It therefore appears that there can be multiple transcriptional subtypes, “endophenotypes”, within a single classification of users of a specific substance. In other words, within a single diagnostic classification (e.g., cocaine abuse) there may be multiple “endophenotypes” which can be identified by examining changes in gene expression. These transcriptional endophenotypes may be related to the time since last use, the manner and chronicity of use, or be complicated by other comorbid disease21–22,26, including other neuropsychiatric disorders.23,40 Since polysubstance use appears to be the rule, not the exception, in substance users41, gene expression may also be differently impacted by a complex, comorbid use/abuse of multiple drug classes. Additional differences in transcriptional profiles for substance users may arise from comorbid neuropsychiatric disorders, the presence of which has been estimated to range from 10% to 75% depending on the drug of abuse and clinical diagnosis.42–44 Cases belonging to different subtypes within the same diagnostic substance use classification, may exhibit significant differences in gene expression. These differences could result in changes in transcription patterns which are not identified when an entire diagnostic classification (e.g.,
