Could positive allosteric modulators of the cannabinoid CB1 receptor be efficacious and safe for the treatment of chronic pain?

Abstract

Cannabinoids are effective analgesics but induce adverse cannabimimetic effects and the development of tolerance. Allosteric ligands of the cannabinoid CB₁ receptor (CB₁) may harness the pain-relieving effects of cannabinoids with reduced adverse effects. CB₁ allosteric ligands bind at a site topographically distinct from the orthosteric binding site. CB₁ allosteric ligands have been shown to be effective pain-relieving drugs that do not appear to result in the production of adverse effects or the development of tolerance. While this therapeutic profile indicates that CB₁ allosteric ligands could be an effective treatment for chronic pain, their molecular mechanism of action remains unclear.