Prenatal Cannabinoids Produce Sex-Specific Changes in Risk Assessment and Shared Increases in Repetitive Behavior in Adult Offspring

The widespread perception of cannabinoids as harmless remedies has led to increasing use of both cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) during pregnancy, yet their long-term impact on offspring behavior remains incompletely characterized. To directly compare these compounds, pregnant mice received daily CBD or THC (3 mg/kg, gestational days 5–18) and adult progeny of both sexes were evaluated (P90–120). To capture complementary dimensions of emotional and defensive responding, we employed the elevated plus maze (EPM) to quantify anxiety-related measures and ethological risk-assessment postures (e.g., stretch-attend) and the marble burying (MB) test to index repetitive/defensive behavior; together these assays provide convergent but distinct readouts that increase sensitivity to cannabinoid-induced effects. In the EPM, prenatal CBD exposure selectively increased stretch-attend postures in females, indicating heightened risk assessment; males were unaffected, and THC produced no comparable effect. Classical EPM indices—time in open or closed arms, preference for open-arms, and total distance traveled—were unchanged across groups, except that THC-exposed females exhibited hyperlocomotion. In contrast, marble burying was increased in both sexes following prenatal exposure to either CBD or THC, indicating a shared enhancement of repetitive/defensive responses. These results show that prenatal cannabinoid exposure yields enduring, sex-dependent alterations in adult behavior, with CBD selectively heightening female risk assessment and both cannabinoids increasing repetitive behavior across sexes, challenging the notion that CBD is a benign alternative to THC during gestation.