Background: Studies across multiple addictions have suggested that repetitive transcranial magnetic stimulation (rTMS) applied to the left dorsolateral prefrontal cortex (L-DLPFC) reduces cue-induced-craving (CIC), however there are no studies in treatment seeking participants with cannabis use disorder (CUD). In this secondary analysis of a previously completed trial, we explore whether a multi-session course of rTMS reduces CIC in CUD. Methods: Seventy-one participants with moderate or severe CUD (age=30.2+9.9SD;37.5% female) were randomized to twenty sessions of active or sham rTMS applied to the left DLPFC (20-sessions, Beam-F3; 10Hz) in a two-site, double-blind, sham-controlled, phase-2 trial where they also received motivational enhancement therapy. Participants rated their craving for cannabis via the short-form of the marijuana craving questionnaire (MCQ-SF) before and after a neutral and cannabis-cue presentation. Participants underwent assessment before (immediate-pre), after (immediate-post), and two-, and four- weeks following the course of rTMS. Results: The MCQ-SF scores increased following the presentation of cannabis cues relative to neutral cues at the immediate-pre timepoint in both treatment groups (p<0.0001). Following study treatment, the percent increase in MCQ-SF following cues diverged between the active and sham groups with significantly reduced CIC in the active group at the two-week post time-point (5.8+7.1%SD sham group, 0.91+4.1%SD active group; p=0.02). Between-group effect sizes (Cohen's d) were 0.24, 0.89, and 0.67 at the immediate-post, 2-week, and 4-week follow-up periods respectively. Conclusions: L-DLPFC applied rTMS may reduce CIC in treatment seeking participants with CUD.

MKS has received research support from the National Institutes of Health, the Patient Centered Outcomes Research Institute, and the Brain and Behavior Research Foundation. She is on a data safety monitoring board for a study funded by the National Institute of Mental Health. She has in the past 3 years consulted for AbbVie, Alkermes, Alto Neuroscience, Boehringer-Ingelheim, Johnson and Johnson, Karuna Therapeutics, Inc., and Neumora. She receives honoraria from the American Academy of Child and Adolescent Psychiatry and royalties from American Psychiatric Association Publishing. ALM has received research support from PleoPharma and has provided consultation to Indivior. GLS has collaborated with MagVenture and MECTA as part of investigator-initiated trials, consults for and has equity in the company Trial Catalyst, and has provided consultation to Indivior. None of the other authors have any relevant conflicts to disclose.

NCT03144232

This work was supported by the National Institutes of Health. Grant numbers: K23DA043628 (PI: Sahlem; NIH/NIDA); K12DA031794 (Co-PI's McRae-Clark and Gray; NIH/NIDA); K24DA038240 (PI: McRae-Clark; NIH/NIDA).

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This work was approved by the Institutional Review Boards of both The Medical University of South Carolina and Stanford University. This is a secondary analysis paper and further details on informed consent and IRB approval are included in the referenced primary outcomes paper.

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