Cannabinoid receptor gene CNR1 is downregulated in subcortical brain samples and upregulated in blood samples of individuals with schizophrenia: A participant data systematic meta-analysis

Cannabis use leads to symptom exacerbation in schizophrenia patients, and endocannabinoid ligands have been studied as tentative schizophrenia therapeutics. Here, we aimed to characterise the connection between schizophrenia and the cannabinoid receptor 1 gene (CNR1) and explore possible mechanisms affecting its expression in schizophrenia. We performed a participant data systematic meta-analysis of CNR1 gene expression and additional endocannabinoid system genes in both brain (subcortical areas) and blood samples. We integrated eight brain sample datasets (overall 316 samples; 149 schizophrenia and 167 controls) and two blood sample datasets (overall 90 samples; 53 schizophrenia and 37 controls) while following the PRISMA meta-analysis guidelines. CNR1 was downregulated in subcortical regions and upregulated in blood samples of patients with schizophrenia. CNR2 and genes encoding endocannabinoids synthesis and degradation did not show differential expression in the brain or blood, except fatty acid amide hydrolase (FAAH), which showed a downregulation trend in blood. In addition, the brain expression levels of CNR1 and three GABA receptor genes, GABRA1, GABRA6 and GABRG2, were positively correlated (R =.57,.36,.54; p = 2.7 × 10⁻¹⁴, 6.9 × 10⁻⁶ and 1.1 × 10⁻¹², respectively). Brain CNR1 downregulation and the positive correlation with three GABA receptor genes suggest an association with GABA neurotransmission and possible effects on negative schizophrenia symptoms. Further studies are required for clarifying the opposite CNR1 dysregulation in the brain and blood of schizophrenia patients and the potential of endocannabinoid ligands as schizophrenia therapeutics.