Study Results Show Psilocybin Reduces Depression but Is Associated With Adverse Effects

A 25-mg dose of psilocybin reduced depression scores significantly more than a 1-mg dose over a 3-week period.

However, it was associated with adverse effects, according to the results of a phase 2 trial (NCT03775200) of individuals with treatment-resistant depression.

Investigators found that the 10 mg did not yield the same results, and larger and longer clinical trials are needed to determine the efficacy and safety of psilocybin for this disorder.

In the double-blind, phase 2 trial, investigators randomly assigned individuals with treatment-resistant depression to receive a 1-, 10-, or 25-mg dose of psilocybin, along with psychological support. The 1-mg dose was used as a control.

The primary endpoint of the study was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression, Rating Scale (MADRS). The MADRS ranged from 0 to 60, with a higher score indicating more serve depression.

Additionally, the secondary endpoints included response week at week 3, with a 50% or greater decrease from baseline in the MADRS total score, remission at week 3, with a 50% or greater decrease from baseline in the MADRS total score, and sustained response at 12 weeks, which meets response criteria at week 3 and all subsequent visits.

There were 79 individuals in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total scores were 32 or 33 in each group at baseline.

The least-square mean changes from baseline to week 3 were -12 for the 25 mg group, -7.9 for the 10 mg group, and -5.4 for the 1 mg group. The difference between the 25-mg group and the control group was -6.6 and between the 10-mg group and the control group, it was -2.5.

The incidences of remission and response at 3 weeks, without sustained response at week 12, in the 25-mg group were supportive of the primary results.

There were no significant differences between the 1- and 10-mg dosing groups.

However, investigators did report that of 233 individuals, 77% had adverse events, which included dizziness, headaches, and nausea.

Additionally, in all dosage groups, self-injury or suicidal behavior or ideation occurred. Investigators reported that these tendencies were numerically higher in the higher dosing group compared with the control group.

Study limitations included the exclusion of individuals judged to be at a clinically significant risk for suicide, the lack of an active comparator, and the lack of an ethnically diverse population.

Psilocybin therapy was used as a third-, fourth-, or fifth-line treatment for individuals in this trial. The incidence of response at week 3 of 37% in the 25-mg group was lower than in the first-line treatment of major depressive disorder than in other clinical trials investigating other treatments.

However, there was a higher than incidence of response reported for the second-line treatment and on, according to the investigators.

Reference

Goodwin GM, Aaronson ST, Alvarez O, Arden PC, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. N Engl J Med. 2022;387:1637-1648. doi:10.1056/NEJMoa2206443