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
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.