Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review

Serotonergic psychedelics include psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and other agonists of the 5-HT2A receptor. While the efficacy and safety of psychedelics for depression have shown promising initial results in clinical trials, there is much to understand regarding how these effects occur. This narrative review provides an updated evaluation on the hypothesized neurobiology underlying the antidepressant effects of serotonergic psychedelics. Animal models indicate that the involvement of Gqɑ protein signaling pathway of 5-HT2A receptors rather than β-arrestin-2 is required to produce psychedelic effects. However, it is unclear if this pathway is necessary or sufficient for antidepressant effects. Antidepressant effects were observed in animal models despite the absence of hallucinogenic-like effects (e.g., head twitch). Proposed mechanisms of the antidepressant effects of serotonergic psychedelics include post-treatment changes in the default mode network (DMN) and increased neuroplasticity in the hippocampus and prefrontal cortex. Additionally, improved cognitive flexibility was observed after psychedelic administration which may facilitate the efficacy of psychotherapy. Increases in neuroplasticity and cognitive flexibility are likely key mechanisms facilitating antidepressant effects of serotonergic psychedelics. Future research should further explore mechanisms of action. The role of 5-HT2A receptor activation, the psychedelic experience, and accompanying psychotherapy in the overall antidepressant efficacy are key areas of interest in elucidating neurobiological mechanisms of psychedelic treatments.