Tolerance, physical dependence, and Δ9-THC-like interoceptive effects of cannabinol in mice.

Vanegas S.; Marusich J.; Maturano J.; Sarlah D.; Kinsey S. · Drug and alcohol dependence · 2026

**Background & Methods** This preclinical study examined tolerance, physical dependence, and discriminative stimulus effects of cannabinol (CBN) in adult C57BL/6 mice. Mice received twice-daily CBN administration for five days and were evaluated using the tetrad battery (catalepsy, antinociception, hypothermia, locomotor activity), followed by rimonabant administration to assess withdrawal signs and tail suspension testing. **Key Findings** • Repeated CBN administration induced tolerance to cannabimimetic effects, with mice demonstrating reduced catalepsy, antinociception, and hypothermia; cross-tolerance was observed to the CB1/CB2 agonist WIN 55,212-2, indicating shared receptor mechanisms. • Physical dependence developed with CBN use, as evidenced by rimonabant-induced somatic withdrawal signs (head twitches, paw tremors) and increased struggling behavior in the tail suspension test following repeated exposure. • CBN fully substituted for THC in discriminative stimulus tests, demonstrating THC-like psychoactive properties; notably, CBN combined with THC attenuated THC's psychoactive effects, and rimonabant was less effective at reducing CBN-induced psychoactivity compared to THC-induced effects. **Dosage & Administration** Not reported. The abstract does not specify CBN doses, route of administration (though typical for mouse studies would be intraperitoneal or oral), or rimonabant dosing. **Safety & Adverse Effects** Withdrawal effects were documented upon rimonabant administration in CBN-treated mice, including somatic signs (head twitches, paw tremors) and behavioral changes (increased struggling). No other adverse effects were reported. **Evidence Quality** This is a preclinical animal study with significant limitations regarding clinical translational applicability. Findings in mice may not directly translate to humans given differences in metabolism, cannabinoid receptor distribution, and behavioral assessment methods. The study does not specify sample sizes, statistical analyses, or control conditions in detail. As a 2026 publication, this represents emerging evidence on an understudied cannabinoid. The structured tetrad battery and withdrawal assessment protocols are well-established, lending methodological rigor. However, human clinical trials are needed to determine whether CBN tolerance, dependence, and drug interactions occur at clinically relevant doses in patients.

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