Effect of naltrexone pretreatment on ketamine-induced glutamatergic activity and symptoms of depression: a randomized crossover study.
Nature medicine July 24, 2025 Luke A Jelen, David J Lythgoe, James M Stone et al. 29 citations
Blocking the opioid system with naltrexone reduced both the brain glutamate response and the antidepressant effect of ketamine in adults with major depressive disorder. In a double-blind crossover study of 26 adults, naltrexone before ketamine infusion attenuated the rise in glutamate+glutamine relative to N-acetylaspartate in the anterior cingulate cortex and lessened the drop in depression scores the next day. The opioid system modulates ketamine's acute brain effects and subsequent mood improvement, suggesting interactions between glutamate and opioid systems may inform new depression treatments.