Developmental Programming by In Utero Opioid and Cannabis Exposure: Impacts on Offspring Neurocognitive and Cardiometabolic Health

Abstract

Introduction: Opioid and cannabis use during pregnancy poses risks to both maternal and fetal health. While prenatal exposure to each drug has been studied in isolation, health outcomes associated with polysubstance use, particularly regarding long-term neurocognitive health in offspring, remain unclear. Opioid agonist therapy such as buprenorphine (BUP) is the prevalent harm reduction strategy employed for opioid use during pregnancy, but its long-term developmental effects remain uncertain. This study examines the impact of prenatal exposure to fentanyl (FEN) and Δ9-tetrahydrocannabinol (THC) on fetal neurocognitive and cardiometabolic programming. The effects of two harm reduction strategies on improving these outcomes are further explored, specifically involving the transition to an opioid agonist therapy and/or removing cannabis exposure by mid-gestation. Methods: Pregnant CD1 dams were administered FEN alone or a combination of FEN and THC throughout gestation. Additional groups were transitioned at mid-gestation to BUP with or without continued THC exposure. Offspring were monitored from birth to adulthood and underwent longitudinal behavioural assessments of working memory, sociability, and motor coordination across key developmental stages. Cardiometabolic health was evaluated through repeated measures of growth trajectories, blood pressure, glucose regulation, and body composition. Results: Combined FEN+THC exposure produced the most pronounced disruptions, impairing working memory, social behaviour, temperature regulation, and cardiometabolic health in a sex-dependent manner. FEN alone also affected neurocognitive and metabolic outcomes, but to a lesser extent. Transitioning from FEN to BUP without the presence of THC altered offspring development. When THC exposure continued throughout gestation, BUP transition failed to normalize behavioural or metabolic trajectories and, in some cases, exacerbated weight gain and neurocognitive effects. When THC was discontinued, transitioning to BUP attenuated adverse outcomes. Conclusion: Prenatal opioid and cannabinoid exposures have complex and sex-dependent effects. The efficacy of harm reduction via BUP is critically influenced by concurrent THC exposure.