Psychedelics promote plasticity by directly binding to BDNF receptor TrkB

Essentially all antidepressant drugs, including psychedelics, promote neuroplasticity, which is considered a critical component of their therapeutic effect. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB (neurotrophic receptor tyrosine kinase, Ntrk2) are central mediators of plasticity and the therapeutic action of antidepressants10. Recent findings show that antidepressants, including conventional antidepressants such as fluoxetine and imipramine, as well as the rapid-acting ketamine, directly bind to TrkB and allosterically potentiate BDNF signaling11. BDNF and TrkB have also been implicated in the action of psychedelics as downstream effectors of 5-HT2A activation12. In this Article, because psychedelics produce robust spinogenesis and dendritogenesis9,12 and these effects are known to require intact TrkB signaling12,13, we set out to explore whether direct binding to TrkB might mediate the neuroplastic effects behind their therapeutic potential.