We previously identified a consistent subset of significantly changed transcripts in dorsolateral prefrontal cortex from cocaine users with a history of cocaine use and positive cocaine toxicology at death.21 Two distinct transcriptional patterns were present: For one subgroup that mainly displayed increased expression there was, in addition to cocaine, also toxicological evidence of a smoked crack-cocaine metabolite or of morphine, suggesting that the pattern and/or recency of use differentially affected regulation of this subset of genes. A similar scenario of distinct transcriptional patterns for subgroups was demonstrated in a second study examining postmortem anterior prefrontal cortex from a large cohort of substance use cases.22 Hierarchical clustering and principal components analysis of global gene expression profiles identified three main groups of cases (Figure 2), which did not clearly reflect primary substance use by history and/or toxicology. This was in part due to the presence of significant polysubstance use in Groups I-II, while Group III cases had little or no drugs-of-abuse present at death but had significant other comorbid disease and causes of death. A third example was reported in alcoholic cases
