Psychedelics are good for more than having a deep conversation with a houseplant.

These drugs have huge potential for treating a variety of mental illnesses, too! Studies show that people with depression, PTSD, and substance abuse disorders sometimes experience fewer symptoms after a dose of LSD, for example.

There’s just one problem:  We don’t really know why. And since the side effects of  these drugs are not exactly subtle, it would be great if we could find  a way to develop new medications with all the antidepressant  power, and less of the acid trip. Luckily, a researcher named  Bryan Roth at the University of North Carolina has been studying  this stuff his entire career.

His research mapping the  fundamental chemistry of the brain and the ways that these  drugs work has provided some clues as to how psychedelics can improve symptoms. Roth and his team have even  synthesized new molecules that could have the same effect  without the hallucinations. Which sounds like research  we'd like to see in person!

We sent our friend Madelyn Leembruggen to Roth’s lab to learn more  about this far-out solution to some of psychiatry’s most stubborn problems. This is SciShow Field Trips! [♪INTRO] Thanks, Hank! I’m here in Bryan Roth’s lab in the Pharmacology department at UNC, Chapel Hill.

Pharmacology is all about drugs. But for Roth, it isn’t just  the drugs that are fascinating. It’s what they interact with: Chemical receptors.

I went to college in Montana, I  went to this really small college, Carroll College, and, by then, I was convinced, I needed to study the brain.  I need to study these drugs and how they work, basically. But I, you know, I had no concept on how to do that, coming from a small town in Montana. One  year this scientist came.

Ostensibly, he was there to  give us a lecture, but I think he was really there to go trout  fishing, basically, that was, that was the reason he was  there. But he gave his lecture, and his lecture was on how the  brain works, and he mentioned that, you know, neurotransmitters work  through receptors, and he said, This is where drugs act. Are these  receptors?

So I said, right there. Okay, so I need to study receptors. So that's it.

Basically, I saw the word receptor. I said, That's what I want to study. That's  where drugs act.

And that was it. And I have to say, I can see  why he was so excited about it. Because the way this works is really cool.

This is where we sectioned a  brain with an optical microscope. And this is the distribution of the  receptor here in various brain regions. Sort of cool.

And that's sort of a close up. So these are these neurons here in the cortex. These are called Layer 5A Neurons.

This is a picture of neurons, yeah, neurons that are expressing the receptor. All the chemical receptors in our  bodies have a unique shape, and when a certain molecule comes along  that fits into those receptors, they can activate. Scientists call  these activating chemicals agonists.

Neurotransmitters are a type of agonist, since they’re the signaling  molecules that neurons use to send messages throughout the nervous system. Now, even though textbook diagrams  of receptors are just still images, when you zoom down to the cellular level, every molecule in our bodies  is constantly in motion. So the way people usually describe receptors and drugs is that the drug is the  key and the receptor is a lock.

Okay, that's actually not  the way things work at all. Okay, not even close. So technically speaking, that's called the induced fit model  that's called the induced fit, that the key induces something.

Our understanding now is what's  called conformational selection. So the idea is that the receptors are vibrating, they're continually vibrating,  and they will vibrate in a conformation that the drug is  specific for and that binding event causes a small change in the overall  equilibrium of the population. So it's like, it's like the  locks are transiently opening, and the key is just popping in.

Basically, the agonists that can  only fit a little bit of themselves into the receptor aren’t going  to send a very strong signal, and the ones that bind to more surface area will. It’s more complicated than that, trust me. Which is why people like Roth have made a career out of studying these little things.

As a graduate student, Roth  focused on opioid receptors. But when he got a job at the National  Institutes of Health, he switched gears and started studying  something called 5-HT2 receptors. 5-HT is an abbreviation for the  molecule 5-hydroxytryptamine, which is the neurotransmitter  that binds to these receptors. But you’re probably more familiar  with its common name: serotonin.

We have different kinds of 5-HT2  receptors all over our bodies, because serotonin does a lot more  than just regulate your mood. Serotonin plays a role in  everything from digestion to your immune system, and  eve n your blood clotting. And while serotonin and  5-HT2 receptors are buddies, it isn’t the only molecule that can bind to them.

Another molecule that likes  to get groovy with 5-HT2 receptors is the drug lysergic  acid diethylamide, or LSD. LSD is a psychedelic drug, and there are a number of psychedelic drugs: mescaline, which is a psychedelic drug from the peyote cactus, psilocybin for magic mushrooms. So all of these psychedelic drugs  have the same property that they activate this receptor, the 5-HT2A  receptor, and activation of this receptor is responsible for their  psychedelic effects in humans.

LSD is a semi-synthetic compound that yeah, you’ve probably heard of before. It partially comes from a compound  found in fungus that we’ve refined into something with more of a  kick. Well, not me.

Other people. When LSD binds to 5-HT2 receptors, it activates the same  pathways that serotonin does, and it also affects our emotional  and information processing, to the point where people experience hallucinations and disconnect from reality. So these layer five neurons.

These are very important  for integrating information from basically all areas of the brain, all sensory areas and  perceptual and cognitive areas. And what psychedelics do when they activate, when they hit the receptor on those neurons, is they basically cause the neurons to fire, sort of in this disorganized fashion, and then, for reasons that are not entirely clear yet, the mind starts paying  attention to sort of randomly generated information, sensory information, that it then makes a story about, okay, and that's the psychedelic experience. Basically the part of the brain that  tells us what reality looks like.

It's basically like you  injected noise into that system. And so the awareness our mind doesn't  trust that information anymore. Since its most popular use has been recreational, LSD is classified as a  Schedule 1 controlled substance by the United States government.  That’s the group of drugs that are said to have a high risk of dependency and no established medical benefit.

But how do you find out if  there’s a medical benefit if it’s very difficult to test the  stuff? That’s been the issue. Right now it's like a really hot field, though.

I don't know how long that's going  to last, but right now it is. It'd be great if there was money.  So it's not like there's been any more money that's been  appropriated to study psychedelics. So there are all these people  who want to study psychedelics, but there's no money to study psychedelics.

The limiting factor Money is always a problem. Yes. Since LSD binds to the same  receptors that serotonin does, there’s reason to think it could have some similarities with antidepressant medications.

The most common type of  antidepressants are called SSRIs, or selective serotonin reuptake inhibitors. And what they do is right there in the name! After a neuron makes and releases  molecules into a synapse, those molecules pretty quickly get broken down or sucked back inside the  cell—that’s called reuptake.

SSRIs work by preventing  serotonin reuptake, usually by stopping the proteins that  physically transport serotonin. Long term, probably what they  do is they cause compensatory interactions in the circuitry, and  that causes the antidepressant effect. So it's a very indirect effect.

Usually takes, you know, six to  eight weeks for the maximum response. And you know, doesn't work for everybody. So current antidepressants  sort of indirectly juice up the signaling that’s already happening in our brains, rather than directly binding to  and activating 5-HT receptors.

But SSRIs don’t work well for  everyone, especially people with really severe cases of depression. And  we don’t entirely understand why. Like Hank said, there’s some  clinical evidence that taking LSD can also improve mood for people with  certain mental health conditions.

And with LSD, patients sometimes reported feeling better for months after a single dose. Let's say you're depressed  and I started you on Prozac, I would say, you know, probably four  to six weeks before you're going to have much of an effect with  psychedelics, one dose, basically. So in the clinical trial data,  which is quite compelling.

And many, many people, at least according to the early, early trials were  no longer depressed after a single dose of psilocybin, and  12 months later, they were fine. But we’re still a long way off from having any LSD-based options at the pharmacy. I mean, there’s that whole makes you hallucinate and distorts your reality thing.

Not everyone’s down for that  as a medication side effect. And I presented that idea  at the neuroscience meeting, I think in 2017 or something  like that, I gave one of these presidential lectures, there are literally, like, there were like 10,000 people in the audience. It was this humongous auditorium, and I, you know, presented that data.

And on  the slide, one of the slides, I had a bullet point, and  it said, it simply said that it may be possible to separate the therapeutic effect from the psychedelic effect.  And then about a year later, I got a phone call from DARPA.  So there was somebody from DARPA that was at my talk so the  people that invented the internet, GPS, stealth, bombing, you know,  all these, all these great things. It turns out that in the military, the  number one casualty is psychiatric. So by far and away, they have  more soldiers who are disabled because of depression, anxiety, post  traumatic stress disorder and so on, way more than physical casualties.

And you know, they had, they had  seen the promise of psychedelics, but there's no way you're going  to give psychedelics to somebody with a gun. I mean, it's, such a bad idea. So they contacted me, and they  said, you know, is it possible?

Basically? And I said, I sort of hedged my bets. And I said, Well, it's a hypothesis we could test.

So Roth is trying to figure  out how LSD might produce those effects and how to create similar compounds. And he’s starting with the fundamentals. He wants to know what molecules like LSD look like when they’re bound to a 5-HT2 receptor.

As in, what shape do they take, and how strong is the signal that gets produced from their bond. Like any lab working with a controlled substance, there are precautions in place to make sure the research is safe and focused. This, yes, this is the safe  that is the infamous LSD safe.

Not quite what you were expecting, is it? So we have LSD and many, many other schedule one psychedelic drugs, and the  safe is kept in a locked room. That's one of the things.

The other  thing is that there's only one person in the lab that has the combination  to the safe, and that is not me. Because, you know, we don't  want anyone accidentally adjusting these compounds we  have, we have psychedelics that are more potent than  anything that is out there. So, but the amounts that we  have, if we were to open that up, it's just dust, basically  just little, tiny amounts.

They only need an amount of  LSD smaller than a microdose, called a nanodose, since all they need to see is one molecule binding to one receptor. So when we initially saw the  structure of LSD with the serotonin receptor, one of the things that  we noticed was that there was a conformational change when LSD  bound to the receptor, so that a lid came over the top of the receptor  and occluded it, so it stopped LSD from exiting the receptor, so  LSD was sort of trapped in there. And concomitant with this, there  was a different type of signaling event that occurred, which is  called arrestin signaling, okay.

And the normal mode of signaling through the receptor is what's called G protein signaling. Basically, both G proteins and  arrestins are molecules inside your cells that help pass along messages after a neurotransmitter binds to a receptor. But depending on which messenger takes over, it can have very different effects.

When Roth's team realized  that LSD seemed to push the signaling toward the arrestin  pathway, they saw an opportunity. So we had the idea, well, maybe  if we make a drug that's targeting the other pathway, the G protein  pathway, maybe we can diminish the psychedelic effect and  enhance the antidepressant effect. All of this progress would  have been just a pipe dream for researchers like Roth,  even just a decade or two ago.

So, you know, for like, 20  years or so, my goal was to solve this structure of the receptor,  and we couldn't do it basically, because there wasn't appropriate technology. And it wasn't until, you  know, probably 10 years ago, that you could crystallize membrane proteins and study them by X ray  crystallography. In my lab, we actually got the first structure of LSD  with the serotonin receptor by crystallography, but it  was extraordinarily difficult.

Today, structural modeling is much easier. Roth’s lab now uses a tool called cryogenic electron microscopy or cryo-EM for short. So I am a structural biologist, so  what I do is I purify receptors, either from over expression  systems or from tissue, and subject those purified receptors to structural approaches like cryo electron microscopy.

That’s Nicholas Wright. He’s  a postdoc working to analyze the molecular structure of  these candidate compounds. So the kind of idea behind cryo EM  is that the purified material is put on these grids, and you form really  thin vitreous ice, so glass-like ice, by plunge freezing the sample and  liquid ethane, and the cooling happens so fast, the ice doesn't  have time to form regular crystals.

And what that does is it allows you  to get images of single molecules of your receptors, and then, with  computational approaches, you can average all those together to get  a crisp, clean, three dimensional picture of your your protein at the  kind of really high resolution so you can actually see the drug and how  it interacts with the receptor. So because it's frozen so  quickly, then you can use image processing to take out all of the ice molecules, all the water molecules, and  just focus on the candidate Exactly, yeah, okay. And because it's  vitreous or glass, like ice, that gives very low background in the  images, and you kind of capture, like a snapshot of those molecules in action, and you can compute a three dimensional, high resolution picture of them.

They’re currently trying to  discover new molecules that could also bind to the 5-HT2 receptor,  and exploring what effects those molecules might have once they get there. This kind of molecular matching game also used to be a really slow and difficult process. Okay, so this is our robot that is preparing compounds that we're testing.

And down there you can see it's taking little aliquots from the drug plate. All those plates down there are the drug plates, and then it's going to add them to assay plates. And basically it just does  that, and it's, you know, this is repetitive work, right?  So it's perfect for a robot to do.

But thanks to the latest generation  of software, researchers can now estimate what drug binding might  look like for billions of slightly different molecules that no  chemist has even synthesized yet. One promising category of molecules is the tetrahydropyridines, or THPs. We had hooked up with this  amazing chemist at Yale, Jonathan Ellman, who had  invented this new chemistry to make this class of compounds  called tetrahydropyridines.

And he had, he had figured out a way to make, in theory, billions of tetrahydropyridines. So here, this was the idea  we thought, so don't make a you know, we can't test a billion  compounds physically, right? But he could enumerate them computationally.

So, using his reactions, we  were able to enumerate I think, 100 million tetrahydropyridines  that in theory he could make, but no one has ever made before. They calculated the odds of  them binding with what’ s called docking scores. The better the  score, the more likely it is that researchers will try to actually  synthesize it in the lab to test it out.

So the way we do drug discovery  is, first we have a structure. Structures are generally solved  in my lab, and then we collaborate with this amazing computational  person, Brian Choi at UCSF, and his docking program  basically takes the structure of each little molecule and then  brings it into the receptor, and then sort of tries to find a way  in the receptor that it will fit, and then it scores that so  there will be, you know, If it forms a hydrogen bond, it  gets a score, ionic bond, et cetera. And currently, I think we're running a docking campaign with 4 trillion molecules.

And then, you know that the compounds literally have never been made before. They don't exist in the physical universe. So then we have a chemical company just make them when we test them.

And then, then they go here. This is  the testing being done, right here. When they find that a compound binds to a receptor in the test tubes, they  then move on to testing it in mice.

And in this case, they found  something really exciting. Two of these molecules worked  like strong antidepressants, similar to what some people  report after taking LSD. But these new molecules didn’t have the psychedelic side-effects that LSD does.

At least, as best they could tell. Measuring the psychological state  of animals is notoriously difficult, and has to be surmised from  things like head twitching, which mice do when hallucinating. Even so, this could be the first step towards a whole new class of antidepressant medication.

And other potentially powerful  molecules are even further along in the process, but not  for illnesses like depression. When studying another kind of 5-HT2 receptor that is involved in appetite suppression, Roth and his collaborators identified  a molecule they called BMB-101. BMB 101, so this is a compound  that was discovered in a collaboration with Alan  Kosikowski, who was formerly at University of Illinois Chicago,  and Bill Wetsel, who's at Duke.

In 2015, we were developing these  as potential anti-psychotic drugs, and they weren't very  effective anti-psychotic drugs. But Alan by accident, found in a zebrafish screen. So they had a zebrafish  screen which looked for drugs that are effective in  treating seizures or epilepsy.

And it turned out that BMB  101, also known as lumocaserin, was very effective in that screen. And it just finished phase two  clinical trials for seizures, I think, caused a more than 70% decrease in the seizure incident and also improved REM sleep, which is like unheard of  among anti seizure agents. Most people with seizure disorders  actually have impaired sleep.

So this, you know, could be a game changer. Roth thinks researching other  compounds that bind to different 5-HT2 receptors could produce  new medicines for a huge number of disorders, especially those  that are treatment resistant. And for Roth, that really hits  home.

Because one of the people who could’ve been helped by  treatments like these was his mother. Yeah, so my interest in pharmacology actually started at a very young age. My mom was diagnosed with  schizophrenia when I was five or six, and you know, of course,  that had a huge impact on me.

And she was sort of in and  out of, it was in Montana, and it was basically the state mental institution. It was a really pretty, pretty awful place. So she was sort of in and out  of that when I was growing up.

And then I think when I was 13  or so, my sister ended up in the front page of the  newspaper for having taken LSD. I looked up LSD, and it said,  LSD causes a model psychosis. So I thought, Oh, okay.

So this, you  know, this is what I need to study. I basically knew what I wanted to do, but I had absolutely no concept of  how to get there, you know. And it was just this chance, really a chance interaction with a trout fisher.

That’s what led to him to pursue  biology and chemistry in college, which brought him to that fateful  lecture with the image of a receptor, and all the decades of studying them since. We were ultimately able to  get my mom on one of the newer atypical antipsychotic drugs,  this drug called quetiapine transformed her life, and its  action is to block that receptor. And you know, that was still  at the time, we still didn't there was really nothing  known about this receptor.

Okay, we knew that this drug, Clozapine, which was an anti psychotic drug, bound to it, but it wasn't clear that that had  anything to do with its actions. And it wasn't until, actually,  a few years later, that Richard Glennon discovered  that it's the receptor for LSD. So it was, and the thing I was studying was this sort of, this pharmacological curiosity.

So it was, it was a complete accident of fate. Roth’s work has shed light on how some of the drugs for disorders like schizophrenia work, and how other medicines could  be made with fewer side effects. He essentially helped create  a field of science that many thought was impossible  when he was starting his career.

I applied to medical school, and I applied to some MD PhD programs because I wanted to be a scientist But one of the places that  interviewed me was Johns Hopkins, and I went there, and I got  to my last interview. He said, If you could study anything in  the world, what would you study? And I said, I would study the  chemistry of consciousness.

And he said, You cannot study  the chemistry of consciousness. He said it is impossible to study  the chemistry of consciousness. And in fact, that's what I do, and that's what I've done for the last 30 years.

SciShow Field Trips are made with our friends at HHMI Tangled Bank Studios. We’ve come together to bring you face to face with researchers at the cutting  edge of scientific discovery. You can watch more of Tangled Bank’s science content at tangledbankstudios.org. [♪OUTRO]