Emerging cannabinoids differ in behavioral safety margins in mice: a comparative hazard proximity analysis of locomotor suppression and catalepsy-like immobility.

Shirakura S.; Ohta A.; Abe H.; Nakamura K.; Ishida A.; Tokeshi M.; Higashi K.; Takahashi H.; Saitoh A. · Forensic toxicology · 2026

**Background & Methods** This comparative study evaluated the acute neurobehavioral effects of six cannabinoids in male C57BL/6J mice using intraperitoneal administration. Locomotor suppression and catalepsy-like immobility were assessed as indices of psychomotor suppression and toxic motor impairment, respectively, with ED50 values determined for each endpoint to calculate the Hazard Proximity Index (HPI). **Key Findings** • All six cannabinoids (THC, HHC, THCH, THCV, HHCH, HHCP) reduced spontaneous locomotor activity, but differed substantially in catalepsy-like immobility induction. THC, THCH, HHCH, and HHCP produced robust catalepsy, while HHC induced only weak, non-significant immobility and THCV showed dose-dependent effects that did not reach 50% catalepsy within tested ranges. • HPI values revealed substantial variation in behavioral safety margins: HHCP (3.7%) and HHC (5.1%) demonstrated the widest separation between psychomotor and toxic endpoints, while THCH (45.1%) and HHCH (33.2%) showed the narrowest safety margins. THC exhibited an intermediate HPI of 25.6%, with THCV HPI not calculable due to incomplete dose-response data. • Psychomotor suppression consistently occurred at lower doses than catalepsy-like toxicity across all cannabinoids, establishing a dose-dependent hierarchy that may inform relative hazard assessment for emerging synthetic cannabinoids. **Dosage & Administration** Specific doses not reported. Administration route: intraperitoneal injection in mice. Catalepsy-like immobility assessed 20 minutes post-dosing; locomotor activity recorded 35 minutes post-dosing. **Safety & Adverse Effects** Catalepsy-like immobility (motor impairment) was the primary safety concern identified, with differential potencies across cannabinoids. HHC and HHCP demonstrated the most favorable safety profiles based on wide separation between psychomotor and toxic endpoints, whereas THCH and HHCH presented greater toxicological concern due to narrower behavioral safety margins. **Evidence Quality** This is a preclinical animal study (mice) with significant translational limitations regarding human safety. The novel HPI metric is introduced as a screening tool but lacks external validation. Study design does not address chronic effects, dose-response reversibility, or mechanism of action. Findings provide preliminary comparative benchmarking useful for forensic toxicology prioritization but cannot directly inform human clinical safety or risk assessment without further investigation.

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