THC altered cholinergic, glutamatergic, and GABAergic neurotransmission in the hippocampus of female rats, with effects that varied depending on whether estrogen was present, suggesting sex hormones shape how THC affects the brain.
Neuroscientists studying sex differences, researchers investigating cannabis and cognition, clinicians prescribing medical cannabis to women.
Estrogen reversed the direction of THC's effects on hippocampal neurotransmission in female rats
What the researchers found
In the hippocampus of ovariectomized female rats, THC increased cholinergic receptor (CHRNA7), glutamate transporter (VGLUT), and GABA receptor expression when estrogen was absent, but decreased these same markers when estrogen was present. THC also increased CB1 receptor and acetylcholine transporter expression that had been reduced by estrogen.
Why it matters
Most cannabis research uses male animals, leaving a gap in understanding how THC affects the female brain. This study reveals that estrogen status fundamentally changes how THC interacts with hippocampal neurotransmission, which has implications for understanding sex differences in cannabis effects on memory and cognition.
The numbers in context
N=20 female Wistar rats; hippocampal subregions CA1, CA3, DG, hilum examined; 6 neurotransmitter markers assessed; estrogen reversed the direction of THC effects on multiple markers.
How the study worked
Twenty female Wistar rats were ovariectomized at 8 weeks and received estradiol benzoate and/or THC. Immunohistochemistry assessed expression of cholinergic (CHRNA7, VAChT), glutamatergic (VGLUT), GABAergic (GABRA, GAD), cannabinoid (CB1), and estrogen (ERalpha) receptors across hippocampal subregions (CA1, CA3, DG, hilum).
What this study cannot tell us
Small animal sample size (N=20). Ovariectomized rats receiving exogenous estrogen do not fully replicate natural hormonal cycling. Results from rat hippocampus may not directly translate to human neurobiology. Does not assess behavioral or cognitive outcomes of the observed neurochemical changes.
How to read the evidence
Preliminary: Small animal study (N=20) providing mechanistic insights that require validation in larger studies and, ultimately, human research.
When this study was published
Published in 2025.
The bigger picture
This study contributes to growing evidence that sex hormones modulate cannabinoid effects on the brain. Given that the hippocampus is critical for memory formation, these findings may help explain why some studies find different cognitive effects of cannabis in women versus men.
Questions still open
- Do these estrogen-dependent effects of THC translate to cognitive differences in humans? How do natural hormonal cycles (menstrual cycle, menopause) affect cannabis sensitivity? Should THC dosing recommendations differ based on hormonal status?
Common questions
Why does estrogen matter for cannabis effects?
Could this explain why cannabis affects men and women differently?
Read the original research
Exogenous Administration of Delta-9-Tetrahydrocannabinol Affects Adult Hippocampal Neurotransmission in Female Wistar Rats.
International journal of molecular sciences, 26(13)
Citation
Neves, Ana M; Leal, Sandra; Fonseca, Bruno M; Sá, Susana I. (2025). Exogenous Administration of Delta-9-Tetrahydrocannabinol Affects Adult Hippocampal Neurotransmission in Female Wistar Rats.. International journal of molecular sciences, 26(13). https://doi.org/10.3390/ijms26136144
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