Marijuana dependence: Not just smoke and mirrors

Abstract

Marijuana (Cannabis sativa) is the most commonly used il-licit drug worldwide as well as in the Unites States. Pro-longed use of marijuana or repeated administration of its primary psychoactive constituent, Δ9-tetrahydrocannabinol (THC), can lead to physical dependence in humans and labo-ratory animals. The changes that occur with repeated can-nabis use include alterations in behavioral, physiological, and biochemical responses. A variety of withdrawal re-sponses occur in cannabis-dependent individuals: anger, ag-gression, irritability, anxiety and nervousness, decreased appetite or weight loss, restlessness, and sleep difficulties with strange dreams. But the long half-life and other phar-macokinetic properties of THC result in delayed expression of withdrawal symptoms, and because of the lack of contigu-ity between drug cessation and withdrawal responses the latter are not readily recognized as a clinically relevant syn-drome. Over the past 30 years, a substantial body of clinical and laboratory animal research has emerged supporting the assertion that chronic exposure to cannabinoids produces physical dependence and may contribute to drug mainte-nance in cannabis-dependent individuals. However, no med-ications are approved to treat cannabis dependence and withdrawal. In this review, we describe preclinical and clini-cal research that supports the existence of a cannabinoid withdrawal syndrome. In addition, we review research eval-uating potential pharmacotherapies (e.g., THC, a variety of antidepressant drugs, and lithium) to reduce cannabis with-drawal responses and examine how expanded knowledge about the regulatory mechanisms in the endocannabinoid system may lead to promising new therapeutic targets.