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

  • Cell Rep. 2023 Mar 28;42(3):112203. doi: 10.1016/j.celrep.2023.112203.
Vern Lewis  1 ,  Emma M Bonniwell  2 ,  Janelle K Lanham  2 ,  Abdi Ghaffari  3 ,  Hooshmand Sheshbaradaran  3 ,  Andrew B Cao  2 ,  Maggie M Calkins  2 ,  Mario Alberto Bautista-Carro  1 ,  Emily Arsenault  1 ,  Andre Telfer  1 ,  Fatimeh-Frouh Taghavi-Abkuh  1 ,  Nicholas J Malcolm  2 ,  Fatema El Sayegh  1 ,  Alfonso Abizaid  1 ,  Yasmin Schmid  4 ,  Kathleen Morton  4 ,  Adam L Halberstadt  5 ,  Argel Aguilar-Valles  6 ,  John D McCorvy  7
Affiliations
  • 1. Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
  • 2. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
  • 3. BetterLife Pharma Inc., Vancouver, BC V6H 1A6, Canada.
  • 4. Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA.
  • 5. Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: [email protected].
  • 6. Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address: [email protected].
  • 7. Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: [email protected].
PMID: 36884348 DOI: 10.1016/j.celrep.2023.112203
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.

Keywords
5-HT2A; 5-HT2B; CP: Molecular biology; CP: Neuroscience; G protein-coupled receptor; depression; hallucinogen; neuroplasticity; psychedelic; serotonin; stress; tolerance.
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