br Methods This study was approved by the University

Methods This study was approved by the University of Texas at Dallas (UTD) and University of Texas Southwestern Medical Center (UTSW) Institutional Review Boards. All participants were recruited from the Dallas-Ft.Worth metro area via flyers and advertisements. Following informed consent, MJ users completed two sessions – a baseline appointment for collecting demographic, psychosocial and behavioral measures and a thorough substance use history. Three days later the participants returned for a neuroimaging appointment. Prior to their scanning session, participants were asked to be abstinent from MJ use for 72h, from alcohol for 24h, and from caffeine and cigarettes for the preceding 2h. These were confirmed by self-report (MJ, alcohol, caffeine and cigarettes), quantitative THC urinalysis (MJ), and by breath alcohol level of .000 (alcohol) at the start of their session.
Results
Discussion Our findings did not find the expected age of onset differences previously reported in marijuana users (Gruber et al., 2012, 2014). This inconsistency suggests that the age of onset effects may be more robust in TCEP white matter connectivity (Gruber et al., 2014) and function (Gruber et al., 2012) than brain surface morphometry. To date, the few studies that have described altered cortical morphology in MJ users have led to mixed findings. Mata et al. (2010) identified brain regions with decreased sulcal depth suggestive of lower gyrification in a study of adult MJ users. Jacobus and Tapert (2014) recently reported increased cortical thickness in the entorhinal cortex among 24 adolescent MJ users (mean age=17.7, mean MJ onset age=15.4) relative to peer controls. However, the authors also reported a negative relationship between cortical thickness and total MJ use in the right paracentral gyrus, and they observed consistent positive relationships in various brain regions between age of MJ onset and thickness. In the only other known adolescent study of cortical thickness and MJ, Lopez-Larson and colleagues studied 18 adolescent heavy MJ users (similar in age and MJ onset as Jacobus and Tapert, 2014) and reported mixed findings of increased thickness in prefrontal/insula regions and decreased thickness in posterior/temporal lobe areas in the MJ users compared to controls. In contrast to Jacobus and Tapert (2014), Lopez-Larson et al. (2011) found areas of the frontal lobe and insula that were thinner with increased urine THC metabolites and thicker with earlier age of onset. Select findings from the current study align with aspects of both of these studies, with a consensus supporting findings of a negative dose-dependent relationship between MJ use and cortical thickness. Given the low availability of studies to compare, this consensus is very limited. Although Jacobus et al. and Lopez-Larson et al. found the opposite effect of age of onset on thickness, the pattern of divergence among early vs. late onset users in the current study is more consistent with the latter study, whereby we saw early onset users exhibit thicker cortex with continued MJ use. Taken together, findings of increased thickness related to early MJ onset accompanied by negative dose-dependent relationships with MJ exposure may reflect two distinct processes. One process may be specific to the interactions with cortical development during early adolescence, likely leading to a disruption in pruning, and, the other, specific to the pharmacological effect with heavy chronic MJ use. In the only known study to examine the curvature-morphology of the cortex in adult MJ users, Mata et al. (2010) identified decreased sulcal concavity and thinner sulci in 23MJ users compared to controls (n=44), also in prefrontal areas. However, they did not observe significant relationships with age, MJ onset age, or cumulative MJ use. It is interesting that the authors detected group level differences (MJ vs. controls) but no correlations with MJ use characteristics such as dose or age of onset, whereas our primary findings are the consistent effects of continued MJ use differing after early or late adolescent onset. There are substantial methodological explanations for this disparity. For example, the current study did not compare morphology in MJ users to a normative control sample, therefore, it is feasible that group-level differences may emerge with such a comparison. Likewise, we deliberately covaried for current age in order to control for brain changes with aging and thus optimize our interrogation of developmental effects of early onset age and of aspects of continued use.