Psilocybin therapy linked to lasting depression remission five years later

A new long-term follow-up study has found that a significant majority of individuals treated for major depressive disorder with psilocybin-assisted therapy were still in remission from their depression five years later. The research, which tracked participants from an earlier clinical trial, suggests that the combination of the psychedelic substance with psychotherapy can lead to lasting improvements in mental health and overall well-being. The findings were published in the Journal of Psychedelic Studies.

Psilocybin is the primary psychoactive compound found in certain species of mushrooms, often referred to as “magic mushrooms.” When ingested, it can produce profound alterations in perception, mood, and thought. In recent years, researchers have been investigating its potential as a therapeutic tool when administered in a controlled clinical setting alongside psychological support.

The rationale for this line of research stems from the limitations of existing treatments for major depressive disorder. While many people benefit from conventional antidepressants and psychotherapy, a substantial portion do not achieve lasting remission, and medications often come with undesirable side effects and require daily, long-term use.

Psychedelic-assisted therapy represents a different treatment model, one where a small number of high-intensity experiences might catalyze durable psychological changes. This new study was conducted to understand the longevity of the effects observed in an earlier, promising trial.

The research team, led by Alan Davis, an associate professor and director of the Center for Psychedelic Drug Research and Education at The Ohio State University, sought to determine if the initial antidepressant effects would hold up over a much longer period. Davis co-led the original 2021 trial at Johns Hopkins University, and this follow-up represents a collaborative effort between researchers at both institutions.

The investigation was designed as a long-term extension of a clinical trial first published in 2021. That initial study involved 24 adults with a diagnosis of major depressive disorder. The participants were divided into two groups: one that received the treatment immediately and another that was placed on a wait-list before receiving the same treatment.

The therapeutic protocol was intensive, involving approximately 13 hours of psychotherapy in addition to two separate sessions where participants received a dose of psilocybin. The original findings were significant, showing a large and rapid reduction in depression symptoms for the participants, with about half reporting a complete remission from their depression that lasted for up to one year.

For the new follow-up, conducted an average of five years after the original treatment, the researchers contacted all 24 of the initial participants. Of those, 18 enrolled and completed the follow-up assessments. This process involved a series of online questionnaires designed to measure symptoms of depression and anxiety, as well as any functional impairment in their daily lives.

Participants also underwent a depression rating assessment administered by a clinician and took part in in-depth interviews. These interviews were intended to capture a more nuanced understanding of their experiences and life changes since the trial concluded, going beyond what numerical scores alone could convey.

The researchers found that 67% of the original participants were in remission from their depression. This percentage was slightly higher than the 58% who were in remission at the one-year follow-up point.

To ensure their analysis was robust, the scientists took a conservative approach when handling the data for the six individuals who did not participate in the long-term follow-up. They made the assumption that these participants had experienced a complete relapse and that their depression symptoms had returned to their pre-treatment levels.

“Even controlling for those baseline estimates from the people who didn’t participate in the long-term follow-up, we still see a very large and significant reduction in depression symptoms,” said Davis, who also holds faculty positions in internal medicine and psychology at Ohio State. “That was really exciting for us because this showed that the number of participants still in complete remission from their depression had gone up slightly.”

The study also revealed that these lasting improvements were not solely the product of the psilocybin therapy sessions from five years earlier. The reality of the participants’ lives was more complex. Through the interviews, the researchers learned that only three of the 18 follow-up participants had not received any other form of depression-related treatment in the intervening years. The others had engaged in various forms of support, including taking antidepressant medications, undergoing traditional psychotherapy, or trying other treatments like ketamine or psychedelics on their own.

However, the qualitative data provided important context for these decisions. Many participants described a fundamental shift in their relationship with depression after the trial. Before undergoing psilocybin-assisted therapy, they often felt their depression was a debilitating and all-encompassing condition that prevented them from engaging with life. After the treatment, even if symptoms sometimes returned, they perceived their depression as more situational and manageable.

Participants reported a greater capacity for positive emotions and enthusiasm. Davis explained that these shifts appeared to lead to important changes in how they related to their depressive experiences. This newfound perspective may have made other forms of therapy more effective or made navigating difficult periods less impairing.

“Five years later, most people continued to view this treatment as safe, meaningful, important, and something that catalyzed an ongoing betterment of their life,” said Davis, who co-led the 2021 trial at Johns Hopkins University. “It’s important for us to understand the details of what comes after treatment. I think this is a sign that regardless of what the outcomes are, their lives were improved because they participated in something like this.”

Some participants who had tried using psychedelics on their own reported that the experiences were not as helpful without the supportive framework provided by the clinical trial, reinforcing the idea that the therapeutic context is a vital component of the treatment’s success.

Regarding safety, 11 of the participants reported no negative effects since the trial. A few recalled feeling unprepared for the heightened emotional sensitivity they experienced after the treatment, while others noted that the process of weaning off their previous medications before the trial was difficult.

The researchers acknowledge several limitations of their work. The small sample size of the original trial means that the findings need to be interpreted with caution and require replication in larger studies. Because the study was a long-term follow-up without a continuing control group, it is not possible to definitively attribute all the observed benefits to the psilocybin-assisted therapy, especially since most participants sought other forms of treatment during the five-year period. It is also difficult to know how natural fluctuations in mood and life circumstances may have influenced the outcomes.

Future research should aim to include larger and more diverse groups of participants, including individuals with a high risk for suicide, who were excluded from this trial. Despite these limitations, this study provides a first look at the potential for psilocybin-assisted therapy to produce durable, long-term positive effects for people with major depressive disorder. The findings suggest the treatment may not be a simple cure but rather a catalyst that helps people re-engage with their lives and other therapeutic processes, ultimately leading to sustained improvements in functioning and well-being.

The study, “Five-year outcomes of psilocybin-assisted therapy for Major Depressive Disorder,” was authored by Alan K. Davis, Nathan D. Sepeda, Adam W. Levin, Mary Cosimano, Hillary Shaub, Taylor Washington, Peter M. Gooch, Shoval Gilead, Skylar J. Gaughan, Stacey B. Armstrong, and Frederick S. Barrett.