Three promising intermediate phenotypes are craving, withdrawal, and sensitivity to the acute effects of marijuana. Each is mediated by mesocorticolimbic dopamine transmission, which is modulated by CB1 binding (Gessa et al. 1998; Mascia et al. 1999). Craving and loss of control over drug-seeking behavior drive end-stage addiction (e.g., Kalivas and Volkow 2005) and cue-elicited craving, initiated by exposure to drug-related cues, is especially potent (e.g., Rohsenow et al. 1990; Payne et al. 1991; Johnson et al. 1998). Marijuana-related imagery scripts (Singleton et al. 2002), visual cues (Wölfling et al. 2008), and tactile cues (Haughey et al. 2008) induce craving in heavy users. Craving is mediated by the repeated pairing of drug cues with activation of mesocorticolimbic dopamine pathways (Robinson and Berridge 1993; Berridge and Robinson 1998). Nearly all frequent marijuana users experience cannabis withdrawal symptoms when they abstain from use (Budney et al. 1999, 2003, 2004), and the experience of these symptoms during abstinence is associated with rapid relapse to dependence (Cornelius et al. 2008). Withdrawal is accompanied by decreased mesocorticolimbic dopamine transmission, an effect mediated by decreased CB1 binding
