This study examined the effect of cannabinoid ligands on human tonsillar B-cells activated either through cross-linking of surface immunoglobulins or ligation of the CD40 antigen. The two synthetic cannabinoids, CP55,940 and WIN55212-2, as well as Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana, caused a dose-dependent increase of B-cell proliferation and displayed EC(50) at low nanomolar concentrations. This cannabinoid-induced enhancing activity mas inhibited by pertussis toxin which suggested a G-protein-coupled receptor process. In addition, the absence of antagonistic effect of SR141716A, a specific CB1 receptor antagonist, together with the demonstration that human B-cells displayed large amount of CB2 receptor mRNAs, led us to assume that the growth enhancing activity observed on B-cells at very low concentrations of cannabinoids could be mediated through the CB2 receptor.