AbstractBackgroundDeficient regulation of stress plays an important role in the escalation of substance use, addiction and relapse. Accumulating evidence suggests dysregulations in cognitive and reward-related processes and the underlying neural circuitry in cannabis dependence. However, despite the important regulatory role of the endocannabinoid system in the stress response, associations between chronic cannabis use and altered stress processing on the neural level have not been systematically examined.MethodsAgainst this background, the present functional magnetic resonance imaging (fMRI)study examined psycho-social stress processing in cannabis-dependent males (n = 28) and matched controls (n = 23) using an established stress-induction paradigm (Montreal Imaging Stress Task) that combines computerized (adaptive) mental arithmetic challenges with social evaluative threat.ResultsDuring psycho-social stress exposure, but not the no-stress condition, cannabis users demonstrated impaired performance relative to controls. In contrast, levels of experienced stress and cardiovascular stress responsivity did not differ from controls. Functional MRI data revealed that stress-induced performance deteriorations in cannabis users were accompanied by decreased precuneus activity and increased connectivity of this region with the dorsal medial prefrontal cortex.LimitationsOnly male cannabis-dependent users were examined, the generalizability in female users remains to be determined.ConclusionTogether, the present findings provide first evidence for exaggerated stress-induced cognitive performance deteriorations in cannabis users. The neural data suggest that deficient stress-related dynamics of the precuneus may mediate the deterioration of performance on the behavioral level.