Unexplainable - Are psychedelics breaking science?

Episode Date: October 23, 2024

Drugs like ecstasy and mushrooms have shown promise as mental health treatments, but they’re also exposing some major cracks in how scientists study the brain. Guests: Jonathan Lambert, science journalist; Boris Heifets, professor at Stanford University of Medicine; Amy Mcguire, professor at Baylor College of Medicine For show transcripts, go to vox.com/unxtranscripts For more, go to vox.com/unexplainable And please email us! [e-mail] We read every email. Support Unexplainable by becoming a Vox Member today: vox.com/members Learn more about your ad choices. Visit podcastchoices.com/adchoices

Frozen lasagna, medium power, 15 minutes. Sounds like Ojo time. Let's play. Feel the fun with Play Ojo. The online casino with all the latest slot and live casino games. What you win is yours to keep with no wagering requirements. Instant payouts and no minimum withdraws. Hey, I just won.

Woohoo. Feel the fun. Play Ojo. Honey, forget about the lasagna. Let's celebrate. 19 plus Ontario only. Please play responsibly. Concerned about your gambling or that of someone close to you. Call 1866-531-2600 or visit conexontario.ca.

Visit BetMGM casino and check out the newest exclusive. The Price is Right Fortune Pick. BetMDM and GameSense remind you to play responsibly. 19 plus to wager. Ontario only. Please play responsibly. If you have questions or concerns about your gambling or someone close to you, please contact connects Ontario at 1-866-531-2,600 to speak to an advisor,

free of charge. BetMGM operates pursuant to an operating agreement with Eye Gaming Ontario. Over the last few years, there's been this flood of positive news about psychedelics and mental health. Studies have shown psychedelics can treat PTSD. People had clinically significant decrease in their PTSD symptoms. They've had promising results for depression. Two-thirds of participants recorded a significant improvement within as little as three weeks. Even addiction.

More than 80% who were given the psychedelic treatment drastically reduced their drinking. Now, politicians have seen these studies, and they've started passing laws that have real-world impacts. In the last few years, Oregon, Colorado, even Australia, have legalized supervised psychedelic therapy. But there's been kind of this, like, major problem lurking under those positive results. That's science reporter Jonathan Lambert. And that's basically that it's virtually impossible to take a psychedelic and not know that you've taken a psychedelic. and that kind of breaks the sort of fundamental logic of how researchers study how medicines work. The gold standard for scientific research is something called a randomized controlled trial.

Scientists give one group of people the drug they're trying to study, and then they'll often give another group of placebo, something like a sugar pill that looks the same but is missing the active ingredient. It's a really important idea called blinding. And it keeps participants from knowing whether they've gotten the actual drug. The idea is to kind of isolate all the non-drug factors like someone's expectations about what the drug might do and just look at, if you take this drug, does it make you better? But psychedelics aren't like a lot of other mental health drugs. The effects are clear and immediate.

It's pretty obvious whether you've taken a psychedelic or a placebo. So people in randomized controlled trials might be kind of like, yeah, seems like I've got this psychedelic. I've heard all of this stuff in the news recently about how much promise psychedelics are showing. I'm going to get better. And the alternative might be that 10 minutes into the trial, someone gets an inert placebo, and it's like, well, shoot, I guess I'm out of luck here. This was a big reason why the FDA rejected a form of psychedelic therapy this summer. A lot of researchers were worried that all of these studies weren't really showing what they claimed to be showing. That all of this accumulating evidence showing psychedelic's real promise doesn't really rest on the biological function of the drug itself,

but people's expectations about it and kind of the overinflated height that these are really sort of magical. powerful substances for healing. And some scientists are wondering whether this is just a problem for psychedelics, or whether this might be the canary in the coal mine for something deeper. It's kind of exposing some of the flaws of this gold standard that we've used for decades. I'm Noah, I'm Hassanfeld, and this week on Unexplanable, how much do we really know about psychedelic therapy? And just how worried should we be about the science?

scientific gold standard. So Jonathan, before we get into what we should do about this problem of not being able to really test psychedelics the way we'd want, assuming they do work, what do we actually know about how they're doing what they seem to be doing? Yeah, so there have been a lot of studies that have tried to understand what these drugs are doing in the brain, and they seem to spark neuroplasticity in an area called the prefrontal cortex, which is involved in sort of higher level cognitive processes. And previous research has shown that these brain areas can kind of atrophy in cases of mental illness. And brain imaging research

has shown that psychedelic sort of spur new growth in these areas. So it's like putting fertilizer on a dormant field or something like that. Yeah. And so that's one idea of how these drugs work. but also they induce these sort of powerful psychedelic experiences. So they've been given in the context of a kind of supportive psychotherapy. And so the view from that kind of perspective of how they work is that the psychedelics are kind of a catalyst for helping talk therapy work a little bit better. They send you into these kind of mind-altering states where you're more open to, psychotherapy than you might be in other contexts, and that that combination of this mind-bending drug and a therapy that's sort of tailored to the experiences that you might have on that

mind-bending drug, that's where sort of the lasting benefit comes. So we got all of these studies that show psychedelics can help with everything from depression to PTSD to addiction. We got some theories about how they might work. But there's also this huge elephant in the room, which is that people getting these drugs pretty much always know they're getting them. Yeah. How big of a deal is this? Does this mean we have trouble kind of knowing whether any of the psychedelic research we've done is real? That's definitely the perspective of some researchers, but I think most people in the psychedelic research community think that it's a problem, but not sort of like a field-ending problem, and that there are

ways to design better trials that can probably not eliminate this unblinding issue, but make it a little better and make it easier to understand the extent to which people's expectations might be shaping their outcomes. What are some of the solutions? So a couple ideas are one, to just design better placebos. So Harriet DeWitt, who's a neuroscientist at the University of Chicago, uses kind of creative placebos in studying psychedelics. So for example, in studying MDMA's effects, she uses methamphetamine, like meth,

as an active control. This is a study that was done with healthy volunteers. They took capsules that contained placebo, a low dose of MDMA, a high dose of MDMA, or 20 milligrams of methamphetamine. Sorry, you're telling me they're testing MDMA, like ecstasy,

and they're using meth as a control? Yeah, yeah. That's very much like not a sugar pill. No, very much not a sugar pill. Okay. But it helps alleviate some of these concerns that it's going to be immediately recognizable which treatment arm you're in.

On all the same questions that MDMA made them feel connected, so did methamphetamine. Wow. Okay, is there any reason they're going for meth? I mean, like, that's... Yeah. You can't go for something, like, weed or something? thing, I don't know. Methamphetamine is chemically related to MDMA.

Okay. And so there's this idea that because of that sort of kinship, it's a good control. Yeah, and I guess at least you're feeling something. Yeah. So it could be a control for MDMA. Yeah. Okay. Another option is that scientists are trying to figure out if they can basically get the

neuroplastic benefit without kind of the baggage of the psychedelic experience. Wait. So like mushrooms without the trip or like diet, psilocybin or something? Yeah, yeah, sort of like diet psilocybin. And that would make psychedelics a lot more accessible because going through psychedelic therapy is a major commitment. Like you have to go to all these preparatory therapy sessions. The actual sessions where you're on the drug can last for hours and hours. And then sort of there's a long follow-up period. And so it's a major commitment that a lot of people struggling with mental illness might not be able to make. And so some people have sort of

looked at this situation and been like, well, if we can strip the psychedelic baggage from psychedelics, we can just give people a pill that will make them better. And so there have been a lot of efforts to try to engineer these tripless psychedelics. And some have shown promise in animal models for inducing the kinds of neuroplasticity without seeming to induce a psychedelic experience. It's hard to know, like, if an animal is tripping? Yeah. Is this mouse experiencing a psychedelic experience? Yeah. But a lot of people see them as a way to get the benefits of psychedelics without the risks. But at the same time, it's possible that the benefits come from the trip, right? Yeah. So while there's sort of a lot of hope that these tripless psychedelics might be beneficial from people,

there are some major skeptics in the field. Is there any way to get around the placebo issue without designing new drugs or, like, using meth? Yeah, so for a long time, researchers that's sort of hypothesized like, oh, the really great way to truly blind a psychedelic study would be to administer a psychedelic to somebody while they're on anesthesia because they sort of by definition can't experience the experience because they're under. And people hadn't really done this until a neuroscientist at Stanford named Boris Haifitz tried this experiment with people who had treatment-resistant depression. So that's what we did. We ran a truly blinded study where patients were coming for surgery. They're getting general anesthesia. And during that anesthetic, we gave an antidepressant dose of ketamine.

And another group got a placebo while they were under anesthesia. With the benefit that patients don't know what group they're in because they're unconscious for surgery. And then measured how much they improved from depression. And we found that ketamine had a bar. As a fact, just like it does every trial in the last 15 years. But so did the people who got a placebo while they were under anesthesia. Both groups were sort of indistinguishable. So they got basically about the same amount better.

What would account for that? Yeah, so it suggests that there's something about the experience of going through a clinical trial that helps people feel better. Leveraging the non-drug factors, we can generate. very similar effect sizes to what's seen in many of these psychedelic trials. Yeah, like the trial itself is doing something. Yeah, there's something about the trial itself that conferred these benefits. Interesting.

Which I think adds a little bit of weight to these concerns about the kind of non-drug factors being really important in driving the benefits of psychedelic assist therapy. Yeah, so then maybe we shouldn't be treating the placebo. is just a control? Like, we're talking about all these ways to avoid this problem of unblinding because people know when they're getting a placebo.

But what if a placebo is just really useful? Yeah, I think you hear the word placebo and it has kind of like a negative connotation. Like it's nothing. Yeah, it's supposed to not do anything. And I think what the ketamine under anesthesia experiment shows is that there might be more to the,

placebo effect than we think. These extra non-drug factors, the sort of almost ritual of going through a clinical trial where people are reaching out to you to ask you about how you're feeling. You're sort of going in to get studied in a way. Like the process of going through those motions, that matters. And there's been some emerging research that it's like something is happening in your brain, during the placebo response that's akin to the kind of response that you get when you're in the active group. And so it just will take a lot more research to try to kind of disentangle

what about those non-drug factors are responsible for the beneficial response. Yeah, and the placebo isn't the only non-drug factor we're dealing with here, right? Like, these drugs are mostly given with therapy. Yeah. Do we know how much the therapy is doing? We know surprisingly little about sort of the role of psychedelic-assisted therapy. I don't think we really even understand as a field how much the therapy component contribute to the efficacy of the drug.

Coming up in a minute, this whole placebo issue is just half of the problem. There's this whole other part of psychedelic therapy, the therapy part, that might be even more of a black box. and it's driving a wedge in the middle of mental health research. It's all about you. And when you fly with Virgin Atlantic in their upper class cabin, they take the VIP treatment to the next level. With a private wing to check in and your own security channel at London Heathrow,

you can glide from your car to their clubhouse, a destination in its own right in 10 minutes or less. On board, you can treat yourself to your own private suite to stretch out in with lots of storage space, a lie flat bed, and delicious dining from beginning to end. Just be sure to leave room for dessert. Their mile high tea with all the little cakes and sandwiches is a showstopper. Go to Virgin Atlantic.com to learn more.

Square knows that in hospitality, efficiency is everything. That's why their system lets you take payments. Track sales, handle inventory, manage staff, send invoices, and keep up with finances all in one place. Fly through orders with zero mistakes. Get the data you need and keep everything working together. So you're ready for whatever's next. Learn more about their customized little plans

at squareup.com. Amazon presents Jeff versus Taco Truck Salsa, whether it's Verde, Roja, or the orange one. For Jeff, trying any salsa is like playing Russian roulette with a flamethrower. Luckily, Jeff saved with Amazon and stocked up on antacids, ginger tea, and milk. Habaniero, more.

Like Habinier, yes. Save the everyday with Amazon. All right. So, Jonathan, we've been talking about this major issue of studying psychedelic medicine, which is that it's pretty hard to figure out a way to have a working placebo, which means we don't really know if the psychedelics are leading to these dramatic mental health improvements or if it's just patient's expectations. But then there's this whole other talk therapy piece that we haven't really talked about a lot.

which is usually part of the equation here. And you're saying that hasn't really been studied either? Yeah, so I talked to Amy McGuire, who's a bioethicist at Baylor College of Medicine about this. And her perspective is that we really have not studied sort of like what role is the psychotherapy playing. I think there certainly needs to be a lot more research into the therapeutic component. A lot of the focus of research over the past several decades is trying to understand the effect. of these drugs so that they can kind of be put through the regulatory pipeline of the FDA. But the FDA doesn't regulate psychotherapy.

If you have a licensed healthcare provider providing a therapy to somebody, the FDA doesn't really have the jurisdiction to regulate what that looks like. So researchers have been really focused on understanding the drug part, and kind of as a consequence of that, they're trying to hold the therapy part constant across all these trials. And so it's unclear sort of what elements of the therapy are most important. This is a larger issue outside of just psychedelics. There's been a lack of research in psychotherapy in general in terms of doing randomized trials to understand what types of therapy are most effective. Also, just from my perspective as someone who has been in therapy, that seems like something that is very

difficult to hold constant. I've had different therapists that are very different and have very different strategies and tones and scheduling. And it feels like if we're trying to hold this constant and test the other thing, which is the drug, it feels like that would create a lot of issues. Yeah. It's definitely a lot harder to study something like psychotherapy. Obviously, that's not going to be blinded. I mean, you'll know if you're giving therapy or not. Therapy is so idiosyncratic and so hard to kind of isolate individual components. So you need a really big sample size to kind of tease out which parts of the therapy are working. And those trials are just very expensive to do.

And there's not a lot of financial incentive to do them. Right. You can patent therapy. Yeah, you can patent a drug, but you can't patent a talk therapy. Yeah. And given that therapy is usually part of these trials, Is it possible therapy is doing the lion's share of the work here? I think it definitely could be possible, and it would take studies that are explicitly comparing, giving somebody psychedelics with therapy versus without therapy to really kind of tease that apart. But those studies haven't really been done in a rigorous way.

There are some companies that are trying to minimize therapy as much as they can. I guess it's still kind of too early to know for sure how well those treatments are working, But it should become more clear kind of in the coming years. But if those non-drug factors are so important, and those are the things that we're kind of struggling to test within this randomized controlled trial framework, is it possible that the randomized controlled trials themselves are the problem? I think some people definitely have that perspective

that is just not the right way to study these drugs and how they work in the real world. I personally think that there is a role for them because they're still kind of the best tool that we have of really homing in on one variable and understanding what impact that has. But I think that the field is sort of at a crossroads right now. How so?

I mean, I think one potential path would be to broaden the kinds of evidence that regulators consider in approving new drugs. But I also think the field might go on this other path, which is to try to strip away the therapy side of things, the experiential side of taking a psychedelic to meet that regulatory bar a little more easily. And I think I and a lot of the scientists who I've spoken with

are worried that the financial incentives are just going to push companies towards that end, and we might kind of miss this chance to maybe expand how we do things. Medicine is both a science and an art, and I think if we over... regulate the practice of medicine, we lose the humanistic side of it, particularly with regard to something as interpersonal as psychotherapy. And I think the more we chip away of that, the more we lose something in our healing practices. Yeah, just stick with me here for a second. Maybe this is a weird thing to say, but it almost feels like the dark matter of psychological

research. Totally, totally. There's just all this stuff that we can't see and touch and we know is shaping everything we can do. And that might be the placebo or the context or the therapy. And it kind of feels like randomized controlled trials are designed to avoid all of that invisible stuff. I think that's right. And some people in the psychedelic space kind of think that psychedelics are,

they're not just failing to meet this gold standard. They're kind of exposing some of the cracks in the gold standard. I guess I feel like all of these issues really sort of show just how, kind of how complicated we are as human beings. And a lot of what we think we know about how our bodies and minds work might be wrong. Or maybe not wrong, but it's certainly not the full story. And to kind of understand that sort of dark matter, as you put it, of the placebo response, we might have to kind of bring in new tools. And if we do that well, there is a lot of potential promise in really shaking up how we approach

treating mental illness in a way that might be more transformative. There are a few other ways of getting around the placebo problem that we didn't end up covering in this episode. And one of the solutions I really find interesting is called an open-label trial. It's where participants are told they're going to get a placebo. And somehow it seems to work. We're going to have an episode all about this out in a couple weeks. So just keep an ear out for that one.

This episode was produced by me, Noam Hassenfeld. We had editing from Matt Collette and Meredith Hodnott, who runs our team, mixing and sound design from Christian Ayala, music from me, and fact-checking from a nuke do-so. Manding Wynne is wondering whether she should give a mouse a cookie. and Bird Pinkerton finally got to the pufferfish queen. She tried to explain why she was there, but she realized she couldn't speak with all her scuba equipment on.

So she started waggling her arms around like an octopus. The queen immediately understood. If you have thoughts about the show, send us an email. We're at Unexplanable at Vox.com, and you can also leave us a review or a rating wherever you listen. It really helps us find new listeners. You can also support this show and all of Vox's. is journalism by joining our membership program today. You can go to vox.com slash members to sign up.

And if you signed up because of us, send us a note. We'd love to hear from you. Thanks as always to Brian Resnick for co-creating the show. Unexplainable is part of the Vox Media Podcast Network, and we'll be back next week.