The mechanistic divide in psychedelic neuroscience: An unbridgeable gap?

In recent years, psychedelics have generated considerable excitement and interest as potential novel therapeutics for an array of conditions, with the most advanced evidence base in the treatment of certain severe and/or treatment-resistant psychiatric disorders. An array of clinical and pre-clinical evidence has informed our current understanding of how psychedelics produce profound alterations in consciousness. Mechanisms of psychedelic action include receptor binding and downstream cellular and transcriptional pathways, with long-term impacts on brain structure and function—from the level of single neurons to large-scale circuits. In this perspective, we first briefly review and synthesize separate lines of research on potential mechanistic processes underlying the acute and long-term effects of psychedelic compounds, with a particular emphasis on highlighting current theoretical models of psychedelic drug action and their relationships to therapeutic benefits for psychiatric and brain-based disorders. We then highlight an existing area of ongoing controversy we argue is directly informed by theoretical models originating from disparate levels of inquiry, and we ultimately converge on the notion that bridging the current chasm in explanatory models of psychedelic drug action across levels of inquiry (molecular, cellular, circuit, and psychological/behavioral) through innovative methods and collaborative efforts will ultimately yield the comprehensive understanding needed to fully capitalize on the potential therapeutic properties of these compounds.