Male rats exposed to THC during adolescence developed memory problems and psychotic-like behaviors tied to disrupted glutamate signaling and inflammation in the hippocampus.
Read this if you want to understand why adolescent cannabis use might affect boys and girls differently at the brain level.
Male rats showed hippocampal glutamate disruption and neuroinflammation; female rats showed prefrontal cortex changes instead
What the researchers found
Male rats that received THC during adolescence showed lasting cognitive deficits and psychotic-like behaviors in adulthood, but no emotional disturbances. This contrasted with female rats from previous work by the same group, who developed emotional problems instead.
At the cellular level, THC-treated males had significantly increased expression of glutamate receptor subunits (GluN2B, GluA1, GluA2) and synaptic markers (synaptophysin, PSD95) in the hippocampus. Glutamate release from hippocampal nerve terminals was also elevated.
The hippocampus also showed persistent neuroinflammation, with increased TNF-alpha, iNOS, and COX-2 alongside reduced anti-inflammatory IL-10. Critically, none of these changes appeared in the prefrontal cortex, suggesting region-specific vulnerability.
Why it matters
This study adds to growing evidence that adolescent cannabis exposure can permanently reshape brain development, and that the effects differ by sex. The finding that males show hippocampal-centered damage while females show prefrontal-centered damage suggests the adolescent brain has region-specific windows of vulnerability to THC.
The numbers in context
GluN2B, GluA1, and GluA2 receptor subunits were all significantly increased in hippocampal post-synaptic fractions. Synaptophysin and PSD95 markers were elevated. Pro-inflammatory markers TNF-alpha, iNOS, and COX-2 were increased while anti-inflammatory IL-10 was reduced. No alterations were found in the prefrontal cortex.
How the study worked
Researchers treated adolescent male rats with escalating doses of THC twice daily from postnatal day 35 to 45 (roughly equivalent to human mid-adolescence). At adulthood, they ran behavioral tests for psychotic-like symptoms, emotional reactivity, and cognition. They then examined hippocampal and prefrontal cortex tissue for glutamate receptor expression, synaptic markers, neurotransmitter release, and inflammatory markers.
What this study cannot tell us
This is an animal study using injected THC at controlled doses, which differs from how humans consume cannabis. The doses and timing may not directly translate to human adolescent use patterns. The study examined only one timepoint in adulthood, so it is unclear whether these changes persist lifelong or eventually resolve.
How to read the evidence
Animal study using controlled THC administration in rats. Provides mechanistic insight but requires human studies to confirm relevance.
When this study was published
Published in 2016. The sex-dependent framework for adolescent THC effects has continued to develop in subsequent research.
The bigger picture
The sex-dependent pattern revealed here and in the companion female study creates a more nuanced picture of adolescent THC risk. Rather than a single uniform harm, THC appears to exploit whichever brain regions are most actively developing at the time of exposure, and this differs between sexes. This has implications for understanding why cannabis-related outcomes vary so widely across populations.
Questions still open
- Would lower or intermittent THC doses produce the same hippocampal effects in males? Do these glutamate and inflammatory changes respond to any intervention after the THC exposure window closes? How do these findings map onto the sex differences observed in human cannabis users?
Common questions
Why did males and females respond differently to adolescent THC?
Does this mean cannabis causes psychosis in teenage boys?
Read the original research
Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.
Pharmacological research, 111, 459-470
Citation
Zamberletti, Erica; Gabaglio, Marina; Grilli, Massimo; Prini, Pamela; Catanese, Alberto; Pittaluga, Anna; Marchi, Mario; Rubino, Tiziana; Parolaro, Daniela. (2016). Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats.. Pharmacological research, 111, 459-470. https://doi.org/10.1016/j.phrs.2016.07.008
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