It is unclear how associations with marijuana
It is unclear how associations with marijuana use and cortical thickness remodeling may be unique compared to alterations in macrostructural volume (e.g., volume comprised of cortical area and thickness). Studies suggest that volume changes are driven by changes in surface area (Im et al., 2008; Pakkenberg and Gundersen, 1997) whereas others suggest thickness as one ages (Storsve et al., 2014), however relationships between these metrics are likely dynamic across the lifespan and represent different neuromaturational mechanisms at different stages of life and disease (e.g., myelination, quantity of cortical columns, cellular organization of cortical columns, dendrites, synapses) (Mountcastle, 1997; Ostby et al., 2009; Rakic, 1988; Storsve et al., 2014). Changes in regional pepstatin volume associated with marijuana use have varied, as some have observed decreased volume (Ashtari et al., 2011; Demirakca et al., 2011; Schacht et al., 2012) and others have identified macrostructural volume increases in CB1-dense brain regions such as neocortex, amygdala, striatum, hippocampus, and cerebellum (Cousijn et al., 2012; Gilman et al., 2014; McQueeny et al., 2011; Medina et al., 2010). In reward-network regions specifically, such as the orbitofrontal cortex (OFC), a recent examination by Filbey and colleauges, found decreased orbitofrontal cortex (OFC) volume in heavy marijuana users compared to controls, and increased structural and functional connectivity within the OFC network. Lorenzetti and collages (2014), did not find OFC differences in their sample of heavy marijuana users, but did see smaller hippocampus and amygdala volumes. Cheetham et al. (2012) found that smaller OFC volume pre-initiation of marijuana use (age 12) predicted progression into use four years later (age 16). Taken together, findings underscore that alterations in cortical metrics are likely dynamic and influenced by age, pre-existing vulnerabilities, and exogenous factors such as marijuana use. Continuing to study associations between cortical metrics and substance use is important given estimates have been linked to cognitive functioning in several studies in our laboratory and others (Ashtari et al., 2011; Jacobus et al., 2014; Squeglia et al., 2012). Alcohol likely has similar deleterious consequences on the brain. The present dose-dependent associations are consistent with our previous findings, as Squeglia et al., found decreases in cortical thickness estimates associated with heavy episodic alcohol use in males (Squeglia et al., 2012), and accelerated declining brain volume trajectories in a large prospective investigation examining individuals (ages 12–24) who transitioned to heavy drinking (Squeglia et al., in press). Alcohol likely interferes with neural development of the cerebral cortex, and thinner cortices observed with more cumulative use reported may represent non-beneficial pruning and/or inhibition of cell generation or cell death (Crews and Nixon, 2009). Limitations of the present study include self-report of substance use, which can introduce measurement error. Further, while this study was prospective, participants were not assessed prior to initiation of substance use. However, previous work in our laboratory finds marijuana-related associations with white matter integrity in a sample of individuals assessed pre- and post-initiation of substance use (Jacobus et al., 2013b). Nevertheless, future work should determine the influence of pre-existing differences on cortical metrics. The current investigation included users of both marijuana and alcohol, and despite controlling for alcohol use, it remains unclear what is precisely the result of marijuana as compared to the combination of co-occurring marijuana and alcohol use. Our sample was predominately male (70%), however gender should be evaluated and future studies will focus on differential gender effects on brain morphometry in adolescent marijuana users. Group did not statistically differ on days since last use of marijuana and alcohol use, likely influenced by the monitored abstinence period, therefore acute effects may not have been captured in our reported findings. A statistically significant within-subjects effect was not widely observed (e.g., decreasing cortical thickness estimates), which may be attributed to the smaller sample size combined with a more restricted age range. We tried to reduce the number of correlational analysis that were conducted, however given that effects were modest, future work should replicate findings.