Comparative Pharmacological Effects of Lisuride and Lysergic Acid Diethylamide Revisited.
Grant C. Glatfelter, Eline Pottie, John S. Partilla, Christophe P Stove, Michael H. Baumann
ACS Pharmacology & Translational Science March 8, 2024 DOI: 10.1021/acsptsci.3c00192 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male C57BL/6J mice |
| Interventions | Lisuride LSD 8-OH-DPAT WAY100635 |
| Topics | LSD |
| Keywords | Brain chemistry Psychedelics Pharmacology Drug interactions |
| Citations | 28 |
| Key findings | Lisuride's partial agonism at 5-HT2A and potent agonism at 5-HT1A together explain its lack of psychedelic effects. |
Abstract
Lisuride is a non-psychedelic serotonin (5-HT) 2A receptor (5-HT2A) agonist and analogue of the psychedelic lysergic acid diethylamide (LSD). Lisuride also acts as an agonist at the serotonin 1A receptor (5-HT1A), a property known to counter psychedelic effects. Here, we tested whether lisuride lacks psychedelic activity due to a dual mechanism: (1) partial agonism at 5-HT2A and (2) potent agonism at 5-HT1A. The in vitro effects of lisuride, LSD, and related analogues on 5-HT2A signaling were characterized by using miniGαq and β-arrestin 2 recruitment assays. The 5-HT1A- and 5-HT2A-mediated effects of lisuride and LSD were also compared in male C57BL/6J mice. The in vitro results confirmed that LSD is an agonist at 5-HT2A, with high efficacy and potency for recruiting miniGαq and β-arrestin 2. By contrast, lisuride displayed partial efficacy for both functional end points (6-52% of 5-HT or LSD Emax) and antagonized the effects of LSD. The mouse experiments demonstrated that LSD induces head twitch responses (HTRs)(ED50 = 0.039 mg/kg), while lisuride suppresses HTRs (ED50 = 0.006 mg/kg). Lisuride also produced potent hypothermia and hypolocomotion (ED50 = 0.008-0.023 mg/kg) that was blocked by the 5-HT1A antagonist WAY100635 (3 mg/kg). Blockade of 5-HT1A prior to lisuride restored basal HTRs, but it failed to increase HTRs above baseline levels. HTRs induced by LSD were blocked by lisuride (0.03 mg/kg) or the 5-HT1A agonist 8-OH-DPAT (1 mg/kg). Overall, our findings show that lisuride is an ultrapotent 5-HT1A agonist in C57BL/6J mice, limiting its use as a 5-HT2A ligand in mouse studies examining acute drug effects. Results also indicate that the 5-HT2A partial agonist-antagonist activity of lisuride explains its lack of psychedelic effects.
Comparable studies
Other preclinical and animal studies on LSD, most cited first.
Citations in the library
Cited by 22
- Serotonin 1A Receptors Modulate Serotonin 2A Receptor-Mediated Behavioral Effects of 5-Methoxy-N,N-dimethyltryptamine Analogs in Mice. ACS Chemical Neuroscience December 18, 2024
- Psychedelic-like effects induced by 2,5-dimethoxy-4-iodoamphetamine, lysergic acid diethylamide, and psilocybin in male and female C57BL/6J mice. Psychopharmacology May 17, 2025
- Psychedelic 5-HT2A receptor agonism alters neurovascular coupling and differentially affects neuronal and hemodynamic measures of brain function Nature Neuroscience October 13, 2025
- Evidence that 5-HT2A receptor signalling efficacy and not biased agonism differentiates serotonergic psychedelic from non-psychedelic drugs. British Journal of Pharmacology June 22, 2025
- Chemistry/structural biology of psychedelic drugs and their receptor(s). British Journal of Pharmacology October 2, 2024
and 17 more in the library
Cites 53
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- Psychedelics reopen the social reward learning critical period Nature June 14, 2023
- Structure-based discovery of nonhallucinogenic psychedelic analogs Science January 27, 2022
and 48 more in the library