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

This mice and cell study of the non-hallucinogenic LSD analogue 2-bromo-LSD (2-Br-LSD) found it to be a partial agonist at the 5-HT2A receptor but it doesn’t activate the 5-HT2B receptor associated with cardiac valvulopathy (disease of heart valves). It also does not induce tolerance and has been shown to promote neuronal structural plasticity and active coping behaviour in mice. Additionally, 2-Br-LSD reverses the effects of chronic stress. These findings suggest that 2-Br-LSD may have therapeutic potential for mood disorders and other indications.


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.

Authors: 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

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

Current pharmacotherapies for major depressive disorder and anxiety disorders have drawbacks, including delayed therapeutic onset, chronic dosing, and large numbers of treatment-resistant patients. Psychedelics have been shown to reduce depression and anxiety after only one or two doses.

The therapeutic effects of serotonergic psychedelics are not entirely clear. Still, the intensity of the psychedelic response is closely related to the level of 5-HT2A occupation, and this correlation may reflect a relationship between therapeutic response and target engagement.

Preclinical models show that some psychedelic analogues do not produce behavioural effects associated with hallucinogenic effects, but retain the ability to promote cortical neuritogenesis, similar to established antidepressant drugs.

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