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LSD May Lead to a New Kind of Medicine
LSD May Lead to a New Kind of Medicine
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0:00
Psychedelics are good for more than
0:02
having a deep conversation with a houseplant.
0:04
These drugs have huge potential for
0:06
treating a variety of mental illnesses, too!
0:08
Studies show that people with depression, PTSD,
0:11
and substance abuse disorders sometimes experience
0:14
fewer symptoms after a dose of LSD, for example.
0:17
There’s just one problem: We don’t really know why.
0:20
And since the side effects of these drugs are not exactly subtle,
0:23
it would be great if we could find a way to develop new medications
0:26
with all the antidepressant power, and less of the acid trip.
0:30
Luckily, a researcher named Bryan Roth at the University of
0:33
North Carolina has been studying this stuff his entire career.
0:37
His research mapping the fundamental chemistry of the brain
0:39
and the ways that these drugs work has provided some
0:42
clues as to how psychedelics can improve symptoms.
0:45
Roth and his team have even synthesized new molecules
0:48
that could have the same effect without the hallucinations.
0:51
Which sounds like research we'd like to see in person!
0:54
We sent our friend Madelyn Leembruggen to
0:56
Roth’s lab to learn more about this far-out solution to
0:59
some of psychiatry’s most stubborn problems.
1:02
This is SciShow Field Trips!
1:05
[♪INTRO]
1:07
Thanks, Hank! I’m here in Bryan Roth’s lab in the
1:10
Pharmacology department at UNC, Chapel Hill.
1:13
Pharmacology is all about drugs.
1:15
But for Roth, it isn’t just the drugs that are fascinating.
1:19
It’s what they interact with: Chemical receptors.
1:22
I went to college in Montana, I went to this really small college,
1:24
Carroll College, and, by then, I was convinced,
1:28
I needed to study the brain. I need to study these drugs
1:32
and how they work, basically. But I, you know,
1:35
I had no concept on how to do that, coming from
1:39
a small town in Montana. One year this scientist came.
1:42
Ostensibly, he was there to give us a lecture, but I think
1:45
he was really there to go trout fishing, basically, that was,
1:50
that was the reason he was there. But he gave his lecture,
1:53
and his lecture was on how the brain works, and he mentioned that,
1:59
you know, neurotransmitters work through receptors, and he said,
2:03
This is where drugs act. Are these receptors? So I said, right there.
2:07
Okay, so I need to study receptors. So that's it.
2:10
Basically, I saw the word receptor. I said,
2:13
That's what I want to study. That's where drugs act. And that was it.
2:19
And I have to say, I can see why he was so excited about it.
2:22
Because the way this works is really cool.
2:25
This is where we sectioned a brain with an optical microscope.
2:29
And this is the distribution of the receptor here in various brain regions.
2:34
Sort of cool. And that's sort of a close up.
2:35
So these are these neurons here in the cortex.
2:39
These are called Layer 5A Neurons.
2:42
This is a picture of neurons, yeah,
2:44
neurons that are expressing the receptor.
2:46
All the chemical receptors in our bodies have a unique shape, and
2:50
when a certain molecule comes along that fits into those receptors,
2:53
they can activate. Scientists call these activating chemicals agonists.
2:58
Neurotransmitters are a type of agonist,
3:00
since they’re the signaling molecules that neurons use
3:03
to send messages throughout the nervous system.
3:05
Now, even though textbook diagrams of receptors are just still images,
3:09
when you zoom down to the cellular level,
3:12
every molecule in our bodies is constantly in motion.
3:15
So the way people usually describe receptors and
3:19
drugs is that the drug is the key and the receptor is a lock.
3:23
Okay, that's actually not the way things work at all.
3:29
Okay, not even close. So technically speaking,
3:34
that's called the induced fit model that's called the induced fit,
3:37
that the key induces something.
3:37
Our understanding now is what's called conformational selection.
3:40
So the idea is that the receptors are vibrating,
3:45
they're continually vibrating, and they will vibrate in a
3:51
conformation that the drug is specific for and that binding event
3:57
causes a small change in the overall equilibrium of the population.
4:01
So it's like, it's like the locks are transiently opening,
4:05
and the key is just popping in.
4:07
Basically, the agonists that can only fit a little bit of themselves
4:10
into the receptor aren’t going to send a very strong signal,
4:14
and the ones that bind to more surface area will.
4:16
It’s more complicated than that, trust me.
4:20
Which is why people like Roth have made
4:21
a career out of studying these little things.
4:23
As a graduate student, Roth focused on opioid receptors.
4:27
But when he got a job at the National Institutes of Health, he switched
4:30
gears and started studying something called 5-HT2 receptors.
4:34
5-HT is an abbreviation for the molecule 5-hydroxytryptamine,
4:39
which is the neurotransmitter that binds to these receptors.
4:42
But you’re probably more familiar with its common name: serotonin.
4:46
We have different kinds of 5-HT2 receptors all over our bodies,
4:49
because serotonin does a lot more than just regulate your mood.
4:53
Serotonin plays a role in everything from digestion
4:55
to your immune system, and eve n your blood clotting.
4:58
And while serotonin and 5-HT2 receptors are buddies,
5:02
it isn’t the only molecule that can bind to them.
5:05
Another molecule that likes to get groovy with 5-HT2
5:09
receptors is the drug lysergic acid diethylamide, or LSD.
5:14
LSD is a psychedelic drug, and there
5:18
are a number of psychedelic drugs:
5:21
mescaline, which is a psychedelic drug from
5:24
the peyote cactus, psilocybin for magic mushrooms.
5:28
So all of these psychedelic drugs have the same property that they
5:32
activate this receptor, the 5-HT2A receptor, and activation of this
5:39
receptor is responsible for their psychedelic effects in humans.
5:43
LSD is a semi-synthetic compound that yeah,
5:46
you’ve probably heard of before.
5:48
It partially comes from a compound found in fungus that we’ve refined
5:52
into something with more of a kick. Well, not me. Other people.
5:57
When LSD binds to 5-HT2 receptors,
6:00
it activates the same pathways that serotonin does,
6:04
and it also affects our emotional and information processing,
6:07
to the point where people experience
6:09
hallucinations and disconnect from reality.
6:12
So these layer five neurons.
6:14
These are very important for integrating information
6:16
from basically all areas of the brain,
6:20
all sensory areas and perceptual and cognitive areas.
6:23
And what psychedelics do when they activate,
6:26
when they hit the receptor on those neurons,
6:28
is they basically cause the neurons to fire,
6:32
sort of in this disorganized fashion, and then,
6:35
for reasons that are not entirely clear yet,
6:37
the mind starts paying attention to sort of randomly
6:41
generated information, sensory information,
6:44
that it then makes a story about, okay,
6:47
and that's the psychedelic experience.
6:49
Basically the part of the brain that tells us what reality looks like.
6:54
It's basically like you injected noise into that system.
6:58
And so the awareness our mind doesn't trust that information anymore.
7:04
Since its most popular use has been recreational,
7:07
LSD is classified as a Schedule 1 controlled substance
7:10
by the United States government. That’s the group of drugs
7:13
that are said to have a high risk of dependency
7:15
and no established medical benefit.
7:17
But how do you find out if there’s a medical benefit if
7:20
it’s very difficult to test the stuff? That’s been the issue.
7:24
Right now it's like a really hot field, though.
7:27
I don't know how long that's going to last, but right now it is.
7:30
It'd be great if there was money. So it's not like there's been any
7:35
more money that's been appropriated to study psychedelics.
7:39
So there are all these people who want to study psychedelics,
7:44
but there's no money to study psychedelics.
7:47
The limiting factor
7:49
Money is always a problem. Yes.
7:51
Since LSD binds to the same receptors that serotonin does,
7:55
there’s reason to think it could have some
7:57
similarities with antidepressant medications.
7:59
The most common type of antidepressants are called SSRIs,
8:03
or selective serotonin reuptake inhibitors.
8:06
And what they do is right there in the name!
8:08
After a neuron makes and releases molecules into a synapse,
8:12
those molecules pretty quickly get broken down
8:14
or sucked back inside the cell—that’s called reuptake.
8:18
SSRIs work by preventing serotonin reuptake, usually
8:22
by stopping the proteins that physically transport serotonin.
8:25
Long term, probably what they do is they cause compensatory
8:31
interactions in the circuitry, and that causes the antidepressant effect.
8:36
So it's a very indirect effect.
8:39
Usually takes, you know, six to eight weeks for the maximum response.
8:43
And you know, doesn't work for everybody.
8:46
So current antidepressants sort of indirectly juice up the
8:50
signaling that’s already happening in our brains,
8:53
rather than directly binding to and activating 5-HT receptors.
8:58
But SSRIs don’t work well for everyone, especially people with really
9:02
severe cases of depression. And we don’t entirely understand why.
9:06
Like Hank said, there’s some clinical evidence that taking LSD can
9:09
also improve mood for people with certain mental health conditions.
9:13
And with LSD, patients sometimes reported
9:15
feeling better for months after a single dose.
9:19
Let's say you're depressed and I started you on Prozac,
9:23
I would say, you know, probably four to six weeks before you're going
9:28
to have much of an effect with psychedelics, one dose, basically.
9:33
So in the clinical trial data, which is quite compelling.
9:33
And many, many people, at least according to
9:35
the early, early trials were no longer depressed after
9:39
a single dose of psilocybin, and 12 months later, they were fine.
9:45
But we’re still a long way off from having
9:47
any LSD-based options at the pharmacy.
9:50
I mean, there’s that whole makes you
9:52
hallucinate and distorts your reality thing.
9:55
Not everyone’s down for that as a medication side effect.
9:57
And I presented that idea at the neuroscience meeting,
10:01
I think in 2017 or something like that, I gave one of these
10:04
presidential lectures, there are literally, like,
10:06
there were like 10,000 people in the audience.
10:08
It was this humongous auditorium, and I, you know,
10:11
presented that data. And on the slide, one of the slides,
10:14
I had a bullet point, and it said, it simply said that
10:17
it may be possible to separate the therapeutic
10:20
effect from the psychedelic effect. And then about a year later,
10:24
I got a phone call from DARPA. So there was somebody from
10:34
DARPA that was at my talk so the people that invented the internet,
10:37
GPS, stealth, bombing, you know, all these, all these great things.
10:37
It turns out that in the military, the number one casualty is psychiatric.
10:43
So by far and away, they have more soldiers who are disabled
10:49
because of depression, anxiety, post traumatic stress disorder and so
10:54
on, way more than physical casualties.
10:58
And you know, they had, they had seen the promise of psychedelics,
11:02
but there's no way you're going to give psychedelics to somebody
11:05
with a gun. I mean, it's, such a bad idea.
11:09
So they contacted me, and they said, you know, is it possible?
11:14
Basically? And I said, I sort of hedged my bets.
11:16
And I said, Well, it's a hypothesis we could test.
11:20
So Roth is trying to figure out how LSD might produce
11:23
those effects and how to create similar compounds.
11:27
And he’s starting with the fundamentals.
11:29
He wants to know what molecules like LSD look
11:32
like when they’re bound to a 5-HT2 receptor.
11:35
As in, what shape do they take, and how strong is
11:38
the signal that gets produced from their bond.
11:40
Like any lab working with a controlled substance,
11:43
there are precautions in place to make
11:45
sure the research is safe and focused.
11:47
This, yes, this is the safe that is the infamous LSD safe.
11:52
Not quite what you were expecting, is it?
11:54
So we have LSD and many, many other schedule one
11:59
psychedelic drugs, and the safe is kept in a locked room.
12:03
That's one of the things. The other thing is that there's only one person
12:07
in the lab that has the combination to the safe, and that is not me.
12:12
Because, you know, we don't want anyone accidentally
12:14
adjusting these compounds we have, we have psychedelics
12:17
that are more potent than anything that is out there.
12:21
So, but the amounts that we have, if we were to open that up,
12:24
it's just dust, basically just little, tiny amounts.
12:28
They only need an amount of LSD smaller than a microdose,
12:31
called a nanodose, since all they need
12:34
to see is one molecule binding to one receptor.
12:37
So when we initially saw the structure of LSD with the serotonin
12:42
receptor, one of the things that we noticed was that there was a
12:47
conformational change when LSD bound to the receptor, so that a lid
12:52
came over the top of the receptor and occluded it, so it stopped LSD
12:58
from exiting the receptor, so LSD was sort of trapped in there.
13:02
And concomitant with this, there was a different type of signaling
13:07
event that occurred, which is called arrestin signaling, okay.
13:12
And the normal mode of signaling through
13:14
the receptor is what's called G protein signaling.
13:18
Basically, both G proteins and arrestins are molecules inside
13:22
your cells that help pass along messages
13:24
after a neurotransmitter binds to a receptor.
13:27
But depending on which messenger takes over,
13:29
it can have very different effects.
13:31
When Roth's team realized that LSD seemed to push the
13:34
signaling toward the arrestin pathway, they saw an opportunity.
13:38
So we had the idea, well, maybe if we make a drug that's targeting
13:42
the other pathway, the G protein pathway, maybe we can diminish
13:47
the psychedelic effect and enhance the antidepressant effect.
13:51
All of this progress would have been just a pipe dream
13:53
for researchers like Roth, even just a decade or two ago.
13:56
So, you know, for like, 20 years or so, my goal was to
14:03
solve this structure of the receptor, and we couldn't do it basically,
14:07
because there wasn't appropriate technology.
14:10
And it wasn't until, you know, probably 10 years ago,
14:15
that you could crystallize membrane proteins
14:18
and study them by X ray crystallography. In my lab, we actually
14:23
got the first structure of LSD with the serotonin receptor
14:27
by crystallography, but it was extraordinarily difficult.
14:31
Today, structural modeling is much easier.
14:34
Roth’s lab now uses a tool called cryogenic
14:37
electron microscopy or cryo-EM for short.
14:40
So I am a structural biologist, so what I do is I purify receptors,
14:47
either from over expression systems or from tissue,
14:50
and subject those purified receptors to structural
14:55
approaches like cryo electron microscopy.
14:58
That’s Nicholas Wright. He’s a postdoc working to analyze
15:00
the molecular structure of these candidate compounds.
15:03
So the kind of idea behind cryo EM is that the purified material is put
15:10
on these grids, and you form really thin vitreous ice, so glass-like ice,
15:17
by plunge freezing the sample and liquid ethane, and the cooling
15:21
happens so fast, the ice doesn't have time to form regular crystals.
15:24
And what that does is it allows you to get images of single molecules of
15:29
your receptors, and then, with computational approaches, you can
15:34
average all those together to get a crisp, clean, three dimensional
15:36
picture of your your protein at the kind of really high resolution so you
15:41
can actually see the drug and how it interacts with the receptor.
15:43
So because it's frozen so quickly, then you can use image
15:48
processing to take out all of the ice molecules,
15:50
all the water molecules, and just focus on the candidate
15:54
Exactly, yeah, okay. And because it's vitreous or glass, like ice, that
15:58
gives very low background in the images, and you kind of capture,
16:02
like a snapshot of those molecules in action,
16:05
and you can compute a three dimensional,
16:07
high resolution picture of them.
16:08
They’re currently trying to discover new molecules that could
16:11
also bind to the 5-HT2 receptor, and exploring what effects
16:15
those molecules might have once they get there.
16:17
This kind of molecular matching game also
16:20
used to be a really slow and difficult process.
16:22
Okay, so this is our robot that is
16:26
preparing compounds that we're testing.
16:29
And down there you can see it's taking
16:32
little aliquots from the drug plate.
16:35
All those plates down there are the drug plates,
16:38
and then it's going to add them to assay plates.
16:41
And basically it just does that, and it's, you know,
16:41
this is repetitive work, right? So it's perfect for a robot to do.
16:46
But thanks to the latest generation of software, researchers can now
16:49
estimate what drug binding might look like for billions of slightly
16:53
different molecules that no chemist has even synthesized yet.
16:57
One promising category of molecules
16:59
is the tetrahydropyridines, or THPs.
17:02
We had hooked up with this amazing chemist at Yale,
17:06
Jonathan Ellman, who had invented this new chemistry
17:10
to make this class of compounds called tetrahydropyridines.
17:13
And he had, he had figured out a way to make,
17:15
in theory, billions of tetrahydropyridines.
17:19
So here, this was the idea we thought, so don't make a
17:19
you know, we can't test a billion compounds physically, right?
17:23
But he could enumerate them computationally.
17:26
So, using his reactions, we were able to enumerate I think,
17:32
100 million tetrahydropyridines that in theory he could make,
17:37
but no one has ever made before.
17:39
They calculated the odds of them binding with what’ s called
17:42
docking scores. The better the score, the more likely it is that
17:45
researchers will try to actually synthesize it in the lab to test it out.
17:49
So the way we do drug discovery is, first we have a structure.
17:52
Structures are generally solved in my lab, and then we collaborate
17:57
with this amazing computational person, Brian Choi at UCSF,
18:04
and his docking program basically takes the structure of
18:07
each little molecule and then brings it into the receptor,
18:12
and then sort of tries to find a way in the receptor that it will fit,
18:17
and then it scores that so there will be, you know,
18:20
If it forms a hydrogen bond, it gets a score, ionic bond, et cetera.
18:26
And currently, I think we're running a docking
18:29
campaign with 4 trillion molecules.
18:31
And then, you know that the compounds
18:33
literally have never been made before.
18:36
They don't exist in the physical universe.
18:38
So then we have a chemical company just
18:40
make them when we test them.
18:41
And then, then they go here. This is the testing being done, right here.
18:44
When they find that a compound binds
18:45
to a receptor in the test tubes, they then move on to testing it in mice.
18:49
And in this case, they found something really exciting.
18:52
Two of these molecules worked like strong antidepressants,
18:56
similar to what some people report after taking LSD.
18:59
But these new molecules didn’t have
19:01
the psychedelic side-effects that LSD does.
19:04
At least, as best they could tell.
19:06
Measuring the psychological state of animals is notoriously difficult,
19:09
and has to be surmised from things like head twitching,
19:12
which mice do when hallucinating.
19:14
Even so, this could be the first step towards
19:16
a whole new class of antidepressant medication.
19:19
And other potentially powerful molecules are even further
19:22
along in the process, but not for illnesses like depression.
19:25
When studying another kind of 5-HT2 receptor
19:28
that is involved in appetite suppression,
19:30
Roth and his collaborators identified a molecule they called BMB-101.
19:35
BMB 101, so this is a compound that was discovered in a
19:39
collaboration with Alan Kosikowski, who was formerly at
19:44
University of Illinois Chicago, and Bill Wetsel, who's at Duke.
19:49
In 2015, we were developing these as potential anti-psychotic drugs,
19:54
and they weren't very effective anti-psychotic drugs.
19:59
But Alan by accident, found in a zebrafish screen.
20:06
So they had a zebrafish screen which looked for drugs
20:10
that are effective in treating seizures or epilepsy.
20:13
And it turned out that BMB 101, also known as lumocaserin,
20:18
was very effective in that screen.
20:21
And it just finished phase two clinical trials for seizures,
20:26
I think, caused a more than 70% decrease in the
20:29
seizure incident and also improved REM sleep,
20:32
which is like unheard of among anti seizure agents.
20:36
Most people with seizure disorders actually have impaired sleep.
20:39
So this, you know, could be a game changer.
20:41
Roth thinks researching other compounds that bind to different
20:45
5-HT2 receptors could produce new medicines for a huge number
20:49
of disorders, especially those that are treatment resistant.
20:53
And for Roth, that really hits home. Because one of the people
20:56
who could’ve been helped by treatments like these was his mother.
21:00
Yeah, so my interest in pharmacology
21:02
actually started at a very young age.
21:05
My mom was diagnosed with schizophrenia when I was five or six,
21:11
and you know, of course, that had a huge impact on me.
21:16
And she was sort of in and out of, it was in Montana,
21:20
and it was basically the state mental institution.
21:25
It was a really pretty, pretty awful place.
21:27
So she was sort of in and out of that when I was growing up.
21:32
And then I think when I was 13 or so, my sister ended up in
21:39
the front page of the newspaper for having taken LSD.
21:43
I looked up LSD, and it said, LSD causes a model psychosis.
21:54
So I thought, Oh, okay. So this, you know, this is what I need to study.
21:59
I basically knew what I wanted to do, but I had
22:02
absolutely no concept of how to get there, you know.
22:07
And it was just this chance, really
22:09
a chance interaction with a trout fisher.
22:14
That’s what led to him to pursue biology and chemistry in college,
22:18
which brought him to that fateful lecture with the image of a receptor,
22:22
and all the decades of studying them since.
22:25
We were ultimately able to get my mom on one of the newer
22:28
atypical antipsychotic drugs, this drug called quetiapine
22:32
transformed her life, and its action is to block that receptor.
22:38
And you know, that was still at the time, we still didn't
22:41
there was really nothing known about this receptor.
22:44
Okay, we knew that this drug, Clozapine,
22:48
which was an anti psychotic drug, bound to it,
22:50
but it wasn't clear that that had anything to do with its actions.
22:54
And it wasn't until, actually, a few years later, that
22:58
Richard Glennon discovered that it's the receptor for LSD.
23:02
So it was, and the thing I was studying
23:03
was this sort of, this pharmacological curiosity.
23:10
So it was, it was a complete accident of fate.
23:15
Roth’s work has shed light on how some of
23:17
the drugs for disorders like schizophrenia work,
23:19
and how other medicines could be made with fewer side effects.
23:22
He essentially helped create a field of science that
23:25
many thought was impossible when he was starting his career.
23:28
I applied to medical school, and I applied to some
23:32
MD PhD programs because I wanted to be a scientist
23:35
But one of the places that interviewed me was Johns Hopkins,
23:38
and I went there, and I got to my last interview. He said,
23:44
If you could study anything in the world, what would you study?
23:50
And I said, I would study the chemistry of consciousness.
23:54
And he said, You cannot study the chemistry of consciousness.
24:00
He said it is impossible to study the chemistry of consciousness.
24:04
And in fact, that's what I do, and that's
24:09
what I've done for the last 30 years.
24:14
SciShow Field Trips are made with our
24:16
friends at HHMI Tangled Bank Studios.
24:19
We’ve come together to bring you face to face with
24:21
researchers at the cutting edge of scientific discovery.
24:24
You can watch more of Tangled Bank’s
24:26
science content at tangledbankstudios.org.
24:32
[♪OUTRO]
