Neurology · Medical Literature
The Use of a Handheld Non-Invasive Vagal Nerve Stimulation (nVNS) Device for the Treatment of Long COVID: A Pilot Randomized Controlled Trial.
Abstract
ObjectivesLong-term symptoms following infection with acute respiratory syndrome coronavirus-2 (SARS-CoV-2), termed post-acute sequelae of SARS-CoV-2 infection (PASC) or Long COVID (LC), persist beyond 90 days and may impact at least 10% of patients with acute infection. The exact cause of LC remains unknown, but several theories include persistent viral particles, immune dysfunction, and autonomic nervous system (ANS) imbalance, particularly involving the vagus nerve. Given the role of the vagus nerve in inflammation regulation, vagal nerve stimulation (VNS) is being explored as a treatment option. The present study aimed to evaluate the feasibility, safety, and exploratory effects of a handheld external transcutaneous cervical non-invasive VNS (tcVNS) on the primary endpoint of Post-COVID Functional Status (PCFS) grade, alongside secondary outcomes such as LC-related fatigue and other symptoms.MethodsParticipants from our Post COVID Care Clinic were randomized into treatment (tcVNS treatments two minutes, three times a day) and control (no VNS) groups for a study period of 12 weeks. Participants completed validated questionnaires, PET-CT scans, and inflammatory cytokines at baseline and 12 weeks.ResultsAll randomized patients (8 tcVNS, 10 control) completed the 12-week study. Participants randomized to tcVNS were observed to have improvements in PHQ-9, PROMIS-F, and COMPASS-31 when compared to controls, but these differences were not statistically significant. Cortisol and DHEA were also observed to increase less in the tcVNS group when compared to the control group, but these changes were also not statistically significant.ConclusionstcVNS was well tolerated and may be a promising therapeutic approach for LC, a chronic disease with no approved treatments and very low rates of complete recovery.
Clinical relevance
Long COVID (PASC) affects at least 10% of individuals following acute SARS-CoV-2 infection and currently has no approved treatments, with very low rates of complete recovery. This pilot RCT addresses a critical therapeutic gap by evaluating transcutaneous cervical non-invasive vagal nerve stimulation (tcVNS) — a non-pharmacologic, handheld intervention — targeting proposed mechanisms of ANS imbalance and vagus nerve dysfunction. Given the scale of the post-COVID disease burden and the lack of evidence-based interventions, clinicians managing post-COVID care clinics and neuro-autonomic complications need early feasibility and safety data such as these.
Key findings
1. Study population was small (n=18 total; 8 tcVNS, 10 control), all of whom completed the full 12-week protocol, demonstrating 100% retention and supporting feasibility of the intervention. 2. The tcVNS dosing regimen was 2 minutes of stimulation, three times daily for 12 weeks, applied transcutaneously to the cervical region — a fully non-invasive and outpatient-compatible protocol. 3. Improvements were observed in the PHQ-9 (depression), PROMIS-F (fatigue), and COMPASS-31 (autonomic symptom burden) scores in the tcVNS group compared to controls; however, none of these differences reached statistical significance, likely reflecting the underpowered sample size. 4. The primary endpoint — Post-COVID Functional Status (PCFS) grade — showed a trend favoring tcVNS, but no statistically significant between-group difference was reported. 5. Cortisol and DHEA levels increased less in the tcVNS group than in controls, suggesting a possible attenuation of the hypothalamic-pituitary-adrenal (HPA) axis stress response, though this difference was also not statistically significant. 6. tcVNS was well tolerated with no safety signals reported; participants also underwent PET-CT imaging and inflammatory cytokine panels at baseline and 12 weeks, though no specific cytokine effect sizes were reported in the abstract.
Practice implications
Clinicians managing Long COVID patients with autonomic dysfunction, fatigue, and mood symptoms may consider transcutaneous cervical VNS as a low-risk, non-pharmacologic adjunctive intervention, particularly given the absence of approved therapies and the favorable tolerability profile observed in this pilot. Patient selection should prioritize those with documented ANS imbalance or dysautonomia features (e.g., elevated COMPASS-31 scores), and the regimen of 2 minutes three times daily appears safe and feasible for outpatient self-administration. These findings are hypothesis-generating only — given the small sample size and lack of statistical significance across all endpoints, larger adequately powered RCTs are essential before tcVNS can be recommended as standard of care or incorporated into formal Long COVID treatment pathways.