Transcutaneous Auricular Vagal Nerve Stimulation Against Fatigue Syndrome in Patients with Long COVID: Results of the Randomized, Placebo-Controlled Clinical Pilot Trial COVIVA

Fatigue is the most prevalent symptom in “long COVID”, affecting 6–7% of patients after COVID-19 infection. Its pathophysiology remains unclear, with viral persistence, immune dysregulation, and mitochondrial dysfunction among proposed mechanisms. Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive neuromodulatory approach, has been suggested as a potential treatment. We conducted a randomized, sham-controlled, single-blinded pilot study to evaluate adherence and clinical effects of taVNS in long COVID-related fatigue. Forty-five patients were randomized 1:1:1 to sham stimulation, sub-threshold taVNS, or above-threshold taVNS for 4 weeks using the Conformité Européenne (CE)-certified tVNS-L device (25 Hz, 250 µs, 4 h/day). The primary co-endpoints were fatigue severity (MFI-20) and adherence, defined as mean daily stimulation duration. Secondary endpoints included depressive symptoms (BDI-II), health-related quality of life (SF-36), and post-COVID symptom burden (PCS). Of 45 enrolled patients (mean age 42.4 years; 73% female), 4 (8.9%) dropped out early. Mean stimulation time was 236 min/day, fulfilling the adherence criterion in > 80% of participants. Adverse events were mild, including skin irritation (6.7%) and vertigo (6.7%). Across all groups, questionnaire scores improved over time; however, no statistically significant differences were observed between the sham and active stimulation groups. Baseline fatigue and quality-of-life scores were markedly impaired compared with normative data. taVNS was safe, feasible, and associated with high adherence in long COVID-related fatigue, but showed no superiority over sham stimulation. Larger multicenter trials with more homogeneous populations and objective biomarkers are required to determine whether taVNS confers therapeutic benefit in this condition. The trial was approved by the ethics committee (23/7798) and registered at the German Clinical Trials Register, identifier DRKS00031974. Many people with long COVID experience severe and persistent tiredness, known as fatigue, which can last for weeks or months and significantly interfere with daily life. At present, the causes of this fatigue are not well understood and no specific treatment is available. We investigated transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive method in which a small device placed on the ear delivers mild electrical impulses to a nerve connected to the brain. This technique has previously been used safely in conditions such as epilepsy and depression. Forty-five people with long COVID-related fatigue were randomly assigned to one of three groups: perceptible stimulation, very weak imperceptible stimulation, or sham stimulation without electrical current. Participants used the device for 4 hours daily over 4 weeks. Adherence was high, with most participants using the device for nearly 4 hours per day. Only mild side effects, such as skin irritation or dizziness, were reported. Fatigue and quality of life improved in all groups, but no differences were observed between them. taVNS appears safe and well accepted, but did not reduce fatigue more effectively than sham treatment, suggesting a possible placebo effect. Larger studies are needed to clarify its therapeutic potential.