Cannabis Use Disorder (CUD) is a common condition with well-documented adverse effects (Budney et al., 2019, Meier, 2021, Sahlem et al., 2018a) and concordantly high demands for treatment (Manthey et al., 2021, Rhee and Rosenheck, 2022). The incidence of frequent cannabis use and CUD may be increasing (Hasin et al., 2015, UNITED NATIONS, 2020) with increasing legalization and decreased perceived risk (Levy et al., 2021), and now more than 16-million people in the United States alone meet criteria for CUD (Key Substance Use and Mental Health Indicators in the United States: Results from the 2021 National Survey on Drug Use and Health, 2021). The frequency of daily cannabis use has also risen in recent years in the United States—potentially further increasing the risk of an increased incidence of CUD in the future (Patrick et al., 2022). Though there are promising pharmacologic treatments in the pipeline (Gray et al., 2012, Lintzeris et al., 2019, Mariani et al., 2021, McRae-Clark et al., 2021), no medication has distinguished itself as clearly effective in the treatment of CUD, and in general, all medications have side-effects. Further, although consistently demonstrating a beneficial effect, studies testing behavioral therapies for CUD have resulted in moderate effects (Davis et al., 2015)—and access to evidence-based behavioral treatments is limited. As such, there remains a need to develop new therapeutics for CUD.

Repetitive transcranial magnetic stimulation (rTMS) works via the principles of magnetic induction and long-term potentiation (Brown et al., 2021, Deng et al., 2013, Huang et al., 2007), and can focally alter circuit function in the brain (Hanlon et al., 2013, Hanlon et al., 2016, Hanlon et al., 2017). Trials applying serial applications of rTMS in a variety of neuropsychiatric conditions have demonstrated that by varying the location of stimulation and the treatment paradigm, it is possible to derive a therapeutic benefit in different illnesses, and rTMS is now cleared by the US Food and Drug Administration for the treatment of Major Depressive Disorder (Blumberger et al., 2018, Levkovitz et al., 2015, O’Reardon et al., 2007), Obsessive Compulsive Disorder (Carmi et al., 2019), and Tobacco Use Disorder (Zangen et al., 2021). In line with the several indications for treatment, there has been increasing promise that rTMS may become a therapeutic option across addictions, including CUD (Ekhtiari et al., 2019). Studies in non-treatment seeking participants in human laboratory paradigms have suggested rTMS has the potential to effect behavioral aspects of addiction (McNeill, 2018, Newman-Norlund et al., 2020, Rose et al., 2011, Sheffer et al., 2018) and engage its neurocircuitry (Hanlon et al., 2017, Kearney-Ramos et al., 2018, Li et al., 2017). When serial sessions of rTMS are applied in treatment seeking outpatient populations there have been suggestions of clinical efficacy. Several neurocircuit targets have emerged for study in therapeutic trials, with early promising results for the left dorsolateral prefrontal cortex (DLPFC) (Li et al., 2020), the frontal pole (McCalley et al., 2022), the dorsomedial prefrontal cortex (Harel et al., 2022), and the anterior-insula / inferior frontal gyrus (Zangen et al., 2021), although not all trials have resulted in a beneficial effect (Perini et al., 2020).

Our group and others (Kearney-Ramos and Haney, 2021) have explored the potential effect of applying rTMS to the left DLPFC, first in non-treatment-seeking participants with CUD (Sahlem et al., 2018b) and then participants with CUD who were interested in reducing their use of cannabis (Sahlem et al., 2020). Our early findings suggested that a single-session of rTMS could be feasibly applied to participants with CUD, was generally well tolerated, and may reduce the purposefulness aspect of craving (Sahlem et al., 2018b). In a subsequent study, we found that it was infeasible to deliver daily sessions of rTMS for two-weeks in treatment-seeking participants with CUD. However, those participants who did attend daily sessions reported less craving and reduced cannabis use that persisted 4-weeks after receiving rTMS (Sahlem et al., 2020). The findings from our preliminary work and other therapeutic studies in other addictive disorders applying rTMS to the DLPFC, suggested therapeutic promise for CUD, albeit with a treatment paradigm that differed from daily applications. Both data (Galletly et al., 2012, Harel et al., 2014, Kokdere et al., 2020) and clinical experience suggest it is possible to get a therapeutic effect using rTMS even if treatments are delivered less frequently than daily. Based on both trial experience and qualitative discussions with participants from our pilot treatment trial, we hypothesized that delivering study-treatments twice each week would be feasible and have a clinical effect. We subsequently designed the present phase-2 study to preliminarily determine if rTMS applied to the DLPFC twice-weekly had the potential to help treatment-seeking participants with CUD reduce their cannabis use. Specifically, we hypothesized that participants receiving active-rTMS would have reduced craving and more weeks of abstinence than participants receiving sham-rTMS.