A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

Introduction

Psychedelic compounds and dissociatives such as psilocybin, LSD and ketamine produce atypical conscious states and have attracted growing interest for their therapeutic potential in mood disorders. Savalia and colleagues note that ketamine, at subanaesthetic doses, produces rapid antidepressant effects within hours that can last at least a week, and small clinical studies suggest serotonergic psychedelics may produce rapid and sometimes enduring mood improvements. A central puzzle is that these compounds act at distinct molecular targets yet show convergent behavioural and plasticity-related outcomes: both ketamine and serotonergic psychedelics have been reported in rodents to increase synaptic proteins, promote dendritic spine formation or remodeling, and engage neurotrophic signalling pathways. This opinion article develops a conceptual, dendrite-focused framework to account for these similarities. Rather than emphasising a single receptor-level mechanism, the authors propose that ketamine and serotonergic psychedelics converge functionally on dendritic excitability—each drug class producing both excitatory and suppressive effects on dendrites by different pathways. The framework aims to explain selectivity of drug action across cell types and brain regions, dose–response boundaries affecting toxicity, and how acute dendritic effects could initiate Ca2+-dependent plasticity that outlasts the short plasma half-lives of the drugs (reported plasma half-lives noted in the extraction are ~79 min for ketamine and ~74 min for psilocybin).