Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics

• Published in: Trends in pharmacological sciences (Regular ed.) 2021-11, Vol.42 (11), p.929-942
• Main Authors: Aleksandrova, Lily R., Phillips, Anthony G.
• Format: Article
• Language: English
• Subjects: Antidepressive Agents - pharmacology; glutamate; Glutamic Acid; Hallucinogens - pharmacology; Humans; Ketamine - pharmacology; LTP; Neuronal Plasticity; rapid-acting antidepressants; serotonin; synaptic plasticity; synaptogenesis
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2021.08.003

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. Region-specific dysregulation of neuroplasticity is implicated in depression.Ketamine (NMDAR antagonism) and classical psychedelics (5-HT2AR agonism) trigger a long-lasting state of enhanced glutamate-driven neuroplasticity in frontocorticolimbic pyramidal neurons.Shared neurobiological mechanisms involve complex interactions between glutamate, serotonin, and regional synaptic homeostasis.Effects may 'reset the system' by counteracting synaptic deficits, neuronal atrophy, and loss of connectivity in depression, leading to behavioral plasticity and symptom reduction.Ketamine and psychedelics engage mechanisms rapidly and appear to induce long-lasting structural adaptations that sustain therapeutic activity without the need for chronic dosing.Neuroplasticity substrates serve as potential targets for clinical intervention and drug development related to mental ill-health.