Evidence library

This page is intended for UK healthcare professionals. It summarises the trial and real-world evidence for transcutaneous vagus nerve stimulation across its four EU MDR approved indications, with attention to study quality, blinding, and the limits of the active-control sham conditions used in much of this literature.

How to read this page

Three caveats apply to almost every randomised controlled trial of tVNS, and they are worth stating once at the top.

The active-control sham problem. Most tVNS RCTs use either a low-frequency (1 Hz) cymba conchae stimulation as the active control, or stimulation of the earlobe (which has essentially no vagal innervation). Neither is a clean sham. 1 Hz stimulation may itself be biologically active in ways that suppress between-group separation. Earlobe sham reduces blinding fidelity, because patients can sometimes distinguish active from sham by the location of the stimulation. The implication is that pooled effect estimates may underrepresent the true effect.

Heterogeneous parameters. Trials have used a range of frequencies (1 Hz to 25 Hz), pulse widths (200 to 500 µs), session durations (30 minutes to 4 hours daily), and trial durations (4 weeks to 20 weeks). Heterogeneity attenuates pooled estimates and complicates dose-response analysis.

Outcome variability. Indication-specific endpoints are not always uniform across trials. Responder definitions in epilepsy use ≥50% seizure reduction, but the time horizon varies. Migraine endpoints differ between episodic and chronic populations. Depression endpoints sometimes use HAMD-17, sometimes MADRS, sometimes PHQ-9. Pooling across instruments requires care.

These are not reasons to dismiss the literature. They are reasons to read it carefully.

Drug-resistant epilepsy

The strongest indication. Two substantial randomised controlled trials, multiple pilot studies, real-world prospective cohort data over 1 to 2 years, and two meta-analyses of the randomised trials, both published in 2025.

Every study below carries a reference line with its DOI. Only one is attributable to this device's lineage: the cMPsE02 trial was run with the Cerbomed NEMOS, from which the tVNS E descends. The Yang 2023 trial used a different manufacturer's device, the TVNS-100 (Xinzhile, Jiangxi, China), and the Liao 2025 cohort does not name the device used. We cite both as evidence for auricular tVNS in general, not for this specific product. No trial has compared auricular tVNS directly with implanted VNS.

Bauer et al., 2016 (cMPsE02)

A randomised, double-blind, parallel-group trial of 76 adults with drug-resistant focal epilepsy. Patients were randomised 1:1 to active stimulation (25 Hz, n=39) or low-frequency active control (1 Hz, n=37) at the cymba conchae over 20 weeks.

Primary endpoint. Reduction in seizure frequency at 20 weeks. ITT analysis: 23.4% reduction in active vs −2.9% in control, p=0.146 (not statistically significant). The 34.2% figure (p=0.034) is a within-group change from baseline in the 26 of 39 patients in the 25 Hz group who completed treatment, not a between-group comparison. Responder rates were similar in both groups. The authors concluded that superiority of 25 Hz over 1 Hz could not be proven.

Interpretation. The first randomised double-blind trial of tVNS in DRE, and a negative result on its primary endpoint. Two factors may have contributed: 1 Hz stimulation acting as a partial active rather than a true sham (the 1 Hz group also received about double the current), and the trial being underpowered. An active control makes a between-group difference harder to show, but it does not turn a non-significant result into a positive one. The within-group completer figure also carries regression to the mean, placebo and diary effects. Four serious adverse events were reported, including one SUDEP in the 1 Hz group assessed as not treatment-related.

Reference: Bauer S, Baier H, Baumgartner C, et al. Transcutaneous vagus nerve stimulation (tVNS) for treatment of drug-resistant epilepsy: a randomized, double-blind clinical trial (cMPsE02). Brain Stimul. 2016;9(3):356-363. doi:10.1016/j.brs.2015.11.003

Yang et al., 2023

The largest randomised trial of auricular tVNS in epilepsy. A 150-patient multi-centre, double-blind RCT across four Chinese epilepsy centres, randomising adults with DRE 2:1 to active tVNS (n=100; 25 Hz, 250 µs, 30s on/30s off, 2 hours daily, maximum tolerated intensity, ear conch) or a low-dose active control (n=50; 1 Hz at minimum perceptible intensity, not a sham) for 20 weeks. Device: TVNS-100 (Xinzhile, Jiangxi, China), not the tVNS Technologies device.

Primary endpoint. ≥50% responder rate at 20 weeks: 44.74% active vs 16.67% control, p<0.05, among the 112 of 150 analysed (76 active, 36 control). Not significant at 4 or 12 weeks.

Secondary endpoints. Mean seizure frequency at 20 weeks did not differ significantly between groups (3.08 vs 6.05, p=0.130). The relative reduction in the active completers (30.75%) was reported as significantly greater than control. The anti-seizure effect was cumulative, becoming statistically significant only at 20 weeks; earlier time points showed numerical separation but not significance.

Safety. No severe adverse events in either group. The active group reported one episode of self-resolving sinus bradycardia.

Quality. Pre-registered. Independent monitoring. Standardised seizure diary. The control was active low-dose stimulation, not a sham, so the active-control problem applies here too. About a quarter of those randomised were not analysed.

Interpretation. A responder rate just under 45% among completers, for a non-invasive adjunctive intervention in a population by definition refractory to first-line care. The cumulative time course has direct practical implications: 20 weeks is the minimum useful trial duration in this indication.

Reference: Yang H, Shi W, Fan J, et al. Transcutaneous auricular vagus nerve stimulation (ta-VNS) for treatment of drug-resistant epilepsy: a randomized, double-blind clinical trial. Neurotherapeutics. 2023;20(3):870-880. doi:10.1007/s13311-023-01353-9

Liao et al., 2025 (Beijing Tiantan Hospital real-world study)

A single-centre prospective real-world study of 99 adult DRE patients receiving tVNS at Beijing Tiantan Hospital, enrolled between January 2023 and December 2024, with 1 to 2 years of follow-up. Uncontrolled. 65 of the 99 had successful follow-up (16 lost, 18 refused follow-up). The device is not named.

Overall efficacy rate (≥50% seizure reduction): 61.54% of the 65 followed up. Counting the 34 not followed up as non-responders gives about 40% (40 of 99).

• 23.1% achieved >90% seizure reduction
• 12.3% achieved 75 to 90% reduction
• 26.2% achieved 50 to 75% reduction

Adverse events. Mild, transient, in 10 patients (15%); ear tingling, transient tinnitus. No severe events.

Interpretation. The higher efficacy rate compared with the RCTs may reflect longer follow-up, a completers-only denominator, a motivated patient population, and possibly higher real-world adherence. Efficacy was independent of measured clinical variables, suggesting broad applicability across DRE phenotypes. As an uncontrolled study, it cannot speak to placebo effect; but the durability of response over 12 to 24 months is informative. The authors also report that patients with a higher baseline seizure frequency responded more often.

Reference: Liao J, Zuo J, Dai Y, et al. Efficacy and safety of transcutaneous auricular vagus nerve stimulation in drug-resistant epilepsy: a single-center prospective real-world study. Ther Adv Neurol Disord. 2025;18:17562864251396022. doi:10.1177/17562864251396022

Meta-analyses

Two pooled analyses of the randomised trials were published in 2025.

Moro et al., 2025. Four RCTs, 368 patients, tVNS against sham. Significant reduction in seizure frequency at the end of treatment (mean difference of 3.0 seizures per month, and a 17.6 percentage-point greater reduction, both with no heterogeneity). The pooled responder rate favoured tVNS (odds ratio 2.0) but did not reach significance (p=0.06). No difference in seizure freedom, depression, or quality of life. Adverse events mostly mild and transient. The authors note significant methodological concerns in some included studies.

Reference: Moro P, Rocha Dos Santos MA, Balduino de Souza AL, et al. Can transcutaneous auricular vagus nerve stimulation be considered a viable adjunctive therapy in drug-resistant epilepsy? A systematic review and meta-analysis of randomized controlled trials. Epilepsy Behav. 2025;167:110394. doi:10.1016/j.yebeh.2025.110394

Makkawi et al., 2025. Four RCTs, 417 subjects, searched to December 2023. Significant reductions in seizure frequency at 8, 12, 16, and 52 weeks; no significant difference in responder rate between tVNS and control. Adverse effects generally mild and transient. The authors flag variation in methods and a high risk of bias, and call for higher-quality trials.

Reference: Makkawi S, Alsamiri GY, Halabi MH, et al. Efficacy of transcutaneous vagus nerve stimulation (t-VNS) in treating drug-resistant epilepsy: a systematic review and meta-analysis. Epilepsy Res. 2025;215:107583. doi:10.1016/j.eplepsyres.2025.107583

The pattern across both is the same: seizure frequency falls significantly, the pooled responder rate does not reach significance, and the active-control problem (1 Hz is not a true sham) may contribute, alongside small trials and a high risk of bias. The Yang 2023 trial, which also used a 1 Hz active control, reported the largest responder-rate difference among completers. The certainty of the evidence is low; the pooled results should be read as they stand.

Key point. The epilepsy evidence base now includes two substantial RCTs, multiple pilot studies, real-world prospective data, and two meta-analyses. Responder rates range from just under 45% among completers in the largest RCT active arm (versus about 17% on a low-dose control; a different manufacturer's device) to around 62% among the 65 of 99 followed up in an uncontrolled real-world cohort (about 40% counting those lost). Both 2025 meta-analyses found the pooled responder difference did not reach significance, and the largest European trial, with this device's predecessor, missed its primary endpoint. The evidence is low certainty and mixed. The safety profile is favourable. There is no head-to-head trial against implanted VNS, which has the longer and stronger evidence record.

Read the clinician page on tVNS for epilepsy

Depression

The depression evidence base is younger than the epilepsy literature and substantially more variable. The mechanistic rationale is shared (noradrenergic and serotonergic modulation through brainstem relays), but the controlled trial base is smaller.

Implanted VNS for context

Implanted vagus nerve stimulation has FDA approval for treatment-resistant depression (TRD) since 2005. Long-term cohort studies report response rates around 67% at 24 months in TRD populations, materially higher than continued pharmacotherapy alone in the same population. The implanted VNS evidence is the strongest single piece of evidence that vagal modulation has a clinical antidepressant effect; the question for tVNS is whether transcutaneous delivery engages enough of the same circuitry to produce a comparable, even if smaller, clinical effect.

Reference: Aaronson ST, Sears P, Ruvuna F, et al. A 5-year observational study of patients with treatment-resistant depression treated with vagus nerve stimulation or treatment as usual: comparison of response, remission, and suicidality. Am J Psychiatry. 2017;174(7):640-648. doi:10.1176/appi.ajp.2017.16010034

Hein et al., 2013

An early sham-controlled randomised trial of tVNS in 37 patients with major depression. Active stimulation produced a statistically significant reduction in BDI scores compared with sham. Small sample, short duration (2 weeks), but the first controlled signal that auricular tVNS has an antidepressant effect. The clinician-rated HAMD did not change significantly, and the authors note a risk of unblinding.

Reference: Hein E, Nowak M, Kiess O, et al. Auricular transcutaneous electrical nerve stimulation in depressed patients: a randomized controlled pilot study. J Neural Transm (Vienna). 2013;120(5):821-827. doi:10.1007/s00702-012-0908-6

Rong et al., 2016

A 12-week nonrandomized, single-blind, sham-controlled study of 160 patients with mild to moderate major depression: a first cohort of 91 received active taVNS only, and a second cohort of 69 received four weeks of sham before crossing over to active. Active taVNS produced significantly greater reductions in HAM-D-24 scores than sham; at four weeks there were 24 responders (a 50% or greater reduction) in the active group versus none in the sham group (p < 0.00001), with improvement continuing through 12 weeks.

Reference: Rong P, Liu J, Wang L, et al. Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study. J Affect Disord. 2016;195:172-179. doi:10.1016/j.jad.2016.02.031

Tan et al., 2023 (meta-analysis)

Twelve randomised trials, 838 participants. Auricular tVNS improved depression scores and achieved higher response rates than sham, with response rates comparable to antidepressants in the head-to-head data. The certainty of the evidence was rated low to very low by GRADE, which is the honest summary of the field: a consistent signal from small, heterogeneous trials.

Reference: Tan C, Qiao M, Ma Y, et al. The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: a systematic review and meta-analysis of randomized controlled trials. J Affect Disord. 2023;337:37-49. doi:10.1016/j.jad.2023.05.048

What the depression literature does not yet show

• Head-to-head comparison with implanted VNS in TRD.
• Trials with a sham designed to sit below biological activity rather than a 1 Hz or earlobe control.
• Adequately powered trials specifically in TRD as defined by failure of two or more antidepressant trials at adequate dose and duration.
• Long-term outcome data beyond 6 to 12 months.

Key point. The depression evidence base supports tVNS as an adjunctive intervention with a credible antidepressant signal across multiple sham-controlled trials. It does not yet support tVNS as a first-line intervention or as a replacement for pharmacological or psychological care. The mechanistic rationale is strong; the trial evidence is moderate and improving.

Read the clinician page on tVNS for depression

Migraine and headache disorders

The migraine evidence base sits across two related modalities: cervical transcutaneous vagus nerve stimulation (tcVNS, the gammaCore device) and auricular transcutaneous vagus nerve stimulation (taVNS, the tVNS® device). These engage different branches of the vagus and use different stimulation parameters. The tcVNS literature is larger; the taVNS literature is smaller but consistent in direction.

Cervical tVNS

Goadsby et al., 2014 (acute migraine). An open-label, single-arm, multi-centre pilot study using the cervical gammaCore device: of 30 patients enrolled, 27 treated 80 attacks. The pain-free rate at two hours was about 21 to 22% (12 of 54 moderate or severe attacks; 4 of 19 for the first treated attack). doi:10.1177/0333102414524494

EVENT trial (Silberstein et al., 2016) (preventative chronic migraine). A randomised sham-controlled pilot trial of 59 patients, with safety and tolerability as the primary endpoints. Active cervical tVNS produced a non-significant reduction in headache days at 8 weeks but a significant reduction at the open-label extension at 6 months. doi:10.1212/WNL.0000000000002918

ACT1 and ACT2 trials (cluster headache). Two pivotal sham-controlled trials of cervical nVNS (gammaCore) for the acute treatment of cluster headache attacks. Neither met its primary endpoint in the whole population; both showed significant benefit in episodic cluster headache and none in chronic cluster headache. ACT1: doi:10.1111/head.12896. ACT2: doi:10.1177/0333102417744362. Prophylaxis was tested separately in the PREVA trial (Gaul et al., 2016): adding cervical nVNS to standard care reduced attacks by about 3.9 per week more than standard care alone (a between-group difference; 5.9 active vs 2.1 control; 95% CI 0.5-7.2, p=0.02). doi:10.1177/0333102415607070 These trials used the cervical (neck) device, not the auricular tVNS device distributed here.

These results led to FDA clearance for episodic cluster headache (2017) and chronic migraine (2018) for the cervical device.

Auricular tVNS

Straube et al., 2015. A sham-controlled randomised trial of auricular tVNS in 46 patients with chronic migraine. 12 weeks of treatment. The 1 Hz auricular stimulation arm produced significantly greater reductions in headache days than the 25 Hz arm (7.0 versus 3.3 fewer headache days per 28 days, per protocol), an unexpected result that highlighted the dose-response complexity in this indication. Both arms improved on disability scores. Note that the tVNS E delivers 25 Hz; see the migraine page.

Reference: Straube A, Ellrich J, Eren O, Blum B, Ruscheweyh R. Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial. J Headache Pain. 2015;16:543. doi:10.1186/s10194-015-0543-3

Smaller open-label and pilot studies. Several studies of auricular tVNS in migraine and chronic tension-type headache have reported reductions in headache days, attack frequency, and analgesic consumption. Effect sizes vary; methodological quality is moderate at best.

What the migraine literature shows

Auricular tVNS has a smaller and less rigorous evidence base than cervical tVNS for headache disorders. The mechanistic case is consistent: vagal afferents converge with trigeminal afferents in the spinal trigeminal nucleus, and vagal stimulation modulates descending pain inhibition pathways. The clinical signal is real but more variable than in epilepsy.

For chronic migraine, taVNS is a reasonable adjunctive option in patients who have failed at least one preventative agent and who prefer a non-invasive approach. The expected effect size is moderate. The evidence is weaker than in epilepsy and the time course may be shorter (12 weeks rather than 20 in some protocols).

Key point. The migraine evidence base is mixed but moving in a constructive direction. Cervical tVNS has the stronger data, particularly in cluster headache. Auricular tVNS has smaller trials with consistent direction. The mechanism is plausible across both modalities. We do not oversell.

Read the clinician page on tVNS for migraine

Prader-Willi syndrome

The smallest published evidence base of the four indications. EU MDR approval is specifically for temper outbursts, which are among the most distressing behavioural features of the syndrome and a major source of carer and family burden.

Manning et al., 2019 (a foundational case series)

A non-blind single-case study (modified ABA design) of 5 adults with PWS, aged 22 to 41, using tVNS. Participants received four hours of stimulation daily for 12 months. Four of the five who completed the study showed a statistically significant reduction in the number and severity of temper outbursts after approximately nine months of daily use. The study was non-blind, uncontrolled beyond within-participant baselines, and small, but it is the principal published study behind clinical interest in this indication. It used the Cerbomed NEMOS device, the predecessor of the tVNS E.

Reference: Manning KE, Beresford-Webb JA, Aman LCS, et al. Transcutaneous vagus nerve stimulation (t-VNS): a novel effective treatment for temper outbursts in adults with Prader-Willi syndrome indicated by results from a non-blind study. PLoS One. 2019;14(12):e0223750. doi:10.1371/journal.pone.0223750

Subsequent case reports and small series

Several case reports and small case series have been published describing reductions in temper outburst frequency, improvements in carer burden, and qualitative improvements in mood and engagement. None reaches the methodological standard of an RCT.

Why the evidence base is small

PWS is a rare condition (UK prevalence approximately 1 in 25,000). Recruiting an adequately powered RCT is genuinely difficult. Beyond rarity, the heterogeneity of the syndrome's behavioural phenotype and the practical difficulty of objective endpoint measurement in this population have limited the size and quality of the published trials.

What we tell families and clinicians

The honest framing is that the published evidence is limited but not absent, the mechanistic rationale (modulation of arousal and emotion-regulation circuits) is plausible, the safety record across all tVNS indications is favourable, and the alternative pharmacological approaches for outbursts in PWS have their own limitations. tVNS is a regulated option in this population. We do not present it as a guaranteed solution, and we are particularly attentive to expectation-setting in families who have already lived with multiple disappointing interventions.

Key point. The PWS evidence base is the smallest of the four indications. The regulatory status is real, the mechanistic case is plausible, the safety record is good. The clinical case rests more on the absence of better alternatives in some patients and on the willingness of families to try a non-pharmacological adjunctive intervention than on a robust trial literature.

Read the clinician page on tVNS for Prader-Willi syndrome

Trials in progress

Two independently funded randomised trials on this manufacturer's hardware are under way. Neither has reported. We state them here because clinicians will find them, and because both are strengths of the platform that deserve to be described accurately rather than discovered.

TRAVAST (drug-resistant epilepsy, Germany)

A trial under the G-BA Erprobung (testing) directive, DRKS00039592: 164 adults with drug-resistant epilepsy, triple-blind, active tVNS against a low-intensity sham (around 100 µA at 1 Hz), across about 15 German sites. Primary endpoint: 50% responder rate at 52 weeks. Started in 2026, projected to end in March 2028, with results expected in 2028. tVNS Technologies supply the trial device but do not bear the device costs; the trial is commissioned and funded through the G-BA process, which exists to decide whether statutory insurance will pay for a treatment. It addresses two of the gaps listed at the foot of this page in one design: a one-year primary endpoint, and a sham chosen to sit below the threshold of biological activity rather than the 1 Hz active control that has clouded earlier trials.

TRICEPS (chronic stroke, UK)

Funded by the NIHR Efficacy and Mechanism Evaluation programme and led from Sheffield (ISRCTN20221867; protocol published in BMJ Open, 2025). A movement-activated tVNS system from tVNS Technologies, paired with rehabilitation, in people with chronic stroke across 15 UK stroke centres, with 12 weeks of stimulation; recruitment has passed 200 participants. Results have not been published. The trial device is a movement-triggered variant, not the tVNS E, and stroke is outside the certified indications. A positive result would need its own regulatory route and should not be read across to the home device or presented as evidence for it.

Off-label and emerging applications

A non-exhaustive summary of the literature in conditions outside the four approved indications, included here for completeness. We do not market the device for any of these.

Stroke rehabilitation

A 2022 meta-analysis of vagus nerve stimulation paired with rehabilitation (seven randomised trials, 263 analysed participants) found a medium effect on motor function after the intervention and a large effect at follow-up, with no difference for daily living or mental health, and larger effects in the auricular subgroup (doi:10.1136/jnnp-2022-329275). A 2026 meta-analysis restricted to auricular tVNS (ten randomised trials, 512 patients, most from Chinese centres) reported significant improvements in motor function and daily living (doi:10.3389/fneur.2026.1786103). The trials are small and heterogeneous, and the pooled effect sizes should be read in that light. The mechanism is plausible: vagal afferent activation produces cortical state changes that may enhance motor learning during paired rehabilitation. The UK TRICEPS trial (see Trials in progress above) will add a randomised dataset when it reports, with the caveat that it tests a movement-activated variant rather than the home device.

Functional gastrointestinal disorders

Systematic reviews of functional dyspepsia and irritable bowel syndrome report improvements in symptoms, quality of life, and mood after taVNS protocols of 4 to 8 weeks. The mechanism is consistent with the vagus nerve's role in the brain-gut axis and in inflammation modulation.

Spinal cord injury

Small pilot studies have explored taVNS in autonomic dysreflexia, blood pressure regulation, and inflammation modulation in SCI. The literature is early-stage but mechanistically motivated.

Chronic pain

The convergence of vagal afferents with descending pain-inhibitory pathways provides a rationale for taVNS in fibromyalgia, chronic primary pain, and post-surgical pain. Published trials are small and heterogeneous. We are unwilling to overclaim on the basis of the current literature.

Cardiac rehabilitation, Parkinson's disease, multiple sclerosis, traumatic brain injury

All have small, mechanistically motivated published literatures. None has yet reached the maturity required for regulatory approval as a tVNS indication. We are happy to discuss the available studies on request.

Two specific reading recommendations

For clinicians who want to read the original literature rather than summaries:

1. Yang et al., 2023. Transcutaneous Auricular Vagus Nerve Stimulation (ta-VNS) for Treatment of Drug-Resistant Epilepsy: A Randomized, Double-Blind Clinical Trial. Neurotherapeutics. The largest randomised trial of auricular tVNS in epilepsy, run with a different manufacturer's device (TVNS-100, Xinzhile) and a low-dose active control. doi:10.1007/s13311-023-01353-9
2. Kraus, Hösl, et al., 2007. BOLD fMRI Deactivation of Limbic and Temporal Brain Structures and Mood Enhancing Effect by Transcutaneous Vagus Nerve Stimulation. J Neural Transm. The foundational human imaging paper, in 22 healthy volunteers, with earlobe stimulation as the sham. doi:10.1007/s00702-007-0755-z

Both are worth reading in original form.

What the literature does not yet say

For honest framing, the gaps that matter most:

• Long-term outcomes beyond 2 years in any indication.
• Head-to-head comparison with implanted VNS in epilepsy or depression.
• Adequately powered RCTs in TRD-defined depression.
• Closed-loop tVNS is research-grade only.
• Optimal parameter space is empirically supported but not formally dose-optimised.
• Predictive biomarkers for response at the individual patient level are not yet established.

We mention these because the absence of evidence is not the same as the evidence of absence, and because clinicians making real decisions in real clinics deserve to know where the certainty ends.

Where to next

Read the clinician overview

Read the practice guide

Browse the condition pages

Book a demo or call to discuss the evidence

tVNS is a Class IIa medical device manufactured by tVNS Technologies GmbH, Germany. Distributed in the UK by Anatomical Concepts UK Ltd. Its approved indications are epilepsy, depression, migraine, and Prader-Willi syndrome.