threshold. As in all studies of substance abusing humans, cause-effect associations are difficult to establish, because most studies are cross-sectional, and baseline status is difficult to verify. That is, it may be that other neurobiologically-based trait factors (e.g. sensation seeking: (37)) influence who will go on to use substances in large quantities, and these trait factors may be the foundation of any observed neural differences during or after prolonged use. Moreover, interpretation is frequently complicated by several confounds including concomitant use of other drugs, the presence of comorbid psychiatric disorders that can exert independent effects on brain structure, and lack of attention to premorbid characteristics that could affect outcomes given that most work is cross-sectional (see (7) for review).
