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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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The non-hallucinogenic LSD analog 2-Br-LSD promoted neuroplasticity and antidepressant-like effects without inducing tolerance or 5-HT2B-mediated cardiac risk.
Synthesized
Comparable studies
Other preclinical and animal studies on LSD for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling Male rats (olfactory bulbectomised and sham-operated) | 2014 | Animal model study | |
| LSD's rapid antidepressant effects are modulated by 5-HT2B receptors. Naive rats and naive mice | 2025 | Experimental study | |
| 401. Prophylactic effects of LSD on inflammatory rodent model of depression Male mice and male rats | 2026 | Preclinical animal study |