Therefore, additional or supplementary statistical analyses to the analyses involving the primary Selleckchem Everolimus objective of the study were conducted with age and IQ as covariates (Figures S2 and S3 in Supplementary Material). However, these covariates did not substantially change our

findings: we again observed larger activation in healthy controls when compared to dAMPH users at baseline, along with an interaction effect of the MPH challenge. This observation strengthens the hypothesis that our findings are related to stimulant use and not to mismatched characteristics. Thirdly, because we did not include a placebo challenge we cannot completely rule out the possibility that differences between the groups in expectation of drug effect may have affected our results. However, none of the groups had previous experience with MPH and did not know (exactly) what to expect. Moreover, a previous study only found a small expectancy effect on brain hemodynamics with i.v. administration of MPH, whereas in the current study MPH was given orally (probably resulting in an even smaller expectancy effect; Volkow et al., 2006). In addition, this expectancy effect during i.v. MPH Pomalidomide cell line administration

was observed only on resting state MRI and not on task-related brain hemodynamics. These observations suggest that in the current study drug expectancy may have affected the results only minimally, if at all. Fourth, we did not use an actual monetary reward. However, our results on whole brain activation to the anticipation of gain are very similar to earlier results obtained with this task. This task itself has been applied with modified rewards in previous studies as well (points with which subject could purchase snacks (Peters et al., 2011), monetary reward with a maximum thresholds or globally linking performance to size of compensation for study participation Unoprostone (Jia et al., 2011)). Hahn et al. (2011) and Stoy et al. (2011) do not specify whether or not actual money was used. Interestingly, similar results were obtained in all these modified reward studies. Because

the Knutson group who designed our task found robust activation of reward related systems in the anticipation of interactive game playing, involving no other reward than playing the game itself (Cole et al., 2012), we feel that our results are trustworthy even with only the fictitious winning of money. To our knowledge, this is the first study investigating DAergic dysfunction in recreational users of dAMPH using a monetary incentive delay task with fMRI. We not only observed a blunted brain activation response during anticipation of reward in dAMPH users, but we also following a DAergic challenge with MPH. These findings provide further evidence for frontostriatal DA dysfunction in recreational dAMPH users and in our opinion are consistent with preclinical data suggesting neurotoxic effects of chronic dAMPH use.