Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics

Ketamine and classical psychedelics (psilocybin, LSD, and DMT) work as fast-acting antidepressants by promoting neuroplasticity. Evidence from preclinical and clinical studies shows these compounds trigger synaptic, structural, and functional changes, especially in pyramidal neurons of the prefrontal cortex. They increase glutamate release, activate AMPA receptors, and stimulate BDNF and mTOR signaling, leading to the expression of synaptic proteins and synaptogenesis. This adaptive rewiring of pathological neurocircuitry may explain their robust and sustained therapeutic effects.

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Abstract

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, α-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.