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<p>Prenatal cannabis use is associated with neurodevelopmental deficits, likely due to exposure to the psychoactive cannabinoid, (-)-Δ<sup>9</sup>-tetrahydrocannabinol, and its active metabolite, (±)-11-OH-Δ<sup>9</sup>-tetrahydrocannabinol. To determine causality, preclinical studies mimicking human fetal cannabinoid exposure must be conducted. Here we show cannabinoid concentrations across gestation in maternal plasma and paired fetal tissues in trimester 1 and 2 and maternal plasma and fetal umbilical venous plasma in trimester 3. The mean ± SD trimester 1 and 2 (-)-Δ<sup>9</sup>-tetrahydrocannabinol fetal brain/maternal plasma is 0.50 ± 0.18 (<i>n</i> = 3), 0.45 ± 0.28 (<i>n</i> = 14), respectively; trimester 3 (-)-Δ<sup>9</sup>-tetrahydrocannabinol umbilical venous plasma/maternal plasma is 0.35 ± 0.13 (<i>n</i> = 18). To predict fetal cannabinoid exposure at different prenatal cannabis doses (oral or inhaled), we used a verified maternal-fetal physiologically based pharmacokinetic model. At an inhalational and oral dose of 10 mg (-)-Δ<sup>9</sup>-tetrahydrocannabinol, the model-predicted average fetal brain steady-state (-)-Δ<sup>9</sup>-tetrahydrocannabinol/(±)-11-OH-Δ<sup>9</sup>-tetrahydrocannabinol concentrations, at gestational week 15,&#xa0;are 3.7/7.0 nM and 0.73/8.9 nM, respectively. Our maternal-fetal physiologically based pharmacokinetic model can guide future studies to inform risks associated with prenatal cannabis use.</p>

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Quantification and prediction of human fetal (-)-Δ9-tetrahydrocannabinol/(±)-11-OH-Δ9-tetrahydrocannabinol exposure during pregnancy to inform fetal cannabis toxicity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月18日

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  • Aditya R. Kumar,
  • Lyndsey S. Benson,
  • Erica M. Wymore,
  • Jocelyn E. Phipers,
  • Jennifer C. Dempsey,
  • Lucinda A. Cort,
  • Jashvant D. Unadkat

摘要

Prenatal cannabis use is associated with neurodevelopmental deficits, likely due to exposure to the psychoactive cannabinoid, (-)-Δ9-tetrahydrocannabinol, and its active metabolite, (±)-11-OH-Δ9-tetrahydrocannabinol. To determine causality, preclinical studies mimicking human fetal cannabinoid exposure must be conducted. Here we show cannabinoid concentrations across gestation in maternal plasma and paired fetal tissues in trimester 1 and 2 and maternal plasma and fetal umbilical venous plasma in trimester 3. The mean ± SD trimester 1 and 2 (-)-Δ9-tetrahydrocannabinol fetal brain/maternal plasma is 0.50 ± 0.18 (n = 3), 0.45 ± 0.28 (n = 14), respectively; trimester 3 (-)-Δ9-tetrahydrocannabinol umbilical venous plasma/maternal plasma is 0.35 ± 0.13 (n = 18). To predict fetal cannabinoid exposure at different prenatal cannabis doses (oral or inhaled), we used a verified maternal-fetal physiologically based pharmacokinetic model. At an inhalational and oral dose of 10 mg (-)-Δ9-tetrahydrocannabinol, the model-predicted average fetal brain steady-state (-)-Δ9-tetrahydrocannabinol/(±)-11-OH-Δ9-tetrahydrocannabinol concentrations, at gestational week 15, are 3.7/7.0 nM and 0.73/8.9 nM, respectively. Our maternal-fetal physiologically based pharmacokinetic model can guide future studies to inform risks associated with prenatal cannabis use.