The therapeutic potential of psychedelics: the European regulatory perspective

This paper is a regulatory perspective and expert commentary rather than an original empirical study or systematic review. The analysis and arguments are informed by the authors' work with regulatory bodies and scientific organisations, including the European Medicines Agency (EMA), the EMA's Central Nervous System Working Party, and the European College of Neuropsychopharmacology (ECNP). The extracted text does not report systematic search methods, eligibility criteria, or quantitative synthesis; instead, it synthesises regulatory experience and the existing research literature to highlight key issues for development programmes and regulatory assessment of psychedelic therapies. Because the piece is a commentary, there are no participants, interventions, or statistical analyses to report. Rather, the authors discuss methodological problems observed in the emerging clinical trial literature (for example, blinding and expectancy effects), safety considerations based on pharmacology and reported adverse effects, and regulatory tools and pathways that could be used in Europe to manage benefit–risk assessment, conditional access, and post-authorisation monitoring.

Drummond and colleagues identify several interrelated challenges that must be resolved if classic psychedelics are to be developed and authorised as medicines in Europe. Methodological issues in clinical trials are emphasised: maintaining double blinding is difficult because the psychedelic experience is often obvious to participants and raters, and common mitigation strategies (such as low-dose comparators or active placebos) have their own limitations and may bias effect estimates. The authors stress the potential influence of positive expectancy on measured efficacy and of disappointment or negative expectancy (nocebo) on symptom worsening; they recommend quantifying unblinding and expectancy and using independent, blinded external raters, including raters who are psychedelic-naive, where feasible. Dose optimisation and inter-individual variability are highlighted as important outstanding questions. The paper calls for investigation of optimal dosing regimens, the relationship between acute psychedelic experiences and longer-term clinical benefit, and whether dosing should be individualised according to factors such as age, sex, weight, and pharmacokinetics. The authors also underline the need to determine the added value of the psychedelic compound itself versus psychotherapy or psychological support, since most trials incorporate preparatory and post-dose therapy. They note that preparatory psychotherapy may increase expectancy and unblinding and that the differing content and intensity of psychological support complicate comparisons between studies. Safety considerations receive detailed attention. The authors list acute and subacute adverse effects that warrant further characterisation, including anxiety with derealisation, headaches, transient increases in blood pressure and tachycardia, and potential suicidal ideation or behaviours. They also call for more safety data on drug–drug interactions, particularly given likely co-administration with other psychotropic medications, and for clarity on whether acute psychedelic effects can be separated from long-term therapeutic benefits. Regulatory decision-making will need explicit conditions for safe use at the time of approval, including who may administer treatments, appropriate clinical settings, and monitoring requirements before, during, and after administration. In terms of regulatory pathways and risk management, the commentary outlines several tools the EMA and national systems can use: summary of product characteristics, risk management plans, pharmacovigilance studies, educational materials, staff training, and controlled-access programmes. The authors note precedents for such measures in the EU since esketamine's authorisation in 2019. They also describe mechanisms for early engagement between developers, regulators, and health-technology-assessment bodies — for example, EMA scientific advice, parallel consultation with EUnetHTA, the Innovation Task Force, and special regulatory pathways such as the priority medicines scheme or accelerated assessment. The new EMA Clinical Trials Regulation is mentioned as a potential facilitator of larger, harmonised trials across Europe. Broader legal and implementation issues are considered. The authors question whether the United Nations Schedule I classification of many psychedelics remains appropriate given emerging therapeutic evidence, noting that classic psychedelics show low addiction potential. They further raise practical and financial challenges for national health systems in implementing psychedelic treatments, which may require specialised clinical facilities and training capacity. Finally, the paper calls for larger clinical trials to evaluate efficacy and safety rigorously and for a thorough scientific benefit–risk assessment, encouraging early and sustained engagement with EMA regulatory processes and platforms. The extracted text also reports that several authors disclosed financial relationships with companies or funding bodies involved in psychedelic research or related activities.