Researchers at King’s College London have found that trigeminal nerve stimulation (TNS), a non-invasive brain stimulation treatment approved by the U.S. Food and Drug Administration (FDA) for treating attention-deficit/hyperactivity disorder (ADHD), does not reduce core symptoms in children and adolescents. The findings, published in Nature Medicine, were derived from a large, multi center, double-blind, randomized controlled trial that enrolled 150 participants and run counter to the evidence used to supported FDA clearance in 2019.
TNS is designed as an alternative to drug treatments for ADHD. The method delivers a low electrical current through electrodes placed on the forehead to stimulate branches of the trigeminal nerve. “Sensory inputs from the trigeminal nerve fibers activate the locus coeruleus, raphe nuclei and nucleus tractus solitarius that innervate in a bottom-up manner several other brain regions, most prominently thalamic, frontal and limbic regions,” the researchers wrote. The intent of TNS is to stimulate these pathways that play a role in arousal and attention, which are diminished in people with ADHD.
TNS was cleared by the FDA based on data from a small U.S. pilot study of 62 children that reported ADHD symptom improvement after four weeks of nightly use. That study used a “sham” condition in which electrodes for TNS were still applied to the children every night for four weeks, but these subjects received no stimulation and served as the control group.
“Our study shows how important it is to design an appropriate placebo condition in clinical trials of brain therapies,” said senior author Katya Rubia, PhD, a professor of cognitive neuroscience at the Institute of Psychiatry, Psychology & Neuroscience at King’s College London. “There is a large placebo effect with high-tech brain therapies, in particular for patients and families that have an expectation that they can adjust brain differences associated with ADHD. It is hence paramount to control for placebo effects in modern brain therapies to avoid false hopes.”
Added first author Aldo Conti, PhD, a postdoc at King’s College: “This multicenter trial was designed to address key limitations of the previous pilot study that informed FDA clearance of TNS for ADHD.” He noted that the new study used “a rigorously controlled sham condition that supported successful blinding across the treatment period.” The trial also included adolescents, an age group that is often in need of alternative treatments for ADHD due to poor long-term adherence to medication.
For this trial the researchers recruited patients aged eight to 18 years old. Half received real TNS for approximately nine hours every night for four weeks, while the other half received sham stimulation that delivered 30 seconds of low-frequency stimulation per hour, intended to feel similar but be biologically inactive. ADHD symptoms were assessed primarily using parent-rated scales, alongside measures of attention, hyperactivity, mood, sleep, mind-wandering, and objective physiological markers.
Data from the new trial showed no significant difference between real and sham TNS on the primary outcome or on almost all secondary outcomes, while also noting the device was safe and well tolerated, with no serious adverse events and similar side effect profiles in both groups.
Nevertheless, both groups showed substantial improvement over the six months of the trial, with ADHD symptoms decreasing by 26% in the real TNS group and 29% in the sham group. The researchers attributed this to a pronounced placebo response. “Evidence shows that the placebo effect is greater in trials involving technology, such as neurofeedback and neurostimulation,” they wrote, pointing to the role played by expectations, especially in younger participants and families seeking non-drug options. They described this as a “neurotechnology-induced placebo effect or ‘neuro-enchantment’.”
The enhanced sham condition was central to interpreting the findings. Unlike the earlier FDA-supporting trial, participants in this study were successfully blinded at four weeks, reducing the likelihood that perceived sensations revealed whether they were receiving the treatment or not.
The researchers did note one positive effect of TNS: a reduction in mind-wandering scores. But the team cautioned that this result should be interpreted carefully due to multiple comparisons and the lack of corroborating effects in older adolescents or objective attention measures.
For clinical care, the findings suggest that TNS should not be recommended as an effective treatment for ADHD, despite its safety profile. While the treatment is approved for use in the U.S., it is not recommended for use in the U.K. by National Institute for Health and Care Excellence (NICE) guideline. Based on their findings, the King’s College team suggested that U.S. regulators have reason to revisit the original evidence.
Continuing this research, the investigators will continue to analyze imaging data collected during the trial to better understand why the proposed mechanisms of TNS did not produce a clinical benefit and to help design more rigorous future studies of non-pharmacological interventions for ADHD.
