A non-hallucinogenic LSD analog with therapeutic potential for mood disorders.
Vern Lewis, Emma M. Bonniwell, Janelle K. Lanham, Abdi Ghaffari, Hooshmand Sheshbaradaran, Andrew B. Cao, Maggie M. Calkins, Mario Alberto Bautista-Carro, Emily Arsenault, Andre Telfer, Fatimeh-Frouh Taghavi-Abkuh, Nicholas J Malcolm, Fatema El Sayegh, Alfonso Abizaid, Yasmin Schmid, Kathleen Morton, Adam L. Halberstadt, Argel Aguilar-Valles, John D. Mccorvy
Cell Reports March 28, 2023 DOI: 10.1016/j.celrep.2023.112203 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice and cultured rat cortical neurons |
| Interventions | 2-bromo-LSD (2-Br-LSD) LSD volinanserin (M100907) |
| Topics | Depression Neuroplasticity Serotonin LSD |
| Keywords | 5-ht2a 5-ht2b Cp: molecular biology Cp: neuroscience G protein-coupled receptor Stress Tolerance Psychedelics hallucinogens Psychedelic compounds Neuroscience neuroplasticity Neural connections Brain science Mental health depression Antidepressants |
| Citations | 129 |
| Key points | 2-Br-LSD is a non-hallucinogenic 5-HT2A partial agonist that promotes neuroplasticity and antidepressant-like effects without inducing tolerance or 5-HT2B-mediated cardiac risk. |
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-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A 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-HT2A-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.