April 15, 2021 — The psychedelic drug psilocybin – found in “magic mushrooms” performed just as well as a widely used antidepressant in easing the symptoms of major depression, and outperformed the common prescription medication on a range of secondary measures, results of a small-scale phase II study show.
In a 6-week trial that included 59 patients with moderate-to-severe depression, there was no significant difference between the impact of high-dose psilocybin and that of selective serotonin reuptake inhibitor (SSRI) escitalopram, sold under the brand name Lexapro.
Patients in the group that received psilocybin did show a much more rapid improvement in the main measure of depression than those taking escitalopram, but this gap narrowed over the span of the trial until it was no longer statistically significant.
“It’s very clear that psilocybin therapy has a faster antidepressant onset than escitalopram. And psilocybin was consistently superior on the ancillary outcomes, but it wasn’t different on the primary,” the study’s lead author Robin Carhart-Harris, PhD, head of the Centre for Psychedelic Research at Imperial College London, told reporters during a news briefing.
Results of the phase II, double-blind, randomized study were published online April 15 in the New England Journal of Medicine.
Secondary Outcomes
Investigators found that psilocybin bested escitalopram in several secondary outcomes, including feelings of well-being, the ability to express emotion, and social functioning.
Still, the team cautioned that they could draw no conclusions from these secondary measures because larger and longer trials are required.
“But the secondaries were highly suggestive — tantalizingly suggestive — of the potential superiority of psilocybin therapy to treat not just depression, but these ancillary symptoms,” Carhart-Harris said.
The 59 patients were randomly assigned to receive psilocybin and 29 patients to receive escitalopram. Every procedure was mirrored in both groups.
At the 2 “dosing days” scheduled during the 6-week trial, all patients received an oral dose of psilocybin. However, the escitalopram group received 1 milligram, versus 25 milligrams for the psilocybin group.
“And the reason why we did that is because we can standardize expectation. We say to everyone, you will receive psilocybin. It’s just the dosage might differ,” Carhart-Harris said.
He conceded that most patients — though not all — were able to determine which group they were in following the first dosing day based on the drugs’ effects.
Supportive Therapy
Following the oral dose, volunteers would spend 6 hours reclining on a bed, surrounded by pillows and a curated selection of music and supported by two “guides” or therapists. The guides were on-hand to support patients though their psychedelic experience but did not chat or otherwise interfere.
The next day, patients attended a session with their two therapists to talk through their experiences.
Between dosing days, patients in the high-dose psilocybin group would take daily capsules containing a placebo. The low-dose group received a course of escitalopram.
The incidence of adverse effects was similar in each group. None was serious.
The study’s principal investigator, David Nutt, DM, of Imperial College London, said many patients in the psilocybin group reported great insights during dosing days.
“Very often, for the first time, people have actually come to understand why they’re depressed,” he told reporters.
The word psychedelic, coined in 1957 by psychiatrist Humphry Osmond, derives from the Greek words “psyche,” which means “soul” or “mind,” and “delos,” which means “reveal.”
“Profound Experiences”
Certainly, patients in the psilocybin group received enough of the compound to induce what Carhart-Harris called “very profound experiences.”
The researchers said the results, while promising, should not encourage anyone to self-medicate with psychedelic substances, which are still illegal in most countries.
“I view this very much — and I think most colleagues do as well — as a combination treatment,” Carhart-Harris said. “And we strongly believe that the psychotherapy component is as important as the drug action.”
The team stressed that the absence of an entirely placebo group limit conclusions that can be drawn about either treatment.
Carhart-Harris also said he would have liked a more diverse group of patients. Participants were mostly white and mostly male, with an average age of 41, and a high educational attainment. Of the 59 enrolled, only 34% were women.
Volunteers underwent MRI scans to track changes in metabolism at the start and end of the trial. The team will analyze the results to see if there is an impact on brain function. They also plan a trial examining the effect of psilocybin on anorexia.
“I think it’s fair to say the results signal hope that we may be looking at a promising alternative treatment for depression,” Carhart-Harris said.
Unanswered Questions
In an accompanying editorial, Jeffrey A Lieberman, MD, Lawrence C. Kolb, professor and chairman of the Department of Psychiatry at Columbia University College of Physicians and Surgeons in New York City, warned that there remain many unanswered questions about using psychedelics for medical purposes.
They were considered potential miracle cures for a range of mental disorders in the 1960s, only to be banned in the 1970s due to “the perceived dangers and corrosive effects” on society, he wrote.
“The Carhart-Harris study notwithstanding, we are still awaiting definitive proof of the therapeutic efficacy of psychedelics and their capacity to improve the human condition,” Lieberman writes.
“Should the mind-bending properties of the psychedelics prove to be the panacea their proponents professed, informed consent and safety standards must be established. How do we explain mystical, ineffable, and potentially transformative experiences to patients, particularly if they are in a vulnerable state of mind? What is their potential for addiction?”
David Owens, professor emeritus of clinical psychiatry at the University of Edinburgh in the United Kingdom, described Lieberman’s comments as “spot-on.”
“This is a small, exploratory study with numbers too small to analyse fully,” he said.
” One might say this is an ‘interested’ population, willing to go for novel approaches and with no placebo group, the extent of the placebo response cannot be assessed.”