Objectives: Empirical evidence suggests substance dependence creates stress system dysregulation which, in turn, may limit the efficacy of verbal-based treatment interventions, as the recovering brain may not be functionally capable of executive level processing. Treatment models that target implicit functioning are necessary. Methods: An RCT was conducted to examine the effects of a dual-processing (DP) intervention compared to a didactic standard care (RP) model on brain function change in substance-dependent adults (N = 29). Results: fMRI analyses showed decreased amygdala activation simultaneous with increased frontal lobe (medial frontal gyrus and ACC) activation in the DP group during passive watch condition, while the RP group showed continued amygdala activation simultaneous to frontal lobe activation during drug stressor presentation at post-treatment. Conclusions: Our study offers preliminary evidence that DP acts on neural functioning in ways that increase regulatory response in the presence of drug stressor cues by enhancing top-down functioning and diminishing amygdala reactivity.