Characterizing non-hallucinogenic psychedelics beyond the head twitch response: phenotypic fingerprinting of lisuride and LSD

The head-twitch response (HTR) is widely used as a preclinical assay for the hallucinogenic potential of compounds, with its utility based on 5HT_2AR 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_2AR-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.