Cannabis use and glutamate across the psychosis spectrum: in vivo evidence from 7T proton magnetic resonance spectroscopy
David R. Roalf, Tyler M. Moore, Jacquelyn Stifelman, Maggie Pecsok, Ally Atkins, Monica E. Calkins, Mariella de Biasi, Christian G. Kohler, Christina Mastracchio, Arianna Mordy, Heather Robinson, Ravinder Reddy, Ravi Prakash Reddy Nanga, Kosha Ruparel, Sage Rush‐Goebel, Daniel H. Wolf, Raquel E. Gur, J. Cobb Scott
Molecular Psychiatry June 27, 2026 DOI: 10.1038/s41380-026-03705-1 via OpenAlex
Summary
AI-generated from the abstractCannabis use is linked to higher psychosis risk, and this study examined whether brain glutamate levels in the anterior cingulate cortex (ACC) relate to symptoms depending on cannabis use. Among 79 participants across the psychosis spectrum, higher ACC glutamate independently predicted greater positive and negative symptoms. However, in cannabis users, lower glutamate was associated with more positive symptoms. Psychosis patients who used cannabis had lower ACC glutamate, suggesting glutamatergic dysfunction may amplify symptom severity. The findings implicate ACC glutamate as a transdiagnostic correlate of symptom burden, especially in cannabis users with psychosis.
Study at a glance
| Characteristics | Cross-sectional Longitudinal Peer reviewed |
|---|---|
| Sample size | 79 |
| Population | Typically developing controls, clinical high-risk individuals, and patients with psychosis |
| Topics | Cannabis |
| Keywords | Glutamatergic Psychosis Glutamate receptor Effects of cannabis Anterior cingulate cortex |
| Key finding | Lower ACC glutamate levels were associated with higher positive symptoms in cannabis users, and ACC glutamatergic dysfunction is linked to symptom burden across the psychosis spectrum, especially in cannabis users with psychosis. |
Abstract
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 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 surveys, urine toxicology, and ultra-high-field 7T 1 HMRS quantification of anterior cingulate cortex (ACC) glutamate levels. Linear models assessed the main and interactive effects of ACC glutamate and cannabis use on positive and negative symptoms. Self-reported cannabis use showed strong concordance with urine toxicology. Cannabis use was associated with higher positive and negative symptoms. Independently, higher ACC glutamate predicted greater positive and negative symptoms. Notably, lower glutamate levels were associated with higher positive symptoms in cannabis 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.