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

Author

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  • Aditya R. Kumar

    (University of Washington School of Pharmacy)

  • Lyndsey S. Benson

    (University of Washington School of Medicine)

  • Erica M. Wymore

    (University of Colorado School of Medicine)

  • Jocelyn E. Phipers

    (University of Colorado School of Medicine)

  • Jennifer C. Dempsey

    (University of Washington School of Medicine)

  • Lucinda A. Cort

    (University of Washington School of Medicine)

  • Jashvant D. Unadkat

    (University of Washington School of Pharmacy)

Abstract

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.

Suggested Citation

  • Aditya R. Kumar & Lyndsey S. Benson & Erica M. Wymore & Jocelyn E. Phipers & Jennifer C. Dempsey & Lucinda A. Cort & Jashvant D. Unadkat, 2025. "Quantification and prediction of human fetal (-)-Δ9-tetrahydrocannabinol/(±)-11-OH-Δ9-tetrahydrocannabinol exposure during pregnancy to inform fetal cannabis toxicity," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55863-5
    DOI: 10.1038/s41467-025-55863-5
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