Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double‐blind randomized controlled trial

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double-blind RCT in 262 chronic smokers meeting DSM-5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilateral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue-induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four-week continuous quit rate (CQR) until Week 18 in the intent-totreat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent-to-treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X 2 =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X 2 =7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smoking cessation for adults.

Repetitive Transcranial Magnetic Stimulation (rTMS) as a Promising Treatment for Craving in Stimulant Drugs and Behavioral Addiction: A Meta-Analysis

“…Even so, we can also hypothesize that the "downregulated craving and improved control" therapeutic interval induced by rTMS may offer the possibility of breaking the addiction cycle by enabling patients to gain more benefit from standard drug treatment and rehabilitation programs. Further protocols could also evaluate the efficacy of maintaining rTMS sessions after successful response to initial stimulations, as proposed in depression [123] or in a recent multicenter randomized control trial in tobacco use disorder [124]. Long-term positive results of these protocols have also been suggested by an observational study in a large cohort in cocaine use disorder [125].…”

Noninvasive Brain Stimulation for Nicotine Dependence in Schizophrenia: A Mini Review

“…Multiple studies support the use of rTMS for nicotine dependence in healthy smokers (15)(16)(17)(18)(19)(20)(21). Most of these studies have used high frequency 10 Hz rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC) ranging from a 15-min single-session (17) to multi-session experiments (15,16,19,21).…”

“…Multiple studies support the use of rTMS for nicotine dependence in healthy smokers (15)(16)(17)(18)(19)(20)(21). Most of these studies have used high frequency 10 Hz rTMS delivered to the left dorsolateral prefrontal cortex (DLPFC) ranging from a 15-min single-session (17) to multi-session experiments (15,16,19,21). High frequency stimulation of the DLPFC has been proposed to activate this region and thereby improve "top-down" regulation of brain regions involved in craving and drug-seeking behavior (22).…”

Repetitive Transcranial Magnetic Stimulation for Comorbid Major Depressive Disorder and Alcohol Use Disorder

“…The insula was hypothesized to be a promising target, due to it being an important region in interoception and integrating internal states and strongly associated with craving [ 71 ]. Furthermore, this stimulation protocol was intended to parallel the protocol that was shown to be effective in smoking cessation [ 72 , 73 ]; however, these smoking trials used an H4 coil, which stimulated not only the insula, but also the bilateral prefrontal (which the H8 coil does not). Lastly, two studies of single-session cTBS to a total of 3600 pulses to the MPFC demonstrated the ability to modify fronto-striatal activity on functional MRI but not on self-reported craving [ 66 , 67 ], and requires further study with a full course of treatment.…”

“…These protocols aim to exploit mechanisms of task-dependent plasticity, as once a disorder specific neurocircuit is “activated”, it may be more primed for neuromodulation by rTMS. For example, dTMS for the treatment of nicotine addiction is done with the pairing of smoking-related cues during treatment [ 73 ]. This combined method resulted in clinically significant findings within a multi-site RCT, which led to FDA approval.…”