Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.
Level 5 - mechanism / opinion, no new human data
Bench binding assays and animal (mouse) behavioral and mechanistic models
PubMed 37280397 · doi:10.1038/s41593-023-01316-5
What was done
The authors investigated the binding of psychedelics (LSD and psilocin) to the BDNF receptor TrkB in vitro and compared their binding sites and affinities to conventional antidepressants. They evaluated downstream neurotrophic signaling, neuroplasticity, antidepressant-like behavior, and head-twitch responses in mice to determine the specific contributions of TrkB binding versus serotonin 2A (5-HT2A) receptor activation.
What was found
LSD and psilocin directly bound to the transmembrane domain of TrkB dimers with approximately 1,000-fold higher affinity than other antidepressants, utilizing distinct but partially overlapping binding sites. In mice, the neurotrophic signaling, plasticity, and antidepressant-like effects of these compounds depended on TrkB binding and endogenous BDNF signaling but were independent of 5-HT2A activation. Conversely, LSD-induced head twitching depended on 5-HT2A activation and was independent of TrkB binding. Exact numerical binding constants and behavioral effect sizes were not provided in the abstract.
Why it matters
This study identifies direct TrkB binding as a primary mechanism driving psychedelic-induced neuroplasticity and antidepressant-like actions, demonstrating that these therapeutic effects can be mechanically dissociated from 5-HT2A-mediated hallucinogenic effects in rodents.
Limits
The study is entirely preclinical, relying on in vitro assays and mouse models, which may not translate directly to human clinical outcomes. The abstract does not report sample sizes, quantitative binding affinities, or specific behavioral effect estimates.
Cited by
- supports Psilocybin increases brain-derived neurotrophic factor (BDNF), which helps increase brain connections and neuroplasticity.