Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics

The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has inspired tremendous interest in the underlying neurobiological mechanisms. We review preclinical and clinical evidence supporting neuroplasticity as a convergent downstream mechanism of action for these novel fast-acting antidepressants. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N, N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex. These include increased glutamate release, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins, and synaptogenesis. Such influences may facilitate adaptive rewiring of pathological neurocircuitry, thus providing a neuroplasticity-focused framework to explain the robust and sustained therapeutic effects of these compounds.

Automated summary

The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has sparked considerable interest in the mechanisms underlying neuroplasticity. Preclinical and clinical evidence suggests that these drugs induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex, resulting in adaptive rewiring of pathological neurocircuitry.