“Background: Recent preclinical studies have shown sex-dependent antidepressant-like responses of cannabidiol in adolescence, which were dependent on biological sex, early-life stress, and dose. In particular, cannabidiol (10 mg/kg) induced acute and sustained antidepressant-like responses in adolescent male rats, while it lacked efficacy in females. This follow-up study aimed at further characterizing cannabidiol’s effects in adolescence, in an attempt to overcome female unresponsiveness, while also evaluating its long-term safety profile in adulthood.
Methods: Groups of adolescent rats of both sexes were treated (ip) with cannabidiol (10, 30, 60 mg/kg) or vehicle (1 ml/kg) for 7 days. Acute (30 min post-injection) and repeated (24 h post-treatment) antidepressant-like responses were measured in the forced-swim test. Brains were collected to evaluate several neurochemical correlates in the hippocampus (CBR1, CBR2, BDNF, and cell proliferation) after adolescent cannabidiol exposure (acute and repeated). Some rats were left undisturbed until adulthood, when long-term effects on cognition were measured in the Barnes maze (short- and long-term memory) or affective-like responses in the forced-swim test. Data was analyzed with two-way ANOVAs (independent variables: sex and treatment).
Results: While the dose of 10 mg/kg of cannabidiol induced antidepressant-like effects in adolescent rats, higher doses had no effect in adolescent rats of both sexes. No changes were observed in any of the hippocampal neuroplasticity markers evaluated. Adolescent cannabidiol exposure did not induce long-term changes in cognitive performance or affective-like behavior.
Conclusions: Overall, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects of moderate magnitude without compromising long-term cognition in rats.”
https://pubmed.ncbi.nlm.nih.gov/40522606/
“To conclude, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects without compromising long-term cognition in rats. In particular, it reinforces prior studies by including more doses of cannabidiol tested during adolescence, while demonstrating efficacy mainly in male rats. Based on the literature, the combination of another antidepressant with cannabidiol might be a good strategy for attempting to induce efficacy in adolescent female rats, and should be further explored. Since no molecular print could be found to parallel the antidepressant-like potential of cannabidiol in adolescence, future studies should explore other avenues while searching for the specific role of sex hormones in the lack of response in females. Finally, and in line with the results that demonstrate that cannabidiol improves cognitive performance, this study adds to this existing literature by providing long-term results on this topic following adolescent cannabidiol exposure in rats of both sexes.”
https://link.springer.com/article/10.1007/s43440-025-00750-5