Targeting the NMDA–AMPA Axis to Restore Synaptic Plasticity in Trauma-Related Disorders: Mechanistic Principles and Clinical Observations

Chronic exposure to severe stress is known to erode synapses in prefrontal-limbic circuits, a biological change that can be reversed by treatments that push glutamatergic signalling away from NMDA receptors and toward AMPA receptors. Ketamine infusions confirm the value of that mechanism, yet cost, monitoring demands, and dissociative side-effects make the intravenous route hard to scale.This review looks at a fully oral, four-drug strategy intended to mimic ketamine’s neuroplastic effects with inexpensive, widely available medicines. The proposed stack pairs dextromethorphan for NMDA blockade with a strong CYP2D6 inhibitor (fluoxetine, paroxetine, or bupropion) to keep dextromethorphan active longer; adds piracetam to enhance AMPA throughput; and supplements l-glutamine to replenish presynaptic stores of glutamate.Retrospective reports covering complex PTSD, dissociative fugue, and trauma-linked depression suggest that the combination can ease flashbacks, nightmares, somatic over-arousal, and even suicidality within days to a few weeks. Importantly, these benefits have been observed without the dissociation or blood-pressure spikes that often accompany ketamine infusions. Although the evidence is still limited to small case series, the early signal supports formal trials to test efficacy, safety, and the specific contribution of each component.