Clinical Context

Alcohol addiction has a high disease burden but limited treatment options. Transcranial magnetic stimulation (TMS) noninvasively targets pathological brain circuit activity, rather than individual neurochemical systems.

Study Synopsis and Perspective

Deep, repetitive TMS is safe and effective in decreasing symptoms of alcohol addiction and brain reactivity, new research suggests.

In a randomized, double-blind, sham-controlled trial, participants who received TMS targeting the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC) for 3 weeks showed significantly reduced heavy drinking days compared with a group who received a sham treatment.

The active treatment group also reported significantly less alcohol craving and showed less functional connectivity on MRI in areas of the brain that can trigger craving and relapse.

Clinicians should "keep their eyes open" in the wake of this phase 2 trial, co-corresponding author Markus Heilig, MD, PhD, professor of psychiatry and director at the Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences, Linköping University, Sweden, told Medscape Medical News.

"If and when this replicates in the equivalent of a phase 3 study, we will actually have a completely novel treatment available for this difficult-to-treat and very impactful disease," Dr Heilig said.

The findings were published online December 5 in Biological Psychiatry.

Proof of Concept

In the proof-of-concept trial, researchers enrolled and randomly assigned 51 treatment-seeking adults with moderate to severe alcohol dependence to receive active or sham treatment. Before treatment, participants completed "craving induction," which included holding and smelling but not consuming an alcoholic beverage.

Dr Heilig noted that before stimulating the brain, "you want to make it as malleable as possible," and brain networks tend to be more malleable when they are active.

During the 3-week treatment phase, active or sham stimulations were delivered in five 30-minute sessions per week. During the sessions, all participants wore a helmet with a deep TMS coil.

In the active stimulation group, each session included 100 trains of 30 pulses at 10 Hz (3 seconds) with 15-second intervals, for a total of 3000 pulses. The sham stimulation produced the same acoustic artifact and generated skin sensations mimicking those of the active stimulation, but it did not involve a magnetic field.

Participants, operators, and raters were blinded to the type of coil used.

Five participants relapsed during the first 3 weeks of treatment and were excluded from the analysis. The mean age of those completing treatment (n=23 in each group) was 43 years, and two thirds were men.

The gender makeup of the study reflects "what a real treatment-seeking group looks like," Dr Heilig said.

During the 12-week follow-up phase, 5 additional participants dropped out.

"Pretty Robust" Treatment Effect

The primary outcome was reduction in percentage of heavy drinking days (pHDD), defined as consuming at least five drinks of 12 g alcohol per day for men and at least 4 such drinks for women.

Initially, pHDD dropped in both groups, which is something generally seen in alcohol studies, said Dr Heilig. "The moment people decide to participate in a study, everybody drops their consumption, [which] biases a study like this against picking up an effect," he added.

However, heavy drinking days increased during follow-up in the sham group but remained low in the active-treatment group. The mean pHDD was significantly lower in the active vs sham groups (2.9% vs 10.6%; P=.037).

"So despite the bias, a treatment effect does emerge" and was "pretty robust," Dr Heilig said.

This was supported by a significant group difference in weekly alcohol consumption and a trend-level difference in percentage of alcohol-positive urine samples.

A secondary outcome was change in alcohol craving, assessed with the Penn Alcohol Craving Scale (PACS). PACS scores decreased in both groups during treatment but were more steeply reduced in the active group. During follow-up, craving levels increased to a lesser extent in the active group.

MRI scans showed reduced connectivity from the mPFC to the subgenual ACC, an area involved in negative emotions that can trigger craving and relapse, said Dr Heilig. There was also reduced connectivity between the dorsal ACC and caudate, a circuit involved in the reward system.

In treatment trials, researchers look for a biomarker of target engagement. However, "to date, there has been no study using TMS that has actually demonstrated the intervention had a measurable effect on brain activity. So to me, this is a biomarker; it did something to the brain," Dr Heilig said.

Delving Deeper Into the Brain

The results underline the importance of stimulating deeper parts of the brain, co-corresponding author Abraham Zangen, PhD, head of the Brain Stimulation and Behavior Lab and chair of the PsychoBiology Brain Program, Ben Gurion University, Israel, told Medscape Medical News.

Early TMS studies, which involved superficial brain stimulation, reduced cigarette consumption but was not associated with quitting, Dr Zangen said. "It was only when we targeted deeper parts of the prefrontal cortex that we were able to induce smoking cessation," he added.

It was this research that led to approval by the US Food and Drug Administration of deep TMS for smoking cessation.

This same deep-brain approach was used in the current study. "So the emphasis on the technology that allows penetration into deeper parts of the brain and targeting the relevant pathological circuitry of addiction is a key complement of the success of this study," Dr Zangen said.

Results also showed no serious adverse events. Only a few participants reported transient headaches, which all resolved spontaneously, and frequency did not differ between groups.

Dr Heilig now hopes to carry out a multisite phase 3 study of the intervention and would suggest it involve 4 (instead of 3) weeks of initial treatment and then a weekly booster session. "There are biological reasons to believe that might be more efficient, although we don't have the data," he said.

In contrast, he noted that the longer the trial, the more difficult it might be to recruit patients.

Clinically Significant?

Commenting for Medscape Medical News, Derek Blevins, MD, assistant professor of clinical psychiatry, Columbia University, and research psychiatrist, Division on Substance Use Disorders, New York State Psychiatric Institute, called the research "really exciting."

To date, most TMS studies have been relatively small and looked at a target such as craving. Although these studies did show some effect, the clinical significance of that effect was unclear, said Dr Blevins, who was not involved with the current research.

"I think this new study actually demonstrated a clinically significant effect of a noninvasive treatment for a disease that's very difficult to treat," he said.

A potential limitation of the study, however, was that it required abstinence, Dr Blevins noted. It would be "really helpful" to understand how TMS might aid individuals such as those who relapsed during the study, "because they're the more treatment-refractory individuals we see in clinical practice," he said.

If a multicenter trial is launched, Dr Blevins said that he would also like it to include an ethnically and racially diverse population.

The study was supported by grants from the European Union's Horizon 2020 research and innovation program and the Swedish Research Council. Dr Heilig reports having received consulting fees, research support, or other compensation from Indivior, Camurus, BrainsWay, Aelis Farma, and Janssen Pharmaceuticals. Dr Zangen is an inventor of deep TMS coils and has financial interest in BrainsWay, which produces and markets these coils. Blevins reported no relevant financial relationships.

Biol Psychiatry. Published online December 5, 2021.^[1]

Clinical Implications

• Deep, repetitive TMS safely and effectively reduces alcohol addiction symptoms and brain reactivity in areas triggering craving and relapse.
• The findings provide initial proof-of-concept for dTMS targeting midline frontocortical structures as an alcohol addiction treatment.
• Implications for the Health Care Team: dTMS treatment was shown to be safe and well tolerated, with no serious adverse events.

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