Anecdotal reports of recreational use of cannabis or psychopharmacological studies of marijuana/THC suggests that CB1 activation decreases subjective anxiety (D’Souza et al., 2004; Sethi et al., 1986; Wachtel et al., 2002). An early placebo-controlled study showed that nabilone, a synthetic THC, dramatically reduced anxiety in anxious patients (Fabre and McLendon, 1981). Consistent with this and evidence from rodents, studies in humans using functional magnetic resonance imaging (fMRI) have found that oral THC (vs. PBO) attenuates amygdala reactivity to aversive/fear stimuli using a social-threat paradigm (Phan et al., 2008) and that the level of amygdala reactivity is inversely related to the level of cannabis use (Cornelius et al., 2010), consistent with the notion that THC and other cannabinoids may have an anxiolytic role via central fear mechanisms. The anxiolytic effects of eCB enhancers in rodents and humans have sparked interest in CB1 receptors as a pharmacological target for treating anxiety disorders (Gaetani et al., 2003; Gaetani et al., 2009; Hill and Gorzalka, 2009; Witkin et al., 2005). However, some important issues need to be addressed if CB1 agonists are to be
