Why The Trip Complicates Psychedelic Research
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Hey, short wavers. Chances are you've heard about psychedelics once or twice. And shortwave producer Rachel Carlson has been diving into the science behind them. She's joining me this week to talk all about them. Hey, Rachel. Hey, Gina. So psychedelics are being studied to treat lots of different kinds of conditions. Chronic Lyme disease.

Alzheimer's disease, anorexia nervosa, chronic back pain, obsessive-compulsive disorder, post-traumatic stress disorder. That's Albert Garcia-Romeo. He's a psychologist and psychopharmacologist at Johns Hopkins University.

Oh. Hmm.

She's an agriculture professor. She got a tick bite. She got Lyme disease. But it took doctors four years to get to that diagnosis. Wow, that's a long time. Yeah, and even after she took a course of antibiotics for treatment, she told me she still didn't feel like herself at all. I remember distinctly when I was teaching a class, I literally got up in front of the students and my mind just like almost blanked, stopped. I thought I was

having early symptoms of like Alzheimer's or dementia and was like, something's really wrong with me. So she tried psilocybin in this study. Does she feel better? She does. She told me she felt like she was expressing herself differently. She changed the way she taught her classes, even ones she'd been teaching for years. Usually as professors after, you know, 15, 20 years teaching, you roll out the same PowerPoint as the last time.

But I couldn't do that. I literally stopped myself and I said, I'm seeing things differently. But here's the thing, Gina. Researchers like Albert, they don't know exactly why Lori sees things differently. Is it because the drug altered her brain chemistry? Or was it the journey she took while she was on psilocybin? I called myself like the new Lori. Like there's the Lori before psilocybin and Lori after. But it's like I went through this journey of

Hearing those that I loved that had passed, you know, saying to me, it's okay, you'll be fine. Okay, so Lori has this really powerful emotional experience and maybe that's what helped? Yeah, you know, people often take psychedelics looking for some kind of experience that could transform their lives or change their outlook on everything.

So if you're a scientist, how do you tell if the effect of a psychedelic is because of a change in brain chemistry or because of this spiritual journey? I spoke to Boris Heifetz. He's an anesthesiologist and neuroscientist who works at Stanford. And he said it kind of boils down to one question. How do you control for a transformative experience? And once I heard him say it that way, I couldn't.

So I went on my own journey, not like my stuffed animals are talking to me and I can't look directly into a mirror kind of journey. Not like that. But a reporting journey with lots of scientists who had lots of opinions. ♪

So today on the show, psychedelics. How do we entangle the ways they change our experience of the world with how they might change our brains? Is it possible for researchers to separate those things when weighing their potential benefits? And does the difference matter? We're breaking down the history of psychedelics and some of the roadblocks researchers are facing when it comes to how to study them now. I'm Rachel Carlson. And I'm Regina Barber. You're listening to Shortwave, the science podcast from NPR.

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Okay, Rachel, I have a question. Haven't people been talking about and like studying psychedelics for a long time? Like, why is all this research happening now? All right, quick history lesson. Yes, I love history. Let's do it.

So psychedelic substances have been around for millennia in indigenous medicine. Okay. And in the late 1930s, this guy named Albert Hoffman first synthesized LSD. Then the actual term psychedelics was coined in the 1950s. Okay. Now those drugs like LSD, psilocybin, and mescaline are called classic psychedelics.

In the brain, they all activate something called the serotonin to a receptor. Serotonin is a chemical in our brains. It regulates things like sleep, mood, appetite. And at this specific receptor, classic psychedelics have these very powerful psychoactive effects.

which include feelings of sometimes ego dissolution or what you might think of as feelings of unity where the boundaries of self and other can sort of dissolve. Yeah, I mean this is the sort of thing that I like think of when somebody like mentions psychedelics like this like trippy magic mushroom like experience. Yeah, exactly. So in the 50s and 60s, psychedelics both in recreational use and in research are huge.

But then, in the early 70s, the U.S. does this big crackdown on controlled substances. And that, coupled with tighter regulation on pharmaceutical testing, really shuts down most psychedelics research on humans.

And the next big phase in neuropsychiatry in the 80s is super different. Yeah. Boris told me the goal became to have sort of a one-size-fits-all mental health approach. You know, it's like the industrial revolution in medicine, that you can really reduce things down to a drug, you would take it every day, you know, something that you can define. So Gina, this is when SSRIs come on the scene.

selective serotonin reuptake inhibitors. They also target serotonin receptors. Antidepressants like SSRIs work for about two-thirds of people who take them, but there were still some major problems.

They don't work for the other third, even after trying multiple different drugs. Right, which leaves a lot of people like just in the lurch. Yeah, and I mean, there's other factors too. You have to take them every single day. You have to be on them for at least a few weeks until you can even really feel a change. Yeah. And so there's this urgent need for alternative treatments for mental health conditions, which is why around 2000 or so, researchers start studying another drug called ketamine.

You might know it as a recreational drug, but it's also been used since the 1960s as an anesthetic in clinical settings. So it's not a psychedelic? It's not a psychedelic, at least according to most people I talk to. Okay. But it can have these similar-ish effects depending on the dose. Like it can make people feel numb or give them this sometimes euphoric or dissociated feeling.

And as researchers started to study it more, they realized that... Ketamine produced very rapid antidepressant effects. Effects that appeared within 24 hours as opposed to the couple of weeks that you would need for an SSRI. And this was really paradigm shifting for the field. That's David Olson, a chemical neuroscientist at UC Davis. He studies compounds like psychedelics...

And so, Gina, to summarize all this history, David told me that once people started studying ketamine, they wondered what other kinds of compounds might have similar rapid effects. And remember all that research on psychedelics that got paused? Yeah, yeah. Okay, so that comes up again. Oh, okay. So with that in mind, let's kind of like drill down into like these two questions. Okay.

One, how do we effectively study such a trippy drug? And then two, once you know how to study it, how do you tell what part of the drug is actually helpful? Right. So for the first question, this is really a challenge for all experiments. You want to make sure that you're testing one thing and then comparing it to a control or a placebo to see if it's really the thing you're testing that causes an effect versus like some other factor. Right. And that's even harder when it comes to these drugs in particular. Right.

You typically are going to know within 30 or 45 minutes, I didn't get a placebo. I got something that's pretty much stronger than that or that's influencing my perception of reality in a way that's

Albert told me about a few ways researchers can address this problem. So one is to give people another drug called an active comparator. Usually it's one that can kind of mimic certain effects of something like a psychedelic without having to give people one. Oh, okay. Or another strategy is just to give everyone the drug, sometimes at different doses to see what's most effective. And then you can sort of parse out a threshold for what might work and what might not. Okay. So remember Lori? Yeah.

Every person in the study she was in got psilocybin, so they knew that they were going to get it. Lori told me she met with therapists before and after her treatments, and they were in the room with her over the course of her experience with psilocybin. And that therapy component is pretty common, right? Since like people can have like intense experiences with these drugs, like a bad trip. Yeah, exactly. Most studies have some kind of therapeutic support involved.

And for Lori, on that day that she got her first round of psilocybin, she walked into the room. It was very tranquil. It was like a white couch and they had blankets and towels and tissues and pillowcase that was super soft and comfy.

And the light was dim. She said she felt like she was preparing herself for this big, important moment. I would say in my mind how I perceived it, like sacred, like I'm just not taking a white pill and that's it. And this isn't necessarily unique to psychedelics, right? Because I feel like just the experience of feeling like you're about to make this change in your life could also play a role.

Exactly. And this doesn't take away from the study or what Lori experienced and the fact that she told me she felt so much better after. But it does mean when patients and studies do feel better, it's harder to say what helped them feel better.

And then that can make it hard to know how to give other people that same experience. Here's Boris again. It's very difficult to study experience because really a lot of things are happening. You're getting a drug, you're learning something, there's a learning process, there's hope, expectation, and then there's this like wild phantasmagoric, you know, thing that happens for eight hours in the middle of it.

Okay, so there's this like big debate, right? Like, is it the trip or is it the drug? And does it even matter if we try to separate these things? Yeah. So when I asked David this question, like, why does it matter? He reminded me that not everyone wants to trip or should trip depending on their medical history. For example, most professionals say that if a person has a family history of schizophrenia or bipolar disorder, they probably shouldn't use psychedelics or ketamine.

So if researchers can figure out what matters, like if you don't actually need to trip to get these potentially positive effects, scientists could get more effective treatments for more people. So how are they going to try to settle that debate? Some researchers, like Boris and David, are asking, what happens if you remove the trip altogether? Whoa. They're doing this in really different ways, but they both hope it's going to bring us closer to answering the question. That'll be next time on the show.

I'm Regina Barber. And I'm Rachel Carlson. And if you liked this episode, make sure you never miss a new one, especially episodes two and three of this psychedelic series by following us on whatever podcasting platform you're listening from. This episode was produced by Hannah Chin and edited by Rebecca Ramirez and Jeff Brumfield.

Tyler Jones checked the facts. Kweisi Lee was the audio engineer. Beth Donovan is our senior director. And Colin Campbell is our senior vice president of podcasting strategy. Thank you for listening to Shortwave, the science podcast from NPR.

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