Placebo and “knowcebo” effects are a problem. But they can also help people feel better.
This week I want to look at where we are with psychedelics, the mind-altering substances that have somehow made the leap from counterculture to major focus of clinical research. Compounds like psilocybin—which is found in magic mushrooms—are being explored for all sorts of health applications, including treatments for depression, PTSD, addiction, and even obesity.
Over the last decade, we’ve seen scientific interest in these drugs explode. But most clinical trials of psychedelics have been small and plagued by challenges. And a lot of the trial results have been underwhelming or inconclusive.
Two studies out earlier this week demonstrate just how difficult it is to study these drugs. And to my mind, they also show just how overhyped these substances have become.
To some in the field, the hype is not necessarily a bad thing. Let me explain.
The two new studies both focus on the effectiveness of psilocybin in treating depression. And they both attempt to account for one of the biggest challenges in trialing psychedelics: what scientists call “blinding.”
The best way to test the effectiveness of a new drug is to perform a randomized controlled trial. In these studies, some volunteers receive the drug while others get a placebo. For a fair comparison, the volunteers shouldn’t know whether they’re getting the drug or placebo.
That is almost impossible to do with psychedelics. Almost anyone can tell whether they’ve taken a dose of psilocybin or a dummy pill. The hallucinations are a dead giveaway. Still, the authors behind the two new studies have tried to overcome this challenge.
In one, a team based in Germany gave 144 volunteers with treatment-resistant depression either a high or low dose of psilocybin or an “active” placebo, which has its own physical (but not hallucinatory) effects, along with psychotherapy. In their trial, neither the volunteers nor the investigators knew who was getting the drug.
The volunteers who got psilocybin did show some improvement—but it was not significantly any better than the improvement experienced by those who took the placebo. And while those who took psilocybin did have a bigger reduction in their symptoms six weeks later, “the divergence between [the two results] renders the findings inconclusive,” the authors write.
Not great news so far.
The authors of the second study took a different approach. Balázs Szigeti at UCSF and his colleagues instead looked at what are known as “open label” studies of both psychedelics and traditional antidepressants. In those studies, the volunteers knew when they were getting a psychedelic—but they also knew when they were getting an antidepressant.
The team assessed 24 such trials to find that … psychedelics were no more effective than traditional antidepressants. Sad trombone.
“When I set up the study, I wanted to be a really cool psychedelic scientist to show that even if you consider this blinding problem, psychedelics are so much better than traditional antidepressants,” says Szigeti. “But unfortunately, the data came out the other way around.”
His study highlights another problem, too.
In trials of traditional antidepressant drugs, the placebo effect is pretty strong. Depressive symptoms are often measured using a scale, and in trials, antidepressant drugs typically lower symptoms by around 10 points on that scale. Placebos can lower symptoms by around eight points.
When a drug regulator looks at those results, the takeaway is that the antidepressant drug lowers symptoms by an additional two points on the scale, relative to a placebo.
But with psychedelics, the difference between active drug and placebo is much greater. That’s partly because people who get the psychedelic drug know they’re getting it and are expecting the drug to improve their symptoms, says David Owens, emeritus professor of clinical psychiatry at the University of Edinburgh, UK.
But it’s also partly because of the effect on those who know they’re not getting it. It’s pretty obvious when you’re getting a placebo, says Szigeti, and it can be disappointing. Scientists have long recognized the “nocebo” effect as placebo’s “evil twin”—essentially, when you expect to feel worse, you will.
The disappointment of getting a placebo is slightly different, and Szigeti calls it the “knowcebo effect.” “It’s kind of like a negative psychedelic effect, because you have figured out that you’re taking the placebo,” he says.
This phenomenon can distort the results of psychedelic drug trials. While a placebo in a traditional antidepressant drug trial improves symptoms by eight points, placebos in psychedelic trials improve symptoms by a mere four points, says Szigeti.
If the active drug similarly improves symptoms by around 10 points, that makes it look as though the psychedelic is improving symptoms by around six points compared with a placebo. It “gives the illusion” of a huge effect, says Szigeti.
So why have those smaller trials of the past received so much attention? Many have been published in high-end journals, accompanied by breathless press releases and media coverage. Even the inconclusive ones. I’ve often thought that those studies might not have seen the light of day if they’d been investigating any other drug.
“Yeah, nobody would care,” Szigeti agrees.
It’s partly because people who work in mental health are so desperate for new treatments, says Owens. There has been little innovation in the last 40 years or so, since the advent of selective serotonin reuptake inhibitors. “Psychiatry is hemmed in with old theories … and we don’t need another SSRI for depression,” he says. But it’s also because psychedelics are inherently fascinating, says Szigeti. “Psychedelics are cool,” he says. “Culturally, they are exciting.”
I’ve often worried that psychedelics are overhyped—that people might get the mistaken impression they are cure-alls for mental-health disorders. I’ve worried that vulnerable people might be harmed by self-experimentation.
Szigeti takes a different view. Given how effective we know the placebo effect can be, maybe hype isn’t a totally bad thing, he says. “The placebo response is the expectation of a benefit,” he says. “The better response patients are expecting, the better they’re going to get.” Tempering the hype might end up making those drugs less effective, he says.
“At the end of the day, the goal of medicine is to help patients,” he says. “I think most [mental health] patients don’t care whether they feel better because of some expectancy and placebo effects or because of an active drug effect.”
Either way, we need to know exactly what these drugs are doing. Maybe they will be able to help some people with depression. Maybe they won’t. Research that acknowledges the pitfalls associated with psychedelic drug trials is essential.
“These are potentially exciting times,” says Owens. “But it’s really important we do this [research] well. And that means with eyes wide open.”
This article first appeared in The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, and read articles like this first, sign up here.
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