Conceptual analysis of mechanisms and methods in psychedelic clinical trial design: a narrative review

Clinical trials of psychedelic-assisted therapy face unique challenges beyond those of typical pharmacotherapeutics. The therapeutic container—including preparatory and integrative psychotherapy and supportive dosing sessions—likely affects outcomes, and the therapeutic relationship between subjects and therapists is more impactful than in drug-only trials. The most critical problem is the inability to maintain effective blinding in placebo-controlled settings; all attempted approaches have resulted in significant functional unblinding. This makes it difficult to separate the true therapeutic effect of the psychedelic plus psychotherapy from positive expectancy in active subjects and negative expectancy in placebo subjects. Functional unblinding may be deeply connected to the mechanism of therapeutic action itself. The manuscript discusses advantages and disadvantages of current approaches and proposes conceptual and methodological perspectives.

Study at a glance

Abstract

Clinical trials with psychedelics face several challenges that are not present to such a degree with other pharmacotherapeutics. Psychedelic therapies often include a significant therapeutic container, including preparatory and integrative psychotherapy, along with supportive intervention during dosing sessions. All these are likely to have an effect on the outcomes. Additionally, the influence of the therapeutic relationship between study subjects and study therapists is often more pronounced and more impactful on the outcomes as it is in pharmacotherapies that do not require psychotherapy. Perhaps the most important challenge with psychedelic-assisted therapy trials is the inability to effectively conceal the assignment in placebo-controlled settings. Many different approaches have been tried, however, all have suffered from a complete or significant functional unblinding making it difficult to discern the true therapeutic effect of the psychedelic in conjunction with the psychotherapeutic modalities which accompany it from a positive expectancy effect (often in the subjects receiving active intervention), which is further compounded by an additional negative expectancy effect (often in the subjects receiving placebo). This can be particularly problematic if functional unblinding is not just a nuisance variable but is deeply connected with the mechanism of therapeutic action itself. In this manuscript, we discuss various advantages and disadvantages of currently available approaches utilized in psychedelic trials and propose conceptual and methodological perspectives on approaching these problems.