Neurobiological and Behavioral Consequences of Prenatal Methadone or Buprenorphine Exposure: Insight From Animal...

The marked increase in opioid use over the past three decades has been accompanied by increased use of medications for opioid use disorder (MOUD), including during pregnancy. However, methadone and buprenorphine, the primary MOUDs, cross the placenta and the immature fetal blood-brain barrier, raising concerns about potential effects on offspring development. In this review, we summarize experimental animal studies published over the past 25 years examining neurobiological and behavioral outcomes following prenatal exposure to methadone or buprenorphine. Although animal models cannot fully establish human outcomes, they offer important insights into causal relationships and underlying biological mechanisms that are difficult to study in clinical populations. Our aims were to compare the effects of methadone and buprenorphine, assess sex-specific and intergenerational effects, and identify areas where further preclinical research is needed. In total, 53 studies were identified. Collectively, the findings show that prenatal MOUD exposure is associated with alterations in several key neurobiological processes, including opioid receptor expression and signaling, neurotransmitter systems, neurotrophic pathways, neurogenesis and neuronal maturation, synaptic organization and plasticity, myelination, structural development, and neuroinflammation. Behavioral outcomes include alterations in cognitive function, affective and social behaviors, reward-related behavior, and pain sensitivity. Evidence for sex-specific and intergenerational effects is increasing, but the overall evidence base remains limited. Substantial variability in findings limits the ability to draw definitive conclusions. Future studies should integrate mechanistic and functional approaches and focus on comparisons between methadone and buprenorphine, sex-specific differences, and intergenerational effects using translationally relevant models. More knowledge is crucial for supporting evidence-based decision-making during pregnancy and for minimizing potential long-term risks to offspring.