Sex-specific disruptions in the developmental trajectory of anxiety due to prenatal cannabidiol exposure

Abstract

Many pregnant women use cannabidiol (CBD) as a natural remedy to alleviate symptoms such as nausea, insomnia, anxiety, and chronic pain. As much as 20% of pregnancies in the USA and Canada may involve the use of CBD-only products. CBD crosses the placenta and may affect fetal development, potentially leading to neuropsychiatric conditions later in life. Given the limited understanding of the effects of CBD during pregnancy, we adopted a longitudinal approach to investigate the neurodevelopmental trajectory associated with prenatal CBD exposure. Pregnant mice were administered 3 mg/kg CBD from gestational days 5 to 18. At early adolescence, offspring displayed sex-specific behavioral changes. Females, but not males, exhibited a complex anxiety-like phenotype during the elevated plus maze task. This phenotype persisted into adulthood in the open field test and was accompanied by altered reward responsiveness. Throughout post-natal life, female offspring demonstrated heightened stretch-attend postures, a risk-assessment behavior reflecting approach-avoidance tendencies and anxiety. Finally, prenatal CBD exposure increased repetitive behaviors in adult animals of both sexes, as evidenced by the marble burying task. These results provide strong evidence of sex-specific disruptions in the developmental trajectories of anxiety associated with prenatal CBD exposure. They challenge the perception that CBD is universally safe and highlight vulnerabilities linked to gestational CBD exposure.