Transcranial Magnetic Brain Stimulation to Reduce Cannabis Use in Heavy Cannabis Users

Overview

The growing legalization of cannabis across the U.S. is associated with increases in cannabis use, and accordingly, an increase in the number of individuals with cannabis use problems, including cannabis use disorder (CUD). While there are several medications being investigated as treatment options for CUD, none have been FDA-approved, and there is limited efficacy of traditional behavioral therapy approaches for this population. Consequently, there is a pressing need for the development of new treatments, including approaches that specifically target the brain areas associated with problematic cannabis use behaviors. Elevated attention to drug cues is one of the primary causes of relapse in heavy cannabis users. Preliminary data suggests that repetitive transcranial magnetic stimulation (rTMS), a non-invasive form of brain stimulation, may be a novel brain-based tool to decrease heightened attention to drug cues in people with CUD. Building on prior data, the primary goal of this study is to evaluate the feasibility and effectiveness of TMS as a tool to decrease attention to drug cues and reduce cannabis use. In this study, fifty (50) treatment-seeking, near-daily cannabis users will be recruited to receive either active or sham (placebo) repetitive TMS (rTMS). Participants will complete a total of 25 treatment sessions, delivered as five sessions per day across five days, with sessions flexibly scheduled over a two-week period. Measures of cannabis use and brain activity will be collected before and after treatment using real-time self-report assessments and functional magnetic resonance imaging (fMRI), respectively. Specifically, cannabis use will be assessed in participants' everyday environments using brief text-message surveys during a two-week baseline period, the two-week treatment period, and a four-week follow-up period. The study aims to determine whether active rTMS reduces brain activity in response to cannabis cues, decreases automatic attention to cannabis cues, and leads to meaningful reductions in cannabis use compared to sham treatment.

The expanding legalization of cannabis across the U.S. is associated with increases in cannabis use and, accordingly, an increase in the number of individuals with cannabis use disorder (CUD). One key predictor of relapse is elevated attentional bias to drug cues, coupled with attenuated cognitive control in the presence of those cues. Attentional bias to drug cues is associated with increased activity in the Salience Network (SN), including the anterior cingulate cortex and bilateral anterior insula, as well as reduced activity in the dorsolateral prefrontal cortex (DLPFC) and broader cognitive control circuitry during exposure to cannabis cues. Our prior data demonstrate that neural responses to drug cues can be reduced by attenuating ventromedial prefrontal cortex (VMPFC) and reward circuitry using inhibitory repetitive transcranial magnetic stimulation (rTMS) (Strategy 1). An alternative approach, however, may be to enhance activity in the DLPFC and cognitive control circuitry, which may also reduce neural reactivity to drug cues by inversely regulating SN cue hyper-reactivity (Strategy 2, the focus of this K01). Through the research and training plan outlined in this K01 proposal, I seek to evaluate the ability of left DLPFC-targeted rTMS to attenuate SN drug cue reactivity and attentional bias, and to reduce cannabis use. This will be accomplished by applying accelerated intermittent theta burst stimulation (aiTBS), a novel patterned excitatory form of rTMS, to the L DLPFC in heavy cannabis users. GOAL. The primary objectives of this K01 research project are to: 1. determine whether L DLPFC aiTBS decreases cannabis use using real-time data collected in the natural environment; 2. determine whether aiTBS-induced changes in cannabis use are associated with changes in Salience Network drug cue reactivity; and 3. assess whether L DLPFC aiTBS is feasible, tolerable, and safe relative to sham stimulation. DESIGN. Fifty (50) treatment-seeking, heavy (near-daily) cannabis users will be randomized to receive either active or sham aiTBS targeting the L DLPFC. Participants will complete a total of 25 treatment sessions, delivered as five sessions per day (50-min inter-session interval) across five treatment days, with visits flexibly scheduled over a two-week period. Cannabis use data will be collected throughout the study, and functional magnetic resonance imaging (fMRI) data will be collected before and after aiTBS treatment, as well as following a 4-week follow-up period. Cannabis use in the natural environment will be assessed using Ecological Momentary Assessment (EMA) during a two-week baseline (pre-treatment) period, a two-week treatment period, and a four-week follow-up period. Frequency of use (days per week) and quantity of use (average grams per use day) will be captured via EMA and corroborated during the four follow-up visits using Timeline Followback (TLFB) interviews and urine toxicology to assess cannabis and other substance use and to monitor for adverse events. We will test the hypotheses that active aiTBS will reduce neural reactivity to cannabis cues (Aim 2), reduce cannabis use frequency and/or quantity (Aim 1), and demonstrate non-inferior feasibility, tolerability, and safety compared to sham stimulation (Safety Aim). Over the two-year recruitment period, this project will generate a critical dataset to advance brain stimulation treatment development for CUD. In addition, these data will support a subsequent R01 application aimed at extending this line of treatment development research. Finally, this project will provide essential training in human behavioral pharmacology and clinical trial research design and analysis, supporting my progression toward independence as an interdisciplinary addiction neuroscientist.