A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.
Abstract
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<sub>2A</sub>, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT<sub>2A</sub> partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT<sub>2B</sub> agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT<sub>2A</sub> 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<sub>2A</sub>-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.
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