Prenatal THC exposure produced lasting cognitive deficits in both male and female rat offspring, but through highly divergent sex-specific mechanisms involving different patterns of neural hyperactivity, protein expression changes, and fatty acid deficiencies in the prefrontal cortex and hippocampus.
Developmental neuroscientists, reproductive toxicologists, obstetricians, prenatal cannabis researchers.
Male and female offspring had the same cognitive deficits but completely different brain mechanisms
What the researchers found
Both sexes showed long-term cognitive deficits and hyperactive prefrontal pyramidal neurons. Males showed hippocampal hypoactivity while females showed hyperactivity. Cortical oscillatory activity was strongly sex-divergent. Protein expression disturbances (D1R/D2R, NMDA-2B, synaptophysin, gephyrin, GAD67, PPARalpha) appeared primarily at PD120 in both regions for males, but only in vHIPP for females. MALDI imaging revealed region-, age-, and sex-specific deficiencies in DHA and arachidonic acid.
Why it matters
This is one of the most comprehensive studies of prenatal THC effects, showing that while both sexes suffer cognitively, the underlying biology is radically different. This means treatments for prenatal cannabis effects may need to be sex-specific.
The numbers in context
Both sexes: PFC pyramidal neuron hyperactivity, cognitive deficits. Males: vHIPP hypoactivity, disturbances in both PFC and vHIPP. Females: vHIPP hyperactivity, disturbances mainly in vHIPP. PUFA deficiencies (DHA, ARA) region- and sex-specific.
How the study worked
Rodent model of prenatal cannabis exposure with comprehensive analysis: electrophysiology, cortical oscillations, protein expression at PD21 and PD120, and MALDI imaging mass spectrometry for lipid analysis in prefrontal cortex and hippocampus.
What this study cannot tell us
Rat model with injected THC (not smoked cannabis). Sex-specific findings are at the biological level and may not directly predict sex-specific behavioral outcomes in humans. MALDI imaging provides spatial distribution but not functional significance. Single THC dose regimen.
How to read the evidence
Comprehensive preclinical study with multiple complementary methods. Published in Molecular Psychiatry. Strong mechanistic evidence.
When this study was published
Published in 2023 in Molecular Psychiatry.
The bigger picture
The discovery that prenatal THC depletes specific fatty acids (DHA and arachidonic acid) in brain regions is particularly novel. These PUFAs are essential for endocannabinoid system function, suggesting THC disrupts the very signaling system it activates, creating a long-term deficit.
Questions still open
- Could DHA supplementation during pregnancy protect against THC-induced brain changes?
- Do sex-specific mechanisms explain why some epidemiological studies find different outcomes in boys vs. girls after prenatal cannabis exposure?
Common questions
Does prenatal THC affect boys and girls differently?
What brain changes does prenatal THC cause?
Read the original research
Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.
Molecular psychiatry, 28(10), 4234-4250
Citation
Sarikahya, Mohammed H; Cousineau, Samantha L; De Felice, Marta; Szkudlarek, Hanna J; Wong, Karen K W; DeVuono, Marieka V; Lee, Kendrick; Rodríguez-Ruiz, Mar; Gummerson, Dana; Proud, Emma; Ng, Tsun Hay Jason; Hudson, Roger; Jung, Tony; Hardy, Daniel B; Yeung, Ken K-C; Schmid, Susanne; Rushlow, Walter; Laviolette, Steven R. (2023). Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.. Molecular psychiatry, 28(10), 4234-4250. https://doi.org/10.1038/s41380-023-02190-0
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