Low-intensity focused ultrasound for opioid use disorder: early evidence and open questions

Although effective treatments for opioid use disorder (OUD) exist(1), opioid-related overdose deaths in the United States have risen dramatically in recent years(2). New treatments are needed to improve OUD outcomes.

One avenue for the development of new OUD treatments is neuromodulation, which leverages our growing understanding of the neurobiology of addiction to directly modulate specific brain targets. Through direct neural targeting, neuromodulation offers a novel treatment approach in OUD, and may avoid the off-target adverse effects sometimes seen with medications. Specific neuromodulation approaches tested for OUD include transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and low intensity focused ultrasound (LIFUS). TMS modulates neuronal function by sending magnetic pulses through the skull into the underlying brain region(3). TMS is well studied, has FDA approvals (e.g., for treatment of depression) and is generally well tolerated. However, because TMS coils generally have a penetration depth of a few centimeters(4), TMS cannot reach many subcortical brain regions thought to be critical to the neurocircuitry of addiction, such as the nucleus accumbens (NAc). In addition, TMS often requires regular clinic attendance (e.g., treatments 5 days per week for 4–6 weeks). DBS also has FDA approvals (e.g., for treatment of movement disorders) and changes neuronal activity through chronic or adaptive stimulation delivered via implanted electrodes and a programmable stimulator. While DBS allows targeting of subcortical structures, changing stimulation parameters (e.g., frequency, pulse width, and current) based on response, and the opportunity for local field potential recording from the target, it requires an invasive and costly neurosurgical procedure. Finally, LIFUS focuses an array of ultrasound beams on a specific location in the brain, where waves summate to deliver ultrasonic energy. LIFUS can target deep brain structures(5), and recent work suggests that specific protocols can have either inhibitory or excitatory effects(5). Although in an earlier stage of development than TMS and DBS, and with few human trials to date, early work suggests that LIFUS can modulate subcortical structures like DBS, but without the risks inherent in surgery.

To date, two prior studies have examined LIFUS for OUD. Both were conducted by the same research group as the current study(6), and both examined LIFUS to the nucleus accumbens (NAc). One was a first-in-humans case report(7) and the other a dose-finding study among four participants(8). In this issue, Rezai et al.(6) build on their prior work in a single-arm, open-label, study of LIFUS to the bilateral NAc for severe OUD. Seven participants received a single 20-minute session of LIFUS to the bilateral NAc using an ExAblate Neuro Type 2 device (Insightec; Miami, FL). LIFUS was administered as an adjunct to medication for OUD while participants were admitted to residential treatment. An eighth participant received both the original sonication, and a second sonication after day 60 following relapse to opioid use. Participants were followed for 90 days. Primary outcomes were safety, tolerability, and feasibility of bilateral LIFUS to the NAc. Secondary outcomes were effects on craving, substance use, mood, and functional brain connectivity.

Overall, the LIFUS protocol reported in this paper appears to have been safe, tolerable and feasible when performed during a period of abstinence from substance use. There were no serious adverse events related to the study device/procedure and only one participant opted to end the LIFUS session early due to discomfort. Remarkably, the authors report dramatic reductions in craving both immediately post-sonication and sustained over the 90-day follow-up. In addition, seven participants remained abstinent from all substances at the 30-day follow-up and five at the 60- and 90- day follow-ups. This treatment response is particularly striking given participants had high levels of pre-treatment opioid use, with multiple prior treatment failures.

The results reported by Rezai et al.(6) in this issue may represent a first step toward a significant change in OUD care; they describe a well-tolerated treatment with durable effects and the potential for wide-spread scalability. Given the centrality of the NAc to the pathophysiology of substance use disorders generally, as well as other psychiatric disorders, these results may also herald a new treatment approach with applications beyond OUD. However, this potential must be understood within the limitations of the study itself. The primary aims of this study were safety, tolerability, and feasibility, and as such the study was open label and conducted in only 8 participants. The placebo effect can be powerful, particularly in open-label studies(9). Other important confounds are also difficult to address in an open-label design. For example, all participants were recruited from residential substance use treatment and were receiving medications for OUD; thus, some treatment effects may be attributable to other interventions. Therefore, replication of results in future double-blind sham-controlled trials is critical. The study also raises important fundamental questions.

First, why would a single LIFUS sonication of the bilateral NAc result in a 90-day durable treatment effect? Such an effect is not consistent with the number of stimulation sessions usually required for TMS, or the ongoing approach to stimulation generally used in DBS. Indeed, very long-term durability is typically only seen with irreversible interventions such as ablation. Rezai et al. report on post-LIFUS imaging data which found no evidence of structural damage to the NAc during their protocol, and durability of effects beyond 90 days is unknown. However, the question remains: what mechanism(s) underlie 90-day durable single-sonication effects?

Second, if LIFUS sonication of the NAc can achieve durable treatment effects for most individuals, how should this be interpreted within the context of current neurobiological models of addiction? Although the NAc has long been central to theoretical models of addiction, a modern understanding of the neurobiology of addiction includes multiple circuits and many brain regions(10). Could LIFUS of the NAc impact the negative affective states and stress-related circuitry which play important roles in current models of addiction? If future double-blind placebo-controlled trials demonstrate durable effects of NAc sonication in most patients, it will be important to clarify the influences of LIFUS of the NAc on addiction-related neurocircuitry more broadly.

Taken together, the results reported by Rezai et al. in this issue indicate the promise and potential of LIFUS as a novel treatment modality for OUD. Given the urgent need for new OUD treatments, this is a welcome and meaningful contribution. How far-reaching the implications of the current study are—for OUD treatment, the field of LIFUS, and for addiction psychiatry itself—can be best clarified over time with larger, double-blinded, sham-controlled trials.