Animal models in psychedelic research - Lost in translation?

Abstract

Psychedelic substances show promise for treating psychiatric disorders including depression, anxiety, and PTSD, but the neurobiological mechanisms underlying their therapeutic effects remain poorly understood. Preclinical findings have so far been inconsistent, limiting mechanistic insights. We argue this translational gap is exacerbated by systematic disconnects between conditions thought to shape therapeutic outcomes in humans and those employed in animal research. In this review, we analyse 266 rodent psychedelic studies published between 2014 and 2026 in order to generate a systematic audit of experimental conditions and behavioural assays currently applied in the field. Specifically, we first assessed adherence to welfare practices paralleling "set and setting" factors critical to human therapy. We found that most studies contained stress-inducing factors: only a minority reported active-phase testing (14%), environmental enrichment (7%), or refined handling protocols (21%), while drug administration almost universally relied on stress-inducing, restraint-requiring methods. Second, we evaluated the capacity of behavioural assays to capture experiential dynamics, revealing that most studies rely on brief, constrained testing with isolated behavioural markers that fail to capture the multidimensional, temporally evolving nature of psychedelic states. Beyond these methodological gaps, we identify a third critical factor largely absent from preclinical research: individual differences and social context. Most animal studies use group-level, cross-sectional designs that cannot characterize heterogeneous treatment responses or social mechanisms implicated in therapeutic change. We propose that improving translation requires a fundamental reorientation: from brief testing of stressed, isolated animals toward longitudinal tracking of individuals in enriched social environments using comprehensive behavioural characterization. We end by offering practical advice on how to implement some of these considerations in animal psychedelic research.