Slow receptor kinetics let low-dose psychedelics sustain antidepressant-like effects in mice

A structure-guided study published in Nature Neuroscience reports that β-arrestin signaling downstream of the serotonin 2A receptor (5-HT2AR) is a critical driver of the prolonged antidepressant-like effects of psychedelics in mice. The research team used the design of 5-HT2AR–β-arrestin-biased agonists to separate the signaling events that accompany a psychedelic episode from those that appear to underpin its lasting mood-related behavioral benefits in animal models. According to the authors, the findings uncover the signaling basis of sustained psychedelic efficacy and provide a rational framework for developing nonhallucinogenic psychedelic therapies for psychiatric disorders.

The central insight concerns receptor kinetics. Lysergic acid diethylamide (LSD) dissociates slowly from the 5-HT2AR, and the researchers show that this slow-dissociation behavior allows progressive accumulation of receptor engagement during repeated low-dose administration. Over successive low doses, receptor occupancy builds toward the level achieved by a single acute high dose, while the regimen avoids the high peak concentration that an acute dose produces. This kinetic separation, the authors report, sustains β-arrestin signaling at the receptor while limiting the robust Gαq-mediated calcium responses that accompany strong psychedelic activation.

Consistent with this framework, the regimens tested produced lasting behavioral effects without psychedelic-like disruption. Repeated low-dose LSD produced sustained antidepressant-like behavioral effects in mice, and repeated low-dose psilocybin pretreatment followed by a high-dose psychedelic challenge did so as well. In parallel, these regimens produced no detectable psychedelic-associated behavioral disruption in mice or in cynomolgus macaques, the nonhuman primates used to assess hallucinogenic-like behavioral responses. The findings link a specific downstream signaling pathway, rather than the intensity of the acute experience, to the durability of psychedelic efficacy in the animal models studied.

The paper also characterizes a biased agonist identified through the structure-guided approach. Figure data in the article describe the long-lasting antidepressant-like effect of IHCH-8134, a 5-HT2AR–β-arrestin-biased agonist, alongside a hallucinogenic-like behavioral characterization of the compound and pharmacodynamic profiles of 5-HT2AR downstream signaling pathways. Additional figures document that repeated low-dose psychedelic administration attenuates hallucinogenic-like behavioral responses, and that repeated low-dose psychedelic treatment produces antidepressant-like effects, assembling the evidence chain from molecular signaling to behavior.

The significance of the work lies in the signaling logic it exposes. By demonstrating that β-arrestin signaling can be sustained through repeated low-dose exposure while Gαq-mediated calcium signaling is kept in check, the researchers provide a mechanistic account of how the therapeutic durability of psychedelics might be retained without the high peak receptor activation associated with hallucinogenic effects. Because the reported results are behavioral and pharmacodynamic findings in mice and cynomolgus macaques, they establish preclinical proof of principle rather than clinical efficacy, and translation to human psychiatric treatment would depend on future studies beyond the scope of this paper.

Subject of Research: Sustained antidepressant-like effects of psychedelics through 5-HT2AR–β-arrestin signaling

Article Title: Sustained antidepressant-like effects of psychedelics through 5-HT2AR–β-arrestin signaling

Article References: He, L., Tang, L., Cao, D., Duan, W., Yu, J., Zhang, P., Li, H., Wang, Y., Meng, B., Wang, H., Zhou, Y., Li, W., Li, X., Liu, Z., Zhang, L., Cheng, J., & Wang, S. (2026). Sustained antidepressant-like effects of psychedelics through 5-HT2AR–β-arrestin signaling. Nature Neuroscience. https://doi.org/10.1038/s41593-026-02497-5

Image Credits: AI Generated

DOI: 10.1038/s41593-026-02497-5

Keywords: Sustained, antidepressant-like, effects, psychedelics, HT2AR, arrestin, signaling, scientific research