HMN 2026: How Brain glutamate changes could link cannabis use to a higher risk of psychosis

Cannabis, commonly known as marijuana, is a plant that contains psychoactive compounds that can temporarily alter people’s brain activity and perceptions. While the consumption of this plant for medical or recreational purposes is now legal in a number of regions worldwide, past studies have linked its frequent use to a higher risk of psychosis.

Psychosis is a psychiatric condition characterized by a disrupted perception of reality, hallucinations, strong beliefs that are not supported by evidence (i.e., delusions) and disorganized thinking. While cannabis use has been linked to a higher risk of experiencing this condition, the neurobiological mechanisms underlying this association have not yet been clearly elucidated.

Researchers at the University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia recently carried out a study exploring the possibility that brain glutamate levels could partly explain the relationship between cannabis use and psychotic symptoms. Their paper, published in Molecular Psychiatry, suggests that differences in glutamate levels could be one of the biological pathways linking cannabis use to psychosis.

Glutamate is an excitatory neurotransmitter, or in simpler terms, a chemical messenger that makes neurons more likely to send electrical signals to other brain cells. Higher or lower levels of this chemical in the brain were previously linked to a higher risk of developing various psychiatric conditions, including psychosis.

“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,” wrote David R. Roalf, Tyler M. Moore and their colleagues in their paper.

Probing the brain chemistry behind cannabis-related psychosis

As part of their study, Roalf and his colleagues examined 79 people with varying levels of psychosis vulnerability. Some of these participants had no known psychiatric conditions and were not experiencing any mental health-related symptoms. Others were considered at a high risk of experiencing psychosis. Finally, a portion of participants were diagnosed with psychosis.

All the participants completed clinical assessments to determine whether they were experiencing positive psychosis symptoms (i.e., hallucinations and delusions), negative psychosis symptoms (i.e., low motivation, a reduced ability to feel pleasure, social withdrawal and a lack of emotional expression), or mood-related symptoms. The researchers also collected information about the patients’ cannabis use and analyzed their urine to detect any recent use of the substance.

Finally, the researchers examined the participants’ brains using a technique called ultra-high-field 7 Tesla magnetic resonance spectroscopy (¹HMRS). This technique allowed them to measure the concentration of specific chemicals in the brain, particularly in a brain region called the anterior cingulate cortex (ACC).

“Linear models assessed the main and interactive effects of ACC glutamate and cannabis use on psychopathology symptoms,” wrote the authors. “Self-reported cannabis use showed good concordance with urine toxicology, with the strongest agreement among frequent users. Both lower ACC glutamate and higher cannabis use were independently associated with positive and negative psychosis symptoms.”

When the team analyzed the collected data, they found that both cannabis use and levels of glutamate in the ACC were linked to the presence and severity of psychosis symptoms. Specifically, people who had used cannabis and had lower glutamate levels in their brains presented more positive psychosis symptoms.

“Lower glutamate levels were associated with higher positive symptoms in cannabis users but not cannabis non-users,” wrote Roalf and his colleagues. “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.”

Possible implications and future research directions

The results of this study suggest that cannabis use and glutamate levels could be connected, in some cases potentially contributing to a higher risk of developing psychosis. While the team’s observations are insightful, they are still preliminary, and more research is needed to better understand the relationship between cannabis use, glutamate and psychosis.

“These findings implicate ACC glutamatergic dysfunction as a transdiagnostic correlate of symptom burden, particularly in those with psychosis who are cannabis users,” wrote the authors. “Glutamate-targeted interventions and longitudinal designs will be needed to examine causal pathways linking cannabis exposure to psychosis-relevant outcomes.”

Future studies could try to determine whether cannabis use directly influences glutamate levels in the brain or whether prior differences in glutamate might increase the vulnerability to experiencing psychosis after using cannabis. Eventually, this work could inform the development of new treatment strategies for individuals presenting psychiatric symptoms associated with cannabis use and altered glutamate signaling.

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