Although psychedelic drugs show beneficial effects against a plethora of mental health conditions, the mechanisms behind their powerful effects remain largely unclear. Previous research has shown that antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and ketamine, act by binding to the brain-derived neurotrophic factor (BDNF) receptor TrkB in mice. Antidepressants increase cellular proliferation and survival in the hippocampus, as well as neuronal plasticity in the brain, and their binding to TrkB mediates antidepressant-induced plasticity. Given the antidepressant effects of psychedelics, Moliner et al. hypothesized that psychedelics may share this mechanism of action.
Using molecular modeling methods and NMR spectroscopy, the researchers discovered a binding site for psychedelics in the transmembrane dimers of TrkB. They found that lysergic acid diethylamide (LSD) and psilocin — the active metabolite of psilocybin — bind to TrkB with a 1,000-fold higher affinity than other antidepressants, such as SSRIs and ketamine. Using several in vitro and in vivo assays, the authors showed that the plasticity-promoting and antidepressant-like actions of psychedelics require the presence of BDNF and psychedelics are not direct TrkB agonists, and these actions are separate from their hallucinogenic-like effects. “The finding that TrkB receptors would be the target of psychedelics and mediate their plasticity-related effects is totally novel and not previously reported,” explains Eero Castrén, one of the authors of the study.
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