AbstractObjectiveIn the absence of safety data in humans, the use of cannabidiol (CBD) is not recommended during pregnancy. Yet >50% of pregnancies in women with epilepsy are unintended, making fetal exposure to CBD possible. As a small‐molecule, highly lipid‐soluble drug, CBD is likely to be distributed into the placenta and cross it. To estimate the placental distribution profile of CBD and its potential short‐term placental effects, we conducted an ex vivo perfusion study in human placentas.MethodsPlacentas were obtained from healthy women undergoing cesarean deliveries. Selected cotyledons were cannulated and perfused for 180 min with a CBD‐containing medium (250 ng/mL, .796 μmol·L⁻¹; representative of a low therapeutic concentration; n = 8). CBD concentrations were determined at 180 min in the medium and placental tissue using liquid chromatography–tandem mass spectrometry. A customized gene panel array was used to analyze the expression of selected genes in the perfused placental cotyledons as well as in placentas perfused with 1000 ng/mL CBD (3.18 μmol·L⁻¹; high therapeutic concentration; n = 8) and in those exposed to the vehicle.ResultsCBD was sequestered in the placental tissue, exhibiting significant variability across samples (median = 5342 ng/g tissue, range = 1066–9351 ng/g tissue). CBD concentrations in the fetal compartment were one fifth of those measured in the maternal compartment (median = 59 ng/mL, range = 48–72 ng/mL vs. 280 = ng/mL, range = 159–388 ng/mL, respectively; p < .01). Placental gene expression was not significantly altered by CBD.SignificanceThe placenta acts as a depot compartment for CBD, slowing down its distribution to the fetus. This phenomenon might yield flatter but prolonged fetal CBD levels in vivo. The attenuated transplacental CBD transfer does not imply that its use by pregnant women is safe for the fetus. Only pregnancy registries and neurocognitive assessments would establish the risk of being antenatally exposed to CBD.