A new study published in JAMA Psychiatry provides evidence that young adults at risk of developing psychosis show reduced brain connectivity, a deficit that cannabis use appears to exacerbate. Researchers at McGill University identified a decrease in synaptic density—connections between neurons—among individuals at high risk for psychosis, compared to a healthy control group. This finding provides insight into how cannabis use may disrupt brain development and offers a potential target for developing treatments for psychosis.
Schizophrenia and related psychotic disorders often emerge during adolescence or early adulthood, periods marked by critical brain development. These conditions are associated with disruptions in synaptic pruning, a natural process where the brain refines and eliminates weak synaptic connections to optimize neural efficiency. Previous studies have hinted at the role of synaptic dysfunction in psychosis, but most evidence has come from indirect methods like postmortem examinations and genetic studies.
Cannabis use has long been linked to an increased risk of psychosis, with frequent users facing a significantly heightened risk. However, the biological mechanisms behind this association remain poorly understood. By directly measuring synaptic density in living participants using advanced imaging techniques, the new study aimed to explore whether synaptic deficits are present in early psychosis and in those at high risk of developing the condition. The researchers also examined whether cannabis use exacerbates these deficits.
“As psychiatrists, we know schizophrenia is one of the most challenging mental health disorders, significantly impacting patients and their families,” said study author M. Belén Blasco, a PhD student at McGill University and member of Romina Mizrahi’s Clinical & Translational Sciences (CaTS) lab.
“Psychiatry still faces enormous obstacles to provide treatments that enable these individuals to lead fulfilling lives. Evidence suggests that the way connections between neurons form during development may be disrupted in schizophrenia, and we believe studying this is key to advancing prevention in psychiatry.”
The study included 49 participants recruited from the Montreal area, divided into three groups: individuals with a recent diagnosis of psychosis, individuals at clinical high risk for psychosis, and healthy controls. All participants underwent comprehensive medical and psychiatric assessments to ensure they met the study’s inclusion criteria. Participants with psychosis were required to have been diagnosed within the past three years, while those in the high-risk group exhibited prodromal symptoms indicative of potential psychosis development.
Using a specialized imaging technique called positron emission tomography (PET), the researchers measured levels of synaptic vesicle glycoprotein 2A (SV2A), a protein found on synaptic vesicles that serves as a marker of synaptic density. This method allowed the team to directly quantify synaptic density in key brain regions linked to psychosis, such as the prefrontal cortex, hippocampus, and striatum. Participants also underwent magnetic resonance imaging (MRI) to assess gray matter microstructure, providing additional insights into how synaptic deficits relate to broader brain changes.
Cannabis use was a specific focus of the study. Participants completed drug screenings, and the researchers examined whether cannabis users showed different patterns of synaptic density compared to non-users. Clinical measures of psychosis symptoms, including both positive symptoms (e.g., hallucinations and delusions) and negative symptoms (e.g., social withdrawal and lack of motivation), were also assessed to explore relationships between synaptic deficits and symptom severity.
The researchers observed reductions in synaptic density in both the psychosis and high-risk groups compared to healthy controls. These deficits were particularly pronounced in brain regions like the anterior cingulate cortex, prefrontal cortex, and striatum—areas critical for cognitive and emotional functioning. Individuals at high risk for psychosis showed lower synaptic density even before the onset of full-blown symptoms, suggesting that these changes may precede the development of psychotic disorders.
Cannabis use was associated with further reductions in synaptic density across the study groups, reinforcing the hypothesis that cannabis disrupts the brain’s natural pruning process. This disruption appears to be most relevant during critical periods of brain maturation, such as adolescence and early adulthood. The study found that cannabis use had the greatest impact on synaptic density in the striatum, a region involved in reward processing and motivation, which could explain its role in psychosis risk.
“Using innovative brain imaging techniques, we measured synaptic density in individuals at early stages of schizophrenia and others at high clinical risk,” Blasco told PsyPost. “Synapses are the connections between neurons that enable communication in the brain. We found that patients in the early stages of schizophrenia and those at high clinical risk showed reduced synaptic density compared to healthy individuals. Cannabis appears to interfere with the brain’s natural process of refining synapses, which is vital for healthy brain development.”
In addition to the observed synaptic deficits, the researchers found that reduced synaptic density was closely linked to negative symptoms of psychosis, such as diminished social engagement and emotional expression. These symptoms, which are notoriously difficult to treat with current medications, may be driven by underlying disruptions in synaptic connectivity. The study did not find a significant relationship between synaptic density and positive symptoms like hallucinations, suggesting that different mechanisms may underlie these symptom domains.
“We observed that reduced synaptic density was linked to symptoms such as social withdrawal and lack of motivation—symptoms that are particularly difficult to treat with current medications,” Blasco explained. “Interestingly, these changes occur early in psychosis, even before the full range of symptoms emerges. This suggests that focusing on synaptic health could lead to new treatments that better address social and motivational challenges.”
But as with all research, there are some caveats. The sample size was relatively small, which is common in PET imaging studies due to the high cost and complexity of the technique. This limits the generalizability of the findings and underscores the need for larger, multicenter studies to confirm these results. Additionally, while the study focused on cannabis use, it did not assess the potential impact of other substances, nor did it explore the effects of different patterns or intensities of cannabis use.
The cross-sectional design of the study also means that it cannot establish causality. For example, it remains unclear whether cannabis use directly causes synaptic deficits or whether individuals with pre-existing vulnerabilities are more likely to use cannabis. Longitudinal studies are needed to determine whether synaptic density changes predict the onset of psychosis and whether reducing cannabis use can mitigate these changes.
Finally, the researchers acknowledged that SV2A is an indirect marker of synaptic density, and alternative interpretations of their findings are possible. While the use of advanced imaging techniques provides a significant advantage, further validation of these methods is necessary.
The findings offer several promising avenues for future research. Longitudinal studies could track individuals at high risk for psychosis over time to determine whether synaptic density changes predict the transition to full-blown psychosis. Such studies could also explore whether interventions like cannabis cessation or targeted therapies can prevent or reverse synaptic deficits.
Developing treatments that specifically address synaptic dysfunction may also offer new hope for individuals with psychosis, particularly those with severe negative symptoms that are poorly managed by current medications. By targeting the biological mechanisms underlying these symptoms, researchers may be able to improve outcomes and quality of life for individuals with psychotic disorders.
“Not everyone who uses cannabis will develop psychosis, but for some individuals, cannabis appears to disrupt the brain’s natural process of refining synapses, which is essential for healthy brain development,” Blasco noted. “Our study raises the question of whether this disruption might be particularly relevant during critical periods of brain maturation, such as adolescence or early adulthood. Further research is needed to understand why some people are more vulnerable to this process than others.”
“Future research should investigate whether these brain changes can help predict the onset of psychosis, enabling early intervention before more severe symptoms appear. Understanding the role of factors like cannabis use or stress in synaptic health will be key to prevention. Additionally, developing new medications targeting synaptic density could fill crucial gaps in current treatments.”
“Our study would not have been possible without the help from the staff at the Montreal Neurological Institute (Dr. Gassan Massarweh, Dr. Jean-Paul Soucy, Chris Hsiao) and the exceptional team at the psychiatric emergency service of the Douglas Hospital (Dr. Cohen),” Blasco added. “We also thank CIHR for funding the study, and the organizations supporting the lead student (FRQS, Stratas Foundation, and Dolansky Foundation).”
The study, “Synaptic Density in Early Stages of Psychosis and Clinical High Risk,” was authored by M. Belen Blasco, Kankana Nisha Aji, Christian Ramos-Jiménez, Ilana Ruth Leppert, Christine Lucas Tardif, Johan Cohen, Pablo M. Rusjan, and Romina Mizrahi.
