External trigeminal nerve stimulation in youth with ADHD: a randomized, sham-controlled, phase 2b trial
External trigeminal nerve stimulation (TNS) received US Food and Drug Administration clearance in 2019 as the first device-based, non-pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), based on a small pilot sham-controlled randomized controlled trial (RCT) that reported symptom improvement in 62 children with ADHD. Here we conducted a confirmatory multicenter, double-blind, randomized, sham-controlled, parallel-group, phase 2b RCT to investigate short-term and long-term efficacy (6 months) of real versus sham TNS in 150 children and adolescents with ADHD. Participants were randomized to receive real TNS (n = 75, mean age (s.d.) = 12.6 (2.8) years) or sham TNS (n = 75, mean age (s.d.) = 12.6 (2.8) years) nightly for approximately 9 hours for 4 weeks. Bilateral stimulation targeted V1 trigeminal branches using battery-powered electrodes applied to the forehead. Sham TNS delivered 30 seconds of stimulation per hour at lower frequency and pulse width. Intention-to-treat analysis showed no significant differential treatment effects on ADHD symptoms (primary outcome) (estimated adjusted mean difference = 0.83; 95% confidence interval: -2.47 to 4.13; P = 0.622; Cohen's d = 0.09). No serious adverse events were reported, and side effects did not differ between groups. In conclusion, TNS is a safe intervention but does not demonstrate clinical efficacy for pediatric ADHD. Trial registration: ISRCTN82129325 .
Authors
- Katya Rubia
- Mitul A. Mehta (ORCID: https://orcid.org/0000-0003-1152-5323)
- Joshua Hyde (ORCID: https://orcid.org/0000-0001-6987-023X)
- Dominic Stringer (ORCID: https://orcid.org/0000-0001-5624-1733)
- Giovanni Giaroli (ORCID: https://orcid.org/0000-0002-0248-7903)
- Aldo Alberto Conti (ORCID: https://orcid.org/0000-0002-0467-9431)
- Paramala Santosh (ORCID: https://orcid.org/0000-0003-4830-5893)
- Andrea Bilbow (ORCID: https://orcid.org/0000-0002-1888-4049)
- Robert Marhenke (ORCID: https://orcid.org/0000-0001-7760-8661)
- Federico Fiori (ORCID: https://orcid.org/0000-0001-6346-4820)
- Lena Johansson (ORCID: https://orcid.org/0000-0002-4473-1134)
- Sahid El Masri
- Holan Liang
- Irem Ece Eraydin
- Ben Carter
- Natali Bozhilova
- Samuele Cortese
Institutions
- University of Hertfordshire (GB)
- Manisa Celal Bayar University (TR)
- King's College London (GB)
- South London and Maudsley NHS Foundation Trust (GB)
- University of Cambridge (GB)
- Florence Nightingale Foundation (GB)
- Isle of Wight NHS Trust (GB)
- UK Dementia Research Institute (GB)
- Attention Deficit Disorder Treatment Center (US)
- University of Southampton (GB)
- University of Bari Aldo Moro (IT)
- New York University (US)
- Technische Universität Dresden (DE)
Publication Details
- Journal
- Nature Medicine
- Published
- 2026-01-16
- DOI
- https://doi.org/10.1038/s41591-025-04075-x
- Primary Topic
- Attention Deficit Hyperactivity Disorder
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Granulosa Cell Tumor of the Ovary Foundation
- South London and Maudsley NHS Foundation Trust
- King's College Hospital NHS Foundation Trust
- United Kingdom Clinical Research Collaboration
- Solent NHS Trust
- National Institute for Health and Care Research
- British Heart Foundation
- Department of Health and Social Care
- Nuffield Foundation
- King's College London
- European Commission
- Rosetrees Trust
- King's Health Partners
- Medical Research Council
- Research Executive Agency
- St. George's, University of London
- National Institute for Health Research Applied Research Collaboration South London