Drugs targeting the human serotonin 2A receptor (5-HT2AR) are used for neuropsychiatric diseases, but many have hallucinogenic effects. Structures of 5-HT2AR complexed with psilocin, LSD, serotonin, and lisuride reveal that serotonin and psilocin show a second binding mode. This insight enabled design of the psychedelic IHCH-7113 and several 5-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice without hallucinogenic effects. These structures provide a foundation for designing safe, nonhallucinogenic psychedelic analogs with therapeutic potential.
New compounds designed to activate the serotonin 2A receptor without causing hallucinations show antidepressant effects in mice. Building on the structures of the antipsychotic aripiprazole and a previously reported lead compound, two series of novel 5-HT2A partial agonists were synthesized and tested. Several compounds demonstrated potent activity in G protein coupling and β-arrestin2 recruitment assays. One compound, 28c, reduced depressive-like behavior in the mouse tail-suspension test without producing head-twitch responses, a rodent correlate of hallucinogenic effects. These results add to the growing collection of nonhallucinogenic 5-HT2A agonists that could potentially provide rapid and enduring antidepressant effects.
A Chinese version of the Near-Death Experience Content (NDE-C) scale was translated and validated on 79 near-death experience testimonies. The translation used Brislin's back-translation model, and the scale showed good internal consistency (Cronbach's α = 0.846). Confirmatory factor analysis supported the scale's structure. This new Chinese NDE-C scale is now available to screen people who have had near-death experiences or near-death-like experiences (e.g., from meditation) and to quantify their subjective experiences, enabling further research on this phenomenon in Eastern cultural contexts.