Clinical Trial of Maternal Choline Supplements to Mitigate Effects of Prenatal Cannabis Exposure on Early Brain Development. - PROJECT SUMMARY Cannabis use during pregnancy is increasing with its legalization in many states and the belief by many that it is a safe and effective treatment for pregnancy-related nausea. This proposal investigates to what extent prenatal maternal supplementation with phosphatidylcholine (PChol) mitigates the effects of prenatal cannabis exposure on the fetus and subsequent child behavior. Higher maternal levels of choline have been shown to improve brain development. Choline in the amniotic fluid activates fetal alpha7-nicotinic receptors, before cerebral cholinergic innervation fully develops, late in gestation. Alpha7-nicotinic receptors and cannabinoid CB1 receptors are expressed on the same cerebral interneurons. Choline activation promotes interneuron development, whereas THC, by interfering with endogenous signaling, retards their development. Consistent with this translational model, a preliminary clinical observational investigation found that mothers with higher gestational choline levels have newborns with more normal fetal development of cerebral inhibition, even if mothers continued moderate cannabis use during pregnancy despite clinical advice. The child’s subsequent ability to pay attention is increased. We propose a randomized, double-blind, placebo-controlled trial of phosphatidylcholine supplementation in 120 pregnant women who use cannabis during pregnancy. Pregnant women will be randomly assigned to receive (1) 7200mg PChol, equivalent to 1028mg choline (Treatment Group, n=60) or (2) corn oil placebo (Placebo Group, n=60). The first aim of this project tests the hypothesis that maternal choline supplementation will interact with maternal cannabis use on the P50 auditory evoked response inhibition, an electrophysiological marker of the development of inhibitory neurotransmission, one month after birth. Aim 2 tests the hypothesis that maternal choline supplementation will interact with maternal cannabis use to mitigate its adverse effects on offspring’s development of attention, temperament, and cognitive behaviors. Prenatal cannabis use, assessed from mothers’ self-report and urine and serum metabolite levels, returned pill count, estimates of choline intake from the mother’s recall of her diet, and plasma levels of choline and its metabolites will be obtained at 14, 16, 22, 28, 34 and 40 weeks of gestation. Cannabis use in the postnatal period and breast milk cannabinoid and choline levels will also be measured. Neonate and infant hair will be analyzed for cannabinoids to detect 3rd trimester and postnatal exposure. The two aims together will document the possible effectiveness of prenatal choline supplementation to protect the fetus’s brain development from exposure to cannabis during gestation. The outcomes of this proposal could have an innovative public health effect to protect the brain development of fetuses whose mothers continue to use cannabis despite medical advice to abstain. These effects may result in decreased risk of mental problems in the children.
