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.
Frontiers in Pharmacology
December 3, 2020
Lauri Elsilä, Nuppu Korhonen, Petri Hyytiä et al.
13 citations
Acute doses of LSD at 0.025, 0.1, and 0.2 mg/kg did not alter reward-driven decision making in mice performing a touch-screen version of the Iowa Gambling Task, nor did the serotonin 2A receptor agonist 25CN-NBOH. The highest LSD dose (0.4 mg/kg) reduced premature responses and increased omission rates without affecting option selection. Amphetamine decreased correct responses and premature responding while increasing omission rates. Mice can perform previously learned decision-making tasks under LSD at commonly used doses.
bioRxiv Preprint Server
December 12, 2024
Lauri V. Elsilä, Elina Nagaeva, Jari-Pekka Luukkonen et al.
1 citation
preprint
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.