Numlock Sunday: Shayla Love on why psychedelic research needs cleverness
By Walt Hickey
Welcome to the Numlock Sunday edition.
This week, I spoke to Shayla Love who wrote Scientists Gave People Psychedelics—and Then Erased Their Memory for WIRED. Here's what I wrote about it:
There’s renewed interest in psychoactive and psychedelic drugs from a clinical or scientific standpoint, with drugs such as MDMA, ketamine and even LSD the subject of scientific inquiry regarding their possible efficacy in treating things like major depressive disorder or PTSD. The problem is, it’s actually pretty hard to effectively run a double-blind randomized clinical drug trial when you’re talking psychedelics, as the placebo group is pretty good at discerning they’re in the control group based on the mere fact that they’re not tripping balls. One analysis looked at randomized trials of psychedelics conducted from 1940 to May 2020 and found that while 94 percent claimed to be blinded, only 17 percent actually assessed whether the blinding worked.
This is a fascinating field of study, and I love how it demands researchers to get clever in their attempts to learn more about a very unique batch of substances.
Love can be found on Twitter.
This interview has been condensed and edited.
You wrote a really fascinating story over at Wired all about how there's this new increased interest scientifically in psychedelics, but that presents a number of different problems for the scientists trying to research them. Just backing out a bit, why are psychedelics interesting to science right now?
Well, they're interesting for lots of reasons because scientists have been banned from studying them for a long time, both on a stigma level and then also, legally, it's been really hard to access them to study.
It's been a really exciting time because there's been not a lot of development of new drugs in psychiatry over the past 50, 60 years. So people are really looking at this as something novel that might be really helpful that they can offer patients in the next few years. That's what a lot of the research that people are most excited about is on right now.
Just to get into the science of it, before we get into this too deep, do you want to talk a little bit about how clinical trials are run and what double-blind and blinded studies mean?
Yeah, for sure. Usually when you're trying to test if a drug works, you want to make sure that it's the drug itself that's having effects on people and not just other factors like the placebo effect, which is that when people think that something is going to make them better, they often do feel better.
But if you're going to give a psychoactive drug that might have side effects, you want to know how efficacious it is on its own. So the way we get around this is that people do double-blind randomized clinical trials, which are called RCTs for short. And what you do is you have two groups of people, or sometimes more than two groups of people, and some of them are getting a placebo and some of them are getting an active drug. And nobody knows who's getting what. So the scientists don't know, the therapists don't know, the patients don't know. And the goal is that this "blinding" is supposed to help isolate just what the drug’s effects alone are outside of the placebo effect and expectation.
So psychedelic drugs are used recreationally because their effects are, shall we say, noticeable. This presents an issue, no?
Yes, absolutely. The problem with psychedelics is that let's say you're doing a double-blind RCT for an anti blood pressure medication like Lipitor, or you're doing it for a cancer drug. These drugs might have some side effects, but in general, you're not going to notice it right away when you take it. But psychedelics, it's pretty obvious. When you've taken a high dose of psilocybin or LSD, like you said, that's why people take these drugs for fun, because they have visual effects, and they change the way you think, and you see or hear things completely differently; music sounds really differently, your body might feel really differently. So it poses this huge problem with blinding where, how can you effectively blind the group that gets the psychedelics, and also how can you trick the placebo group into thinking that they got something psychoactive that has a really, really strong effect?
How are some folks attempting to address that?
So one thing that you can do is you can use an active placebo. And that means that instead of just using an inert substance, you are using a drug that has its own psychoactive effects. So they did this back in the '50s during the first wave of psychedelic research. There's a famous experiment called the Good Friday Experiment where they gave seminary students psilocybin, they gave some of them the active drug; and they gave some of them a high dose of niacin, which is a B vitamin, which can cause facial flushing and some other psychoactive effects. But the problem is that even with an active placebo, people still can tell if they got a psychedelic or not. So in the Good Friday Experiments, a bunch of people suddenly started to see God, and then the rest of the people just had a face flushing. And then they were like, "Oh, it's very clear that we are not in that group."
More recently in the esketamine trials, which is another chemical version of ketamine, they made the placebo taste more bitter to try to make it taste more like ketamine. There's also been a study that tried to make a fake version of ayahuasca, which just involved them making a disgusting brown sludgy liquid to try to make people think that they were taking regular ayahuasca. But one of the big problems is that a lot of these studies haven't always asked if the blinding works. So in the few cases that we have where they did act, most of the people can still correctly guess which group they were in. Because even with active placebos, it can be very, very hard to trick people because psychedelics’ effects are so specific.
You went through a few recent studies that went through the history of this. And it's not that common that people actually check to see if their blinding worked.
This is something that I had learned that really surprised me, actually. So in 2021, there was a paper that found that in 43 percent of the studies, no one had measured what people expected to happen in the trial beforehand, which is like this, it's called pretreatment expectancy. And then only five measured blinding, but none of them used blinding measures or scale that were already out there. So there was only one study in this review that actually successfully maintains the blind based on asking people in the study. And then there was a much more recent paper in May, which looked at every single randomized trial of psychedelics in humans from 1940 through May 2020. And 94 percent of the studies said that they were blinded, but only 17 percent of them included any assessment on blinding. And only eight of the 14 of those that included them actually used those measurements.
We're saying that these are double-blind randomized clinical trials, and they are based on the study design, but a lot of them are not checking to make sure people are actually blinded, or the measurements to check whether people are blinded are aren't totally consistent. The reason this matters is that we know that if there's no blinding, it can overestimate the effects of a drug because of the placebo effect.
And then also importantly, it can heighten the nocebo effect. If you are in that group at the church, and you're seeing your friend see God, then you're going to be like, "Oh," you get bummed out. You get a nocebo effect. You feel worse because you know you're not in the active group. So if you have treatment-resistant depression, and you're aware that you're in the placebo group, you might think, "This was my last hope, and I didn't get the active drug. And now, I'm even more depressed." So there are these negative effects in the placebo group outside of just the expectations of the active group, making people feel better.
Yeah, that's really important. You also wrote about a study that actually used anesthesia in a clever way. How did that go?
Yeah, so this was a study recently out of Stanford from Boris Heifets and his colleagues. I think people are trying to understand, how can we get around expectation or how can we understand the role of expectation? So what they did is they gave people either ketamine or a placebo, but they did it while everybody was under surgical anesthesia.
So everybody was unconscious, but they still gave somebody ketamine or placebo, and they were told beforehand, you're either going to get ketamine or placebo. And at the end, there was not a clinically significant difference between the groups in terms of depression improvement. So it suggests that there could be a really powerful role of expectation if there was no difference between the placebo group and the ketamine group, and they didn't experience anything.
Now, of course, this study is really fascinating and it's caused a lot of conversation throughout the psychedelic community because it's very complicated. These people were going in for surgery. We do know that after surgery, people often feel better because they're like, "Oh, thank God. My surgery's over." You're combining ketamine with another really powerful drug, which is the anesthetic, unknown if that has some impact, or maybe it counters the ketamine. Maybe the anesthetic is an antidepressant on its own.
So there are a lot of caveats, but I think what the scientists are really trying to grapple with is that the double-blind RCT has been the gold standard for trying to assess accuracy for a long time with other forms of medical interventions. With psychedelics, we keep running into this problem with blinding. And it might be the case that we need other kinds of study designs to really understand them in a bigger picture way. I think there'll always be a role for RCTs. But with psychedelics in particular, people are branching out and starting to do these out-of-the-box study designs, where you're having to do a lot more maneuvering to get around these problems in psychedelics, I suppose.
It's such a clever question: How do you measure the impact of a drug that can only be measured by you directly feeling the impacts of the drug?
Something that I think psychedelics do is that they heighten problems that exist elsewhere. This has been a problem in the antidepressant literature for a long time. For every other mental health drug, there's been this question of, "Well, how much of it is placebo, and how can we really tell? And if people feel better, does it really matter? But maybe it does matter." This has been a conversation that's been swirling for a while, but with psychedelics, because they're just so extreme, you just can't ignore it. It's like, you have to do something about it, and we need different methodology. There was a study that I wrote about in the piece that I thought was very clever from Harriet de Wit. The question that they were wondering is whether MDMA improves the way touch feels. Like, does it make touch from another person feel better?
You could say, "Of course it does." Everybody knows that from taking MDMA. But it could be a placebo effect. It could be what people expect to happen. So they want to know, is this a drug-specific effect? Is it coming from the drug itself? What they did is, they gave people MDMA or methamphetamine, and then they had them say how pleasant other people touching them felt. And then they asked them to guess which drug they got. So the people who believed that they got MDMA, but who actually got methamphetamine, that was used as the control group because you knew that they were tricked by the active placebo. So they had all these expectations of MDMA, but they didn't actually get the drug.
And if you compare those two groups, the ones who believe they got MDMA but actually got methamphetamine were like, "Meh, the touch didn't really feel that much better when I was on this drug." But the ones who did get actually MDMA were like, "Yeah, touch me more. That feels amazing." That is a better way to indicate that the improvement of the feeling of touch is a drug-specific effect of MDMA, because you strip away the expectation with the control group. This is more complicated than a double-blind RCT. There's still blinding involved, but it requires more thinking about what does the blind mean? And it requires asking people what they think about the blind, and what their expectations are. So I think that psychedelics will require a lot more participant interaction, and asking people about their beliefs and what they think about what they're feeling, and what they're attributing it to try to understand where everything's coming from.
That's exciting. I don't know. I always love deconstructions of standard operating procedures, and it just seems like these are such a demanding way of attacking it that it's exciting. The story's in Wired. You're all over the place now, though. Where can folks find you, and where can they find your work?
I am freelancing now. So the best place is on Twitter. I'll always post everything I'm writing, but I'm also working part-time at Psyche, which is a mental health publication attached to Aeon, spelled A-E-O-N. So it's a psychological website, but it also touches on philosophy, history. And it's really a pluralistic, well-rounded look at the psychological world, which is exciting.