This systematic review (s=8) analyses completed controlled trials of psychedelics for depression, including psilocybin, LSD, ayahuasca, and DMT, all in Phase II or I/II. It evaluates methodological patterns against the draft European Medicines Agency guideline revision, highlighting challenges such as unblinding, expectancy, and adverse event characterisation, while calling for larger studies to assess long-term efficacy and safety.
Abstract of A review of psychedelics trials completed in depression, informed by European regulatory perspectives
“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.“
Authors: Francisca Silva, Florence Butlen-Ducuing, Lorenzo Guizzaro & Pavel Balabanov
Summary of A review of psychedelics trials completed in depression, informed by European regulatory perspectives
Interest in the clinical application of psychedelics has grown significantly in recent years, with increasing research exploring their therapeutic potential for various mental health conditions. Classic psychedelics such as psilocybin, LSD, DMT, and ayahuasca act primarily on serotonin 2A receptors, inducing altered states of consciousness. Regulatory bodies, including the European Medicines Agency (EMA), have taken note of this development. The EMA’s recent revision of its guideline on clinical investigations for depression now includes considerations for psychedelic-assisted therapies.
Despite this interest, no classic psychedelic has received marketing authorisation as a treatment for depression. While regulatory frameworks in the United States, Canada, and Australia have evolved to allow special access programmes, efforts to secure full approval remain ongoing. For instance, the first application for MDMA-assisted psychotherapy in the United States was rejected in 2024, highlighting the regulatory challenges still faced in this field. Given the significant burden of depression worldwide, including treatment-resistant depression (TRD), further research into innovative treatments is critical.
The present review systematically evaluates the methodological approaches used in completed clinical trials investigating psychedelics for the treatment of depression. The authors assess trial design, population selection, interventions, outcome measures, and safety considerations while discussing these features in light of regulatory expectations.
Methods
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https://doi.org/10.1016/j.nsa.2025.105516
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Cite this paper (APA)
Silva, F., Butlen-Ducuing, F., Guizzaro, L., & Balabanov, P. (2025). A review of psychedelics trials completed in depression, informed by European regulatory perspectives. Neuroscience Applied, 105516.
Study details
Compounds studied
DMT
LSD
Psilocybin
Ayahuasca
Topics studied
Depression
Study characteristics
Literature Review
Participants
595
Humans
Compound Details
The psychedelics given at which dose and how many times
Psilocybin 1 - 25mg | 2x LSD 25 - 200
μg | 2x DMT 21.5 mg | 2x Ayahuasca 0.36 mg | 1x
Linked Clinical Trial
SPL026 (DMT Fumarate) in Healthy Subjects and MDD PatientsSPL026 (N,N-dimethyltryptamine [DMT] fumarate) is a psychedelic tryptamine being developed as a therapy for patients with major depressive disorder (MDD).
LSD Therapy for Persons Suffering From Major Depression
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Clinical, Neurocognitive, and Emotional Effects of Psilocybin in Depressed Patients - Proof of Concept
Effects of serotonin 2A/1A receptor stimulation by psilocybin on mood and emotion processing in major depressive disorder: a randomized double-blind placebo-controlled study
An Open Label Study of the Safety and Efficacy of Psilocybin in Participants With Treatment-Resistant Depression (P-TRD)
The primary objective of this study is to evaluate the efficacy of psilocybin (25 mg) administered under supportive conditions to adult participants with severe TRD, in improving depressive symptoms.
Long Term Follow Up Study to COMP 001 And COMP 003 Trials (P-TRD LTFU)
The primary objective of this study is to assess the long-term efficacy of psilocybin with respect to use of new antidepressant treatment, hospitalisations for depression, suicidality, and depressive severity rated using the Montgomery and Asberg Depression Rating Scale (MADRS) over a total of 52 weeks (compared across the 1 mg, 10 mg and 25 mg psilocybin groups from COMP 001).
Psilocybin vs Escitalopram for Major Depressive Disorder: Comparative Mechanisms
This is a randomised double-blind clinical trial. The aim is to compare the efficacy and mechanisms of action of psilocybin, the primary psychoactive substance in 'magic mushrooms', with the SSRI (selective serotonin reuptake inhibitor) escitalopram for major depressive disorder (MDD).
Effects of Psilocybin in Major Depressive Disorder
The proposed pilot study will assess whether people with major depressive disorder experience psychological and behavioral benefits and/or harms from psilocybin.
Antidepressant Effects of Ayahuasca: a Randomized Placebo Controlled Trial in Treatment Resistant Depression
The purpose of the present trial is to test the efficacy of Ayahuasca in treatment-resistant depression.