it that we know the world, what exists in the world? The sort of metaphysical problems that I think most neuroscientists start out with and eventually give up on because they realized that they're very hard and we're never going to be able to have sort of mechanistic detail on them. In that moment, in that class, I had the idea that psychedelics would really be the

tool to help us answer those big questions. And I continue you to feel that, although I'm really excited that now seems to be the time to be able to do it, because I think when I was in undergrad we were still very much in the middle of the war on drugs, and I mean, obviously your listeners don't know a lot about that, but this shift that we've seen, even in the last three or four years, it's not

complete yet. I mean, I'm still struggling to get funding from the nih for this kind of research because even though the higher ups are saying, yes, we're interested, there's still a lot of minds that need to be changed

to see their potential. But for me, beyond the clinical aspects of it, I really am still incredibly motivated by the opportunity I see to use these as tools for discovering answers to the big questions like consciousness, right, And when it comes to your reticence about talking about whether or how what you might have done, it is part of that about needing government funding, or part of about fear about the climate shifting, or part of it that you're not yet a senior professor with a big chair

and all this sort of stuff. What holds you back in that? I mean, I think it's a little bit of all of those things. But also people often tend to think of science as a metaphysics, you know, a certain this is what's in the world, right, And I don't think of science that way. I think science is an epistemology. In other words, science is how do we learn the world? What are the methods we use for

discovering what is and isn't in the world. And there is an older scientific tradition where it was acceptable to know the world through direct personal experience. I mean, there have been Nobel Prizes one for that kind of and equals one science, right, but especially in neuroscience, that is not something that is necessarily thought to be good science. And especially this might be true with psychedelics because they do have this no edic property of you know, when

you take them. You have this sense that like, oh okay, now I really really know, like everything I knew before is not as true as what I know now because of the psychedelics. And I think this leads some people to narcissism in science. I think it has the potential to lead to sort of confirmation bias and um So, you know, at least in my own research, I have been very very um careful and nervous to over extropically personal experiences to the research because I think, especially with psychedelics,

confirmation bias is a real problem. I can't say that I've fully succeeded in that because you know, but nevertheless it's something I worry about. Well, well, I've just learned so much from our conversation as well as preparing for our conversation. Thanks so much for joining me on Psychoactive. I think it's only a matter of short time before you're gonna be another one of those big shot some psycholic studies with your own chair, and you already have

your huge program. You're already making quite a name for yourself. But this is fascinating. I really am curious to see where your research goes into other areas. So thanks so much for joining me on Psychoactive. My pleasure and thank you very much for having me. If you're enjoying Psychoactive, please tell your friends about it, or you can write us a review at Apple Podcasts or wherever you get

your podcasts. We love to hear from our listeners. If you'd like to share your own stories, comments and ideas, then leave us a message at one eight three three seven seven nine sixty that's eight three three psycho zero, or you can email us at Psychoactive at protozoa dot com, or find me on Twitter at Ethan Natalman. You can also find contact information in our show notes. Psychoactive is a production of I Heart Radio and Protozoa Pictures. It's

hosted by me Ethan Nadelman. It's produced by Noam Osband and Josh Stain. The executive producers are Dylan Golden, Ari Handel, Elizabeth Geesus and Darren Aronofsky from Protozoa Pictures, Alex Williams and Matt Frederick from My Heart Radio and me Ethan edelmid Our music is by Ari Blucien and Especial Thanks to a Brio, s f Bianca Grimshaw and Robert BB. Next week I'll be talking with Plaul Armentano, Normal's longtime

deputy director about marijuana and driving. If we didn't have that linear correlation, we wouldn't have per SE levels for alcohol. In fact, per SE levels for alcohol only date back about forty or fifty years. The reason we don't have these levels for cannabis or opioids or a number of other drugs that we don't impact driving performance is because there is no linear correlation. Subscribe to Cycoactive now see it, don't miss it.