Psychedelic-assisted therapy as a complex intervention: implications for clinical trial design

Abstract

Psychedelic-assisted therapy (PAT) has typically been evaluated using conventional randomised controlled trials (RCTs), which assess treatment efficacy under highly controlled conditions. However, PAT constitutes a complex intervention, integrating pharmacological, psychotherapeutic and contextual elements that interact dynamically with patient experiences and healthcare settings. Conventional RCTs, designed for simple interventions, may fail to capture these complexities. Pragmatic trials, by contrast, evaluate interventions under real-world conditions, assessing their effectiveness across diverse clinical environments and patient populations. This position paper advocates for the application of the UK Medical Research Council's (MRC) framework for complex interventions to the development and evaluation of PAT. This framework emphasises the necessity of articulating the underlying theory of therapeutic change, structuring intervention development into defined phases, accounting for contextual interactions and incorporating stakeholder perspectives throughout the research process. We argue that employing pragmatic trial designs, guided by the PRECIS-2 tool, will better align PAT research with the practicalities of healthcare delivery and facilitate the translation of research findings into clinical practice. Further, we address the philosophical divergence in the field between conceptualising PAT as primarily pharmacological versus psychotherapy-augmented, noting the implications of these positions for trial design and interpretation. We propose the integration of qualitative methodologies, adaptive trial designs and comparative effectiveness research to refine PAT interventions and address limitations inherent in conventional double-blind RCT approaches. Finally, we advocate for a pluralistic evidentiary model, combining academic and community-led research, to support the rigorous, equitable and sustainable development of psychedelic-assisted therapies and to avoid the historical setbacks that previously hindered progress in this field.