Imaging the Effects of Intermittent Thetaburst Stimulation on Cannabis Self-Administration in Heavy Cannabis Users

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PROJECT SUMMARY/ABSTRACT 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 predictor of relapse is an elevated attentional bias to drug cues and attenuated cognitive control in the presence of drug cues. Attentional bias to drug cues is associated with elevated activity in the Salience Network (anterior cingulate cortex and bilateral anterior insula), and attenuated activity in the dorsolateral prefrontal cortex (DLPFC) and cognitive control circuitry when users are exposed to cannabis cues. Data from our laboratory demonstrates that it is possible to decrease the neural response to drug cues by attenuating the VMPFC and reward circuitry (Strategy 1) with inhibitory repetitive transcranial magnetic stimulation (rTMS). It is possible, however, that elevating activity in the DLPFC and cognitive control circuitry will also decrease the neural response to drug cues (Strategy 2 - topic of this K01). Through the research and training plan outlined in this K01 proposal, I seek to evaluate the ability of DLPFC rTMS to attenuate Salience Network drug cue reactivity and reduce cannabis self- administration. This will be achieved by applying intermittent theta burst stimulation (iTBS), a form of excitatory rTMS, to the DLPFC in heavy cannabis users. GOAL: The primary objectives of this K01 research project are to (1) determine if DLPFC iTBS decreases cannabis self-administration, both inpatient and outpatient in the natural ecology, and (2) determine if iTBS-induced changes in cannabis self-administration are related to changes in Salience Network drug cue reactivity. DESIGN: Sixty (60) non-treatment-seeking, heavy (near daily) cannabis smokers will be randomized to receive 10 daily sessions of either active or sham iTBS to the DLPFC. Participants will remain inpatient for 17 days. During the inpatient stay, cannabis self- administration and fMRI data will be collected before and after the 10 iTBS sessions. Cannabis use in the natural ecology will be measured outpatient for 2 weeks prior to admission (baseline) and for 2 weeks following discharge using Ecological Momentary Assessment (EMA). Time to first use and amount of resumed cannabis use will be measured using EMA and corroborated by 3 follow-up visits where TLFB and urine toxicology will capture cannabis and other drug use. We will test the hypotheses that active iTBS treatment will reduce neural reactivity to cannabis cues (Aim 2) and will reduce cannabis self-administration, both inpatient (Aim 1), and in the natural ecology (Exploratory Aim). Through this 5-year proposal, I will acquire a critical dataset that is needed in the field of brain stimulation for treatment development in CUD. Additionally, it will provide me with critical data for a subsequent R01 application wherein I plan to extend this line of treatment development research. Furthermore, this project will greatly facilitate the training in human behavioral pharmacology and clinical research design and analysis that I seek for advancement into an independent, interdisciplinary clinical addiction neuroscientist.