Syner-G: Antidepressant action of psychedelics at the glutamatergic interface of brain, behavior and the immune system
July 3, 2025 Natasha L. Mason, Pablo-Alexandre Mallaroni, Attila Szabo et al. preprint
The long-term antidepressant effects of classic psychedelics may arise from changes in behavioral processes (decreased rumination, enhanced cognitive flexibility), central processes (downregulation of the hippocampal-prefrontal cortex axis, normalization of glutamate concentrations, increased neuroplasticity), and peripheral processes (downregulation of inflammatory markers). These interconnected changes collectively trigger a sustained therapeutic response, with the glutamatergic system serving as the main interface orchestrating them. The proposed Syner-G model emphasizes glutamatergic-dependent signaling as the primary unifying and synergizing interface between these processes. Future research avenues are suggested to advance understanding of psychedelic mechanisms and neuropsychiatric disease.