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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_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.

SUBMITTER: Lewis V

PROVIDER: S-EPMC10112881 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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

Lewis Vern V Bonniwell Emma M EM Lanham Janelle K JK Ghaffari Abdi A Sheshbaradaran Hooshmand H Cao Andrew B AB Calkins Maggie M MM Bautista-Carro Mario Alberto MA Arsenault Emily E Telfer Andre A Taghavi-Abkuh Fatimeh-Frouh FF Malcolm Nicholas J NJ El Sayegh Fatema F Abizaid Alfonso A Schmid Yasmin Y Morton Kathleen K Halberstadt Adam L AL Aguilar-Valles Argel A McCorvy John D JD

Cell reports 20230306 3

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 ...[more]

PMID: 36884348

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

Publications

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

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