Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up

This 12-month follow-up study (n=24) assessed the efficacy and safety of psilocybin in depressed participants from a previous trial. A durable antidepressant effect was observed with treatment response (⩾50% reduction in GRID-HAMD score from baseline, Cohen d = 2.4) and rate of remission at 75% and 58%, respectively, at 12 months. No serious adverse events related to psilocybin were observed.

Abstract

“Background: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes.

Aims: This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received psilocybin.

Methods: This randomized, waiting-list controlled study enrolled 27 patients aged 21–75 with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they received two doses of psilocybin with supportive psychotherapy. Twenty-four participants completed both psilocybin sessions and were followed through 12 months following their second dose.

Results: All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were observed at 1-, 3-, 6-, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside of the context of the study. Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months but did not predict improvement in depression.

Conclusions: These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through 12 months following acute intervention in some patients.”

Authors: Natalie Gukasyan, Alan K. Davis, Frederick S. Barrett, Mary P. Cosimano, Nathan D. Sepeda, Matthew W. Johnson & Roland R. Griffiths

Notes

One of the major benefits of psychedelic-assisted therapy appears to be the long-lasting effects one or two doses of a given psychedelic have on mental health disorders like depression, anxiety and PTSD. Conventional treatments for these disorders, such as SSRIs and SNRIs, often require chronic administration for weeks, if not months, to alleviate the symptoms a person may be experiencing. In contrast, psychedelics appear to have the profound ability to induce long-lasting relief for months after dosing sessions.

In 2021, Alan Davis and his colleagues at Johns Hopkins published the results of the first trial to explore the effects of two psilocybin-assisted therapy (PAT) sessions in persons with major depressive disorder (MDD). Prior to this, the majority of psychedelic studies had been carried out in people with treatment-resistant depression (TRD) whereas the category of MDD is about three times broader than that of TRD. In this trial, researchers found that PAT produced rapid reductions in depressive symptoms in most participants and half of these participants achieved remission through the four-week follow-up.

Now, 12-months from the original trial results, Natalie Gukasyan and the rest of the research team at Johns Hopkins published the findings from a number of follow-up sessions they had with participants in the trial which assessed the effects their psilocybin experience had on their depressive symptoms over the course of the year. Throughout the year, all 24 participants attended all follow-up visits 1-, 3-, 6-, and 12-months. As in the original study, the GRID-Hamilton Depression Rating Scale (GRID-HAMD) was used to assess symptoms of depression. Treatment response was defined as a ⩾50% reduction in GRID-HAMD score from baseline. A number of measures, including Mystical Experience Questionaire (MEQ-30), was also used to assess participant-rated measures of session experiences as predictors of subsequent overall well-being and changes in depression severity.

The long-term effects:

• Large decreases from baseline in GRID-HAMD scores were observed at 1-, 3-, 6-, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively).
• Treatment response and remission were 75% and 58%, respectively, at 12 months.
• Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months but did not predict improvement in depression.
• The MEQ30 was not correlated with decreases in depression at any time point but it was significantly correlated with well-being at all four follow-up timepoints.
• Psilocybin was well tolerated as there were no serious adverse events, suicidal ideation remained low and there were no instances of self-injurious behavior.

An insightful thread on Dr. Gukasyan’s Twitter states that they “observed durable antidepressant effects through 12-month follow up, with treatment response and remission on par with what was observed at 1 week and 1-month post-treatment. There were also no serious safety concerns noted during follow up.”

Despite these positive results, there are some limitations to consider. Out of the trial participants, 33% used antidepressants during the follow-up period so therefore it cannot be determined if the anti-depressant is related to psilocybin alone in those patients. Additionally, while the randomized waiting list-control design of the study allowed for comparison of short-term treatment effects to the control group the design did not allow for a comparison group at long-term follow-up.

Nonetheless, despite the small sample size, a 75% response rate a year on from treatment with no serious adverse effects is positive news for psilocybin-assisted therapy and psychedelic medicine.

Summary of Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up