The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid (CB) CB 1 and CB 2 receptors, the endocytic cycle of CB 1 receptors, G protein-coupled receptor regulatory kinases (GRK), and associated signaling (mammalian target of rapamicin (mTOR) and 70kDa ribosomal protein S6 kinase (p70S6K)) in brain cortices of drug abusers and cocaine- and cannabinoid-treated rodents. The main results indicate that in cocaine adddicts, but not in mixed cocaine/opiate or opiate abusers, CB 1 receptor protein in the prefrontal cortex (PFC) was reduced (−44%, total homogenate) with a concomitant receptor redistribution and/or internalization (decreases in membranes and increases in cytosol). In cocaine addicts, the reductions of CB 1 receptors and GRK2/3/5 (−26% to −30%) indicated receptor desensitization. CB 2 receptor protein was not significantly altered in the PFC of cocacine addicts. Chronic cocaine in mice and rats also reduced CB 1 receptor protein (−41% and −80%) in the cerebral cortex inducing receptor redistribution and/or internalization. The CB 1 receptor agonist WIN55212-2 caused receptor downregulation (decreases in membranes and cytosol) and the antagonists rimonabant and AM281 induced opposite effects (receptor upregulation in membranes and cytosol). Rimonabant and AM281 also behaved as inverse agonists on the activation of mTOR and its target p70S6K. Chronic cocaine in mice was associated with tolerance to the acute activation of mTOR and p70S6K. In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB 1 receptor signaling was dampened. The dysregulation of CB 1 receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts.