With regard to the cortical findings the right
With regard to the cortical findings, the right TPJ and bilateral dlPFC showed greater activation to neutral faces than angry faces in the control group. The right TPJ has been implicated in theory of mind, social processing, and face processing (Allison et al., 2000; Saxe and Kanwisher, 2003; Saxe and Powell, 2006). Furthermore, the right superior temporal gyrus encodes biologically relevant motion (Grossman et al., 2000; Puce and Perrett, 2003; Saygin, 2007). Therefore this cluster may represent a signal of social salience related to the moving face stimuli. In contrast to controls, post hoc t-test results show the cannabis-experimenting group fails to process angry faces differently from neutral faces within the right TPJ (see Fig. 2). As this region was also the only region to exhibit significant dosage effects, a higher degree of cannabis experimentation may contribute to a departure from healthy social processing. Interestingly, as none of the regions exhibited a significant correlation with age of onset for any drugs of abuse, we are unable to make claims regarding face processing and cannabis use in relation to age of onset with other drugs. With regard to the amygdala findings, it is unclear whether amygdala hypersensitivity preceded cannabis use or was a consequence of use since this was a cross-sectional study. If amygdala hypersensitivity preceded use, which might seem most plausible given the low levels of reported use, then it\'s possible that these individuals may have been inclined to self-medicate for the drug\'s acute anxiolytic effects (Phan et al., 2008). Consistent with this interpretation, recent evidence has identified altered angry face processing in the ventromedial PFC (vmPFC) to predict future binge drinking (Whelan et al., 2014) and the vmPFC is part of a pi3k activation circuit that attenuates amygdala activity (Banks et al., 2007; Urry et al., 2006). If, however, the amygdala hypersensitivity is a consequence of cannabis use, then it is likely that this is due to exogenous stimulation of the endocannabinoid system. If confirmed, these findings would raise concerns regarding the risks associated with cannabis consumption and emotional health in adolescent users. Animal studies suggest exogenous cannabinoids inhibit GABAergic neurotransmission in the amygdala (Katona et al., 2001). Interestingly, this effect is magnified when the animal is given THC and placed in a threatening environment (Patel et al., 2004). Together these findings suggest that cannabinoids may compromise the major neuronal inhibitory mechanism within the amygdala and lower the threshold for activation, especially during signals of threat. Consistent with this interpretation, the angry faces used in the task were not exceptionally potent signals of threat yet the cannabis-experimenting group showed a heightened reactivity to them, an effect that is not observed in healthy controls viewing the same stimuli (Grosbras and Paus, 2006). The amygdala\'s role in affective processing serves an important role in evolutionary biology as it directs attention towards aversive stimuli. However, mounting evidence suggests that over-recruitment of the amygdala is associated with various mood disorders. Greater signal change in the amygdala, specifically during affective face processing, is exhibited by children with anxiety (Thomas et al., 2001), and adults with major depressive disorder (Drevets, 2001; Fu et al., 2008; Sheline et al., 2001) and generalized social phobia (Evans et al., 2008; Phan et al., 2006). Thus, cannabis use in adolescence may contribute to the etiology of mood disorders in adulthood. Moreover, relatively light use by an early age may contribute to an early marker of maladaptive affective processing. Nonetheless, major longitudinal studies are needed to illuminate these hypotheses as the current study is unable to infer causality. The results reported here are inconsistent with those of Phan and colleagues (2008) and Gruber and colleagues (2009) who both found attenuated amygdala reactivity to threat signals in adults following acute THC administration, and chronic non-intoxicated users, respectively. In contrast, we report trait-related increased amygdala reactivity to threat signals in adolescence. Hence, we report divergent effects in adolescents compared to adults. As previous research demonstrates divergent findings between adolescents and adults during affective face processing (Guyer et al., 2008a,b), we do not hypothesize adolescent data to mirror the adult data. Indeed, our results support the notion that adolescence is period of sensitive affective development that can be perturbed even with very low levels of cannabis experimentation.