Long-term efficacy of psilocybin with adjunct psychotherapy in treatment-resistant major depression: 6- and 12-month naturalistic follow-up of a phase 2b trial : innovations
Introduction: Psilocybin shows promise for treatment-resistant depression (TRD), but long-term data are limited. This study examined the antidepressant effect of one or two doses of psilocybin with adjunct psychotherapy in TRD until 12 months. Methods: This is a naturalistic follow-up of a phase 2b,...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
May 27, 2026
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| In: |
Psychotherapy and psychosomatics
Year: 2026, Pages: 1-18 |
| ISSN: | 1423-0348 |
| DOI: | 10.1159/000552272 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1159/000552272
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| Author Notes: | Lea J. Mertens, Felix Betzler, Manuela Brand, Ricarda Evens, Andrea Jungaberle, Henrik Jungaberle, Laura Kärtner, Tomislav Majić, Christian N. Schmitz, Andreas Ströhle, Dennis Scharf, Moritz Spangemacher, Max Wolff, Zahra Assadi, Scharif Bahri, Lilith Becher, Luca V. Färber, Henry Harder, Niklas Kirchen, Eugenia Kulakova, Linda C. Kunz, Andy Meijer, Barbara Rohrmoser, Stefan Wellek, Moritz M. Berger, Michael Koslowski, Gerhard Gründer |
| Summary: | Introduction: Psilocybin shows promise for treatment-resistant depression (TRD), but long-term data are limited. This study examined the antidepressant effect of one or two doses of psilocybin with adjunct psychotherapy in TRD until 12 months. Methods: This is a naturalistic follow-up of a phase 2b, randomized, active placebo-controlled trial in adults with TRD, where participants were randomized to receive two drug administrations 6 weeks apart, embedded within seven psychotherapeutic sessions: (1) active placebo (100 mg nicotinamide), then 25 mg psilocybin, (2) 5 mg psilocybin, then 25 mg psilocybin, (3a) 25 mg psilocybin, then 5 mg psilocybin, or (3b) 25 mg psilocybin twice. The controlled phase ended at 12 weeks, after which participants could pursue other treatments, with follow-ups at 6 and 12 months. The primary follow-up endpoint was change from baseline on the Hamilton Rating Scale for Depression (HAMD17). Results: Overall, 126/144 randomized participants (51 females, 40%) completed at least one follow-up visit. Mean baseline HAMD17 scores across groups ranged from 21.6 to 22.2. A generalized additive mixed regression model for change in HAMD17 scores showed a significant time effect across groups for both follow-up time points, with estimated average changes from baseline of −7.93 (95% CI: −9.17 to −6.70, adj. p < 0.0001) at 6 months and −7.74 (95% CI: −9.04 to −6.43, adj. p < 0.0001) at 12 months, without significant group differences. Results were consistent when controlling for antidepressant pharmacotherapy and psychedelic use. Re-initiation of antidepressant pharmacotherapy during follow-up was strongly associated with higher HAMD17 scores (β = 3.79, 95% CI: 1.98 to 5.60). Conclusion: This is the largest and most complete systematic follow-up of any clinical psychedelic trial. The findings demonstrate a stable and clinically meaningful long-lasting antidepressant effect of one or two 25 mg doses psilocybin with adjunct psychotherapy up to 12 months in TRD. Depression that does not improve with standard treatments is called treatment-resistant depression. Psilocybin is a natural compound found in certain mushrooms and a so-called “psychedelic”, meaning that it can temporarily affect a person’s thoughts, feelings, and perception of the world. It has shown promise in the treatment of depression when used together with psychotherapy, but it is not yet clear how long its therapeutic effects last. This study followed adults with treatment-resistant depression who had taken part in a clinical trial of psilocybin. Participants received two drug administrations 6 weeks apart along with several sessions of psychotherapy: (1) active placebo (a dummy treatment with mild acute subjective but no therapeutic effects), then 25 mg psilocybin, (2) 5 mg, then 25 mg psilocybin, (3a) 25 mg, then 5 mg psilocybin, or (3b) 25 mg psilocybin twice. After the initial 13-week study period, participants could choose other treatments if needed. Researchers reassessed participants’ symptoms again after 6 and 12 months. Depressive symptoms were measured using the Hamilton Rating Scale for Depression (HAMD17), a standard scale rated by clinicians. On average, participants showed meaningful improvements in their symptoms at both 6 and 12 months compared to before treatment. These improvements were similar regardless of the dosing regimen used. The results remained consistent when antidepressant medication or additional psychedelic use during follow-up were taken into account. Overall, the findings suggest that psilocybin, when combined with psychotherapy, may lead to lasting improvements in depression symptoms for up to one year in people with treatment-resistant depression. |
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| Item Description: | Gesehen am 20.08.2026 |
| Physical Description: | Online Resource |
| ISSN: | 1423-0348 |
| DOI: | 10.1159/000552272 |