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November 11, 2022
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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.

PC1122Goodwin_Graphic_01_WEB

Data derived from: Goodwin G, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2206443.

“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.”