Psilocybin improves treatment-resistant depression, but linked to adverse events

A 25 mg dose of psilocybin was associated with improvements in treatment-resistant depression over a 3-week period, but with adverse events, a recent study found.

Citing the difficulty in managing patients with treatment-resistant major depressive disorder (MDD), Guy M. Goodwin, DPhil, FMedSci, a professor in the department of psychology at the University of Oxford, and colleagues noted that psilocybin — deriving from psilocybe mushrooms — has previously shown antidepressant efficacy in preliminary cancer studies.

“Amelioration of symptomatic depression in pilot studies of major depressive disorder, including those that compared psilocybin with escitalopram, and that investigated its use in treatment-resistant depression, has suggested therapeutic potential for this agent,” they wrote in The New England Journal of Medicine.

The current phase 2 study consisted of 233 participants with a mean age of 39 years, 112 (52%) of whom were women. Only 14 participants (6%) had previously been exposed to psilocybin, and 222 (95%) had a history of recurrent MDD episodes.

The researchers used the Montgomery-Åsberg Depression Rating Scale (MADRS) to evaluate participant depression. MADRS scores range from 0 to 60, with scores of 20 to 30 indicating moderate depression and scores of 30 or greater indicating severe depression, according to Goodwin and colleagues.

“At baseline, depression was moderate in 30% of the participants and severe in 68% of the participants,” they reported.

Participants were randomly assigned into one of three groups to receive:

• 25 mg dose of psilocybin (n = 79; mean baseline MADRS score, 31.9);
• 10 mg dose of psilocybin (n = 75; mean baseline MADRS score, 33); or
• 1 mg dose of psilocybin (n = 79; mean baseline MADRS score, 32.7).

Following a 3- to 6-week period of tapering off current antidepressant medication, participants received an administration of psilocybin that lasted 6 to 8 hours and were monitored for 12 weeks afterwards.

Goodwin and colleagues found that the least-squares mean change in MADRS total score from baseline to the third week was:

• -12 in the 25 mg group;
• -7.9 in the 10 mg group; and
• -5.4 in the 1 mg group.

The difference in MADRS total score was significantly greater in the 25 mg group vs. the 1 mg group, according to the researchers. The least-squares change differential between the groups was -6.6 (95% CI, -10.2 to -2.9).

“The incidence of response at week 3 was 37% in the 25 mg group, 19% in the 10 mg group, and 18% in the 1 mg group,” the researchers wrote, pointing out the incidence of response for the 25-mg dose was notably lower than that seen in previous first-line MDD treatment trials.

However, occurrences of adverse events were also significant in the 25-mg group (n = 66, 84%), and more common than in the 10-mg group (n = 56, 75%) and the 1 mg group (n = 57, 72%).

Participants who received the 25 mg dose experienced headaches (24%), nausea (22%) and dizziness and fatigue (6%).

In addition, “some participants had suicidal ideation or self-injurious behavior, and the proportions of these participants were numerically higher in the 25 mg and 10 mg groups than in the 1 mg group,” Goodwin and colleagues wrote.

The 25 mg group also more frequently reported severe adverse events (9%) compared with the 10 mg group (7%) and 1 mg group (1%).

The researchers concluded that “longer and larger trials, including comparison with existing treatments for depression, are required to determine the efficacy and safety of psilocybin for treatment-resistant depression.”