Envisioning Cannabinoid CB1 Receptor Biased Signaling as a Therapeutic Target for Schizophrenia.
The American journal of psychiatry April 17, 2026 Shih-Hsuan Ku, Sierra J Stringfield, Mary M Torregrossa et al.
Cannabis use is more common among people with schizophrenia than the general population, partly due to shared genetic risk. Beyond overlapping risks, cannabis pharmacologically worsens an already altered cortical system. Cannabis use dose-dependently increases the likelihood of a schizophrenia diagnosis, acutely worsens symptoms, and leads to poorer long-term outcomes. The psychoactive component, Δ9-tetrahydrocannabinol, acts on the cannabinoid CB1 receptor (CB1R), a G protein-coupled receptor. This review examines recent advances in understanding CB1R biology, sex differences, alterations in schizophrenia, and the impact of comorbid cannabis use. Cell type-specific findings reconcile past discrepancies, and new knowledge of GPCR pharmacology and biased ligands offers opportunities for CB1R-targeted therapeutics for schizophrenia, especially with comorbid cannabis use.