Characterizing non-hallucinogenic psychedelics beyond the head twitch response: phenotypic fingerprinting of lisuride and LSD
Jillian L. King, Devin P. Effinger, Cameron Basquez-Pfeifer, Janae R. Wallingford, Joselynn R. Calderon, Caden K. O’connell, Scott M. Thompson
Translational Psychiatry June 13, 2026 DOI: 10.1038/s41398-026-04174-4 via OpenAlex
Summary
AI-generated from the abstractThe head-twitch response (HTR) in mice, a standard test for hallucinogenic potential, fails to reliably indicate overall psychoactivity. Lisuride, which did not produce HTR, caused impaired movement, coordination, stress, cognitive disruption, and reduced prefrontal cortex EEG power. LSD, which triggered strong HTR, had minimal effects on these measures. Neither compound's effects beyond HTR depended on 5-HT₂A receptors. The HTR alone is insufficient and should be combined with other assessments.
Study at a glance
| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Lisuride Lysergic acid diethylamide (LSD) MDL 100907 |
| Dose | 0.5 mg/kg lisuride, 0.1 mg/kg LSD |
| Keywords | Lisuride Phenotype Schizophrenia object-oriented programming Head geology Psychosis |
| Key finding | The head-twitch response alone does not reliably indicate psychoactivity, as lisuride produced broad behavioral and physiological disruptions without HTR, while LSD produced HTR with minimal other effects. |
Abstract
The head-twitch response (HTR) is widely used as a preclinical assay for the hallucinogenic potential of compounds, with its utility based on 5HT 2A R activation. Here, we examine how the polypharmacological agonists lisuride and lysergic acid diethylamide (LSD) influence behavioral and physiological outcomes in mice to test whether the HTR reliably reflects overall psychoactivity. Lisuride (0.5 mg/kg) elicited no HTR yet impaired locomotion and coordination, evoked a pronounced stress response, disrupted cognitive function, and markedly reduced prefrontal cortex (PFC) electroencephalogram (EEG) power across several frequency bands. In contrast, LSD (0.1 mg/kg) produced a robust 5HT 2A R-dependent HTR but had minimal impact on locomotion, coordination, stress responsivity, cognitive function, or PFC EEG power. None of these other behavioral or physiological effects of lisuride or LSD were mediated by 5-HT₂A receptors, as pretreatment with the selective antagonist MDL 100907 did not alter outcomes. These results reveal a striking dissociation: the compound that evoked no HTR produced broad behavioral, physiological, and cortical disruptions, while the compound that elicited robust HTRs had little effect. Our findings demonstrate that the HTR alone is not sufficient to identify psychoactivity and is best used in conjunction with other endpoints.