First-of-its-kind study pits psilocybin against a common antidepressant

Can psilocybin, the active ingredient in psychedelic mushrooms, match the depression-combatting capabilities of a commonly prescribed antidepressant?

The first head-to-head comparison, conducted by scientists at the Center for Psychedelic Research at Imperial College London and published Wednesday in the New England Journal of Medicine, indicated that the psychedelic reduced the symptoms of condition at least as well as escitalopram, an antidepressant better known by the brand name Lexapro. Outside experts, though, said the study was designed in a way that made it impossible to know whether psychedelic mushrooms were actually more effective than escitalopram with regard to other measures of well-being, a limitation they described as “unfortunate.”

Those researchers lauded the study authors for paving new ground with more rigorous research into psilocybin — a sizable feat for a stigmatized and in many places illegal drug. But they also criticized the decision to make a single, basic depression questionnaire the study’s primary outcome, given that the researchers also performed a number of other assessments of well-being that appeared to give psilocybin an edge.

“What’s important about this is it’s the first randomized study with an appropriate [drug] comparison group to look at how effective psilocybin might be,” said Boris Heifets, a neuroscience researcher at Stanford who studies psychedelics and was not a part of the new study.

But although there were “many strong positive signals that psilocybin actually outperformed the antidepressant, the study was designed in a way that prevents drawing any conclusion about those results,” Heifets added.

With regard to those signals, “it’s a wash,” he said.

Robin Carhart-Harris, the lead author on the paper and the head of the Imperial Center for Psychedelic Research, said he regretted the decision to designate the depression metric as the study’s primary outcome, but noted the measure is one international drug regulators have recognized in the past.

“In hindsight I wish we’d made these other measures of well-being the primary outcome measure,” he said. “However the world — the Food and Drug Administration, the European Medicines Agency — doesn’t recognize those measures as valid.”

Carhart-Harris and his co-authors included the other metrics in the study’s supplementary materials even though they could not be used to make any clinical conclusions in the paper.

The research, a randomized controlled trial which took place over the course of six weeks, involved treating participants with medication and intensive psychotherapy, including a mix of in-person and phone-based sessions during which participants were invited to discuss their illness and any concerns about the study. There were also two lengthy psilocybin therapy sessions where participants were paired with two mental health professionals including a psychologist or psychiatrist who supervised their psychedelic experience.

The study’s 59 participants aged 18 to 80 — 66% of whom were men and 88% of whom were white — were split into two treatment groups. One received daily antidepressants and two very small doses of psilocybin during the sessions; the other received daily placebo pills in place of the antidepressants and two heavy doses of psilocybin during the sessions.

All of the participants met the clinical definition of major depressive disorder and were told to stop any current medication before starting the study. Neither the researchers nor the participants were told which treatment they would receive. To keep expectations the same across the board, both cohorts were told they would receive psilocybin, but the dose amounts were not disclosed.

Psilocybin is known to produce powerful, vivid hallucinations and colorful visualizations, so the researchers worked to create a kind of safe haven for participants during the sessions. These took place at an Imperial College research facility on two days spaced three weeks apart.

“It’s often a very intense emotional, roller-coaster journey for people,” said Rosalind Watts, the clinical lead for the Imperial Center for Psychedelic Research and a co-author of the paper.

Under the care of two mental health professionals including one to two psychiatrists or psychologists, participants were invited to lay down, cover their eyes, tune into a playlist of gentle forest breezes, chirping birds, soft guitar, and low chanting, and even hold hands with one of the professionals.

While members of the psychedelic cohort received 25 milligrams of psilocybin during the sessions, considered a medium-to-heavy dose of the drug, those in the antidepressant group received 1 milligram. Such a low dose is typically provided in psychedelic studies in lieu of a placebo to control for the impact of disappointment on the results. Without it, “you might see what’s called a nocebo effect where people know they’re in the placebo arm and it actively worsens their psychiatric state,” said Heifets.

At the beginning and end of the six-week study, participants filled out the primary depression questionnaire, a 16-item self assessment designed to assess depression severity called the QIDS-SR-16. They also did 10 other well-being tests, including one designed to assess their sense of connection with nature and other people, one to gauge anxiety levels, and another to evaluate functionality at work and in social settings. No severe adverse events were reported in the study, and rates of any such event were similar between the two groups.

The depression scores showed no statistically significant difference in improvement outcomes between the two groups; on average, depression scores dropped — meaning they improved — by eight points in the psychedelic group and six points in the antidepressant group. Nearly all of the other 10 tests showed more of a benefit with psilocybin than escitalopram.

“Out of the nearly dozen clinical scales they used to measure depression symptoms, they somehow happened to pick the one scale that showed no difference between the two treatments as their major [primary] outcome measure,” said Heifets.

And as secondary measures, those other 10 scales lack the detailed statistical analysis required of primary measures, so no definitive clinical conclusions can be drawn about them or included in the study results.

As for what might have caused the differences observed between the two drugs in those secondary outcomes, Carhart-Harris, Heifets, and Watts have some theories.

Psychedelics are believed to produce their antidepressant effects by interfering with negative and isolating thought patterns, instead encouraging larger and more expansive feelings of connectedness with other people, nature, or both.

Previous studies have suggested this helps partially explain why the drugs appear to act as enhancers of psychotherapy: They encourage openness to intense emotions and appear to enable fresh perspectives on previous and current behaviors. Watts and Heifets said they believed they were seeing those effects peek out at them through the lines of the study’s supplementary materials, where psilocybin participants saw higher improvements in social and work functionality and reported more emotional breakthroughs.

“The mechanism of the change almost seems to be that the people in the psilocybin group are really flourishing, and showing a whole load of things all related, really, to this kind of connectedness,” said Watts.

Heifets agreed. “This does demonstrate that psychedelics are catalyzing a process of human connection,” he said. “That’s what’s so remarkable here. It’s assisted psychotherapy.”

Olivia Goldhill contributed reporting.