Deficits in emotion regulation and inhibitory control in addicted individuals and enhancement of PFC activity by direct drug administration (see above and Supplementary information S2 (table)) together could support the self-medication hypothesis131,132. According to this hypothesis, drug self-administration — and the associated increases in PFC activity — ameliorate the emotional and cognitive deficits that are present in drug-addicted individuals. Such a self-medication effect has previously been recognized by the treatment community, as evidenced by using methadone (a synthetic opioid) as a standard agonist substitution therapy for heroin dependence. In an fMRI study, watching heroin-related cues was associated with less craving during a post-dose than during a pre-dose methadone session in heroin-addicted individuals, with concomitant decreases in cuerelated responses in the bilateral OFC133 (Supplementary information S4 (table)). Empirical support is starting to accumulate for a similar effect in cocaine-addicted individuals. For example, intravenous cocaine (which increases extracellular dopamine levels) in cocaine users improved inhibitory control in a go/no-go task, and this was associated with normalization of ACC activity and enhanced right DLPFC activation during the task134. Intravenous MPH (which also increases
