A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT 2A , and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT 2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT 2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT 2A β-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT 2A -selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications. [Display omitted] • 2-Br-LSD is a 5-HT 2A partial agonist but lacks 5-HT 2B agonism • 2-Br-LSD lacks head-twitch responses and tolerance; blocks psychedelics • 2-Br-LSD treatment promotes neuronal structural plasticity dependent on 5-HT 2A • 2-Br-LSD produces active coping behavior and reverses chronic stress deficits Lewis et al. perform an extensive pharmacological characterization of 2-Br-LSD, finding distinct aminergic GPCR polypharmacology, including 5-HT 2A partial agonism and lack of psychedelic-like effects in vivo. Further, 2-Br-LSD induces dendritogenesis and spinogenesis in vitro while promoting active coping behavior in vivo , effects dependent on 5-HT 2A activation. [ABSTRACT FROM AUTHOR]