Unlike conventional antidepressants that primarily target the serotonin system, ketamine acts on the glutamate system — the brain’s most abundant excitatory neurotransmitter. As an NMDA receptor antagonist, ketamine triggers a cascade of neurochemical events that promote synaptic plasticity.

This process leads to the rapid formation of new neural connections in brain regions involved in mood regulation and pain processing — particularly the prefrontal cortex and hippocampus. This “rewiring” effect is believed to underlie ketamine’s remarkably fast therapeutic onset, often within hours rather than the weeks required by traditional antidepressants.

Additionally, ketamine modulates the mTOR signaling pathway and increases brain-derived neurotrophic factor (BDNF), further supporting neuronal growth and resilience. For chronic pain, ketamine’s NMDA blockade interrupts central sensitization pathways, resetting pain signaling.