Synthetic cannabinoid AKB48 affected female mice more on first dose but males caught up by second exposure

First AKB48 injection impaired sensorimotor responses, temperature, analgesia, and breathing more in females than males. The second injection induced stronger effects in males. By the third injection, both sexes showed weaker responses (tolerance). Females had higher blood AKB48 levels, higher baseline CB1 receptor density, and faster CB1 receptor downregulation in cerebellum and cortex.

Male and female CD-1 mice received repeated AKB48 injections. Sensorimotor responses, body temperature, pain threshold, breathing, and motor activity measured after each dose. CB1 receptor antagonist confirmed receptor-mediated action. Blood pharmacokinetics tracked. CB1 receptor immunohistochemistry performed in brain regions.

Synthetic cannabinoid intoxications are a growing clinical problem. Finding that sex dramatically affects the response pattern and speed of tolerance suggests that treatment of intoxication may need to account for sex differences.

Most synthetic cannabinoid research uses only male animals. This study demonstrates that ignoring sex leads to an incomplete picture, with females showing both greater initial vulnerability and faster neuroadaptation, which has direct implications for emergency medicine responses.

Mouse model with controlled dosing does not reflect human recreational use patterns. AKB48 is one of many synthetic cannabinoids with different pharmacological profiles. Only acute and short-term repeated dosing studied.