Psilocybin hype over depression risks twisting studies

A recently published study on psilocybin suggests it may have an immediate and profound effect on depression. It’s important research. But magic mushrooms aren’t the magic bullet that some purport.

Psilocybin, and more generally the field of psychedelics, has been undergoing something of a renaissance in recent years as researchers (and the public) revisit the notion that the drugs could have a profound effect on our wellbeing. Academic labs are finally seeing some funding to conduct real trials, and biotech firms are trying to capitalise on the swell of interest. Meanwhile, hobbyists have taken to “microdosing,” or taking tiny amounts of the drugs with the goal of enhancing creativity or sharpening focus.

The hype threatens to undermine the good that might come out of rigorous studies of psychedelics. Psilocybin might help people with depression — and given the need, I sincerely hope so. But that’s still an open question. We can’t ignore the limitations of clinical trials, or the still-wide gaps in our knowledge about when, whom, and in what settings psilocybin might help.

Most depression medications work by increasing levels of serotonin in the brain with the goal of improving signalling between nerve cells. But not everyone benefits from these pills, and those who do see an improvement typically need to take them for weeks before an effect sets in.

The hope for psychedelics centres on the notion that they act more rapidly on those same signalling pathways. Studies of psilocybin in animals suggest the drug can quickly and profoundly alter the circuitry in areas of the brain that help control things like motivation, reward, fear and anxiety.

The new trial, sponsored by Compass Pathways, which is trying to develop psilocybin into a Food and Drug Administration-approved drug, is one of several exploring how that effect might help people with depression. In the study, 233 people who hadn’t been helped by conventional antidepressants were given one of three doses of psilocybin: 25mg, 10mg or 1mg (a dose that was used as the placebo). About 29% of the people in the high-dose group were in remission by the third week of the study, and 37% saw a significant improvement in their depression.

Taken at face value, that effect is profound in a field in desperate need of innovation. But dig deeper, and the benefits aren’t as clear.

The first caveat is the size of the study. Only 79 people got the highest dose, and 75 received the medium dose, which did not elicit an effect. The magnitude of the response in small studies of psychiatric treatments is often more modest in larger trials — and can be further diminished when a treatment is used out in the real world. That’s been true of now available antidepressants, and if it holds true — and I suspect it will — for psilocybin, might make its benefits feel far less profound, or even comparable to existing treatments.  

Placebo arm

And by the end of the 12-week study, even the effects for the high-dose group began to fade. This isn’t a permanent fix, and more studies are needed to determine whether, for example, repeated use of psilocybin can offer longer-term benefits — or might come with risks. A small number of people in every arm of the trial experienced suicidal thoughts and harmed themselves.

The bigger elephant in the room is that it’s nearly impossible to run a trial of psychedelics with a true placebo arm, a situation that could be swaying the outcome of these studies. Untangling a drug’s true effect on depression is always difficult — studies of now-available antidepressants suffer from a significant placebo effect, in which a sizeable group of people improve in a trial despite not receiving the drug.

But psilocybin studies face a different challenge: the drug’s hallucinogenic effects make it clear to patients whether they’ve got the therapy, and their behaviour and experiences during treatment mean the therapists and staff do, too.

That matters because the treatment being offered isn’t psilocybin alone. In the Compass study, volunteers received the drug in a specialised, calming setting and were monitored for at least six hours by a therapist and an assistant therapist. In the months after treatment, study volunteers had “integration sessions”, or visits with those same therapists to discuss what insights were gleaned from the experience.

One of the main predictors of a benefit from psychotherapy is the relationship with the psychotherapist, says Suresh D Muthukumaraswamy, a professor at the University of Auckland who studies psychedelics. These studies create “the perfect conditions” for there to be a difference in that relationship between the people who did and did not receive the psychedelic, he says. Imagine, he says, the type of conversation that someone in the high dose group might have compared to someone who did not receive a psychoactive dose of the drug.

More data

None of this is to say that the impact of psilocybin on depression (or in any of the other areas it is being studied, like smoking cessation or alcohol use disorder) is an illusion. Even with study limitations, “it’s remarkable that a single dose of a drug can have that treatment response”, says Natalie Gukasyan, a psychiatrist and assistant professor at Johns Hopkins University, who is part of a group studying psilocybin in another type of depression.

But it’s still early. We need more data.

Compass is starting a phase 3 study of psilocybin this year, with the goal of enrolling more than 900 people worldwide. It’ll try to overcome that fading effect by testing repeated dosing of the drug and comparing that to single-dose therapy.

While we wait for the field to sort out the genuine impact of these drugs, the hype machine needs to slow down. That hype could even be deleterious to the field if it causes people to seek out trials — or experiment on themselves — expecting a miraculous recovery.

For now, the one thing that is clear: The “magic” in mushrooms might be a help, but it is not a cure. 

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