Several limitations should be considered for our study. One relates to polysubstance use, a common confound for most addition studies. While we focused on the major substance of abuse in these subjects, opiates, some individuals also had evidence of other substance use, particularly in the Manhattan cohort. However, the European population was predominantly heroin abusers, and opiate was the drug common in each cohort studied. It is nevertheless important to emphasize that neurobiological disturbances of dopamine-glutamate interactions is expected to be a core feature of addictive behaviors in general,49 so the current findings may extend to other drugs of abuse and addiction-related phenotypes such as reward sensitivity, inhibitory control, etc. Another limitation relates to the lifetime drug-free status or unknown Reward Deficiency Syndrome in control subjects. While it is not possible in post-mortem populations to rule out potential previous drug use or other addictive behavior in their lifetime, psychiatric interviews were conducted in the Manhattan population. As such, we were able to ascertain these patterns, and only alcohol use was evident in some control subjects. Although undocumented addictive phenotype in
