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

The takeaway

The synthetic cannabinoid AKB48 impaired sensorimotor function more in female mice initially, but males showed stronger effects on second exposure, with both sexes developing tolerance by the third dose and females showing faster brain receptor changes.

People interested in synthetic cannabinoid toxicity and sex differences in drug responses.

Females more impaired initially; faster brain receptor adaptation

What the researchers found

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.

Why it matters

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.

The numbers in context

Females had higher blood AKB48 levels and higher baseline CB1 receptor expression. Tolerance emerged by third injection in both sexes. Repeated dosing caused progressive blood AKB48 accumulation (suggesting cytochrome inhibition). Females showed faster CB1 receptor downregulation.

How the study worked

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.

What this study cannot tell us

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.

How to read the evidence

Comprehensive animal study with behavioral, pharmacokinetic, and neuroanatomical measures in both sexes. Limited to one synthetic cannabinoid and mouse model.

When this study was published

Published in 2024 in the British Journal of Pharmacology.

The bigger picture

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.

Questions still open

Do human women show similar increased vulnerability to first-time synthetic cannabinoid effects? Is the faster female CB1 receptor downregulation protective or does it have negative consequences? Would sex-specific dosing of antidotes improve clinical outcomes?

Common questions

Do synthetic cannabinoids affect men and women differently?

This mouse study found females were more affected by the first dose of AKB48, with higher blood levels and more brain receptors for the drug. Males caught up by the second dose. Both sexes developed tolerance, but females adapted faster at the brain receptor level.

Why were females more affected initially?

Females had higher blood levels of AKB48 (suggesting slower metabolism) and higher baseline CB1 receptor density in the brain, both of which would increase the drug's initial impact.

Read the original research

Sex-specific behavioural, metabolic, and immunohistochemical changes after repeated administration of the synthetic cannabinoid AKB48 in mice.

British journal of pharmacology, 181(9), 1361-1382

View on PubMed ↗Publisher’s paper ↗

Citation

Corli, Giorgia; Roda, Elisa; Tirri, Micaela; Bilel, Sabrine; De Luca, Fabrizio; Strano-Rossi, Sabina; Gaudio, Rosa Maria; De-Giorgio, Fabio; Fattore, Liana; Locatelli, Carlo Alessandro; Marti, Matteo. (2024). Sex-specific behavioural, metabolic, and immunohistochemical changes after repeated administration of the synthetic cannabinoid AKB48 in mice.. British journal of pharmacology, 181(9), 1361-1382. https://doi.org/10.1111/bph.16311