Could Cannabis Trigger Psychosis by Disrupting Glutamate Brain Pathways?

What the researchers found

The review synthesizes three lines of evidence: cannabis is associated with psychosis in a subset of users, glutamate dysregulation is a feature of schizophrenia, and cannabis affects the glutamate system. The authors hypothesize that cannabis perturbs glutamate neuronal connectivity in the brains of genetically high-risk individuals, potentially initiating psychosis.

Why it matters

Despite strong epidemiological evidence linking cannabis and psychosis, the biological mechanism remains unclear. This review proposes a specific, testable mechanism (glutamate disruption in the default mode network) that could be verified with existing brain imaging technology.

The numbers in context

Most cannabis users are unaffected; a portion develop acute psychotic symptoms; in some, symptoms continue after cessation; review proposes combining MRS and fMRI to test the glutamate hypothesis.

How the study worked

Narrative review examining the intersection of cannabis-psychosis associations, glutamate abnormalities in schizophrenia, and cannabis effects on glutamate pathways, proposing a testable hypothesis using combined MRS and fMRI.

What this study cannot tell us

Narrative review with a proposed hypothesis that has not yet been tested. Selective citation of supporting evidence. The glutamate-cannabis-psychosis connection remains speculative. Does not account for all potential mechanisms of cannabis-related psychosis.

How to read the evidence

Moderate: Integrates multiple lines of evidence into a testable hypothesis, though the specific mechanism proposed has not yet been experimentally validated.

When this study was published

Published in 2025.

The bigger picture

Schizophrenia research has increasingly moved beyond the dopamine hypothesis to include glutamate dysfunction. This review places cannabis at the intersection of these two systems, suggesting that cannabis may trigger psychosis through glutamate pathways rather than (or in addition to) direct dopamine effects.

Questions still open

• Would MRS studies show glutamate differences between cannabis-using and non-using psychosis patients? What genetic variants determine vulnerability to cannabis-induced glutamate disruption? Could glutamate-targeting interventions prevent cannabis-related psychosis in high-risk individuals?

Common questions

Read the original research

The Relationship of glutamate signaling to cannabis use and schizophrenia.

Current opinion in psychiatry, 38(3), 177-181

Citation

Niznikiewicz, Margaret; Lin, Alexander; DeLisi, Lynn E. (2025). The Relationship of glutamate signaling to cannabis use and schizophrenia.. Current opinion in psychiatry, 38(3), 177-181. https://doi.org/10.1097/YCO.0000000000001003

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