A mouse study found that early chronic THC exposure rewired serotonin 2A receptors in the brain toward a pro-hallucinogenic signaling pattern, and blocking the Akt/mTOR pathway with rapamycin prevented these changes.
Neuroscience researchers studying cannabis-psychosis mechanisms; clinicians working with adolescent cannabis users; anyone interested in the biological basis of cannabis-related psychosis risk.
Rapamycin fully blocked THC-induced pro-hallucinogenic serotonin receptor changes
What the researchers found
Researchers exposed mice to chronic THC during an early developmental window and then examined serotonin 2A receptor (5-HT2AR) function in the frontal cortex.
Chronic THC shifted the receptor toward coupling with inhibitory G-proteins (Gαi1, Gαi3, Gαo, and Gαz) rather than the standard Gαq/11 pathway. This specific signaling pattern has been linked to psychotic symptoms in humans.
THC-treated mice also showed disrupted prepulse inhibition, a standard lab measure of sensory gating deficits seen in schizophrenia.
Critically, the drug rapamycin (which blocks the Akt/mTOR pathway) prevented both the receptor signaling shift and the schizophrenia-like behavioral effects.
This is the first mechanistic explanation for how chronic cannabis exposure during early life could increase psychosis risk later on, pointing to a specific molecular pathway rather than a vague association.
Why it matters
Epidemiological data have long linked adolescent cannabis use to later psychosis risk, but the biological mechanism was unknown. This study identifies a specific molecular pathway (Akt/mTOR-driven changes in serotonin receptor signaling) that could explain the connection, which matters for understanding who might be most vulnerable.
The numbers in context
THC induced supersensitive coupling of 5-HT2AR to four inhibitory G-proteins (Gαi1, Gαi3, Gαo, Gαz) without changing the canonical Gαq/11 pathway. Rapamycin fully blocked these signaling changes and the associated behavioral deficits.
How the study worked
Mouse study using chronic THC administration during early development. Measured 5-HT2AR G-protein coupling using [35S]GTPγS binding assays. Behavioral testing included prepulse inhibition. Rapamycin was used to test whether blocking Akt/mTOR could prevent the observed changes.
What this study cannot tell us
Mouse study, so direct translation to human adolescent cannabis use is uncertain. THC doses and exposure timing may not map cleanly onto human patterns. The study used pure THC without CBD, which may modulate these effects in whole-plant cannabis.
How to read the evidence
Preliminary. Animal model with novel mechanistic findings, but not yet replicated or tested in humans.
When this study was published
Published in 2018. The Akt/mTOR pathway has since been explored further in cannabis neuroscience research.
The bigger picture
This study adds mechanistic depth to the epidemiological link between adolescent cannabis use and psychosis. Rather than just showing correlation, it identifies a druggable pathway (Akt/mTOR) that mediates the effect, which could eventually inform prevention strategies for at-risk individuals.
Questions still open
- Does CBD co-administration prevent these serotonin receptor changes? Do humans with genetic variants affecting the Akt/mTOR pathway show different psychosis risk from cannabis? Could rapamycin-like drugs be protective for high-risk cannabis users?
Common questions
What does "pro-hallucinogenic signaling" mean?
Does this mean all adolescent cannabis users will develop psychosis?
What is rapamycin and could it be used to prevent cannabis-related psychosis?
Read the original research
Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(10), 2028-2035
Citation
Ibarra-Lecue, Inés; Mollinedo-Gajate, Irene; Meana, J Javier; Callado, Luis F; Diez-Alarcia, Rebeca; Urigüen, Leyre. (2018). Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(10), 2028-2035. https://doi.org/10.1038/s41386-018-0076-y
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