Syner-G: Antidepressant action of psychedelics at the glutamatergic interface of brain, behavior and the immune system

Promising results have emerged in the use of psychedelic drugs for treating depression. Despite multiple neural models attempting to elucidate the acute psychedelic experience, and an increased focus on potential mechanisms driving persistent change, the connections between the acute state and the enduring therapeutic outcomes remain elusive. This targeted review aims to bridge this gap by identifying and discussing common denominators among behavioral, central, and peripheral processes shared between the (sub)acute effects of classic psychedelics and depression. We review evidence that suggests the long-term antidepressant effects of psychedelics may result from changes in behavioral (decreased rumination, enhanced cognitive flexibility), central (downregulation of the hippocampal-prefrontal cortex axis, normalization of glutamate concentrations, increased neuroplasticity) and peripheral processes (downregulation of inflammatory markers). We posit that, while each individual process can independently produce a therapeutic response, the interconnection of these processes implies they don’t operate in isolation. Rather these changes collectively interact to trigger a sustained therapeutic response. Within this framework, the glutamatergic system emerges as the main interface orchestrating these interconnected processes. Introducing the Syner-G model of antidepressant action of psychedelics, we emphasize glutamatergic-dependent signaling as the primary unifying and synergizing interface between these independent processes. As the model contains a number of principles that inherently form scientific propositions, we conclude by proposing avenues for future research that may advance our understanding of the mechanisms of psychedelic drugs, and may shed light on mechanisms of neuropsychiatric disease.