The Cannabinoid CB₁ Receptor in Schizophrenia

Converging lines of evidence from epidemiological, preclinical, and experimental studies indicate that the endocannabinoid system may be involved in the pathophysiology of schizophrenia and suggest that the cannabinoid CB₁ receptor may be a potential therapeutic target. In view of this, we first provide an overview of the endocannabinoid system and systematically review the evidence for CB₁ receptor alterations in animal models of schizophrenia and clinical studies in schizophrenia. MEDLINE, EMBASE, PsycArticles, and PsycINFO were systematically searched from inception until January 7, 2020. Of 1187 articles, 24 were included in the systematic review, including 8 preclinical studies measuring the CB₁ receptor in the context of an established animal model of schizophrenia and 16 clinical studies investigating the CB₁ receptor in schizophrenia. The majority of preclinical studies (6 of 8) have shown that the CB₁ receptor is reduced in the context of animal models of schizophrenia. Moreover, the majority of in vivo clinical imaging studies that used arterial blood sampling to quantify the radiotracer kinetics (3 of 4) have shown reduced CB₁ receptor availability in schizophrenia. However, mixed findings have been reported in ex vivo literature, including reports of no change in receptor levels (5 of 11), increased receptor levels (4 of 11), and decreased receptor levels (2 of 11). We review methodological reasons for these discrepancies and review how CB₁ receptor dysfunction may contribute to the pathophysiology of schizophrenia, drawing on the role of the receptor in regulating synaptic transmission and synaptic plasticity. We also discuss how the CB₁ receptor may be a potential therapeutic target.