Scientists compared psilocybin against antidepressants for the first time

Why aren’t people with depression prescribed magic mushrooms instead of Zoloft or Prozac?

The first antidepressants were invented in the 1950s. Meanwhile, psilocybin — the naturally occurring psychedelic compound — was heavily researched in the ‘60s as a treatment for depression until before the federal government declared it a Schedule 1 drug in the ‘70s.

But there’s a chance psilocybin could once more enter the mainstream. The past decade has seen a scientific renaissance around the therapeutic use of psychedelics when paired with therapy.

The most recent advancement is a study published this week in The New England Journal of Medicine.

What was discovered — Volunteers with moderate to severe depression were given either two high doses of psilocybin and a placebo or a very low dose of psilocybin and six weeks of daily escitalopram, an antidepressant with the brand name Lexapro. Everyone in the study also engaged in talk therapy.

The results suggest both methods were equally good at reducing symptoms of depression. But it’s possible psilocybin outperformed Lexapro by some measurements.

Unfortunately, the way the study was designed makes it difficult to confirm some promising signs. The study authors report psilocybin worked faster than Lexapro, was well tolerated, and had few adverse effects.

“... psilocybin therapy may have advantages over current standard of care.”

While the study does not report what sensations the participants felt while using psilocybin, past research suggests it is a dose-dependent subjective experience that can involve experiencing a euphoric state, changes to visual perception, and what’s called ego dissolution — the stripping away of one’s idea about themself. Previous studies have identified mild negative effects like feeling nausea or post-treatment headaches. Critically, during psilocybin-assisted therapy, all subjects are guided through the experience by trained therapists. Not so for every user of Lexapro — though all participants in this study received therapy.

“The main message carried in the data is that psilocybin therapy may have advantages over current standard of care and may, in time, be a licensed option for clinicians treating and patients suffering from depression,” first author Robin Carhart-Harris tells Inverse.

Carhart-Harris is head of the Center for Psychedelic Research at Imperial College London and a leading expert in the therapeutic use of psychedelic drugs.

“Psilocybin therapy didn’t just decrease depressive symptoms, but improved patients’ quality of life and functioning more generally,” he says. “For example, their sense of well-being and life satisfaction increased to a significantly greater extent.”

The experiment — Over the course of six weeks, 59 people (66 percent men and 88 percent white) were enrolled in the randomized controlled trial. One group received daily placebo pills and two heavy doses (both doses were 25 milligrams) of patented psilocybin named COMP360. The other group received daily antidepressants and 1 milligram of psilocybin — a dose so low that it’s considered non-active.

Depression was evaluated with a standard self-reported measurement tool called QIDS-SR-16. Before the study, the psilocybin group averaged a score of 14.5. By the end of the study, the average was 6.5.

The conclusions of this study are limited because it did not include a straight placebo group, but the signs are encouraging. While some people with major depression do respond to antidepressant treatment, roughly 10 to 30 percent do not. Because of this, experts say there is an urgent need for new forms of treatment and some are on the hunt.

In turn, scientists like Cahart-Harris are returning to methods first evaluated 60 years ago, eager to unlock the potential of psychedelic substances. In 2020, for example, a team of international researchers constructed a model of the brain and found psilocybin causes the brain to create a feedback loop of neuron activity and neurotransmitter release, suggesting the compound acts as a reset button.

The future of psilocybin therapy — This new study, meanwhile, is the first to put psilocybin and antidepressants toe-to-toe in people. Both activate the serotonin system but in different ways, Cahart-Harris explains. “The psychedelic is more specific in its action, directly stimulating an aspect of the serotonin system concerned with plasticity or change,” he says.

Now that this paper is published, he hopes the “information inspires other scientists to step up efforts to do related research on psilocybin therapy, funders to back relevant research, and medical developers to step in to take it to the next level.”

In the background of all this is a conversation over the legal status of psilocybin. It’s increasingly understood that its categorization as a Schedule 1 drug was a “War on Drugs” effort to associate certain communities with danger. (For a deeper dive, read this).

To qualify as Schedule 1, a drug has to be considered to have the highest potential for abuse and dependence and of no medical value. Meanwhile, an increasing number of studies associate psilocybin with a very low risk of abuse and dependence, and that it does have medical value as a therapeutic. Accordingly, some medical experts and activists are advocating for its reclassification. (In 2020, Oregon became the first state to legalize psilocybin.)

The work in the lab is ongoing: Cahart-Harris and colleagues have just begun recruiting for a clinical trial evaluating the use of psilocybin therapy for anorexia. “We hope to answer whether psilocybin therapy is a safe and potentially effective treatment for this often tragic condition,” he says.