I'm on the outskirts of Atlanta, on
the campus of Mercer University.
And today I'm taking a tour
of the lab where
researchers are giving mice
psychedelics.
Yeah, so we're walking
to our behavioral
testing lab.
Clint Canal is one of those
researchers, and he's my tour guide
here.
To get to the lab, we have to make
our way through this maze of
security doors.
There are signs posted everywhere
asking visitors to be quiet and
mindful of the animals.
I don't see any mice right away,
but once we reach the lab, Clint
starts to whisper.
And so do I.
And I know we're whispering.
Yeah, basically out of respect for
the animal. Obviously we're
predators to them.
So just trying to stay
calm so that they also
stay calm.
I know it might seem a little odd to
keep calm and whisper in reverence
for mice that are about to be given
a psychedelic and sometimes
sacrificed, as the researchers
call it.
But scientists like Clint see these
little black mice as part of a
larger mission: tackling
the growing mental health crisis.
Their goal is to develop novel
psychedelics, new compounds,
with the hope that these new drugs
can one day treat depression, PTSD,
and other mental illnesses and
neurological disorders.
Conditions that in some cases have
no effective treatments.
But before any of these drugs can
make it to the point where they are
tested in humans, scientists
first need to test them on mice.
Clint is a neuroscientist
and a professor of pharmaceutical
sciences. And what that means is
he studies how cells in the brain
fire and communicate, and
how that communication breaks
down in certain disorders.
He's especially interested in how
drugs, including psychedelics, can
influence neural pathways.
And one way he does this is by
studying mice on psychedelics.
This is a male C-57
Black 6J mouse
just walking casually in
an open field.
When a mouse is having a
psychedelic-like experience, they
react with this very specific
behavior.
And that is what I am here to
see. But for someone like me
who's never seen this, it can be
really hard to catch.
So before I see the real thing,
Clint gives me a quick video
tutorial to train my eyes.
Do you want the slow or the real
time?
Maybe let's do the real time first.
This is a two second
video. It's just very quick.
So we're huddled around his computer
watching black and white footage of
a mouse.
The mouse in the video has been
given a dose of a psychedelic drug,
mostly used in research, called DOI.
I always tell students just pay
attention to the ears and just
look for any kind of head movement
that you typically don't observe
when an animal has not been given a
drug. So just look at the ears
and then you'll start to see it.
At first, nothing seems unusual.
Just a mouse doing mouse things,
sniffing, wandering, exploring
corners.
But then, the mouse
makes a quick jolt, a
twitch, this side-to-side
head shake.
You know when a wet dog twists
its body to dry off?
It kinda looks like that.
And it is quick, like half
a second.
I completely miss it the first time
around.
There.
Oh, okay.
It almost looks like as if
it were shaking off
some bug that might have landed on
its head or something like that.
That movement is not random.
It's called the head twitch
response.
In the world of drug development,
this tiny twitch is a big
deal. Scientists are interested in
the head twitch response because it
can use it as an indicator,
this kind of shorthand, to figure
out whether a newly created compound
is likely to have psychedelic-like
effects.
This week is a science week here on
the podcast. We're gonna talk about
animal testing in psychedelic
research, because as it turns
out, much of what we know about
psychedelic science comes from
research on animals.
In the late 80s, the Food and Drug
Administration approved the first
selective serotonin reuptake
inhibitors, or SSRIs.
And now some companies are looking
to psychedelics as they try to
develop the next generation of
patented blockbuster drugs to
treat depression and mental health
issues.
And behind much of this research
are these twitching mice.
What can we really learn about
our brains or consciousness
from these rodents?
I'm Arielle Duhaime-Ross, and this
is Altered States.
Reporter Alexa Lim investigates.
Clint has always been curious about
the big questions philosophy,
psychology, how the mind works,
even as a kid.
I had this really great grammar
teacher and he had this poster
on the wall that was the quote from
Socrates, the unexamined
life is not worth living.
And that really resonated with me at
the time, thinking about
philosophical questions and
how that relates to the mind
and eventually to the brain.
Clint studied psychology and
philosophy in college, and somewhere
along the way, he stumbled upon
LSD.
I was extremely fascinated by LSD
that this molecule at
such a low dose can produce
such mind altering and
self altering experiences.
How can a drug that's so
small produce such profound changes
in cognition?
That curiosity led him to
neuroscience, where he felt like he
could tackle those larger questions.
And to do that, he decided to
start small, much smaller.
He got interested in receptors.
They're those tiny docking molecules
on brain cells that respond to
neurotransmitters and psychoactive
drugs. They regulate things like
mood, memory, and perception.
You can modulate the activity
of one receptor and
affect psychology and
then affecting people's
worldview how they view the
world after a psychedelic
experience can affect them
on a philosophical level.
So that's really what got me
interested in it.
Clint began to see the real world
potential of psychedelics.
And not just as tools for exploring
the mind, but as treatments for
serious mental illness.
His research shifted in that
direction.
But this was more than just
research.
It was personal.
He told me that a few family members
had severe mental health issues.
He witnessed what they went through,
and it changed him.
Clint eventually landed a postdoc
position in a lab focused on a very
specific type of serotonin
receptor.
And the researchers were using
psychedelics to study it.
And this was his first encounter
with the twitching mouse.
How many head twitches do you
estimate you've counted in your
life?
I don't know.
Hundreds?
Thousands? I don't know about
thousands, maybe.
Today, he still studies the brain
in receptors, trying to find
treatments for these illnesses.
He says it almost feels like a
calling.
Easy room in my area.
So if you guys want to see I'm like
set for it. Okay.
Back in the lab, Clint and a
graduate student named Richa Tyagi
are running a test on a mouse.
They're working with a psychedelic
compound currently being developed
by a pharmaceutical company.
Clint is careful not to share too
many details.
But the company, Cybin,
is known for developing new
proprietary psychedelics
aimed at treating depression,
anxiety, and other central nervous
system disorders.
Yeah, I was seeing there it was
really calm.
They are really calm.
The test starts when Richa injects
the mouse with the drug.
Then, she places the mouse
in a large glass tank.
And she watches closely, waiting
to count how many times the mouse
twitches its head.
We just use a tally counter.
Just whenever they have to
click the button.
It's one of those silver handheld
counters that you might see someone
using to count how many people enter
a water park or a concert.
And each time Richa observes a
twitch.
Two compounds can produce very
different scale of H
T Rs. Traditionally you just do
number of head twitch responses
over time.
But now I guess people are more
interested in how these head
twitch responses evolve
over time.
At first, the twitching is
a little sporadic, but
after the three minute mark, things
start to pick up.
It's just like what I saw in the
video.
Then things really start to get
twitchy.
What is your tally so far?
So far I've had thirty-eight heads
responses within a time span of
fifteen minutes.
By the 15th minute mark, Richa
has clicked the counter 38
times.
38 head twitches.
Head twitch sounds pretty simple.
Give a mouse a drug and note
whether or not it twitches.
But exactly why it twitches
is still something of a mystery.
One thing scientists do know is
that all the classic psychedelics,
the ones that affect the serotonin
system, think LSD, psilocybin,
DMT, they all reliably
produce the head twitch in mice.
And most importantly, the head
twitch seems to be connected to one
particular serotonin receptor
called 5HT2A,
or 2A for short.
The serotonin two way receptor,
we tend to think about it as being a
brain receptor.
The prefrontal cortex is part of the
brain involved in planning,
decision-making, and self-awareness.
And it has a dense concentration of
these 2A receptors.
You know, that's where we believe
the seats of consciousness are and
thoughts, ideas, planning,
executive functions.
And if you give a psychedelic to a
mouse or a human and the two way
receptor has been blocked or
switched off, the psychedelic
effects don't happen.
That means shut down two way
signaling and the trip disappears.
The one thing is though, we don't
head twitch.
Yeah.
Yeah. We don't head twitch.
That's true.
So why don't we head switch?
I asked Clint.
This is such a important question
though. Like if you look at the
mouse brain compared to a human
brain, the neural structures
are organized the same way.
Why do they hedge which and humans
don't? Is the same circuitry
engaged?
Scientists aren't sure.
These head twitch tests that Clint
and Richa are running, they're only
the beginning.
In fact, there's a whole gauntlet
of tests, including animal behavior
experiments that researchers use to
see if a drug might have
antidepressant qualities.
For example, there's something
called the forced swim test.
Scientists put a mouse in a
container full of water and it can't
escape. And in this test,
swimming is seen as a proxy for
mental fitness.
So a happier, less depressed
mouse will swim for longer, trying
to escape, while a depressed
mouse gives up sooner and just
floats.
They sometimes call this the
behavioral despair test.
And side note, the mice are rescued
before they drown.
Researchers have been using the
forced swim test to model depression
for decades.
But what can a mouse that stops
swimming really tell us about human
despair?
And is a mouse trip a stand-in
for a human one?
What can we really learn from a
twitching mouse?
I talked to a bunch of scientists
and their opinions were all over the
map. Some seem almost irritated
by the head twitch response, while
others dismissed it as barely
relevant to humans at all.
But even if they didn't like it, the
scientists I talked to agreed
that it's the one tool they have.
The twitch is a pretty reliable
indicator of 2A receptor
activation in the mouse brain.
Here's Clint again.
There aren't many
solid pharmacodynamic
models like this in the neuroscience
field where you can just
administer a drug
and see a behavior that's caused
by a specific receptor in the
brain. There aren't a lot of models
like that. It is really fascinating.
It's a wonderful model that's
really reliable and easy to measure.
Today, the head switch response is a
standard measure in psychedelic
research in rodents.
Scientists know what they're looking
for, they know what to expect.
But that was not always
the case.
Many psychoactive compounds have
been part of the natural world for
ages. And by the time the term
psychedelic emerged in the 1950s,
these substances had found their way
into labs.
And eventually into lab animals
too. And things got,
well, kind of weird.
Scientists gave spiders high doses
of LSD.
The pattern of the drug web
is characteristic for each
type of drug.
Actually, one can identify
drug actions through
their effects on web
building.
And cats got LSD too.
A study was made of the effect of
one of these on a cat, which,
prior to receiving a dose of the
agent, reacted normally when
confined with a mouse.
When exposed to an extremely small
amount of the agent, the cat's
personality completely changed.
This Noah's Ark of tripping lab
animals marched on.
Dolphins were injected with LSD.
Hello.
[Dolphin Sound]
Then of course there's the CIA,
which for years conducted and backed
LSD experiments on cats, rabbits,
even an elephant, to see
if the drug might be used in mind
control.
As this 1952 CIA
memo says, the aim
is controlling an individual
to the point where he will do our
bidding against his will
and even against such fundamental
laws of nature as self-preservation.
Some of the research was done as
part of a secret project called MK
Ultra, which the CIA ran in
the nineteen fifties and sixties.
It was the most secret
program ever conducted
by the CIA in the United
States.
In this era, researchers were not
studying psychedelics for their
treatment potential.
In fact, they were often using
these substances to mimic and model
psychosis.
Meanwhile, two microbiologists
at Merck Institute for Therapeutic
Research in New Jersey were quietly
working on their own little
psychedelic study.
The authors were Doris Keller
and Wayne Umbright.
They gave mice LSD
and noticed a distinct and
predictable shaking.
They published a brief two-page
study in the journal Science in
1956.
And that was the first paper to
name and describe the head twitch
response.
From what I can tell, neither Doris
nor Wayne produced any other studies
on psychedelics afterwards.
Doris went on to develop drugs to
treat diseases like arthritis and
inflammatory bowel disease at Merck.
And Wayne was best known for his
work on vitamins, especially B6.
But their small study would end
up having an outsized influence on
the future of psychedelic research.
After the break, we'll hear how
scientists today are using head
twitch to discover new drugs.
So we heard how the head twitch is
correlated to activation of the
serotonin receptor called 5HT2A.
Scientists are now using 2A as
a target for developing new drugs.
And the head twitch response is a
kind of guidepost in that hunt.
I'm very interested in finding
ways to accelerate drug
discovery so that it doesn't take
ten years from making
a compound in the lab.
To getting it to patients.
This is Jason Wallach.
He's a pharmacologist and a
professor at St. Joseph's University
in Philadelphia.
And he studies the basic biology
behind how drugs work, including
psychedelics.
And he's trying to design new ones
in the lab.
He's worked with the biotech company
Compass Pathways.
Jason's kind of like a psychedelic
architect.
He studies the chemical scaffolding
so he can break it down and rebuild
it in new ways.
You're starting from a known
molecule that you know already binds
the receptor.
And you begin to modify it and
study what happens when I add this,
what happens when I remove this,
what happens when I lock this
chain into a ring.
Right? As I tinker with this
part, what happens?
I get more potent compounds.
They become more efficacious.
They become less selective, more
selective. It's this very iterative
process of tinker test,
tinker test.
Each time you learn more and more
about the rule set that
governs that pharmacology.
If Jason's new compound doesn't pass
the head switch test, meaning
it's not activating 2A,
not acting like a classic
psychedelic, he'll need to
make some adjustments.
He's constantly tweaking and
testing and looking for that twitch.
And Jason's really interested in
fine-tuning one certain part.
So, in the pharmacology world,
there is something called agonism.
Basically, what that means is that a
molecule activates the 2A receptor.
Agonist, things like LSD,
bind to the receptor and activate
it. How strong that effect is
depends in part on the dose.
Jason, he likes to use this analogy
of a gas pedal on a car.
Full agonist push the pedal
all the way down.
But what if you can make molecules
that only push the pedal part of the
way? 2A still gets activated,
but not fully.
And the idea, creating a psychedelic
that keeps the therapeutic benefits,
but removes a lot of the trippy
parts, is a major deal in
drug development.
A lot of these patients might not
mind taking a psychedelic once a
year, but some of them do.
You know, it's an intense
experience. It's six to eight
hours. So if you could come up with
a pill that they take that does
the exact same thing
therapeutically, but does not
cause any distortions
and sensory perception or
hallucinations, many of those
patients would almost certainly
choose that option.
And that could be especially useful
for patients who might not want to
or shouldn't have a full psychedelic
experience.
I think it ultimately it will depend
on the indications, the patient
population.
I'm always an advocate for having
lots of medications, lots of options
for patients and doctors.
You know, more tools the better.
This idea of creating a psychedelic
without the trip part is pretty
controversial.
And scientists, they're divided
on whether the approach will
actually work.
Clint, the neuroscientist that took
us into his lab in Georgia, he's
not so sure.
There's been a lot of public
debates about this.
I think the jury's still out.
Where do you fall on that jury?
I try to stay as agnostic
as possible and just stay
abreast of the literature and also
what we're observing in our lab
until we have some
conclusions.
I think if you
were to like dig into me and
find my implicit bias,
it would be that I
believe that the psychedelic
experience is a component
of the therapeutic effects,
especially in depression.
I'm open to the possibility
that non-psychedelic
serotonin 2A agonists
could also have some therapeutic
efficacy.
And what that looks like, what are
they therapeutic for?
What indications?
That's a big question mark.
There are about 50 biotech companies
working in the psychedelic drug
space, and the market is expected
to grow to $6.7 billion
by 2027.
But all these novel psychedelics are
a big question mark.
We won't really know if they work
until they're tested in humans.
And that is starting to happen.
Cybin, the company Clint was
testing novel compounds for.
Well, it's already testing those on
humans in clinical trials using
its own psilocybin analog
aimed at treating major depressive
disorder.
The head twitch response is a simple
test with a very specific but
important purpose.
And it won't tell you how a drug
will affect mental illness or what
it might do in humans.
It's not the finish line, far
from it.
But it is a starting point,
a signal that a compound might
be worth exploring further.
And it does open up other questions,
the kind that Clint likes to think
about.
I guess the biggest question is
are the animals having an
animal-like psychedelic experience?
And is that reflected
somehow in the head twitch?
Nobody knows the answer to that
question. And so again,
like everything gets distilled
into well, it's it's just a good
model of seeing whether this drug
gets into the brain and activates
that receptor and is
a psychedelic or not, based
on whether the head twitch or not.
But for Jason, the question doesn't
really matter all that much.
Researchers tend to avoid projecting
human thoughts or emotions onto lab
mice.
Instead, they focus on what the data
can tell them, without assuming what
the animals might be experiencing.
I don't think head twitch is like
a sign that they are tripping
or having a psychedelic experience.
I think it's just so happens when
you activate the 2A receptor,
you get this response.
Like it doesn't really matter at the
end of the day whether the mice
are hallucinating or not.
It's whether it can
be useful in the way you're
trying to use it.
So do mice actually trip?
Do they have some kind of subjective
psychedelic experience?
We don't really know.
The question of animal consciousness
has been debated for a long time.
But zoologists, neuroscientists,
and philosophers are starting to
think about this differently.
And many are increasingly open
to the idea that animals have a
sense of self and consciousness.
I asked Clint what he thought.
I really have no idea.
I mean, I really don't.
It's just pure conjecture,
right? I don't know.
If a mouse brain is just
I'm not saying it is, but if
it if a mouse brain is just a
much smaller human brain,
then presumably it has all the
same neural circuits that just
wouldn't be as robust.
And so then
maybe it has some primitive
form of like consciousness
like humans have.
So is there a tipping point from
no consciousness to consciousness?
Or is it more of like
a scale or a spectrum?
Like a little bit of consciousness,
more, more, more.
Altered States is a production of
the UC Berkeley Center for the
Science of Psychedelics and PRX.
This story was reported and produced
by Alexa Lim.
Adizah Eghan is our senior editor.
Our executive editor is Malia
Wollan. Jennie Cataldo is
our senior producer, and our
researcher is Cassady Rosenblum.
Our associate producer is Jade Abdul
Malik, and our audio engineers are
Terence Bernardo and Jennie Cataldo.
Fact checking by Graham Hacia.
Special thanks to Michael Silver.
Our executive producers are Malia
Wollan and Jocelyn Gonzales.
And our project manager is Edwin
Ochoa.
Our theme music is by Thao Nguyen
and Nate Brenner.
And I'm your host, Arielle
Duhaime-Ross.
Be sure to subscribe, rate, and
review Altered States wherever you
get your podcasts.
Most well known psychedelics remain
illegal around the world, including
in the United States, where it is a
criminal offense to manufacture,
possess, dispense, or supply most
psychedelics, with few exceptions.
Altered States does not recommend or
encourage the use of psychedelics
or offer instructions in their use.