Cannabis use and glutamate across the psychosis spectrum: in vivo evidence from 7T proton magnetic resonance spectroscopy
Molecular psychiatry · 2026 Jun 27
Abstract
Cannabis use is linked to elevated psychosis risk, yet the neurobiological mechanisms that couple use to symptom expression remain unclear. Because glutamatergic dysregulation has been implicated in both cannabis effects and psychosis vulnerability, we examined whether brain glutamate relates to dimensional psychosis symptoms as a function of cannabis use across the psychosis spectrum. Seventy-nine participants-typically developing controls, clinical high-risk individuals, and patients with psychosis-completed dimensional clinical assessments, detailed cannabis use surveys, urine toxicology, and ultra-high-field 7T magnetic resonance spectroscopy ( 1 HMRS) of the anterior cingulate cortex (ACC). Linear models assessed the main and interactive effects of ACC glutamate and cannabis use on psychopathology symptoms. Self-reported cannabis use showed good concordance with urine toxicology, with strongest agreement among frequent users. Both lower ACC glutamate and higher cannabis use were independently associated with positive and negative psychosis symptoms. Notably, lower glutamate levels were associated with higher positive symptoms in cannabis users but not cannabis non-users. Exploratory analyses suggested interactions for depressive and manic symptoms, indicating that glutamatergic abnormalities may amplify the overall severity of cannabis-related symptoms. Sensitivity analyses revealed lower ACC glutamate in psychosis patients-especially cannabis users-highlighting diagnostic group differences and reinforcing the link between cannabis exposure and glutamatergic dysfunction. These findings implicate ACC glutamatergic dysfunction as a transdiagnostic correlate of symptom burden, particularly in those with psychosis who are cannabis users. Glutamate-targeted interventions and longitudinal designs will be needed to examine causal pathways linking cannabis exposure to psychosis-relevant outcomes.
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