Psychedelics promote plasticity by directly binding to BDNF receptor TrkB
Nature Neuroscience June 1, 2023 Rafael Moliner, Mykhailo Girych, Vera Kovaleva et al. 439 citations
Psychedelics such as LSD and psilocin produce fast and lasting antidepressant effects by directly binding to the TrkB receptor, the receptor for brain-derived neurotrophic factor (BDNF). These compounds bind to TrkB with affinities 1,000 times higher than other antidepressants like fluoxetine and ketamine, and they interact with a distinct but partially overlapping site within the transmembrane domain of TrkB dimers. In mice, the neuroplasticity and antidepressant-like effects of psychedelics depend on TrkB binding and endogenous BDNF signaling, not on serotonin 2A receptor activation. However, LSD-induced head twitching requires serotonin 2A activation and is independent of TrkB binding. This suggests that high-affinity TrkB positive allosteric modulators without serotonin 2A activity could retain antidepressant benefits without hallucinogenic effects.