“This review examines the development of cannabinoid CB1 receptor antagonists as a new class of therapeutic agents for drug addiction. Abused drugs [alcohol, opiates, Δ9-tetrahydrocannabinol (Δ9-THC), and psychostimulants, including nicotine] elicit a variety of chronically relapsing disorders by interacting with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems, and virtually all abused drugs elevate dopamine levels in the nucleus accumbens. Cannabinoid CB1 receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of Δ9-THC and nicotine. Rimonabant (SR141716), a CB1 receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of Δ9-THC in animals. Blockade of CB1 receptor activity by genetic invalidation also decreases rewarding effects of opiates and alcohol in animals. Although CB1 receptor blockade is generally ineffective in reducing the self-administration of cocaine in rodents and primates, it reduces the reinstatement of extinguished cocaine-seeking behavior produced by cocaine-associated conditioned stimuli and cocaine-priming injections. Likewise, CB1 receptor blockade is effective in reducing nicotine-seeking behavior induced by re-exposure to nicotine-associated stimuli. Some of these findings have been recently validated in humans. In clinical trials, Rimonabant blocks the subjective effects of Δ9-THC in humans and prevents relapse to smoking in exsmokers. Findings from both clinical and preclinical studies suggest that ligands blocking CB1 receptors offer a novel approach for patients suffering from drug dependence that may be efficacious across different classes of abused drugs.”
“Cannabinoid CB1 Receptor Blockade: A Step Forward in Drug-Dependence Therapy?”
“Despite advances in the understanding of neurobiological and behavioral mechanisms that lead to drug dependence over the last 20 years, no effective treatment is yet available for cocaine or Δ9-THC dependence. Moreover, medications available for ethanol, nicotine, or opioid dependence are ineffective in many subjects. For example, the rate of smoking cessation by subjects entering into clinical trials that combine effective medication and behavioral and cognitive therapy is around 30% at one year; most subjects relapse. Cannabinoid CB1 receptor antagonists represent a potentially useful tool not only for blocking the direct reinforcing effects of Δ9-THC, nicotine, and ethanol, but also for preventing relapse to the use of various drugs of abuse, including cocaine, methamphetamine, and heroin. In addition, environmental stimuli seem to be one of the major factors that can trigger relapse to drug use in abstinent drug abusers. This process is not only critical for psychostimulant abuse, but also for nicotine and heroin abuse, and probably for other drugs of abuse such as ethanol. By reducing the motivational effects of drug-related environmental stimuli, cannabinoid CB1 receptor antagonists might, therefore, provide an effective means for preventing relapse to drug-seeking behavior in abstinent drug abusers, providing a promising new tool for the treatment of dependence on a wide range of abused drugs.”