Psilocybin combined with psychotherapy can lead to long-term improvements in depressive symptoms in people with treatment-resistant depression. This has been shown by a recently published long-term follow-up study conducted by the Central Institute of Mental Health (CIMH), Charité – Universitätsmedizin Berlin, and the MIND Foundation. The antidepressant effects persisted for up to twelve months. According to the researchers, this is the most comprehensive long-term follow-up of a clinical trial involving psychedelics to date. The results were published in the journal “Psychotherapy and Psychosomatics.”
126 people included in long-term analyses
To date, there has been little research into whether the antidepressant effects of psychedelic therapies persist over the long term. The long-term data from the EPIsoDE study, which have now been analyzed, suggest that the antidepressant effects of psilocybin-assisted therapy may persist for up to twelve months.
The study included 144 patients with treatment-resistant depression. Of these, 126 were included in the long-term analyses at six and twelve months. All participants had received at least one treatment with 25 mg of psilocybin in combination with psychotherapeutic support as part of the clinical trial.
Long-term effects remain stable even after accounting for subsequent antidepressant use
Depressive symptoms remained significantly reduced on average throughout the entire observation period. This was assessed, among other methods, using the internationally established Hamilton Depression Rating Scale (HAMD17), a clinical tool for evaluating depressive symptoms. Even after twelve months, depressive symptoms on the HAMD17 scale were, on average, about eight points lower than before treatment. This is considered a clinically significant improvement in symptoms.
Of particular note is the fact that the observed antidepressant effects persisted even after statistically accounting for whether participants resumed taking conventional antidepressants following the study treatment.
A great need for new treatment approaches
“The long-term stability of the antidepressant effects is a particularly important finding of our study,” says Prof. Dr. Gerhard Gründer, head of the Department of Molecular Neuroimaging at the Central Institute of Mental Health and one of the study’s corresponding authors. “There is a great need for new treatment approaches that go beyond short-term improvements, especially in cases of treatment-resistant depression,” adds Gründer.
The data comes from the EPIsoDE study, which was conducted in Mannheim and Berlin between 2021 and 2024. In addition to the psilocybin sessions, the treatment also included a structured psychotherapeutic setting with preparatory and integration sessions.
“Unlike traditional antidepressants, psilocybin is not taken continuously, but is used in just a few sessions alongside psychotherapy. This makes the results particularly remarkable,” says Lea Mertens, the study’s first author and a researcher at the CIMH. “The psychotherapeutic context likely plays a central role in the long-term processing and integration of the experiences. However, the exact interplay of the psychological and biological factors involved in the therapy still needs to be further investigated.”
The results should be interpreted with caution
At the same time, the researchers emphasize that the results must be interpreted with caution. The analysis now published is a long-term follow-up study conducted over the entire 12-month period without an additional control group. After the study concluded, participants were able to resume regular treatments, and they had the option to join an ongoing monthly integration group. “The experiences during treatment were very intense and personally meaningful for many participants. That is why we offered a monthly support group, which many people attended,” says Dr. Michael Koslowski, a specialist in psychiatry and psychotherapy at Charité – Universitätsmedizin Berlin.
According to the researchers, further randomized long-term studies are needed to confirm the results and to examine the long-term efficacy of this approach compared to existing treatment methods.
Psilocybin is a psychedelic compound that was used in the EPIsoDE study exclusively under controlled clinical conditions and with intensive psychotherapeutic support. The study was funded by the Federal Ministry of Research, Technology, and Space (BMFTR; formerly BMBF).
Publication
Mertens LJ et al. Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression (EPIsoDE): 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial. Psychother Psychosom. 2026. DOI: 10.1159/000552272
https://doi.org/10.1159/000552272
Further information
Additional information about the EPIsoDE study: https://www.zi-mannheim.de/episode