All subjects included in this study were unrelated and their four grandparents were Spanish, of European, non-Roma origin. Patients were in methadone maintenance for treating heroin dependence (DSM-IV: 304.02;[21]), and all of them reported heroin as their primary drug of choice. Non-opioid substance use was not an exclusion criterion in the present study for two reasons: first, because heroin-dependent Spanish patients frequently report use of alcohol, benzodiazepines, cannabis, and cocaine as a secondary drug [22]; second, because DRD2 is potentially a nonspecific genetic factor for substance abuse or dependence. Therefore, the exclusion of heroin-dependent patients who frequently use non-opioid substances would have reduced the external validity of our study, without improving its internal validity. In the present study, non-opioid substance use was defined as a regular and/or maladaptive use pattern during a lifelong cumulative period longer than a year. Control individuals were blood donors and clinical staff members, who declared that they did not suffer SUD, with the exception of nicotine dependence. The present study was approved by the IRB of Sant Pau Hospital (Barcelona), and written informed consent was obtained from all participants.
