Psychedelic drugs are being investigated as a new class of rapid-acting antidepressants, but their mechanisms remain unclear—specifically whether antidepressant and psychedelic effects arise from related or independent processes. This review examines behavioral methods used in animal studies to measure both the psychedelic and antidepressant effects of these drugs. It highlights conceptual and methodological challenges, stresses the importance of using doses comparable to those in human clinical use, and calls for attention to potential sex differences in preclinical research. Understanding these mechanisms could help identify new drug targets and improve treatments.
Public and academic interest in psychedelics has grown due to clinical evidence of their potential benefits for treating major depressive disorder. Mechanistic studies in rodents remain relatively few but are crucial for understanding the neurobiological underpinnings of therapeutic effects. Findings from rodent studies will benefit patients only if they achieve translational validity. This chapter critically appraises rodent assays traditionally used to study cognition and affect, summarizing existing findings with psychedelics, and highlights novel, translationally valid assays. The authors argue that adopting translational assays is critical for interpreting animal studies of psychedelic effects, and that such studies can help unravel therapeutic mechanisms only if they involve relevant doses.
Antidepressant doses used in conventional rodent models of depression often exceed those used in clinical practice by 1.5 to 25 times, potentially engaging mechanisms irrelevant to human therapeutic effects. A review of forced swim test studies found median doses of 10 mg/kg across antidepressants, while the more recently developed affective bias test showed doses closer to clinical levels. In a separate analysis of 232 ketamine and 202 fluoxetine rodent studies, median doses were also 10 mg/kg, exceeding animal equivalent doses by 1.6–6.5 times. This mismatch may explain why positive preclinical results often fail to translate into clinical efficacy.