Clinical and Functional Connectivity Outcomes of 5-Hz Repetitive Transcranial Magnetic Stimulation as an Add-on Treatment in Cocaine Use Disorder: A Double-Blind Randomized Controlled Trial

  • Eduardo A. Garza-Villarreal
    Address correspondence to Eduardo A. Garza-Villarreal, M.D., Ph.D.
    Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM) campus Juriquilla, Queretaro, Mexico

    Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz,” Mexico City, Mexico
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  • Ruth Alcala-Lozano
    Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz,” Mexico City, Mexico
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  • Sofia Fernandez-Lozano
    Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz,” Mexico City, Mexico

    Faculty of Psychology, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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  • Erik Morelos-Santana
    Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz,” Mexico City, Mexico

    Faculty of Psychology, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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  • Alan Dávalos
    Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz,” Mexico City, Mexico

    Faculty of Medicine, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
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  • Viviana Villicaña
    Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz,” Mexico City, Mexico

    Faculty of Psychology, Universidad Anahuac Sur, Mexico City, Mexico
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  • Sarael Alcauter
    Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM) campus Juriquilla, Queretaro, Mexico
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  • F. Xavier Castellanos
    Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, New York, New York

    Nathan Kline Institute for Psychiatric Research, Orangeburg, New York
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  • Jorge J. Gonzalez-Olvera
    Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz,” Mexico City, Mexico
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Published:January 25, 2021DOI:



      Cocaine use disorder (CUD) is a global condition lacking effective treatment. Repetitive transcranial magnetic stimulation (rTMS) may reduce craving and frequency of cocaine use, but little is known about its efficacy and neural effects. We sought to elucidate short- and long-term clinical benefits of 5-Hz rTMS as an add-on to standard treatment in patients with CUD and discern underlying functional connectivity effects using magnetic resonance imaging.


      A total of 44 patients with CUD were randomly assigned to complete the 2-week double-blind randomized controlled trial (acute phase) (sham [n = 20, 2 female] and active [n = 24, 4 female]), in which they received two daily sessions of rTMS on the left dorsolateral prefrontal cortex (PFC). Subsequently, 20 patients with CUD continued to an open-label maintenance phase for 6 months (two weekly sessions for up to 6 mo).


      rTMS plus standard treatment for 2 weeks significantly reduced craving (baseline: 3.9 ± 3.6; 2 weeks: 1.5 ± 2.4, p = .013, d = 0.77) and impulsivity (baseline: 64.8 ± 16.8; 2 weeks: 53.1 ± 17.4, p = .011, d = 0.79) in the active group. We also found increased functional connectivity between the left dorsolateral PFC and ventromedial PFC and between the ventromedial PFC and right angular gyrus. Clinical and functional connectivity effects were maintained for 3 months, but they dissipated by 6 months. We did not observe reduction in positive results for cocaine in urine; however, self-reported frequency and grams consumed for 6 months were reduced.


      With this randomized controlled trial, we show that 5-Hz rTMS has potential promise as an adjunctive treatment for CUD and merits further research.


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