The cannabinoid (CB) receptors are two of the most widely expressed GPCRs in the body. When coupled to G_i/o proteins their activation can negatively regulate adenylate cyclase and/or positively regulate MAPK signaling. Conversely, when coupled through G_s proteins, CB₁ activation promotes adenylate cyclase signaling. CB₁ also modulates a host of ion channels through Gi/o coupling including A-type inwardly rectifying potassium channels (IRK) and N-type and P/Q-type calcium channels (Ca_v2.2, Ca_v2.1). The two major functions of these receptors are neuromodulatory, inhibiting neurotransmitter release through retrograde signaling, and immunomodulatory, regulating cytokine release and immune cell migration.