BACKGROUND: Opioid use disorder remains a critical health care challenge because current therapeutic strategies have limitations that result in high recurrence and deaths. We evaluated the safety and feasibility of focused ultrasound (FUS) neuromodulation to reduce substance cravings and use in severe opioid and co-occurring substance use disorders. METHODS: This prospective, open-label, single-arm study enrolled 8 participants with severe, primary opioid use disorder with co-occurring substance use. Participants received a 20-minute session of low-intensity FUS (220 kHz) neuromodulation targeting the bilateral nucleus accumbens (NAc) with follow-up for 90 days. Outcome measures included safety, tolerability, feasibility, and effects of FUS neuromodulation by assessment of adverse events, substance craving, substance use (self-report, urine toxicology), mood, neurological examinations, and anatomical and functional magnetic resonance imaging (fMRI) at 1, 7, 30, 60, and 90 days post-FUS. RESULTS: No serious device-related adverse events or imaging abnormalities were observed. Following FUS, participants demonstrated immediate (p , .002) and sustained (p , .0001; mean 91%) reductions in cue-induced opioid craving, with median ratings on a scale from 0 to 10 as follows: 6.9 (pre-FUS) versus 0.6 (90-day post-FUS). Craving reductions were similar for other illicit substances (e.g., methamphetamine [p , .002], cocaine [p , .02]). Decreases in opioid and co-occurring substance use were confirmed by urine toxicology. Seven participants remained abstinent at 30 days; 5 participants remained abstinent throughout 90 days post-FUS. Resting-state fMRI demonstrated decreased connectivity from the NAc to reward and cognitive regions post-FUS. CONCLUSIONS: NAc FUS neuromodulation is safe and a potential adjunctive treatment for reducing drug cravings and use in individuals with severe opioid and co-occurring substance use disorders. Larger, sham-controlled, randomized studies are warranted.