Little is known about the roles of beta-arrestins in the regulation of brain CB1 cannabinoid receptors. This study investigated the role of beta-arrestin2 in cannabinoid behavioral effects using beta-arrestin2 -/- mice and their wild-type counterparts. A variety of cannabinoid ligands from different chemical classes that exhibit a variety of efficacies for activation of CB1 receptors were investigated, including Delta-tetrahydrocannabinol, CP55940, methanandamide, JWH-073, and O-1812. Delta-tetrahydrocannabinol produced both greater antinociception and greater decreases in body temperature in beta-arrestin2 -/- compared with beta-arrestin2 +/+ mice. No significant differences were, however, present in either assay for the other CB1 agonists. Antagonist radioligand binding indicated no difference in the density of cannabinoid CB1 receptors in the cerebellum, cortex, or hippocampus of beta-arrestin2 +/+ and -/- mice. These data demonstrate that beta-arrestin2 may regulate cannabinoid CB1 receptor sensitivity in an agonist-specific manner.