Are psychedelics breaking science?

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Speaker 14 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.

Speaker 13 88% of the people had clinically significant decrease in their PTSD symptoms.

Speaker 14 They've had promising results for depression.

Speaker 13 Two-thirds of participants recorded a significant improvement within as little as three weeks.

Speaker 14 Even addiction. More than 80% who were given the psychedelic treatment drastically reduced their drinking.

Speaker 14 Now, politicians have have seen these studies and they've started passing laws that have real-world impacts.

Speaker 14 In the last few years, Oregon, Colorado, even Australia have legalized supervised psychedelic therapy.

Speaker 15 But there's been kind of this like major problem lurking under those positive results.

Speaker 14 That's science reporter Jonathan Lambert.

Speaker 15 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

Speaker 15 researchers study how medicines work.

Speaker 14 The gold standard for scientific research is something called a randomized controlled trial.

Speaker 14 Scientists give one group of people the drug they're trying to study, and then they'll often give another group a placebo, something like a sugar pill that looks the same, but is missing the active ingredient.

Speaker 15 It's a really important idea called blinding.

Speaker 14 And it keeps participants from knowing whether they've gotten the actual drug.

Speaker 15 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?

Speaker 14 But psychedelics aren't like a lot of other mental health drugs.

Speaker 15 The effects are clear and immediate.

Speaker 14 It's pretty obvious whether you've taken a psychedelic or a placebo.

Speaker 15 So people in randomized controlled trials might be kind kind of like, ah, yeah, it seems like I've got this psychedelic.

Speaker 15 I've heard all of this stuff in the news recently about how much promise psychedelics are showing.

Speaker 15 I'm going to get better.

Speaker 15 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.

Speaker 14 This was a big reason why the FDA rejected a form of psychedelic therapy this summer.

Speaker 14 A lot of researchers were worried that all of these studies weren't really showing what they claimed to be showing.

Speaker 15 That all of this accumulating evidence showing psychedelics' real promise doesn't really rest on the biological function of the drug itself, but people's expectations about it and kind of the over-inflated hype that these are really sort of magical, powerful substances for healing.

Speaker 14 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.

Speaker 15 It's kind of exposing some of the flaws of this gold standard that we've used for decades.

Speaker 14 I'm Noam Hasenfeld and this week on Unexplainable, how much do we really know about psychedelic therapy? And just how worried should we be about the scientific gold standard?

Speaker 14 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?

Speaker 15 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 spark neuroplasticity in an area called the prefrontal cortex, which is involved in sort of higher-level cognitive processes.

Speaker 15 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 psychedelics sort of spur new growth in these areas.

Speaker 14 So it's like putting fertilizer on a dormant field or something like that.

Speaker 15 Yeah. And so that's one idea of how these drugs work.
But also they induce these sort of powerful psychedelic experiences.

Speaker 15 So they've been given in the context of a kind of supportive psychotherapy. And so

Speaker 15 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.

Speaker 15 They send you into these kind of mind-altering states where you're more open to psychotherapy than you might be in other contexts.

Speaker 15 And that

Speaker 15 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.

Speaker 14 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.

Speaker 14 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.

Speaker 14 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?

Speaker 15 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

Speaker 15 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.

Speaker 14 What are some of the solutions?

Speaker 15 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.

Speaker 15 So, for example, in studying MDMA's effects, she

Speaker 15 uses methamphetamine, like meth, as an active control.

Speaker 17 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.

Speaker 14 Sorry, you're telling me they're testing MDMA, like ecstasy, and they're using meth as a control.

Speaker 15 Yeah, yeah.

Speaker 14 It's very much like not a sugar pill.

Speaker 15 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.

Speaker 17 On all the same questions that MDMA made them feel connected, so did methamphetamine.

Speaker 14 Wow. Okay.
Is there any reason they're going for meth? I mean, like, that's. Yeah.
You can't go for something

Speaker 14 like weed or something. I don't know.

Speaker 15 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.

Speaker 14 Yeah. And I guess at least you're feeling something.
Yeah. So it could be a control for MDMA.
Yeah.

Speaker 15 Okay. Another option is that scientists are trying to figure out if they can

Speaker 15 basically get the neuroplastic benefit without kind of the baggage of the psychedelic experience.

Speaker 14 So like mushrooms without the trip or like diet psilocybin or something. Yeah, yeah.

Speaker 15 Sort of like diet psilocybin. And that would make psychedelics a lot more accessible because going through psychedelic therapy is a major commitment.

Speaker 15 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.

Speaker 15 And so it's a major commitment that a lot of people struggling with mental illness might not be able to make.

Speaker 15 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.

Speaker 15 And so there have been a lot of efforts to try to engineer these tripless psychedelics.

Speaker 15 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.

Speaker 15 Is this mouse experiencing a psychedelic experience? Yeah. But a lot of people see them as

Speaker 15 a way to get the benefits of psychedelics without the risks.

Speaker 14 But at the same time, it's possible that the benefits come from the trip, right?

Speaker 15 Yeah. So while there's sort of a lot of hope that these triplet psychedelics might be beneficial for people, there are some major skeptics in the field.

Speaker 14 Is there any way to get around the placebo issue without designing new drugs or like using meth?

Speaker 15 Yeah.

Speaker 15 So for a long time, researchers have 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.

Speaker 15 And people hadn't really done this until a neuroscientist at Stanford named Boris Heifitz tried this experiment with people who had treatment-resistant depression.

Speaker 16 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.

Speaker 15 And another group got a placebo while they were under anesthesia.

Speaker 16 With the benefit that patients don't know what group they're in because they're unconscious for surgery.

Speaker 15 And then measured how much they improved from depression.

Speaker 16 And we found that ketamine had a large effect, just like it does in every trial in the last 15 years.

Speaker 15 But so did the people who got a placebo while they they were under anesthesia. Both groups were sort of indistinguishable.
So they got basically about the same amount better.

Speaker 14 Why would what would account for that?

Speaker 15 Yeah, so it suggests that there's something about the experience of going through a clinical trial that

Speaker 15 helps people feel better.

Speaker 16 Leveraging the non-drug factors, we can generate very similar effect sizes to what's seen in many of these psychedelic trials.

Speaker 14 Yeah, like the trial itself is doing something.

Speaker 15 Yeah, there's something about the trial itself that conferred these benefits. Interesting.

Speaker 15 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 assistive therapy.

Speaker 14 Yeah, so then maybe we shouldn't be treating the placebo as just a control. Like,

Speaker 14 we're talking about all these ways to avoid this problem of unblinding because people know when they're getting a placebo.

Speaker 14 But what if a placebo is just really useful?

Speaker 15 Yeah, I think you hear the word placebo, and it has kind of like a negative connotation.

Speaker 14 Like, it's nothing.

Speaker 15 Yeah, it's supposed to not do anything. And I think what the ketamine under anesthesia experiment shows is that

Speaker 15 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

Speaker 15 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

Speaker 15 the process of going through those motions,

Speaker 15 that matters.

Speaker 15 And there's been some emerging research that it's like

Speaker 15 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.

Speaker 15 And so it just will take a lot more research to try to kind of disentangle

Speaker 15 what about those non-drug factors are responsible for the beneficial response.

Speaker 14 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.

Speaker 14 Do we know how much the therapy is doing?

Speaker 15 We know surprisingly little about sort of the role of psychedelic assisted therapy.

Speaker 19 I don't think we really even understand as a field how much the therapy component contributes to the efficacy of the drug.

Speaker 14 Coming up in a minute, this whole placebo issue is just half of the problem.

Speaker 15 There's this whole other part of psychedelic therapy, the therapy part, that might be even more of a black box.

Speaker 14 And it's driving a wedge in the middle of mental health research.

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Speaker 14 All right.

Speaker 14 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 patients' expectations.

Speaker 14 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.

Speaker 14 And you're saying that hasn't really been studied either?

Speaker 15 Yeah. So I talked to Amy Maguire, who's a bioethicist at Baylor College of Medicine about this.

Speaker 15 And her perspective is that we really have not studied sort of like what role is the psychotherapy playing.

Speaker 19 I think there certainly needs to be a lot more research into the therapeutic component.

Speaker 15 A lot of the focus of research over the past several decades is trying to understand the effects of these drugs so that they can kind of be put through that regulatory pipeline of the FDA.

Speaker 15 But the FDA doesn't regulate psychotherapy.

Speaker 19 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.

Speaker 15 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 of these trials.

Speaker 15 And so it's unclear sort of

Speaker 15 what elements of the therapy are most important.

Speaker 19 This is a larger issue outside of just psychedelics.

Speaker 19 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.

Speaker 14 Also, just from my perspective as someone who has been in therapy,

Speaker 14 That seems like something that is very difficult to hold constant. And I've had different therapists that are very different and have very different strategies and tones and scheduling.
And

Speaker 14 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.

Speaker 15 Yeah, it's definitely a lot harder to study something like psychotherapy.

Speaker 19 Obviously, that's not going to be blinded. I mean, you'll know if you're giving therapy or not.

Speaker 15 Therapy is so idiosyncratic and so hard to kind of isolate individual components. So you'd need a really big

Speaker 15 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.

Speaker 15 You can't patent therapy. Yeah, you can patent a drug, but you can't patent a talk therapy.

Speaker 14 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?

Speaker 15 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.

Speaker 19 But those studies haven't really been done in a rigorous way.

Speaker 15 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,

Speaker 15 but it should become more clear kind of in the coming years.

Speaker 14 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?

Speaker 15 I think some people definitely have that perspective that it's just not the right way to study these drugs and how they work in the real world.

Speaker 15 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.

Speaker 15 But I think that the field is sort of at a crossroads right now.

Speaker 14 How so?

Speaker 15 I mean, I think one potential path would be to broaden the kinds of evidence that regulators consider in approving new drugs.

Speaker 15 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.

Speaker 15 to meet that regulatory bar a little more easily.

Speaker 15 And I think I and a lot of the scientists who I've spoken with are worried that like 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.

Speaker 19 Medicine is both a science and an art.

Speaker 19 And

Speaker 19 I think if we over

Speaker 19 regulate the practice of medicine, we lose the humanistic side of it, particularly with regard to something as interpersonal as psychotherapy.

Speaker 19 And I think the more we chip away at that, the more we lose something in our healing practices.

Speaker 14 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.

Speaker 15 Totally. Totally.

Speaker 14 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.

Speaker 14 And it kind of feels like randomized controlled trials are designed to avoid all of that invisible stuff.

Speaker 15 I think that's right. And some people in the psychedelic space kind of think that psychedelics are,

Speaker 15 they're not just failing to meet this gold standard, they're kind of

Speaker 15 exposing some of the cracks in the gold standard.

Speaker 15 I guess I feel like all of these issues really sort of show just how

Speaker 15 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

Speaker 15 might be wrong.

Speaker 15 Or maybe not wrong, but it's certainly not the full story. And to kind of understand

Speaker 15 that sort of dark matter, as you put it, of the placebo response, we might have to kind of

Speaker 15 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.

Speaker 14 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.

Speaker 14 It's where participants are told they're going to get a placebo, and somehow it seems to work.

Speaker 14 We're going to have an episode all about this out in a couple weeks, so just keep an ear out for that one.

Speaker 14 This episode was produced by me, Noam Hasenfeld.

Speaker 14 We had editing from Matt Collette and Meredith Hodnat, who runs our team, mixing and sound design from Christian Ayala, music from me, and fact-checking from Anuk Dusseau.

Speaker 14 Manding Wynne is wondering whether she should give a mouse a cookie, and Bird Pinkerton finally got to the pufferfish pufferfish queen.

Speaker 14 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.

Speaker 14 The queen immediately understood.

Speaker 14 If you have thoughts about the show, send us an email. We're at unexplainable at vox.com.
And you can also leave us a review or a rating wherever you listen. It really helps us find new listeners.

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Speaker 14 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.

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