Single Psilocybin Dose Again Shows Major Depression Benefit

Just one dose of psilocybin significantly improved depression symptoms and functional disability in patients with major depressive disorder (MDD), a randomized trial found.

Administered with psychological support, a 25-mg dose of synthetic psilocybin resulted in a sustained 12.3-point (95% CI -17.5 to -7.2) greater improvement versus active niacin placebo in Montgomery-Asberg Depression Rating Scale (MADRS) score on day 43, meeting the phase II study’s primary endpoint, according to Charles Raison, MD, of the Usona Institute in Fitchburg, Wisconsin, and colleagues in JAMA.

As early as day 8, investigators observed a 12.0-point (95% CI -16.6 to -7.4) greater reduction in MADRS score favoring the psilocybin group, meeting a key secondary outcome of the trial. Other secondary outcomes demonstrated improvements with psilocybin in disability and sustained response for depressive symptoms.

Treatment was well-tolerated, with the majority of adverse events (AEs) being graded mild or moderate in severity. The most commonly occurring AEs in the psilocybin group were headache (66% vs 24% for niacin), nausea (48% vs 6%), and visual perceptual effects on dosing day (44% vs 6%).

Acting as a tryptamine alkaloid, psilocybin is found in Psilocybe mushrooms, commonly known as “magic mushrooms.” And this isn’t the first trial to demonstrate that psilocybin eases psychiatric conditions, like depression and anorexia.

Another phase IIb trial — sponsored by COMPASS Pathway — showed benefit in MADRS total score at 3 weeks with a single 25-mg psilocybin dose, and significant improvement was seen as early as the second day.

Comparing their two findings, Raison’s group noted that “[i]n contrast to prior psilocybin trials for depression, there was not a significant reduction in depressive symptoms or a psilocybin/placebo difference in depressive symptom status at the day 2 assessment.”

“This may reflect the fact that to maintain central rater blinding, the 7-day recall period used for all other MADRS assessments was maintained at day 2, with the result that the majority of recall period for the day 2 assessment covered the pre-dosing period during which depressive symptoms remained elevated, based on results from the Symptoms of Major Depressive Disorder Scale,” they explained.

The study authors also pointed out a similar rate of severe adverse events in these two trials — 8% here and 10% in the COMPASS Pathway trial. A few patients in the COMPASS trial experienced suicidal ideation as an adverse event (all were deemed non-responders), which was not seen in this current trial.

Here, 41.7% of participants who received 25-mg of psilocybin experienced a sustained response versus 20.3% of the same dose psilocybin patients in the COMPASS trial. Commenting on this, accompanying editorial authors Rachel Yehuda, PhD, and Amy Lehrner, PhD, both of James J. Peters VA Medical Center in New York City, said “it is clear that despite the enthusiasm, psychedelic therapies do not represent a panacea for every patient. There are no silver bullets in psychiatry.”

Because a large proportion of patients in these psilocybin trials don’t respond to this kind of treatment, future studies should focus on identifying exactly who might benefit most, determine the optimal dose, and figure out if “booster” or repeated treatment might be beneficial, Yehuda and Lehrner suggested.

“If psychedelic therapies do prove to have enduring effects after just a single or a few administrations in the context of a few sessions for preparation and integration, they have the potential to offer not just a new approach to mental health care, but an entirely new paradigm of care,” the editorialists wrote.

A total of 104 participants were involved in the current trial, half of whom were women, and the average age was 41. After randomization, 51 were assigned to psilocybin and 53 to the niacin group. Niacin was used in order to aid in blinding because it produces a flushing response.

All were between the ages of 21 to 65 with DSM-5-confirmed MDD of at least 60 days in duration with moderate or higher symptom severity (MADRS score of 28+). Those with a history of psychosis or mania, active substance use disorder, or active suicidal ideation with intent were excluded.

If indicated, psychiatric medications were tapered prior to treatment so participants met criteria for moderate to severe MDD at the baseline assessment.

Among the secondary outcomes, participants on psilocybin also saw a significant reduction in Sheehan Disability Scale scores compared with niacin at day 43 (-2.31, 95% CI -3.50 to -1.11). This disability improvement was greater for psilocybin recipients at all other timepoints after administration, as well — days 8, 15, and 29.

Significantly more psilocybin patients had a sustained response for depressive symptom improvement compared with niacin too (41.7% vs 11.4%), defined as a 50% or greater reduction from baseline MADRS total score at days 8, 15, 29, and 43. This translated to psilocybin recipients having more than a five times higher likelihood of sustained depressive symptom response than niacin recipients (OR 5.60, 95% CI 1.87-16.74).

Psilocybin also trended toward a higher chance of sustained depressive symptom remission as well, defined as a MADRS total score of 10 or less at each post-dose assessment, but this wasn’t statistically significant (OR 3.37, 95% CI 0.99-11.47).

Participants underwent 6 to 8 hours of preparatory sessions with two facilitators prior to dosing and a 7- to 10-hour dosing session performed in a supervised, comfortable room. Participants were encouraged to wear sunglasses and listen to a curated playlist with headphones during dosing. This was followed by a 4-hour post-dose integration session when participants could discuss their experience with facilitators.

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