The ABCs of psychedelics: a preclinical roadmap for drug discovery

There is growing interest in developing psychedelic-inspired drugs for treating psychiatric disorders. However, identifying next-generation psychedelic analogs with ideal receptor selectivity and true therapeutic efficacy remains a major challenge. Recent progress has been driven by advances in determining agonist-induced biased signal transduction, high-content behavioral phenotyping via automated video analysis, drug-evoked structural neural remodeling, and activity-dependent gene expression. In this review, we outline a framework for evaluating psychedelics and non-hallucinogenic serotonin 2A (5-HT 2A ) receptor agonists. We critically examine current methods for assessing (A) agonism, (B) behavior, and (C) cellular plasticity. We highlight emerging techniques that may improve translation to humans. We contend that an effective discovery pipeline must align with specific experimental goals and incorporate multiple approaches to be successful for psychedelic drug development.