A review of psychedelics trials completed in depression, informed by European regulatory perspectives.
Francisca Silva, Florence Butlen-Ducuing, Lorenzo Guizzaro, Pavel Balabanov
Neuroscience Applied 2025 DOI: 10.1016/j.nsa.2025.105516 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Topics | Depression |
| Keywords | Clinical trials Psychedelics: psychedelics Various psychedelics Depression: depression New treatments Innovative depression treatments Their design Successful medicines development European regulators Emerging regulatory guidance Collaboration |
| Citations | 4 |
| Key findings | The eight completed trials of psychedelics for depression varied in methodological approaches, and aligning trial design with emerging regulatory guidance will require attention to unblinding, expectancy, comparator choice, treatment frameworks, and adverse event specification. |
Abstract
There is a growing body of clinical research on the therapeutic potential of psychedelics for the treatment of mental health disorders, notably depression. Accordingly, the new revision of the European Medicines Agency guideline on the clinical investigation of products for depression will incorporate a section covering specific regulatory recommendations for the design of studies with psychedelics. The present review investigated the methodological approaches adopted in completed controlled trials of psychedelics for depression in light of initial considerations included in the draft guideline revision. A systematic search conducted on scientific databases (Embase and Medline) and clinical trial registries (clinicaltrials.gov and WHO ICTPR) identified 8 completed trials as of February 2024. The trials tested psilocybin, LSD, Ayahuasca, and DMT, for major depressive disorder or treatment-resistant depression, and were all pahse 2 or 1/2. Patterns in pre-defined methodological variables pertaining to trial design, population, interventions, outcome measures and safety assessments were analysed and collated against considerations on unblinding and expectancy, choice of comparator, the definition of treatment frameworks, the characterisation of the subjective psychedelic experience and the specification of adverse events in relation to subjective psychedelic effects. Areas for future research, including long-term efficacy and safety and the influence of inter-individual differences, can be investigated in larger studies, necessary for marketing authorisation applications. Ultimately, balancing the intricacies of conducting trials with psychedelics with ensuring adherence to regulatory requirements can be facilitated by early dialogue with medicines regulators, and will be essential for the medical development of psychedelics to address unmet patient needs.
Comparable studies
Other systematic reviews and meta-analyses on depression, most cited first.
Citations in the library
Cited by 4
- How to set up a psychedelic study: Unique considerations for research involving human participants. Neuroscience & Biobehavioral Reviews July 1, 2026
- Bridging the reporting gap: Application of the ReSPCT guidelines in psilocybin clinical trial protocols. European Neuropsychopharmacology January 16, 2026
- Applying the EU Regulatory Framework to Determine the Benefit-Risk Profile of Psychedelics. ACS Pharmacology & Translational Science August 8, 2025
- Psychedelics in Psychiatry: New Treatment Paradigms or Addictive Treatment Strategies? A Narrative Review Pharmaceutical Science December 9, 2025
Cites 20
- Trial of Psilocybin versus Escitalopram for Depression New England Journal of Medicine April 14, 2021
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial Psychological Medicine June 15, 2018
- Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression Frontiers in Pharmacology January 17, 2018
and 15 more in the library