Nature neuroscienceOct 23, 2026

Long-lasting antidepressant-like effects of psychedelics linked to serotonin receptor signaling

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 25, 2026

Abstract

Lysergic acid diethylamide (LSD) shows potential for sustained antidepressant-like effects without hallucinogenic disruption.

5-HT2A receptor engagement increases progressively with repeated low-dose LSD administration.
Slow-dissociation kinetics of LSD may allow for effective receptor occupancy similar to acute high doses without high peak concentrations.
Sustained beta-arrestin signaling is linked to prolonged antidepressant-like effects observed in mice.
Repeated low-dose LSD and psilocybin pretreatment led to sustained behavioral effects following a high-dose psychedelic challenge.
Both regimens resulted in no observable psychedelic-associated behavioral disruption in mice and cynomolgus macaques.

Simplified

Psychedelics produce long-lasting antidepressant effects, but their hallucinogenic properties limit clinical use. Using structure-guided design of 5-HT_2AR-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-HT_2AR 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 Gα_q-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.

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Long-lasting antidepressant-like effects of psychedelics linked to serotonin receptor signaling

Abstract

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