A Randomized Controlled Trial of Medial Prefrontal Cortex Theta Burst Stimulation for Cocaine Use Disorder: A Three-Month Feasibility and Brain Target-Engagement Study.

Background: Cue-induced craving precipitates relapse in drug and alcohol use disorders. Theta burst stimulation (TBS) to the left frontal pole of the medial prefrontal cortex (MPFC) has previously been shown to reduce drinking and brain reactivity to alcohol cues. This randomized, double-blind, sham-controlled target-engagement study aimed to assess whether TBS has similar effects in individuals with cocaine use disorder (CUD).

Methods: Thirty-three participants in intensive outpatient treatment received either real or sham TBS over 10 sessions across 3 weeks (36,000 pulses total; continuous TBS, 110% resting motor threshold, 3600 pulses/session). TBS was administered on days of behavioral counseling. Twenty-five individuals completed all 10 TBS sessions. Brain reactivity to cocaine cues was measured using fMRI at baseline, 1-month, 2-months, and 3-months.

Results: Cocaine abstinence during the 3-month follow-up period was greater in the real TBS group (1-month: 92.0%, 2-month: 100.0%, 3-month: 85.0%) compared to sham (1-month: 66.6%, 2-month: 66.6%, 3-month: 66.6%), though not statistically significant [1-month: 6.00, p=0.14; 2-month OR=:14.30, p=0.09, and 3-month OR=2.75, p=0.30]. However, there was a significant effect on cocaine cue reactivity (treatment effect: F_1,365= 8.92, p=0.003; time*treatment interaction: F_3,365=12.88, p<0.001). Real TBS reduced cocaine cue reactivity in the MPFC (F_3,72=5.46, p=0.02) overall, and in the anterior cingulate (F_3,72=3.03, p=0.04), and insula (F_3,72=3.60, p=0.02).

Conclusions: This early-stage trial demonstrates TBS to the MPFC reduces brain reactivity to cocaine cues in key nodes of the Salience Network in treatment-seeking cocaine users. Future, well-powered trials are warranted to evaluate clinical efficacy outcomes.