Envisioning Cannabinoid CB1 Receptor Biased Signaling as a Therapeutic Target for Schizophrenia.

The relationship between the endocannabinoid system and the emergence and treatment of schizophrenia-related symptoms continues to be a topic of significant interest within psychiatry. Cannabis is the most widely used recreational drug worldwide, and individuals with schizophrenia use it at a much higher rate than the general population. The shared genetic risk for schizophrenia and cannabis use may partially account for this phenomenon. However, the exposure to cannabis in individuals at risk of schizophrenia appears to not only represent the manifestation of overlapping risks, but also pharmacological exacerbation of an already altered cortical system. Thus, cannabis use dose-dependently increases the likelihood of receiving a schizophrenia diagnosis, acutely exacerbates schizophrenia symptoms, and worsens long-term prognosis for individuals with schizophrenia. The psychoactive substance in cannabis, Δ9-tetrahydrocannabinol, targets the cannabinoid CB1 receptor (CB1R), a G protein-coupled receptor (GPCR). This brief review focuses on recent advances that may enable effective therapeutic targeting of CB1R for the treatment of schizophrenia, especially in individuals with comorbid schizophrenia and cannabis use. The authors summarize the current understanding of CB1R relevant to schizophrenia in sections covering the basic cortical biology and sex differences of CB1R; current knowledge of CB1R alterations in schizophrenia and the potential impact of comorbid cannabis use; recent cell type-specific findings that reconcile past discrepant research in the field; and advances in understanding of GPCR pharmacology and biased ligands that provide new opportunities for CB1R-targeted therapeutics. Derived from this more nuanced understanding of CB1R, the authors propose future directions with the potential to develop a CB1R-targeted treatment of schizophrenia.