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.
Psychedelic compounds like LSD are often considered non-addictive, but some patterns of use and subjective effects raise questions about their rewarding potential. This study tested whether LSD and a selective 5-HT2A agonist (25CN-NBOH) produce rewarding effects in mice using conditioned place preference and measured changes in synaptic plasticity in dopamine neurons of the ventral tegmental area. No reliable place preference was found for either drug, supporting the idea that psychedelics have at most weak reinforcing effects. However, single doses, especially of LSD, induced synaptic plasticity in medial VTA dopamine neurons, suggesting the midbrain dopamine system may still play a role in their effects.