A single THC injection during the neonatal period caused spatial memory deficits and altered brain cell structure in female rats — but left males unaffected, revealing a stark sex difference.
Developmental neuroscientists studying sex differences, prenatal exposure researchers, cannabis researchers investigating critical periods of brain vulnerability.
What the researchers found
Rat pups received a single injection of THC (5 mg/kg) or vehicle at postnatal day 3 — a period corresponding to late pregnancy/early postnatal brain development in humans. Weeks later, as young adults (postnatal weeks 6–8), they were tested on behavior and their brains were examined.
The sex difference was dramatic. Female rats exposed to that single neonatal THC dose showed significant spatial memory deficits on the Barnes maze — they were worse at learning and remembering the location of an escape hole. Male rats showed no memory impairment.
Anxiety-like behavior, measured in the open field and elevated plus maze, was not significantly affected in either sex.
Golgi-Cox staining of brain tissue revealed structural changes at the cellular level: THC-exposed animals showed alterations in dendritic morphology and spine density in the frontal cortex and hippocampus — the brain regions most critical for spatial memory and higher cognition. These structural changes provide a biological mechanism for the behavioral findings.
Why it matters
This study is remarkable for two reasons: first, a single dose of THC was sufficient to produce lasting cognitive effects; second, only females were affected. This sex-specific vulnerability suggests that the developing female brain may be more sensitive to endocannabinoid system disruption — a finding with implications for prenatal cannabis exposure, since THC crosses the placenta.
The numbers in context
Single dose: 5 mg/kg THC at postnatal day 3. Female rats: spatial memory deficit on Barnes maze. Male rats: no memory deficit. Neither sex: anxiety changes. Dendritic morphology and spine density alterations in frontal cortex and hippocampus (both sexes structurally affected, but only females showed behavioral consequence).
How the study worked
Male and female Sprague-Dawley rat pups received a single IP injection of THC (5 mg/kg) or vehicle (sesame oil) at postnatal day 3. Behavioral testing at postnatal weeks 6–8: Barnes maze (spatial memory), open field (anxiety), elevated plus maze (anxiety). Golgi-Cox staining for dendritic morphology and spine density in frontal cortex and hippocampus.
Who was studied
Male and female Sprague Dawley rat pups received THC or vehicle at postnatal day 3.
What this study cannot tell us
Single dose at a single timepoint — doesn't model chronic exposure. Neonatal injection is a different route than prenatal placental transfer. Rat brain development timing doesn't perfectly map to human development. Only one THC dose tested. The mechanism connecting structural changes (both sexes) to behavioral effects (females only) needs further investigation.
How to read the evidence
Controlled animal study with behavioral and structural brain outcome measures — strong for demonstrating the sex difference but translation to human neonatal exposure requires caution.
When this study was published
Published in 2026, contributing to the growing evidence that female brains may be more vulnerable to early cannabinoid exposure.
The bigger picture
The sex difference here echoes the prenatal THC mouse MRI study (RTHC-00236), which also found females more affected. The BDNF study (RTHC-00284) provides a potential molecular mechanism — if BDNF changes are also sex-specific, they could explain why females are more vulnerable. The human ABCD data (RTHC-00241, RTHC-00285) can be re-examined for sex differences in prenatal exposure effects. Together, these studies build a consistent picture of female-specific vulnerability to early cannabinoid exposure.
Replication
Not stated in abstract.
Funding
Not reported in abstract.
Conflicts of interest
Not reported in abstract.
Questions still open
- What makes the female brain more vulnerable to neonatal THC exposure? Would multiple doses produce effects in males as well? Does the sex difference in behavioral outcome despite structural changes in both sexes mean females lack a compensatory mechanism that males have?
Read the original research
Sexually Dimorphic Effects of a Single Neonatal Δ9-tetrahydrocannabinol Exposure on Neuronal Dendritic Morphology and Cognitive Functions in Rats.
Cannabis and cannabinoid research, 11(1), 36-48
Cannabis and Cannabinoid Research is a peer-reviewed journal focusing on the science of cannabis and cannabinoids.
Citation
Wadhwa, Meetu; Chinn, Gregory A; Duong, Katrina; Sasaki Russell, Jennifer; Hellman, Judith; Sall, Jeffrey W. (2026). Sexually Dimorphic Effects of a Single Neonatal Δ9-tetrahydrocannabinol Exposure on Neuronal Dendritic Morphology and Cognitive Functions in Rats.. Cannabis and cannabinoid research, 11(1), 36-48. https://doi.org/10.1177/25785125251387835
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