The involvement of cannabinoid CB1 receptors in morphine and cocaine motivational effects was investigated using CB1 knockout mice. For this purpose, we evaluated the rewarding effects in the place conditioning paradigm and the sensitization to the locomotor responses induced by these drugs. The hyperlocomotion induced by acute morphine administration (15 mg/kg, s.c.) was preserved, but the sensitization to this locomotor response induced by chronic morphine treatment was abolished in CB1 mutant mice. Morphine (5 mg/kg, s.c.) induced conditioned place preference in wild-type mice but failed to produce any response in knockout mice, indicating the inability of morphine to induce rewarding effects in the absence of CB1 cannabinoid receptors. When the aversive effects of morphine withdrawal were investigated using the place aversion paradigm, no differences between genotypes were observed. Acute cocaine (10 mg/kg, i.p.) induced hyperlocomotor responses in wild-type and knockout mice and a chronic cocaine treatment produced a similar sensitization to this response in both genotypes. In the conditioning place preference paradigm, cocaine (20 mg/kg, i.p.) produced rewarding responses in both wild-type and knockout mice. These results demonstrate that CB1 receptors are essential for adaptive responses produced by chronic morphine but not by chronic cocaine treatment.