The efficacy of external Trigeminal Nerve Stimulation (TNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD): a multi-centre, double-blind, randomized, sham-controlled, parallel-group, phase IIb trial (ATTENS)

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 investigating short and longer-term efficacy (6 months) of real vs sham TNS in 150 children and adolescents with ADHD. Partricipants were randomized to receive real TNS (<i>n</i>=75, mean age [<i>SD</i>]= 12.6 [2.8 years]), or sham TNS (<i>n</i>=75, mean age [<i>SD</i>]= 12.6 [2.8 years]), nightly for 4 weeks. Bilateral stimulation targeted V1 trigeminal branches using battery-powered electrodes applied to the forehead for ~9 hours/night. Sham TNS delivered 30 seconds of stimulation per hour at a lower frequency. Intention to treat analysis (ITT) showed no significant differential treatment effects on ADHD symptoms (estimated adjusted mean difference [<i>aMD</i>] = 0.83; 95% Confidence interval [CI] = –2.47 to 4.13; <i>p</i> = 0.622; Cohen’s <i>d</i> = 0.09). No differential treatment effects were observed either on the secondary outcomes covering other symptom scales of ADHD and related clinical problems, as well as cognitive and physiological outcomes, except for a small reduction in mind wandering favouring real TNS (<i>aMD</i> = –2.17; 95% CI = –4.33 to –0.01; <i>p</i> = 0.049; Cohen’s <i>d</i> = –0.27). Adherence was 94% and compliance 93%. Blinding was successful. No serious adverse events (SAEs) 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