Matteo Marti

Background and Purpose AKB48 is a synthetic cannabinoid illegally sold for its psychoactive cannabis‐like effects that have been associated with acute intoxication and whose effects are poorly known. Experimental Approach Using a behavioural, neurochemical, and immunohistochemical approach, we investigated the pharmaco‐toxicological effects, pharmacokinetics, and neuroplasticity at cannabinoid CB 1 receptors in the cerebellum and cortex induced by repeated AKB48 administration in male and female mice. Key Results The effects of AKB48 varied significantly depending on sex and treatment duration. The first injection impaired sensorimotor responses and reduced body temperature, analgesia, and breath rate to a greater extent in females than in males; the second injection induced stronger effects in males while the third injection of AKB48 induced weaker responses in both sexes, suggesting emergence of tolerance. The CB 1 receptor antagonist NESS‐0327 prevented the effects induced by repeated AKB48, confirming a CB 1 receptor‐mediated action. Blood AKB48 levels were higher in females than in males and repeated administration caused a progressive rise of AKB48 levels in both sexes, suggesting an inhibitory effect on cytochrome activity. Finally, immunohistochemical analysis revealed higher expression of CB 1 receptors in the cerebellum and cortex of females, and a rapid CB 1 receptor down‐regulation in cerebellar and cortical areas following repeated AKB48 injections, with neuroadaptation occurring generally more rapidly in females than in males. Conclusion and Implications We have shown for the first time that AKB48 effects significantly vary with prolonged use and that sex affects the pharmacodynamic/pharmacokinetic responses to repeated administration, suggesting a sex‐tailored approach in managing AKB48‐induced intoxication.