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 bilat-eral 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-to-treat 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 (X² =5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X² =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 smok-ing cessation for adults.

Keywords: Smoking cessation; addiction medicine; cigarette consumption; cigarette craving; insula; lateral prefrontal cortex; repetitive transcranial magnetic stimulation.

Figure 1

Timeline for treatment and assessments. rTMS – repetitive transcranial magnetic stimulation (active or sham), NUI – Nicotine Use Inventory, TCQ – Tobacco Craving Questionnaire, FTND – Fagerström Test for Nicotine Dependence, VAS – Visual Analogue Scale (before provocation procedure, after provocation procedure, and after rTMS session), MNWS – Minnesota Nicotine Withdrawal Scale, MMSE – Mini‐Mental State Examination, BSRT – Buschke Selective Reminding Test

Figure 2

Four‐week continuous quit rate (CQR) until Week 6 and Week 18 in patients receiving active or sham repetitive transcranial magnetic stimulation. Only participants who were abstinent at Week 6 were followed up to Week 18. ITT – intent‐to‐treat set, CO – completer analysis set. *p<0.05, **p<0.01, ***p<0.001.

Figure 3

Acute changes in Visual Analogue Scale (VAS) craving scores following provocation (VAS2 minus VAS1) and following repetitive transcranial magnetic stimulation (VAS3 minus VAS2) in patients receiving active or sham treatment in the first session. Overall changes in craving during the first session (VAS3 minus VAS1) indicate that craving in the sham group returns to baseline, whereas it is reduced in the active group (F_1,253=5.00, p=0.026). *p<0.05.

Figure 4

Daily changes in baseline craving (VAS1) scores during the first three weeks of treatment in patients receiving active or sham repetitive transcranial magnetic stimulation. ANOVA comparing VAS1 scores on the second vs. the first day of treatment (see box) revealed a significant interaction effect (F_1,165=3.70, p=0.025). Repeated measure ANOVA during the treatment period revealed main effects for group (F_1,159=4.50, p=0.035) and time (F_14,2226=16.79, p<0.0001), as well as for group x time interaction (F_14,2226=1.79, p=0.034). *p<0.05.