<i>In utero</i> chronic cannabis exposure is associated with lower total brain volume in the first month of postnatal life

<i>Background:</i> I<i>n utero</i> cannabis exposure is associated with deleterious offspring neural development and behaviors that emerge across the lifespan. We explored if brain morphology differed in neonates exposed and unexposed to cannabis <i>in utero</i> in the first month of life. <i>Objective:</i> To evaluate differences in global and subcortical regional brain volume (in the amygdala and hippocampus) in neonates in the first month of life according to <i>in utero</i> cannabis exposure. <i>Methods:</i> Prospective pre-birth prospective cohort study of mother-infant pairs selected on the basis of prenatal cannabis use in the absence of alcohol, tobacco, or illegal drug use. The presence of cannabinoids using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was quantified in maternal and neonatal biological samples. Neonatal MRI was conducted to evaluate differences in global and subcortical brain morphology between the exposed and unexposed infants (18 exposed, 21 unexposed). Inverse probability of treatment weighting was utilized in a generalized linear model framework to remove structural confounding bias between exposure groups. Clinical Trial Registration: NCT03718520. <i>Results:</i> The sex distribution of neonates was 43% female. Neonates exposed to cannabis <i>in utero</i> had significantly lower total brain volume (estimated effect size = 26,496.90 mm³, <i>p</i> = .02), independent of confounders including maternal stress, compared to unexposed infants. The unadjusted difference in brain volume was 29,159.82 mm³, <i>p</i> = .05). Regional volumetric differences were not detected in the amygdala or hippocampus. <i>Conclusion:</i> Given the evidence of the adverse effects of exogenous cannabinoids on fetal brain development, it is vital to prioritize prevention and cessation efforts targeting pregnant women.