High-dose psilocybin reduces depression severity in MDD

Treatment with high-dose psilocybin (25 mg) significantly reduced the severity of depression in patients with major depressive disorder (MDD) who were resistant to previous treatments, according to a recent study.

Over a 3-week treatment period with psilocybin, patients treated with a 25-mg dose achieved a 12-point reduction in the MADRS* total score compared with a 5.4-point reduction observed in those treated with a 1-mg dose (treatment difference, -6.6 points; p<0.001). [N Engl J Med 2022;387:1637-1648]

However, similar reductions in MADRS total score were observed among patients treated with either a 10- or 1-mg dose of psilocybin (-7.9 vs -5.4 points, treatment difference, -2.5; p=0.18).

In this trial, psilocybin therapy was a third-, fourth-, or fifth-line treatment, with more than 90 percent of the participants not having previous exposure to psilocybin. One of the main objectives of this trial was to identify an acceptable efficacious dose of psilocybin in patients with a treatment-resistant major depressive episode.

This phase II trial analysed 233 patients (mean age 39.8 years, 52 percent female) with MDD and treatment-resistant depression who were given a single dose of psilocybin 25 mg (n=79), 10 mg (n=75), or 1 mg (n=79; control group) in combination with psychological support. At baseline, MADRS total scores, used to assess the severity of depression with higher scores indicating greater severity of depression, were 31.9, 33.0, and 32.7 points in the 25-, 10-, and 1-mg groups, respectively.

Response (≥50 percent decrease from baseline to week 3 in the MADRS total score) and remission (MADRS total score of ≤10 at week 3) were generally in the same direction as the primary endpoint results.

Headache, nausea, dizziness, and fatigue were the most reported adverse events, which occurred in 84 percent, 75 percent, and 72 percent of the participants in the 25-mg, 10-mg, and 1-mg groups, respectively.

Suicidal ideation or self-injurious behaviour was observed across all psilocybin dose groups, with more patients in the 10-mg group experiencing a worsened suicidal state than those in the 25-mg or 1-mg groups (17 percent vs 14 percent and 9 percent, respectively). Given this result, “suicidality demands clinical vigilance in future trials of psilocybin for depression,” the researchers noted.

“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,” they suggested.

*MADRS: Montgomery–Åsberg Depression Rating Scale