Animal models in psychedelic research – Tripping over translation

Abstract Psychedelic substances show promise for treating psychiatric disorders including depression, anxiety, and PTSD, yet the neurobiological mechanisms underlying their therapeutic effects remain poorly understood. Preclinical animal research, essential for elucidating circuit-level mechanisms, has yielded inconsistent results. We argue this translational gap stems from systematic disconnects between conditions determining therapeutic outcomes in humans and those employed in animal research. Our analysis of 106 rodent psychedelic studies (2019-2024) combined a systematic audit of experimental conditions with a framework-based evaluation of behavioural assays. First, we assessed adherence to welfare practices paralleling “set and setting” factors critical to human therapy, finding that most studies employ stress-inducing conditions: testing during inactive circadian phases (82%), barren housing (89%), injection-based administration (100%), and forceful handling (77%). 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. Competing Interest Statement The authors have declared no competing interest. Footnotes Adjusted the title. Corrected author names to add accented characters. Edited text for improved clarity and flow for figure 1. Adjusted legends for figures 1 and 2 to provide additional information about the content. Edited the text for clarity and removing some repetitive parts. Added acknowledgement section that was missing. Expanded concluding remarks. Changed size of supplementary figures to improve clarity.