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.

OBJECTIVE There were more than 107,000 drug overdose deaths in the US in 2021, the most ever recorded. Despite advances in behavioral and pharmacological treatments, over 50% of those receiving treatment for opioid use disorder (OUD) experience drug use recurrence (relapse). Given the prevalence of OUD and other substance use disorders (SUDs), the high rate of drug use recurrence, and the number of drug overdose deaths, novel treatment strategies are desperately needed. The objective of this study was to evaluate the safety and feasibility of deep brain stimulation (DBS) targeting the nucleus accumbens (NAc)/ventral capsule (VC) and potential impact on outcomes in individuals with treatment -refractory OUD. METHODS A prospective, open -label, single -arm study was conducted among participants with longstanding treatment -refractory OUD (along with other co-occurring SUDs) who underwent DBS in the NAc/VC. The primary study endpoint was safety; secondary/exploratory outcomes included opioid and other substance use, substance craving, and emotional symptoms throughout follow-up and18FDG-PET neuroimaging. RESULTS Four male participants were enrolled and all tolerated DBS surgery well with no serious adverse events (AEs) and no device- or stimulation -related AEs. Two participants sustained complete substance abstinence for > 1150 and > 520 days, respectively, with significant post-DBS reductions in substance craving, anxiety, and depression. One partici- pant experienced post-DBS drug use recurrences with reduced frequency and severity. The DBS system was explanted in one participant due to noncompliance with treatment requirements and the study protocol. 18FDG-PET neuroimaging revealed increased glucose metabolism in the frontal regions for the participants with sustained abstinence only. CONCLUSIONS DBS of the NAc/VC was safe, feasible, and can potentially reduce substance use, craving, and emotional symptoms in those with treatment -refractory OUD. A randomized, sham -controlled trial in a larger cohort of patients is being initiated.

Over 110,000 drug overdose deaths occurred in the U.S. in 2022, the most in recorded history, with >75% involving opioids (1). Moreover, there are 46.3 million people in the United States with a substance use disorder (SUD), with only ∼7% receiving specialty treatment (2). There have been significant efforts to improve treatment outcomes; for example, the combination of behavioral treatment with medication for opioid use disorder (MOUD) has been associated with increased treatment retention and reduced opioid craving and use (3,4).

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).