Structural neuroimaging studies have indicated

Structural neuroimaging studies have indicated that volumes of several calpain inhibitor 1 areas are smaller in heavy adult MJ users especially in areas enriched with cannabinoid 1 (CB1) receptors, such as medial temporal lobe, and prefrontal cortex (Lorenzetti et al., 2010). Studies of adult chronic MJ users note brain volume reductions in temporal lobe, insula, and prefrontal cortex, amygdala and hippocampus (Battistella et al., 2014; Cousijn et al., 2012; Filbey et al., 2014; Matochik et al., 2005; Yucel et al., 2008). Among different characteristics of MJ involvement (e.g., dependence symptoms, use frequency, consumption), the age of initial MJ use is a robust factor that has been associated with smaller brain volumes in users. For example, Battistella et al. (2014) observed left parahippocampal gyrus and right temporal pole structural differences in 25 regular MJ users compared to 22 occasional users, however, even the occasional users who began smoking MJ during adolescence (before age 18) demonstrated similar brain changes as the regular users. Our group has also found links with early MJ use onset (Bava et al., 2009) and structural connectivity with orbitofrontal cortex in a cohort of daily MJ users, suggesting complex neuroadaptive processes related to MJ use in the context of adolescent brain development (Filbey et al., 2014). These findings underscore the potential for significant heterogeneity in brain changes among adult MJ users, especially those who began using MJ during neurodevelopment. Studies comparing early adolescent MJ use to users initiating MJ use in later adolescence provide further evidence for the potential of MJ to cause enduring change. The few studies that have directly investigated the timing of the effects of MJ during adolescence have noted divergent neurodevelopment effects. For example, in an fMRI study by Gruber and colleagues, functional and behavioral differences during an interference task were reported between early (before age 16) and late (after age 16) MJ users (Gruber et al., 2012) (Sagar et al., 2015). The same group also reported decreased white matter integrity in early onset vs. late onset MJ users (mean age 14.46 vs. 17.93) (Gruber et al., 2014). Similar differential effects have also been noted in parietal lobe activation between early and late adolescent binge drinkers during a spatial working memory task (Tapert et al., 2004). These studies highlight the importance of clarifying the differential neural effects of early- and late-adolescent onset use. To that end, in the current study, we compared daily MJ users who were early onset users (<16 years old) versus late onset users (≥16 years old) on measures of cortical morphology that are sensitive to developmental changes. We aimed to characterize both the effect of early onset status on cortical morphology as well as assess for morphological patterns linked to the continued use of MJ after early and late adolescent MJ initiation. We expected early onset users to show a morphological pattern consistent with disruption of early adolescent brain development (e.g., increased cortical thickness, greater gray/white definition of the cortical ribbon via disruptions to adolescent pruning processes) that may be more consistent with indirect impact of MJ of brain development. While gray matter decline has been shown to be associated with marijuana use, particularly in areas rich in CB1 receptors, increased cortical thickness and greater gray/white definition in the cortical ribbon point to potential disruption in neurodevelopment (i.e. synaptic pruning) that may result from MJ use at key developmental stages (i.e. earlier as opposed to later in adolescent neuronal development). Such disruptions may extend to gyrification as well. While this process begins in utero, there is evidence that gyrification is ongoing into adolescence (Armstrong et al., 1995; Alemán-Gómez et al., 2013; Klein et al., 2014) and may also display aberrant developmental patterns in the presence of MJ use.