br Introduction Adolescence is a unique developmental period

Introduction Adolescence is a unique developmental period characterized by major physiological, psychological, and neurodevelopmental changes. These changes typically coincide with escalation of alcohol and marijuana use (Brown et al., 2008), which continues into early adulthood (Sartor et al., 2007). The comorbid use of alcohol and marijuana among teens continues to subtly rise as perception of harm declines. Fifty-eight percent of alcohol drinking adolescents report using alcohol and marijuana simultaneously, (Agosti et al., 2002), 45% of youth endorse a lifetime prevalence of marijuana use by the 12th grade, and 22% of these youth endorse use in the past 30 days (Johnston et al., 2015). The adolescent cox 2 inhibitor undergoes considerable maturation, including changes in cortical volume and refinement of cortical connections (Huttenlocher and Dabholkar, 1997). These neural transformations (e.g., maturing neural circuitry, cortical thinning and fiber projections) leave the adolescent brain more susceptible to potential neurotoxic effects of substances (Brown et al., 2000; Spear, 2000; Spear and Varlinskaya, 2005; Squeglia et al., 2009; Tapert et al., 2002). Although overall brain volume remains largely unchanged after puberty, ongoing synaptic refinement and myelination results in reduced gray matter and increased white matter volume by late adolescence (Casey et al., 2008; Giedd, 2004; Sowell et al., 2003; Yakovlev and Lecours, 1967). Cortical gray matter follows an inverted U-shaped developmental course, with cortical volume peaking around ages 12–14 (Giedd, 2004; Giedd et al., 2009; Gogtay et al., 2004; Sowell et al., 2003). The mechanisms underlying the decline in cortical volume and thickness are suggested to involve pruning and elimination of weaker synaptic connections, decreases in neuropil, increases in intra-cortical myelination, or changes in the cellular organization of the cerebral cortex (Huttenlocher and Dabholkar, 1997; Paus et al., 2008; Tamnes et al., 2009). In contrast, white matter development generally is characterized by linear volume increases driven by progressive axonal myelination (Giedd et al., 2009; Gogtay et al., 2004; Simmonds et al., 2014). These processes refine motor functioning, higher-order cognition, and cognitive control (Bava et al., 2010). Marijuana use during adolescence is associated with altered brain structure. Studies show alterations in white matter integrity in adolescent marijuana users compared to non-users, particularly in fronto-parietal circuitry and pathways connecting the frontal and temporal lobes (Bava et al., 2009). Altered cortical morphometry has also been observed in adolescent marijuana users, with marijuana-using adolescents having larger cerebellar volumes than non-users (Medina et al., 2010), thinner cortices in prefrontal and insular regions, and thicker cortices in posterior regions when compared to controls (Lopez-Larson et al., 2011). Structural neuroimaging studies have also examined whether structural brain alterations were present before onset of marijuana use (Cheetham et al., 2012). Notably, orbitofrontal cortex (OFC) volumes at age 12 predicted initiation of marijuana use at age 16 when controlling for other substance use. Regional volume vulnerabilities may increase risk for initiation and maintenance of marijuana misuse. This study builds on previous work by our laboratory examining the acute and longer-term impact of adolescent marijuana use on cortical thickness pre- and post 28-days of monitored abstinence from marijuana (Jacobus et al., 2014). We found increased temporal lobe thickness estimates in adolescent heavy marijuana users (age 17), and negative associations with cortical thickness and lifetime marijuana use both acutely and following prolonged abstinence from marijuana. It is unclear if such structural alterations of the cerebral cortex persist into young adulthood. The aim of this prospective study was to identify differences in cortical thickness between adolescent heavy marijuana users and control adolescents with minimal substance use histories assessed at three independent time points (∼ages 18, 19 and 21 respectively). We hypothesized that those individuals who initiated heavy marijuana use during adolescence would show thicker cortices over time compared to our control teens by young adulthood in frontal and temporal brain regions.