Changing your mind: neuroplastic mechanisms underlying the therapeutic effect of psychedelics in depression, PTSD, and addiction.

After years of restrictions due to concerns about their potentially harmful effects, research on psychedelics has entered a new era. Increasing attention has been directed toward their immense therapeutic potential, particularly for psychiatric disorders. Pre-clinical and clinical studies have consistently demonstrated that psychedelic treatments produce therapeutic effects within hours of administration, with these effects persisting well beyond their elimination by the organism, hinting at the involvement of neuroplasticity-related mechanisms. This review explores these putative mechanisms, from receptor activation to neuronal and behavioral changes. Among the most studied psychedelics, serotonergic psychedelics and ketamine appear to share common cellular mechanisms. They both recruit glutamatergic neurons to stimulate BDNF-trKB signaling, which promotes synaptogenesis via the mTOR pathway. These changes may explain their efficacy in diseases such as depression, anxiety, PTSD, and addiction. On the other hand, ibogaine exerts its effects primarily through GDF-mediated mechanisms which may underly its beneficial effect in addiction. Finally, MDMA, a therapeutic agent for PTSD, presents a paradox: while it influences synaptogenesis via 5-HT2A-dependant effects on BDNF, it appears to have deleterious effects on neurotrophic signaling in the hippocampus, impacting plasticity differently. Although the modulation of the neurotrophic system by psychedelics clearly contributes to the reduction of depressive symptoms, its role in PTSD and addiction remains less well understood. A better understanding of the downstream pathways activated by neurotrophins may help refine therapeutic approaches and enhance outcomes for individuals with these conditions. Future research should elucidate the precise mechanisms by which psychedelics exert their effects on psychiatric and substance use disorders to fully utilize their therapeutic potential while ensuring safe and effective integration into clinical practice.