External Trigeminal Nerve Stimulation in youth with ADHD:a randomized, sham-controlled, phase 2b trial

External trigeminal nerve stimulation (TNS) received FDA-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. We conducted a confirmatory multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb RCT to investigate short- 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 [SD] = 12.6 [2.8 years]) or sham TNS (n=75, mean age [SD] = 12.6 [2.8 years]) nightly for ~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 (ITT) 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 paediatric ADHD. Trial registration: ISRCTN82129325.