Serotonergic Psychedelics: Experimental Approaches for Assessing Mechanisms of Action

Recent small but well-controlled clinical trials indicate that serotonergic psychedelics such as psilocybin and LSD show promise for treating psychiatric disorders like treatment-resistant depression. Neuroimaging studies reveal dynamic effects on brain activity and connectivity across neural systems, leading to testable hypotheses about mechanisms underlying psychedelic effects and therapeutic benefits. Despite evidence that brain serotonin 5-HT2A receptors are central to these effects, lingering questions about molecular neuropharmacology remain. This chapter discusses these questions in the context of preclinical experimental approaches for studying mechanisms of action of classic and new serotonergic psychedelics.

Study at a glance

Abstract

Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits. Despite these advances and a plethora of preclinical and clinical observations supporting a central role for brain serotonin 5-HT2A receptors in producing serotonergic psychedelic effects, lingering and new questions about mechanisms abound. These chiefly pertain to molecular neuropharmacology. This chapter is devoted to illuminating and discussing such questions in the context of preclinical experimental approaches for studying mechanisms of action of serotonergic psychedelics, classic and new.