Patients with attention‐deficit/hyperactivity disorder (ADHD) are often diagnosed with comorbid substance misuse (SM), which is associated with poor treatment efficacy. Although literature indicates similar inhibitory control deficits in both conditions, it is unclear whether SM in ADHD exaggerates pre‐existing deficits, with additive or distinct impairments in patients. Our aim was to examine SM effects on inhibitory control in ADHD. Behavioural and functional magnetic resonance imaging (fMRI) data from a stop‐signal task were compared across ADHD patients with and without SM (ADHD + SM and ADHD‐only, respectively) and controls (n = 33/group; 79 males, mean age 18.02 ± 2.45). To limit substance use disorder (SUD) trait effects, groups were matched for parental SUD. Overall, we found worse performance for ADHD‐only and/or ADHD + SM compared with controls but no difference between the ADHD groups. Moreover, the ADHD groups showed decreased frontostriatal and frontoparietal activity during successful and failed stop trials. There were no differences between the ADHD groups in superior frontal nodes, but there was more decreased activation in temporal/parietal nodes in ADHD‐only compared with ADHD + SM. During go‐trials, ADHD + SM showed decreased activation in inferior frontal nodes compared with ADHD‐only and controls. Findings during response inhibition showed deficits in inhibition and attentional processes for ADHD patients with and without SM. Despite no evidence for SM effects during response inhibition, results during go‐trials suggest distinct effects on nodes that are associated with several executive functions. Future studies should investigate whether distinct deficits in ADHD + SM relate to poor treatment results and can direct development of distinct ADHD treatment strategies for these patients.
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