Are psychedelics breaking science?
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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,

"Eighty percent of the 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 percent 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

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 a 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, "Ah, 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 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 overinflated hype 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 Noam Hassenfeld, 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? 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 psychedelics 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 talking

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. 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

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

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? 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. 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 and

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 for 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 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 anesthesia.

And people hadn't really done this until a neuroscientist at Stanford named Boris Heifetz

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 give 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 large effect, 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.

Why would, 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-assisted therapy.

Yeah, so then maybe we shouldn't be treating the placebo as 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 the

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. Huh.

I don't think we really even understand as a field how much the therapy component contributes 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. Support for the show comes from Mint Mobile.

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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 patients' 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 effects of these drugs so that they can kind of be put through that regulatory pipeline of the FDA. But the FDA doesn't regulate psychotherapy. If you have a licensed healthcare provider providing drugs

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 of 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 before,

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 getting therapy or not. Therapy is so idiosyncratic and so hard to kind of isolate individual components. So you'd 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't 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, what

Is it possible that the randomized controlled trials themselves are the problem? 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. I personally think that there is a role for them because they're still kind of the best tool that we have of really homogenizing

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 pill.

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 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. Medicine is both a science and an art. And I think if we over-regulate the practice of medicine, we lose the humanistic ability

side of it, particularly with regard to something as interpersonal as psychotherapy. And I think the more we chip away at 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.

Some people in the psychedelic space think that psychedelics are, they're not just failing to meet this gold standard, they're exposing some of the cracks in the gold standard. I guess I feel like all of these issues really show just how complicated we are as human beings. 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 of 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 Hodnot, who runs our team. Mixing and sound design from Christian Ayala. Music from me. And fact checking from Anouk Douceau. Manding Nguyen 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.

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