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

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

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55863-5

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