Given high relapse rates and the prevalence of overdose deaths, novel treatments for substance use disorder (SUD) are desperately needed for those who are treatment refractory. The objective of this study was to evaluate the safety of deep brain stimulation (DBS) for SUD and the effects of DBS on substance use, substance craving, emotional symptoms, and frontal/executive functions. DBS electrodes were implanted bilaterally within the Nucleus Accumbens/Ventral anterior internal capsule (NAc/VC) of a man in his early 30s with >10-year history of severe treatment refractory opioid and benzodiazepine use disorders. DBS of the NAc/VC was found to be safe with no serious adverse events noted and the participant remained abstinent and engaged in comprehensive treatment at the 12-week endpoint (and 12-month extended follow-up). Using a 0-100 visual analog scale, substance cravings decreased post-DBS implantation; most substantially in benzodiazepine craving following the final DBS titration (1.0 ± 2.2) compared to baseline (53.4 ± 29.5; p < .001). A trend toward improvement in frontal/executive function was observed on the balloon analog risk task performance following the final titration (217.7 ± 76.2) compared to baseline (131.3 ± 28.1, p = .066). FDG PET demonstrated an increase in glucose metabolism in the dorsolateral prefrontal and medial premotor cortices at the 12-week endpoint compared to post-surgery/pre-DBS titration. Heart Rate Variability (HRV) improved following the final titration (rMSSD = 56.0 ± 11.7) compared to baseline (19.2 ± 8.2; p < .001). In a participant with severe, treatment refractory opioid and benzodiazepine use disorder, DBS of the NAc/VC was safe, reduced substance use and craving, and improved frontal and executive functions. Confirmation of these findings with future studies is needed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).