Physical dependence on the synthetic cannabinoid-receptor agonist R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate (WIN 55212-2) was demonstrated in rats by the use of a chronic continuous infusion. Spontaneous withdrawal, of moderate intensity, was shown for the first time with this class of drugs of abuse. Behavioral withdrawal signs were also elicited after challenge with (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide.HCl (SR141716A), a specific CB(1) cannabinoid-receptor antagonist. In both instances, the high-dose regimen (4, 8, 16 and 16 mg/kg/day, i.p. on days 1-4, respectively) was sufficient to evoke a typical withdrawal syndrome quantified by the signs wet-dog shakes and facial rubs. These results are discussed relative to those obtained with Delta(9)-tetrahydrocannabinol and anandamide. With Delta(9)-tetrahydrocannabinol, precipitated but not spontaneous or abrupt withdrawal was observed, and this was ascribed to pharmacokinetic properties. Anandamide, which showed little, if any, physical dependence potential, behaved atypically. Possible implications regarding pharmacotherapeutic and human abuse issues are discussed.