2. Academic Validation
  3. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders

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

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: ahalberstadt@health.ucsd.edu.
  • 6 Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address: argel.aguilavalles@carleton.ca.
  • 7 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: jmccorvy@mcw.edu.
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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