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I'm on the outskirts of Atlanta, on

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the campus of Mercer University.

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And today I'm taking a tour

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of the lab where

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researchers are giving mice

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psychedelics.

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Yeah, so we're walking

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to our behavioral

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testing lab.

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Clint Canal is one of those

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researchers, and he's my tour guide

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here.

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To get to the lab, we have to make

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our way through this maze of

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security doors.

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There are signs posted everywhere

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asking visitors to be quiet and

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mindful of the animals.

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I don't see any mice right away,

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but once we reach the lab, Clint

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starts to whisper.

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And so do I.

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And I know we're whispering.

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Yeah, basically out of respect for

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the animal. Obviously we're

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predators to them.

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So just trying to stay

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calm so that they also

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stay calm.

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I know it might seem a little odd to

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keep calm and whisper in reverence

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for mice that are about to be given

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a psychedelic and sometimes

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sacrificed, as the researchers

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call it.

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But scientists like Clint see these

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little black mice as part of a

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larger mission: tackling

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the growing mental health crisis.

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Their goal is to develop novel

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psychedelics, new compounds,

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with the hope that these new drugs

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can one day treat depression, PTSD,

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and other mental illnesses and

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neurological disorders.

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Conditions that in some cases have

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no effective treatments.

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But before any of these drugs can

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make it to the point where they are

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tested in humans, scientists

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first need to test them on mice.

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Clint is a neuroscientist

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and a professor of pharmaceutical

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sciences. And what that means is

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he studies how cells in the brain

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fire and communicate, and

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how that communication breaks

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down in certain disorders.

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He's especially interested in how

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drugs, including psychedelics, can

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influence neural pathways.

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And one way he does this is by

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studying mice on psychedelics.

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This is a male C-57

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Black 6J mouse

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just walking casually in

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an open field.

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When a mouse is having a

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psychedelic-like experience, they

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react with this very specific

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behavior.

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And that is what I am here to

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see. But for someone like me

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who's never seen this, it can be

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really hard to catch.

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So before I see the real thing,

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Clint gives me a quick video

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tutorial to train my eyes.

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Do you want the slow or the real

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time?

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Maybe let's do the real time first.

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This is a two second

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video. It's just very quick.

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So we're huddled around his computer

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watching black and white footage of

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a mouse.

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The mouse in the video has been

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given a dose of a psychedelic drug,

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mostly used in research, called DOI.

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I always tell students just pay

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attention to the ears and just

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look for any kind of head movement

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that you typically don't observe

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when an animal has not been given a

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drug. So just look at the ears

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and then you'll start to see it.

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At first, nothing seems unusual.

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Just a mouse doing mouse things,

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sniffing, wandering, exploring

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corners.

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But then, the mouse

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makes a quick jolt, a

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twitch, this side-to-side

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head shake.

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You know when a wet dog twists

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its body to dry off?

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It kinda looks like that.

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And it is quick, like half

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a second.

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I completely miss it the first time

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around.

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There.

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Oh, okay.

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It almost looks like as if

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it were shaking off

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some bug that might have landed on

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its head or something like that.

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That movement is not random.

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It's called the head twitch

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response.

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In the world of drug development,

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this tiny twitch is a big

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deal. Scientists are interested in

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the head twitch response because it

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can use it as an indicator,

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this kind of shorthand, to figure

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out whether a newly created compound

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is likely to have psychedelic-like

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effects.

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This week is a science week here on

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the podcast. We're gonna talk about

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animal testing in psychedelic

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research, because as it turns

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out, much of what we know about

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psychedelic science comes from

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research on animals.

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In the late 80s, the Food and Drug

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Administration approved the first

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selective serotonin reuptake

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inhibitors, or SSRIs.

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And now some companies are looking

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to psychedelics as they try to

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develop the next generation of

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patented blockbuster drugs to

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treat depression and mental health

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issues.

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And behind much of this research

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are these twitching mice.

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What can we really learn about

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our brains or consciousness

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from these rodents?

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I'm Arielle Duhaime-Ross, and this

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is Altered States.

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Reporter Alexa Lim investigates.

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Clint has always been curious about

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the big questions philosophy,

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psychology, how the mind works,

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even as a kid.

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I had this really great grammar

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teacher and he had this poster

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on the wall that was the quote from

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Socrates, the unexamined

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life is not worth living.

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And that really resonated with me at

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the time, thinking about

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philosophical questions and

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how that relates to the mind

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and eventually to the brain.

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Clint studied psychology and

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philosophy in college, and somewhere

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along the way, he stumbled upon

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LSD.

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I was extremely fascinated by LSD

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that this molecule at

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such a low dose can produce

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such mind altering and

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self altering experiences.

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How can a drug that's so

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small produce such profound changes

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in cognition?

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That curiosity led him to

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neuroscience, where he felt like he

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could tackle those larger questions.

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And to do that, he decided to

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start small, much smaller.

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He got interested in receptors.

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They're those tiny docking molecules

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on brain cells that respond to

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neurotransmitters and psychoactive

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drugs. They regulate things like

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mood, memory, and perception.

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You can modulate the activity

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of one receptor and

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affect psychology and

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then affecting people's

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worldview how they view the

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world after a psychedelic

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experience can affect them

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on a philosophical level.

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So that's really what got me

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interested in it.

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Clint began to see the real world

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potential of psychedelics.

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And not just as tools for exploring

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the mind, but as treatments for

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serious mental illness.

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His research shifted in that

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direction.

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But this was more than just

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research.

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It was personal.

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He told me that a few family members

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had severe mental health issues.

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He witnessed what they went through,

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and it changed him.

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Clint eventually landed a postdoc

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position in a lab focused on a very

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specific type of serotonin

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receptor.

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And the researchers were using

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psychedelics to study it.

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And this was his first encounter

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with the twitching mouse.

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How many head twitches do you

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estimate you've counted in your

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life?

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I don't know.

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Hundreds?

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Thousands? I don't know about

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thousands, maybe.

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Today, he still studies the brain

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in receptors, trying to find

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treatments for these illnesses.

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He says it almost feels like a

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calling.

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Easy room in my area.

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So if you guys want to see I'm like

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set for it. Okay.

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Back in the lab, Clint and a

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graduate student named Richa Tyagi

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are running a test on a mouse.

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They're working with a psychedelic

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compound currently being developed

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by a pharmaceutical company.

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Clint is careful not to share too

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many details.

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But the company, Cybin,

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is known for developing new

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proprietary psychedelics

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aimed at treating depression,

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anxiety, and other central nervous

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system disorders.

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Yeah, I was seeing there it was

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really calm.

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They are really calm.

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The test starts when Richa injects

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the mouse with the drug.

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Then, she places the mouse

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in a large glass tank.

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And she watches closely, waiting

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to count how many times the mouse

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twitches its head.

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We just use a tally counter.

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Just whenever they have to

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click the button.

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It's one of those silver handheld

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counters that you might see someone

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using to count how many people enter

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a water park or a concert.

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And each time Richa observes a

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twitch.

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Two compounds can produce very

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different scale of H

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T Rs. Traditionally you just do

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number of head twitch responses

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over time.

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But now I guess people are more

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interested in how these head

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twitch responses evolve

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over time.

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At first, the twitching is

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a little sporadic, but

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after the three minute mark, things

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start to pick up.

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It's just like what I saw in the

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video.

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Then things really start to get

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twitchy.

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What is your tally so far?

290
00:08:58,190 --> 00:09:00,589
So far I've had thirty-eight heads

291
00:09:00,590 --> 00:09:02,189
responses within a time span of

292
00:09:02,190 --> 00:09:03,539
fifteen minutes.

293
00:09:03,540 --> 00:09:05,938
By the 15th minute mark, Richa

294
00:09:05,939 --> 00:09:07,779
has clicked the counter 38

295
00:09:07,780 --> 00:09:08,578
times.

296
00:09:08,579 --> 00:09:10,098
38 head twitches.

297
00:09:13,140 --> 00:09:15,299
Head twitch sounds pretty simple.

298
00:09:15,300 --> 00:09:17,139
Give a mouse a drug and note

299
00:09:17,140 --> 00:09:18,899
whether or not it twitches.

300
00:09:18,900 --> 00:09:20,818
But exactly why it twitches

301
00:09:20,819 --> 00:09:23,218
is still something of a mystery.

302
00:09:23,219 --> 00:09:25,139
One thing scientists do know is

303
00:09:25,140 --> 00:09:26,979
that all the classic psychedelics,

304
00:09:26,980 --> 00:09:28,578
the ones that affect the serotonin

305
00:09:28,579 --> 00:09:31,218
system, think LSD, psilocybin,

306
00:09:31,219 --> 00:09:33,218
DMT, they all reliably

307
00:09:33,219 --> 00:09:35,059
produce the head twitch in mice.

308
00:09:35,060 --> 00:09:36,499
And most importantly, the head

309
00:09:36,500 --> 00:09:38,259
twitch seems to be connected to one

310
00:09:38,260 --> 00:09:40,098
particular serotonin receptor

311
00:09:40,099 --> 00:09:42,338
called 5HT2A,

312
00:09:42,339 --> 00:09:43,789
or 2A for short.

313
00:09:43,790 --> 00:09:46,109
The serotonin two way receptor,

314
00:09:46,110 --> 00:09:47,629
we tend to think about it as being a

315
00:09:47,630 --> 00:09:49,069
brain receptor.

316
00:09:49,070 --> 00:09:50,829
The prefrontal cortex is part of the

317
00:09:50,830 --> 00:09:52,189
brain involved in planning,

318
00:09:52,190 --> 00:09:54,189
decision-making, and self-awareness.

319
00:09:54,190 --> 00:09:56,029
And it has a dense concentration of

320
00:09:56,030 --> 00:09:57,859
these 2A receptors.

321
00:09:57,860 --> 00:09:59,219
You know, that's where we believe

322
00:09:59,220 --> 00:10:01,219
the seats of consciousness are and

323
00:10:01,220 --> 00:10:03,619
thoughts, ideas, planning,

324
00:10:03,620 --> 00:10:05,619
executive functions.

325
00:10:05,620 --> 00:10:07,059
And if you give a psychedelic to a

326
00:10:07,060 --> 00:10:08,899
mouse or a human and the two way

327
00:10:08,900 --> 00:10:10,099
receptor has been blocked or

328
00:10:10,100 --> 00:10:12,019
switched off, the psychedelic

329
00:10:12,020 --> 00:10:13,379
effects don't happen.

330
00:10:13,380 --> 00:10:14,979
That means shut down two way

331
00:10:14,980 --> 00:10:17,220
signaling and the trip disappears.

332
00:10:19,940 --> 00:10:21,379
The one thing is though, we don't

333
00:10:21,380 --> 00:10:22,380
head twitch.

334
00:10:23,150 --> 00:10:24,269
Yeah.

335
00:10:24,270 --> 00:10:25,869
Yeah. We don't head twitch.

336
00:10:25,870 --> 00:10:26,729
That's true.

337
00:10:26,730 --> 00:10:28,729
So why don't we head switch?

338
00:10:28,730 --> 00:10:29,730
I asked Clint.

339
00:10:30,540 --> 00:10:32,299
This is such a important question

340
00:10:32,300 --> 00:10:33,739
though. Like if you look at the

341
00:10:33,740 --> 00:10:35,899
mouse brain compared to a human

342
00:10:35,900 --> 00:10:37,739
brain, the neural structures

343
00:10:37,740 --> 00:10:39,339
are organized the same way.

344
00:10:39,340 --> 00:10:41,179
Why do they hedge which and humans

345
00:10:41,180 --> 00:10:42,539
don't? Is the same circuitry

346
00:10:42,540 --> 00:10:43,559
engaged?

347
00:10:43,560 --> 00:10:45,319
Scientists aren't sure.

348
00:10:46,680 --> 00:10:48,519
These head twitch tests that Clint

349
00:10:48,520 --> 00:10:50,198
and Richa are running, they're only

350
00:10:50,199 --> 00:10:51,399
the beginning.

351
00:10:51,400 --> 00:10:53,399
In fact, there's a whole gauntlet

352
00:10:53,400 --> 00:10:55,399
of tests, including animal behavior

353
00:10:55,400 --> 00:10:57,238
experiments that researchers use to

354
00:10:57,239 --> 00:10:58,438
see if a drug might have

355
00:10:58,439 --> 00:11:00,279
antidepressant qualities.

356
00:11:00,280 --> 00:11:01,478
For example, there's something

357
00:11:01,479 --> 00:11:03,639
called the forced swim test.

358
00:11:03,640 --> 00:11:05,159
Scientists put a mouse in a

359
00:11:05,160 --> 00:11:06,999
container full of water and it can't

360
00:11:07,000 --> 00:11:08,838
escape. And in this test,

361
00:11:08,839 --> 00:11:10,838
swimming is seen as a proxy for

362
00:11:10,839 --> 00:11:12,198
mental fitness.

363
00:11:12,199 --> 00:11:14,118
So a happier, less depressed

364
00:11:14,119 --> 00:11:15,879
mouse will swim for longer, trying

365
00:11:15,880 --> 00:11:17,718
to escape, while a depressed

366
00:11:17,719 --> 00:11:19,559
mouse gives up sooner and just

367
00:11:19,560 --> 00:11:20,919
floats.

368
00:11:20,920 --> 00:11:22,438
They sometimes call this the

369
00:11:22,439 --> 00:11:24,519
behavioral despair test.

370
00:11:24,520 --> 00:11:26,759
And side note, the mice are rescued

371
00:11:26,760 --> 00:11:27,879
before they drown.

372
00:11:29,079 --> 00:11:30,519
Researchers have been using the

373
00:11:30,520 --> 00:11:32,919
forced swim test to model depression

374
00:11:32,920 --> 00:11:34,358
for decades.

375
00:11:34,359 --> 00:11:36,039
But what can a mouse that stops

376
00:11:36,040 --> 00:11:37,879
swimming really tell us about human

377
00:11:37,880 --> 00:11:38,759
despair?

378
00:11:38,760 --> 00:11:40,838
And is a mouse trip a stand-in

379
00:11:40,839 --> 00:11:41,958
for a human one?

380
00:11:41,959 --> 00:11:43,718
What can we really learn from a

381
00:11:43,719 --> 00:11:45,238
twitching mouse?

382
00:11:45,239 --> 00:11:46,999
I talked to a bunch of scientists

383
00:11:47,000 --> 00:11:48,919
and their opinions were all over the

384
00:11:48,920 --> 00:11:51,159
map. Some seem almost irritated

385
00:11:51,160 --> 00:11:52,838
by the head twitch response, while

386
00:11:52,839 --> 00:11:54,438
others dismissed it as barely

387
00:11:54,439 --> 00:11:57,078
relevant to humans at all.

388
00:11:57,079 --> 00:11:58,838
But even if they didn't like it, the

389
00:11:58,839 --> 00:12:00,838
scientists I talked to agreed

390
00:12:00,839 --> 00:12:02,838
that it's the one tool they have.

391
00:12:02,839 --> 00:12:04,999
The twitch is a pretty reliable

392
00:12:05,000 --> 00:12:06,999
indicator of 2A receptor

393
00:12:07,000 --> 00:12:08,999
activation in the mouse brain.

394
00:12:09,000 --> 00:12:10,999
Here's Clint again.

395
00:12:11,000 --> 00:12:12,919
There aren't many

396
00:12:12,920 --> 00:12:15,399
solid pharmacodynamic

397
00:12:15,400 --> 00:12:18,199
models like this in the neuroscience

398
00:12:18,200 --> 00:12:20,279
field where you can just

399
00:12:20,280 --> 00:12:22,679
administer a drug

400
00:12:22,680 --> 00:12:24,839
and see a behavior that's caused

401
00:12:24,840 --> 00:12:26,679
by a specific receptor in the

402
00:12:26,680 --> 00:12:28,519
brain. There aren't a lot of models

403
00:12:28,520 --> 00:12:30,919
like that. It is really fascinating.

404
00:12:30,920 --> 00:12:32,839
It's a wonderful model that's

405
00:12:32,840 --> 00:12:34,839
really reliable and easy to measure.

406
00:12:37,520 --> 00:12:39,359
Today, the head switch response is a

407
00:12:39,360 --> 00:12:40,879
standard measure in psychedelic

408
00:12:40,880 --> 00:12:42,318
research in rodents.

409
00:12:42,319 --> 00:12:43,919
Scientists know what they're looking

410
00:12:43,920 --> 00:12:46,078
for, they know what to expect.

411
00:12:46,079 --> 00:12:47,919
But that was not always

412
00:12:47,920 --> 00:12:49,279
the case.

413
00:12:49,280 --> 00:12:51,198
Many psychoactive compounds have

414
00:12:51,199 --> 00:12:52,719
been part of the natural world for

415
00:12:52,720 --> 00:12:54,719
ages. And by the time the term

416
00:12:54,720 --> 00:12:57,198
psychedelic emerged in the 1950s,

417
00:12:57,199 --> 00:12:58,959
these substances had found their way

418
00:12:58,960 --> 00:12:59,999
into labs.

419
00:13:00,000 --> 00:13:02,318
And eventually into lab animals

420
00:13:02,319 --> 00:13:04,639
too. And things got,

421
00:13:04,640 --> 00:13:07,279
well, kind of weird.

422
00:13:07,280 --> 00:13:09,198
Scientists gave spiders high doses

423
00:13:09,199 --> 00:13:10,439
of LSD.

424
00:13:10,440 --> 00:13:12,679
The pattern of the drug web

425
00:13:12,680 --> 00:13:14,839
is characteristic for each

426
00:13:14,840 --> 00:13:15,880
type of drug.

427
00:13:16,920 --> 00:13:19,079
Actually, one can identify

428
00:13:19,080 --> 00:13:21,239
drug actions through

429
00:13:21,240 --> 00:13:23,159
their effects on web

430
00:13:23,160 --> 00:13:24,160
building.

431
00:13:26,300 --> 00:13:28,479
And cats got LSD too.

432
00:13:28,480 --> 00:13:29,999
A study was made of the effect of

433
00:13:30,000 --> 00:13:31,839
one of these on a cat, which,

434
00:13:31,840 --> 00:13:33,439
prior to receiving a dose of the

435
00:13:33,440 --> 00:13:35,199
agent, reacted normally when

436
00:13:35,200 --> 00:13:36,959
confined with a mouse.

437
00:13:36,960 --> 00:13:39,039
When exposed to an extremely small

438
00:13:39,040 --> 00:13:40,799
amount of the agent, the cat's

439
00:13:40,800 --> 00:13:42,869
personality completely changed.

440
00:13:42,870 --> 00:13:44,549
This Noah's Ark of tripping lab

441
00:13:44,550 --> 00:13:45,989
animals marched on.

442
00:13:45,990 --> 00:13:48,489
Dolphins were injected with LSD.

443
00:13:48,490 --> 00:13:49,490
Hello.

444
00:13:50,117 --> 00:13:51,117
[Dolphin Sound]

445
00:13:52,270 --> 00:13:54,188
Then of course there's the CIA,

446
00:13:54,189 --> 00:13:55,869
which for years conducted and backed

447
00:13:55,870 --> 00:13:58,188
LSD experiments on cats, rabbits,

448
00:13:58,189 --> 00:14:00,029
even an elephant, to see

449
00:14:00,030 --> 00:14:01,948
if the drug might be used in mind

450
00:14:01,949 --> 00:14:02,619
control.

451
00:14:02,620 --> 00:14:04,859
As this 1952 CIA

452
00:14:04,860 --> 00:14:06,779
memo says, the aim

453
00:14:06,780 --> 00:14:08,699
is controlling an individual

454
00:14:08,700 --> 00:14:10,379
to the point where he will do our

455
00:14:10,380 --> 00:14:12,379
bidding against his will

456
00:14:12,380 --> 00:14:14,379
and even against such fundamental

457
00:14:14,380 --> 00:14:17,279
laws of nature as self-preservation.

458
00:14:17,280 --> 00:14:18,639
Some of the research was done as

459
00:14:18,640 --> 00:14:20,639
part of a secret project called MK

460
00:14:20,640 --> 00:14:22,479
Ultra, which the CIA ran in

461
00:14:22,480 --> 00:14:24,059
the nineteen fifties and sixties.

462
00:14:24,060 --> 00:14:25,978
It was the most secret

463
00:14:25,979 --> 00:14:27,899
program ever conducted

464
00:14:27,900 --> 00:14:29,978
by the CIA in the United

465
00:14:29,979 --> 00:14:30,869
States.

466
00:14:30,870 --> 00:14:32,549
In this era, researchers were not

467
00:14:32,550 --> 00:14:34,069
studying psychedelics for their

468
00:14:34,070 --> 00:14:35,349
treatment potential.

469
00:14:35,350 --> 00:14:37,269
In fact, they were often using

470
00:14:37,270 --> 00:14:39,269
these substances to mimic and model

471
00:14:39,270 --> 00:14:40,390
psychosis.

472
00:14:42,630 --> 00:14:44,629
Meanwhile, two microbiologists

473
00:14:44,630 --> 00:14:46,709
at Merck Institute for Therapeutic

474
00:14:46,710 --> 00:14:48,869
Research in New Jersey were quietly

475
00:14:48,870 --> 00:14:49,989
working on their own little

476
00:14:49,990 --> 00:14:52,149
psychedelic study.

477
00:14:52,150 --> 00:14:54,149
The authors were Doris Keller

478
00:14:54,150 --> 00:14:56,149
and Wayne Umbright.

479
00:14:56,150 --> 00:14:57,989
They gave mice LSD

480
00:14:57,990 --> 00:14:59,589
and noticed a distinct and

481
00:14:59,590 --> 00:15:01,429
predictable shaking.

482
00:15:01,430 --> 00:15:03,189
They published a brief two-page

483
00:15:03,190 --> 00:15:04,549
study in the journal Science in

484
00:15:04,550 --> 00:15:05,989
1956.

485
00:15:05,990 --> 00:15:07,989
And that was the first paper to

486
00:15:07,990 --> 00:15:09,989
name and describe the head twitch

487
00:15:09,990 --> 00:15:11,429
response.

488
00:15:11,430 --> 00:15:13,349
From what I can tell, neither Doris

489
00:15:13,350 --> 00:15:15,109
nor Wayne produced any other studies

490
00:15:15,110 --> 00:15:17,029
on psychedelics afterwards.

491
00:15:17,030 --> 00:15:18,949
Doris went on to develop drugs to

492
00:15:18,950 --> 00:15:20,709
treat diseases like arthritis and

493
00:15:20,710 --> 00:15:22,949
inflammatory bowel disease at Merck.

494
00:15:22,950 --> 00:15:24,629
And Wayne was best known for his

495
00:15:24,630 --> 00:15:27,349
work on vitamins, especially B6.

496
00:15:27,350 --> 00:15:29,189
But their small study would end

497
00:15:29,190 --> 00:15:31,109
up having an outsized influence on

498
00:15:31,110 --> 00:15:34,469
the future of psychedelic research.

499
00:15:34,470 --> 00:15:36,149
After the break, we'll hear how

500
00:15:36,150 --> 00:15:37,669
scientists today are using head

501
00:15:37,670 --> 00:15:39,349
twitch to discover new drugs.

502
00:15:52,030 --> 00:15:53,549
So we heard how the head twitch is

503
00:15:53,550 --> 00:15:54,989
correlated to activation of the

504
00:15:54,990 --> 00:15:56,550
serotonin receptor called 5HT2A.

505
00:15:58,030 --> 00:15:59,948
Scientists are now using 2A as

506
00:15:59,949 --> 00:16:02,029
a target for developing new drugs.

507
00:16:02,030 --> 00:16:03,629
And the head twitch response is a

508
00:16:03,630 --> 00:16:05,599
kind of guidepost in that hunt.

509
00:16:05,600 --> 00:16:07,439
I'm very interested in finding

510
00:16:07,440 --> 00:16:09,599
ways to accelerate drug

511
00:16:09,600 --> 00:16:11,999
discovery so that it doesn't take

512
00:16:12,000 --> 00:16:13,839
ten years from making

513
00:16:13,840 --> 00:16:14,840
a compound in the lab.

514
00:16:15,810 --> 00:16:17,089
To getting it to patients.

515
00:16:17,090 --> 00:16:18,529
This is Jason Wallach.

516
00:16:18,530 --> 00:16:19,809
He's a pharmacologist and a

517
00:16:19,810 --> 00:16:21,729
professor at St. Joseph's University

518
00:16:21,730 --> 00:16:23,009
in Philadelphia.

519
00:16:23,010 --> 00:16:25,009
And he studies the basic biology

520
00:16:25,010 --> 00:16:26,769
behind how drugs work, including

521
00:16:26,770 --> 00:16:27,969
psychedelics.

522
00:16:27,970 --> 00:16:29,569
And he's trying to design new ones

523
00:16:29,570 --> 00:16:30,689
in the lab.

524
00:16:30,690 --> 00:16:32,529
He's worked with the biotech company

525
00:16:32,530 --> 00:16:34,369
Compass Pathways.

526
00:16:34,370 --> 00:16:36,609
Jason's kind of like a psychedelic

527
00:16:36,610 --> 00:16:38,209
architect.

528
00:16:38,210 --> 00:16:40,449
He studies the chemical scaffolding

529
00:16:40,450 --> 00:16:42,369
so he can break it down and rebuild

530
00:16:42,370 --> 00:16:43,789
it in new ways.

531
00:16:43,790 --> 00:16:45,468
You're starting from a known

532
00:16:45,469 --> 00:16:47,389
molecule that you know already binds

533
00:16:47,390 --> 00:16:48,188
the receptor.

534
00:16:48,189 --> 00:16:50,188
And you begin to modify it and

535
00:16:50,189 --> 00:16:52,429
study what happens when I add this,

536
00:16:52,430 --> 00:16:54,188
what happens when I remove this,

537
00:16:54,189 --> 00:16:56,029
what happens when I lock this

538
00:16:56,030 --> 00:16:58,029
chain into a ring.

539
00:16:58,030 --> 00:16:59,869
Right? As I tinker with this

540
00:16:59,870 --> 00:17:00,828
part, what happens?

541
00:17:00,829 --> 00:17:02,828
I get more potent compounds.

542
00:17:02,829 --> 00:17:04,669
They become more efficacious.

543
00:17:04,670 --> 00:17:06,348
They become less selective, more

544
00:17:06,349 --> 00:17:08,509
selective. It's this very iterative

545
00:17:08,510 --> 00:17:10,509
process of tinker test,

546
00:17:10,510 --> 00:17:11,628
tinker test.

547
00:17:11,629 --> 00:17:13,469
Each time you learn more and more

548
00:17:13,470 --> 00:17:15,469
about the rule set that

549
00:17:15,470 --> 00:17:18,499
governs that pharmacology.

550
00:17:18,500 --> 00:17:20,259
If Jason's new compound doesn't pass

551
00:17:20,260 --> 00:17:22,179
the head switch test, meaning

552
00:17:22,180 --> 00:17:24,019
it's not activating 2A,

553
00:17:24,020 --> 00:17:25,219
not acting like a classic

554
00:17:25,220 --> 00:17:27,139
psychedelic, he'll need to

555
00:17:27,140 --> 00:17:29,299
make some adjustments.

556
00:17:29,300 --> 00:17:31,139
He's constantly tweaking and

557
00:17:31,140 --> 00:17:33,699
testing and looking for that twitch.

558
00:17:33,700 --> 00:17:35,379
And Jason's really interested in

559
00:17:35,380 --> 00:17:38,099
fine-tuning one certain part.

560
00:17:38,100 --> 00:17:40,179
So, in the pharmacology world,

561
00:17:40,180 --> 00:17:42,419
there is something called agonism.

562
00:17:42,420 --> 00:17:44,259
Basically, what that means is that a

563
00:17:44,260 --> 00:17:46,819
molecule activates the 2A receptor.

564
00:17:46,820 --> 00:17:48,979
Agonist, things like LSD,

565
00:17:48,980 --> 00:17:50,739
bind to the receptor and activate

566
00:17:50,740 --> 00:17:52,659
it. How strong that effect is

567
00:17:52,660 --> 00:17:54,979
depends in part on the dose.

568
00:17:54,980 --> 00:17:57,219
Jason, he likes to use this analogy

569
00:17:57,220 --> 00:17:59,059
of a gas pedal on a car.

570
00:18:00,740 --> 00:18:02,819
Full agonist push the pedal

571
00:18:02,820 --> 00:18:04,499
all the way down.

572
00:18:04,500 --> 00:18:06,419
But what if you can make molecules

573
00:18:06,420 --> 00:18:08,179
that only push the pedal part of the

574
00:18:08,180 --> 00:18:10,579
way? 2A still gets activated,

575
00:18:10,580 --> 00:18:12,019
but not fully.

576
00:18:12,020 --> 00:18:14,339
And the idea, creating a psychedelic

577
00:18:14,340 --> 00:18:16,259
that keeps the therapeutic benefits,

578
00:18:16,260 --> 00:18:18,099
but removes a lot of the trippy

579
00:18:18,100 --> 00:18:19,939
parts, is a major deal in

580
00:18:19,940 --> 00:18:20,940
drug development.

581
00:18:21,810 --> 00:18:23,409
A lot of these patients might not

582
00:18:23,410 --> 00:18:25,169
mind taking a psychedelic once a

583
00:18:25,170 --> 00:18:26,529
year, but some of them do.

584
00:18:26,530 --> 00:18:27,649
You know, it's an intense

585
00:18:27,650 --> 00:18:29,729
experience. It's six to eight

586
00:18:29,730 --> 00:18:31,489
hours. So if you could come up with

587
00:18:31,490 --> 00:18:33,329
a pill that they take that does

588
00:18:33,330 --> 00:18:34,289
the exact same thing

589
00:18:34,290 --> 00:18:36,129
therapeutically, but does not

590
00:18:36,130 --> 00:18:37,969
cause any distortions

591
00:18:37,970 --> 00:18:39,649
and sensory perception or

592
00:18:39,650 --> 00:18:41,649
hallucinations, many of those

593
00:18:41,650 --> 00:18:43,169
patients would almost certainly

594
00:18:43,170 --> 00:18:44,170
choose that option.

595
00:18:44,970 --> 00:18:46,569
And that could be especially useful

596
00:18:46,570 --> 00:18:48,489
for patients who might not want to

597
00:18:48,490 --> 00:18:50,809
or shouldn't have a full psychedelic

598
00:18:50,810 --> 00:18:51,889
experience.

599
00:18:51,890 --> 00:18:53,329
I think it ultimately it will depend

600
00:18:53,330 --> 00:18:55,009
on the indications, the patient

601
00:18:55,010 --> 00:18:55,809
population.

602
00:18:55,810 --> 00:18:57,729
I'm always an advocate for having

603
00:18:57,730 --> 00:18:59,969
lots of medications, lots of options

604
00:18:59,970 --> 00:19:01,729
for patients and doctors.

605
00:19:01,730 --> 00:19:03,359
You know, more tools the better.

606
00:19:03,360 --> 00:19:05,599
This idea of creating a psychedelic

607
00:19:05,600 --> 00:19:07,519
without the trip part is pretty

608
00:19:07,520 --> 00:19:09,599
controversial.

609
00:19:09,600 --> 00:19:11,678
And scientists, they're divided

610
00:19:11,679 --> 00:19:13,119
on whether the approach will

611
00:19:13,120 --> 00:19:14,239
actually work.

612
00:19:14,240 --> 00:19:16,239
Clint, the neuroscientist that took

613
00:19:16,240 --> 00:19:18,239
us into his lab in Georgia, he's

614
00:19:18,240 --> 00:19:19,469
not so sure.

615
00:19:19,470 --> 00:19:21,309
There's been a lot of public

616
00:19:21,310 --> 00:19:22,429
debates about this.

617
00:19:22,430 --> 00:19:24,189
I think the jury's still out.

618
00:19:24,190 --> 00:19:25,789
Where do you fall on that jury?

619
00:19:25,790 --> 00:19:28,429
I try to stay as agnostic

620
00:19:28,430 --> 00:19:30,429
as possible and just stay

621
00:19:30,430 --> 00:19:32,029
abreast of the literature and also

622
00:19:32,030 --> 00:19:34,509
what we're observing in our lab

623
00:19:34,510 --> 00:19:36,589
until we have some

624
00:19:36,590 --> 00:19:37,469
conclusions.

625
00:19:37,470 --> 00:19:39,309
I think if you

626
00:19:39,310 --> 00:19:41,229
were to like dig into me and

627
00:19:41,230 --> 00:19:43,309
find my implicit bias,

628
00:19:43,310 --> 00:19:45,149
it would be that I

629
00:19:45,150 --> 00:19:47,149
believe that the psychedelic

630
00:19:47,150 --> 00:19:49,549
experience is a component

631
00:19:49,550 --> 00:19:51,389
of the therapeutic effects,

632
00:19:51,390 --> 00:19:54,189
especially in depression.

633
00:19:54,190 --> 00:19:56,429
I'm open to the possibility

634
00:19:56,430 --> 00:19:58,269
that non-psychedelic

635
00:19:58,270 --> 00:20:00,589
serotonin 2A agonists

636
00:20:00,590 --> 00:20:02,749
could also have some therapeutic

637
00:20:02,750 --> 00:20:03,629
efficacy.

638
00:20:03,630 --> 00:20:05,309
And what that looks like, what are

639
00:20:05,310 --> 00:20:06,749
they therapeutic for?

640
00:20:06,750 --> 00:20:07,789
What indications?

641
00:20:07,790 --> 00:20:08,830
That's a big question mark.

642
00:20:12,040 --> 00:20:13,959
There are about 50 biotech companies

643
00:20:13,960 --> 00:20:15,479
working in the psychedelic drug

644
00:20:15,480 --> 00:20:17,398
space, and the market is expected

645
00:20:17,399 --> 00:20:19,799
to grow to $6.7 billion

646
00:20:19,800 --> 00:20:21,319
by 2027.

647
00:20:21,320 --> 00:20:23,079
But all these novel psychedelics are

648
00:20:23,080 --> 00:20:24,439
a big question mark.

649
00:20:24,440 --> 00:20:25,959
We won't really know if they work

650
00:20:25,960 --> 00:20:27,799
until they're tested in humans.

651
00:20:27,800 --> 00:20:29,799
And that is starting to happen.

652
00:20:29,800 --> 00:20:31,638
Cybin, the company Clint was

653
00:20:31,639 --> 00:20:33,398
testing novel compounds for.

654
00:20:33,399 --> 00:20:35,158
Well, it's already testing those on

655
00:20:35,159 --> 00:20:36,999
humans in clinical trials using

656
00:20:37,000 --> 00:20:39,079
its own psilocybin analog

657
00:20:39,080 --> 00:20:41,079
aimed at treating major depressive

658
00:20:41,080 --> 00:20:42,080
disorder.

659
00:20:43,960 --> 00:20:45,959
The head twitch response is a simple

660
00:20:45,960 --> 00:20:47,799
test with a very specific but

661
00:20:47,800 --> 00:20:49,079
important purpose.

662
00:20:49,080 --> 00:20:50,919
And it won't tell you how a drug

663
00:20:50,920 --> 00:20:52,519
will affect mental illness or what

664
00:20:52,520 --> 00:20:54,119
it might do in humans.

665
00:20:54,120 --> 00:20:56,359
It's not the finish line, far

666
00:20:56,360 --> 00:20:57,479
from it.

667
00:20:57,480 --> 00:20:59,799
But it is a starting point,

668
00:20:59,800 --> 00:21:01,719
a signal that a compound might

669
00:21:01,720 --> 00:21:03,559
be worth exploring further.

670
00:21:03,560 --> 00:21:06,039
And it does open up other questions,

671
00:21:06,040 --> 00:21:07,878
the kind that Clint likes to think

672
00:21:07,879 --> 00:21:08,729
about.

673
00:21:08,730 --> 00:21:10,729
I guess the biggest question is

674
00:21:10,730 --> 00:21:12,569
are the animals having an

675
00:21:12,570 --> 00:21:14,969
animal-like psychedelic experience?

676
00:21:14,970 --> 00:21:16,969
And is that reflected

677
00:21:16,970 --> 00:21:18,065
somehow in the head twitch?

678
00:21:19,210 --> 00:21:20,969
Nobody knows the answer to that

679
00:21:20,970 --> 00:21:22,889
question. And so again,

680
00:21:22,890 --> 00:21:24,889
like everything gets distilled

681
00:21:24,890 --> 00:21:26,809
into well, it's it's just a good

682
00:21:26,810 --> 00:21:28,489
model of seeing whether this drug

683
00:21:28,490 --> 00:21:30,169
gets into the brain and activates

684
00:21:30,170 --> 00:21:32,009
that receptor and is

685
00:21:32,010 --> 00:21:34,169
a psychedelic or not, based

686
00:21:34,170 --> 00:21:36,689
on whether the head twitch or not.

687
00:21:36,690 --> 00:21:38,609
But for Jason, the question doesn't

688
00:21:38,610 --> 00:21:40,369
really matter all that much.

689
00:21:40,370 --> 00:21:42,529
Researchers tend to avoid projecting

690
00:21:42,530 --> 00:21:44,449
human thoughts or emotions onto lab

691
00:21:44,450 --> 00:21:45,249
mice.

692
00:21:45,250 --> 00:21:47,409
Instead, they focus on what the data

693
00:21:47,410 --> 00:21:49,249
can tell them, without assuming what

694
00:21:49,250 --> 00:21:51,299
the animals might be experiencing.

695
00:21:51,300 --> 00:21:53,219
I don't think head twitch is like

696
00:21:53,220 --> 00:21:55,138
a sign that they are tripping

697
00:21:55,139 --> 00:21:56,739
or having a psychedelic experience.

698
00:21:56,740 --> 00:21:58,418
I think it's just so happens when

699
00:21:58,419 --> 00:22:00,499
you activate the 2A receptor,

700
00:22:00,500 --> 00:22:01,779
you get this response.

701
00:22:01,780 --> 00:22:03,459
Like it doesn't really matter at the

702
00:22:03,460 --> 00:22:05,539
end of the day whether the mice

703
00:22:05,540 --> 00:22:07,059
are hallucinating or not.

704
00:22:07,060 --> 00:22:09,378
It's whether it can

705
00:22:09,379 --> 00:22:11,299
be useful in the way you're

706
00:22:11,300 --> 00:22:12,709
trying to use it.

707
00:22:12,710 --> 00:22:14,629
So do mice actually trip?

708
00:22:14,630 --> 00:22:16,549
Do they have some kind of subjective

709
00:22:16,550 --> 00:22:18,709
psychedelic experience?

710
00:22:18,710 --> 00:22:19,989
We don't really know.

711
00:22:19,990 --> 00:22:21,749
The question of animal consciousness

712
00:22:21,750 --> 00:22:24,069
has been debated for a long time.

713
00:22:24,070 --> 00:22:26,229
But zoologists, neuroscientists,

714
00:22:26,230 --> 00:22:27,909
and philosophers are starting to

715
00:22:27,910 --> 00:22:30,149
think about this differently.

716
00:22:30,150 --> 00:22:32,069
And many are increasingly open

717
00:22:32,070 --> 00:22:33,669
to the idea that animals have a

718
00:22:33,670 --> 00:22:35,989
sense of self and consciousness.

719
00:22:37,510 --> 00:22:39,899
I asked Clint what he thought.

720
00:22:39,900 --> 00:22:42,299
I really have no idea.

721
00:22:42,300 --> 00:22:44,139
I mean, I really don't.

722
00:22:44,140 --> 00:22:46,059
It's just pure conjecture,

723
00:22:46,060 --> 00:22:47,979
right? I don't know.

724
00:22:47,980 --> 00:22:50,539
If a mouse brain is just

725
00:22:50,540 --> 00:22:52,699
I'm not saying it is, but if

726
00:22:52,700 --> 00:22:54,619
it if a mouse brain is just a

727
00:22:54,620 --> 00:22:56,859
much smaller human brain,

728
00:22:56,860 --> 00:22:58,699
then presumably it has all the

729
00:22:58,700 --> 00:23:00,619
same neural circuits that just

730
00:23:00,620 --> 00:23:02,699
wouldn't be as robust.

731
00:23:02,700 --> 00:23:04,539
And so then

732
00:23:04,540 --> 00:23:06,619
maybe it has some primitive

733
00:23:06,620 --> 00:23:08,539
form of like consciousness

734
00:23:08,540 --> 00:23:10,379
like humans have.

735
00:23:10,380 --> 00:23:12,459
So is there a tipping point from

736
00:23:12,460 --> 00:23:15,259
no consciousness to consciousness?

737
00:23:15,260 --> 00:23:17,339
Or is it more of like

738
00:23:17,340 --> 00:23:19,579
a scale or a spectrum?

739
00:23:19,580 --> 00:23:21,019
Like a little bit of consciousness,

740
00:23:21,020 --> 00:23:22,020
more, more, more.

741
00:23:35,120 --> 00:23:36,559
Altered States is a production of

742
00:23:36,560 --> 00:23:38,158
the UC Berkeley Center for the

743
00:23:38,159 --> 00:23:40,319
Science of Psychedelics and PRX.

744
00:23:40,320 --> 00:23:41,999
This story was reported and produced

745
00:23:42,000 --> 00:23:43,359
by Alexa Lim.

746
00:23:43,360 --> 00:23:45,438
Adizah Eghan is our senior editor.

747
00:23:45,439 --> 00:23:47,279
Our executive editor is Malia

748
00:23:47,280 --> 00:23:49,119
Wollan. Jennie Cataldo is

749
00:23:49,120 --> 00:23:50,478
our senior producer, and our

750
00:23:50,479 --> 00:23:52,718
researcher is Cassady Rosenblum.

751
00:23:52,719 --> 00:23:54,638
Our associate producer is Jade Abdul

752
00:23:54,639 --> 00:23:56,559
Malik, and our audio engineers are

753
00:23:56,560 --> 00:23:58,799
Terence Bernardo and Jennie Cataldo.

754
00:23:58,800 --> 00:24:01,039
Fact checking by Graham Hacia.

755
00:24:01,040 --> 00:24:03,119
Special thanks to Michael Silver.

756
00:24:03,120 --> 00:24:04,958
Our executive producers are Malia

757
00:24:04,959 --> 00:24:07,359
Wollan and Jocelyn Gonzales.

758
00:24:07,360 --> 00:24:08,958
And our project manager is Edwin

759
00:24:08,959 --> 00:24:09,918
Ochoa.

760
00:24:09,919 --> 00:24:11,918
Our theme music is by Thao Nguyen

761
00:24:11,919 --> 00:24:13,599
and Nate Brenner.

762
00:24:13,600 --> 00:24:15,154
And I'm your host, Arielle

763
00:24:15,155 --> 00:24:16,079
Duhaime-Ross.

764
00:24:16,080 --> 00:24:17,759
Be sure to subscribe, rate, and

765
00:24:17,760 --> 00:24:19,519
review Altered States wherever you

766
00:24:19,520 --> 00:24:21,039
get your podcasts.

767
00:24:21,040 --> 00:24:22,878
Most well known psychedelics remain

768
00:24:22,879 --> 00:24:24,638
illegal around the world, including

769
00:24:24,639 --> 00:24:26,559
in the United States, where it is a

770
00:24:26,560 --> 00:24:28,319
criminal offense to manufacture,

771
00:24:28,320 --> 00:24:30,079
possess, dispense, or supply most

772
00:24:30,080 --> 00:24:32,079
psychedelics, with few exceptions.

773
00:24:32,080 --> 00:24:33,999
Altered States does not recommend or

774
00:24:34,000 --> 00:24:35,839
encourage the use of psychedelics

775
00:24:35,840 --> 00:24:37,760
or offer instructions in their use.