“The cannabinoid type-1 (CB₁) receptor, a G-protein-coupled receptor, is an attractive target for drug discovery due to its involvement in many physiological processes. Historically, drug discovery efforts targeting the CB₁ receptor have focused on the development of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind. Research performed over the last several decades has revealed substantial difficulties in translating CB₁ orthosteric ligands into druggable candidates. The difficulty is mainly due to the adverse effects associated with orthosteric CB₁ ligands. Recent discoveries of allosteric CB₁ modulators provide tremendous opportunities to develop CB₁ ligands with novel mechanisms of action; these ligands may potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB₁ receptor. In this paper, we review and summarize the complex pharmacological profiles of each class of CB₁ allosteric modulators, the development of new classes of CB₁ allosteric modulators and the results from in vivo assessments of their therapeutic value.”