Summary: New large-scale genetic research clarifies biological mechanisms linking Cannabis Use Disorder (CUD) and psychosis. A genome-wide meta-analysis found more than 500 genetic loci associated with psychosis, including 122 novel loci. The results indicate that the causal pathway from heavy cannabis use to psychosis operates through specific biological systems—particularly neurodevelopment and neuronal signaling—providing a foundation for identifying people at highest risk and for developing more targeted treatments.
The study shows a stronger causal effect from CUD to psychosis than the reverse and identifies multiple distinct sets of genetic variants that may explain why some individuals develop psychosis after cannabis exposure while others do not.
Key Research Findings
- Bidirectional causal relationship: The analysis supports a two-way causal association between cannabis use and psychosis, but the effect size is substantially larger in the direction from CUD to psychosis than from psychosis to CUD.
- Three distinct biological routes from CUD to psychosis: For the first time, researchers delineated three groups of causal genetic variants that appear to mediate the progression from heavy cannabis use to psychosis. These groups are enriched for genes involved in:
- Neurodevelopment—genes regulating brain growth and maturation;
- Neuronal signaling—genes affecting synaptic communication and neurotransmitter systems;
- Other cellular processes that may influence vulnerability to cannabis-related psychiatric outcomes.
- Role of the glutamate system: Genetic score analyses point to the glutamate neurotransmitter system as a likely key mediator of cannabis-related psychosis risk. Because THC—the principal psychoactive compound in cannabis—affects glutamatergic signaling, variation in genes that regulate glutamate may help explain individual susceptibility to psychosis following cannabis exposure.
- Broader psychosis definition: Instead of focusing only on schizophrenia, investigators combined genome-wide data for schizophrenia and bipolar I disorder to form a broader “psychosis clinical group.” This approach better reflects epidemiological patterns linking cannabis use with a range of psychotic disorders.
- Asymmetry in causal routes: Only one cluster of causal genetic variants was detected for the pathway from psychosis to CUD, consistent with clinical observations that pre-existing psychosis leads to heavier cannabis use in a more uniform way than cannabis use leads to psychosis.
Source: King’s College London
Summary of the study
Researchers from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King’s College London published these findings in Biological Psychiatry Global Open Science. They used updated, large-scale genetic datasets and a meta-analysis of genome-wide association studies (GWAS) for schizophrenia and bipolar I disorder to explore molecular pathways that connect CUD and psychosis.
The combined GWAS approach identified over 500 psychosis-associated genetic loci, 122 of which are newly discovered. Pathway analysis revealed that a greater number of biological pathways were nominally linked to both psychosis and CUD than would be expected by chance, reinforcing a close biological relationship between the two conditions.
Professor Marta Di Forti, Chair in Drug Use, Genetics and Psychosis at King’s IoPPN and senior author of the study, emphasized the public health importance of these findings as debates about cannabis policy continue. The study strengthens evidence for a stronger causal effect from CUD to psychosis and highlights three separate genetic mechanisms that may explain how cannabis use can trigger psychotic episodes. Professor Di Forti noted that these results could ultimately help build prediction tools to identify people at greatest risk and support the development of new, targeted treatments.
Dr Isabelle Austin-Zimmerman, research associate and first author, explained that the biology linking cannabis use and psychosis is complex and likely operates through multiple mechanisms. The findings advance understanding of potentially different causes for psychosis that occurs with versus without cannabis exposure, which could inform more personalized clinical care.
Key Questions Answered:
A: Evidence indicates both directions occur, but the causal influence from heavy cannabis use to psychosis is markedly stronger. The study identifies three DNA-based “routes” that could explain how heavy cannabis exposure may precipitate psychotic episodes in susceptible individuals.
A: THC impacts glutamatergic signaling, and the study found that genetic variation in glutamate-related genes may predict increased psychosis risk with cannabis use. This suggests glutamate-focused genetic profiles could help identify people for whom cannabis use is especially hazardous.
A: Potentially. Demonstrating that psychosis associated with cannabis use has a distinct biological signature opens the door to more tailored, targeted interventions rather than one-size-fits-all approaches.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by staff.
About this genetics and CUD research news
Author: Patrick O’Brien
Source: King’s College London
Contact: Patrick O’Brien – King’s College London
Image: Image credited to Neuroscience News
Original Research: Findings to appear in Biological Psychiatry Global Open Science