Paper. Simon IA, Pottie E, Jensen MK et al.. Journal of Medicinal Chemistry, 8 Oct 2026.
Repeated low-dose LSD sustained antidepressant-like effects in mice without psychedelic-like behaviour.
Structure-guided 5-HT2A agonists biased toward β-arrestin drove the long-lasting effect, and LSD's slow receptor dissociation let repeated low doses accumulate occupancy while avoiding the Gq calcium peak. No psychedelic-associated behavioural disruption appeared in mice or cynomolgus macaques. A separate medicinal chemistry paper mapped a druggable hydrophobic tunnel beside the 5-HT2A orthosteric site using synthesised phenethylamines.
How much weight it carries: Mouse and macaque behaviour plus receptor pharmacology; behavioural proxies for hallucinogenesis do not establish what humans would experience. (Mice, Animals, Preclinical, Mechanism, Drug design)
