Psychedelics produce long-lasting antidepressant effects, but their hallucinogenic properties limit clinical use. Using structure-guided design of 5-HT2AR–β-arrestin-biased agonists, we identified β-arrestin signaling as a critical driver of prolonged antidepressant-like effects in mice. Here we show that the slow-dissociation kinetics of lysergic acid diethylamide (LSD) enable progressive accumulation of 5-HT2AR engagement during repeated low-dose administration, approaching the receptor occupancy achieved by an acute high dose while avoiding its high peak concentration.
This kinetic separation sustains β-arrestin signaling while limiting robust Gαq-mediated Ca2+ responses. Consistent with this framework, repeated low-dose LSD and repeated low-dose psilocybin pretreatment followed by a high-dose psychedelic challenge produced sustained antidepressant-like behavioral effects in mice. In parallel, these regimens produced no detectable psychedelic-associated behavioral disruption in mice and cynomolgus macaques.
Together, these findings uncover the signaling basis of sustained psychedelic efficacy and provide a rational framework for developing nonhallucinogenic psychedelic therapies for psychiatric disorders. This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription Receive 12 print issues and online access Prices may be subject to local taxes which are calculated during checkout Atomic coordinates and structure factors for the crystal structure of the 5-HT2AR-pimavanserin has been deposited in the PDB (accession number 9WZO). The cryo-EM density maps and corresponding atomic coordinates model for the IHCH-8152-bound 5-HT2AR-Gq complex have been deposited in the Electron Microscopy Data Bank (EMD-68650) and PDB (accession number 22TA).
Source data are provided with this paper. Duan, W., Cao, D., Wang, S. & Cheng, J. Serotonin 2A receptor (5-HT(2A)R) agonists: psychedelics and non-hallucinogenic analogues as emerging antidepressants.
Rev. 124, 124–163 https://doi.org/10.1021/acs.chemrev.3c00375 (2024). Single-dose psilocybin for a treatment-resistant episode of major depression. Med. 387, 1637–1648 https://doi.org/10.1056/NEJMoa2206443 (2022).
Carhart-Harris, R. et al. Trial of psilocybin versus escitalopram for depression. Med. 384, 1402–1411 https://doi.org/10.1056/NEJMoa2032994 (2021).
Extract — continue reading at the source.
