A framework and practical guide for conducting double-blind randomized clinical trials combining transcranial electrical stimulation and psychotherapy

Transcranial electrical stimulation (tES) is a non-invasive technique for modulating neural activity with minimal side effects, making it ideal for delivery concurrent with evidence-based psychotherapy. However, combining these modalities introduces unique methodological challenges that should be carefully addressed to ensure rigorous clinical trials with interpretable results. This article provides a conceptual guide and initial framework for designing and conducting double-blind randomized controlled trials that combine tES with evidence-based psychotherapy.

We present a conceptual model for understanding the bidirectional influences between tES and evidence-based psychotherapy, outline critical considerations for study design, and provide practical guidelines for trial implementation. Drawing from recent clinical trials and established best practices, we also address key issues including target identification, blinding procedures, regulatory considerations, personnel requirements, and equipment needs. This guide is intended for investigators planning to conduct tES-psychotherapy studies and aims to enhance the quality and interpretability of research in this emerging field.

CC was supported by NIMH F32MH137993. JR was supported by NIMH R00MH126161. Department of Psychology, Florida State University, Tallahassee, FL, USA Corinne N.

Carlton, Justin Riddle & Angela Qian Program in Neuroscience, Florida State University, Tallahassee, FL, USA Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Zachary J. Stewart, Erin Bondy, Nadia Kako, Crystal E. Schiller & Flavio Frohlich Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Zachary J.

Stewart, Nadia Kako & Flavio Frohlich Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, USA Brain Stimulation Research Center, Duke University, Durham, NC, USA Department of Psychology, University of Denver, Denver, CO, USA Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA F.F. holds equity in and serves as a consultant for Electromedical Products International (EPI). F.F. is the lead inventor of non-invasive brain stimulation technology and receives royalty payments from the University of North Carolina at Chapel Hill. F.F. is the founder and sole owner of Flavio Labs LLC, a coaching and consulting firm, and co-founder and equity holder of Qortical Clinical Partners Inc.

F.F. holds an adjunct professorship at Inselspital, Bern University Hospital (University of Bern, Switzerland) and serves as a consultant to that institution. F.F. receives royalty payments from Academic Press for the textbook Network Neuroscience. Z.S. is a co-founder and equity holder of Qortical Clinical Partners, Inc.