Faculty Collaboration Database

The ABCs of psychedelics: a preclinical roadmap for drug discovery. Trends Pharmacol Sci 2025 Dec;46(12):1224-1240

Date

08/29/2025

Pubmed ID

40877079

Pubmed Central ID

PMC12404667

DOI

10.1016/j.tips.2025.07.017

Scopus ID

2-s2.0-105014293898 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

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.

Author List

Kwan AC, Mantsch JR, McCorvy JD

Authors

John Mantsch PhD Chair, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
John McCorvy PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Drug Discovery
Drug Evaluation, Preclinical
Hallucinogens
Humans
Receptor, Serotonin, 5-HT2A
Serotonin 5-HT2 Receptor Agonists