Chronic THC exposure in adolescent mice triggered pro-psychotic changes in serotonin receptor signaling
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?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?
Trust & Context
- Key Stat:
- Rapamycin fully blocked THC-induced pro-hallucinogenic serotonin receptor changes
- Evidence Grade:
- Preliminary. Animal model with novel mechanistic findings, but not yet replicated or tested in humans.
- Study Age:
- Published in 2018. The Akt/mTOR pathway has since been explored further in cannabis neuroscience research.
- Original Title:
- Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.
- Published In:
- Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 43(10), 2028-2035 (2018)
- Authors:
- Ibarra-Lecue, Inés(2), Mollinedo-Gajate, Irene, Meana, J Javier(2), Callado, Luis F, Diez-Alarcia, Rebeca, Urigüen, Leyre
- Database ID:
- RTHC-01698
Evidence Hierarchy
Tests effects in animals (usually mice or rats), not humans.
What do these levels mean? →Frequently Asked Questions
What does "pro-hallucinogenic signaling" mean?
The serotonin 2A receptor can signal through different G-protein partners. When it shifts toward inhibitory G-proteins (instead of the standard Gαq/11), this signaling pattern is associated with hallucinogenic and psychotic effects. Classic hallucinogens like LSD also work partly through this receptor.
Does this mean all adolescent cannabis users will develop psychosis?
No. This was a mouse study showing one molecular mechanism. Human psychosis risk from cannabis involves multiple genetic and environmental factors. Most adolescent cannabis users do not develop psychosis.
What is rapamycin and could it be used to prevent cannabis-related psychosis?
Rapamycin is an immunosuppressant drug that blocks the mTOR signaling pathway. In this study it prevented THC-induced receptor changes in mice. It is not currently used for this purpose in humans and would need extensive testing before any clinical application.
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Cite This Study
https://rethinkthc.com/research/RTHC-01698APA
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
MLA
Ibarra-Lecue, Inés, et al. "Chronic cannabis promotes pro-hallucinogenic signaling of 5-HT2A receptors through Akt/mTOR pathway.." Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2018. https://doi.org/10.1038/s41386-018-0076-y
RethinkTHC
RethinkTHC Research Database. "Chronic cannabis promotes pro-hallucinogenic signaling of 5-..." RTHC-01698. Retrieved from https://rethinkthc.com/research/ibarra-lecue-2018-chronic-cannabis-promotes-prohallucinogenic
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.