INTRODUCTION to aVNS

For a broader introduction to auricular vagus nerve stimulation (aVNS), please explore our aVNS Clinical Evidence Guide. It provides important background on how aVNS works, together with a detailed review of the clinical research and its potential applications across a wide range of health conditions.

Why We Believe InnateSignal™ Is Worth Exploring 

No treatment works for everyone, and no treatment can guarantee a particular result.

But there are good reasons why we believe aVNS deserves serious consideration rather than being regarded simply as another wellness technology.

THE EFFECTS ARE BIOLOGICALLY MEASURABLE

The case for aVNS does not depend only on people reporting that they “feel better.”

Across different areas of research, investigators have documented objective changes including **altered brain activity on functional imaging, changes in autonomic and cardiac regulation, reductions in inflammatory markers, changes in gastrointestinal function and motility, improvements in cognitive testing, changes in pain processing, objectively recorded reductions in abnormal cardiac rhythm - and even suppression of cancer cell growth. **

These findings are important because they demonstrate that stimulation through the ear can produce measurable physiological effects within the body and brain.

POSITIVE CLINICAL FINDINGS NOW EXTEND ACROSS MULTIPLE BODY SYSTEMS

Encouraging findings have been reported in areas including sleep, autonomic dysfunction, pain, migraine, gastrointestinal disorders, mood, cognition, rehabilitation, inflammatory conditions, cardiovascular regulation, metabolic health and women’s health.

The strength of the evidence is not the same for every condition. Some applications are supported by randomized human trials, while others have smaller clinical studies or are currently supported mainly by compelling preclinical evidence.

But there is an important common thread.

Many of these apparently unrelated conditions involve systems that the vagus nerve helps regulate: autonomic balance, inflammation, brain–body communication, pain processing, stress responses, metabolism and neuroplasticity.

This provides a coherent biological explanation for why vagal stimulation may have effects across seemingly very different areas of health.

ANIMAL RESEARCH HAS PROVIDED IMPORTANT CLUES THAT HAVE LATER BEEN SEEN IN PEOPLE

Some of the most interesting aVNS research begins before a treatment is studied extensively in people.

Animal models allow researchers to investigate not only whether stimulation produces an effect, but also what may be happening inside the brain and body — including changes in inflammatory pathways, neurotransmitters, metabolism, nerve signalling and organ function that would be much more difficult to investigate directly in humans.

Importantly, some effects demonstrated in animal aVNS research have subsequently been observed in human clinical research.

For example, animal studies have reported antidepressant-like effects, metabolic changes and improvements in gastrointestinal function. Subsequent human studies have observed related effects, including improvements in depression, changes in post-meal ghrelin responses and improvements in gastrointestinal symptoms and physiology.

These examples do not mean that every result seen in an animal will occur in a person, nor that the ideal stimulation settings will necessarily be identical between species.

They do, however, demonstrate something important: animal responses to vagal stimulation can provide biologically meaningful clues about effects that may also be relevant in humans.

WHY THIS MATTERS FOR INNATESIGNAL™

This translational history influences how we have developed InnateSignal™.

Where a stimulation approach has already produced meaningful results in human clinical research, those findings are given the greatest weight in developing our programs.

However, we do not believe that promising findings should automatically be ignored simply because human trials have not yet caught up with the laboratory research.

For selected applications, InnateSignal™ therefore also includes exploratory stimulation settings informed by compelling animal research, particularly where the findings are biologically plausible, relevant to an important area of health and consistent with what is already known about vagal physiology.

These exploratory programs are clearly distinguished from settings supported by direct human clinical evidence.

The purpose is not to assume that an animal result will automatically translate to a person. It is to make carefully selected, research-informed stimulation approaches available for exploration while the clinical science continues to develop.

For someone interested in an area where the human evidence is still emerging, this provides an opportunity to explore a stimulation approach based on actual experimental findings rather than arbitrary device settings.

THERE IS EVIDENCE THAT THE EFFECTS CAN BUILD OVER TIME

Another encouraging feature of the research is that aVNS does not necessarily behave like a treatment whose effect exists only while the device is switched on.

In several areas of research, improvement has developed progressively with repeated stimulation. Some studies have also found that benefits persist beyond an individual treatment session or remain detectable after a treatment period has ended.

This suggests that, at least in some circumstances, repeated stimulation may produce longer-lasting changes in the regulatory systems being targeted.

That possibility is particularly relevant to InnateSignal™, where the objective is not simply to create a temporary sensation during treatment, but to support healthier regulation over time.

Why Does InnateSignal™ Use Different Programs? 

One of the most important lessons we have learned from the research is that there is no single universally established “best” aVNS setting. 

Researchers have used different stimulation frequencies, pulse widths, timing patterns and treatment durations—and different approaches have produced encouraging results for different purposes. 

A stimulation pattern used successfully for sleep may be quite different from one studied for migraine, metabolic health, gastrointestinal symptoms, pain, autonomic dysfunction or neurological rehabilitation. 

We therefore do not believe it makes sense to take one generic stimulation setting and assume that it is equally appropriate for every condition. 

This is the principle behind Luminnova InnateSignal™. 

Our approach is evidence-informed and indication-specific 

We have reviewed the published aVNS literature to identify stimulation approaches associated with positive findings for particular conditions and physiological goals. 

Where the published research provides sufficient information, an InnateSignal™ program is designed to reproduce the research protocol as closely as our device allows. 

Where several successful approaches exist, more than one program may be retained because they may act through somewhat different mechanisms or may be better suited to different treatment goals. 

Where the evidence is earlier or incomplete, we may include an adapted or exploratory program based on the closest available scientific evidence. These programs are distinguished from those that directly reproduce a published clinical protocol. 

This creates a growing evidence-informed library of stimulation programs rather than one generic aVNS setting. 

Starting with the person—not simply the diagnosis 

Even people with the same diagnosis can be very different. 

One person’s main difficulty may be poor sleep and autonomic overactivation. Another may have prominent inflammation. Another may be struggling primarily with pain, fatigue, gastrointestinal symptoms, metabolic dysfunction or impaired recovery. 

InnateSignal™ therefore considers both the condition being addressed and the dominant symptoms or physiological problems affecting that individual. 

The initial program provides a rational starting point—not a guarantee that it will be the best program for that particular person. 

Response can then be assessed using what matters most for the treatment goal. Depending on the condition, this might include symptoms, sleep, functional ability, blood pressure, heart rhythm, HRV, laboratory markers, cognitive testing or other objective measurements. 

If the response is incomplete, another evidence-supported stimulation approach may sometimes be considered rather than concluding immediately that the person simply “doesn’t respond” to aVNS. 

That is an important part of the Luminnova philosophy: 

the goal is not simply to deliver stimulation—it is to identify the most appropriate evidence-informed stimulation strategy for the individual and the outcome we are trying to improve. 

A Reasonable Treatment to Explore 

There are still important questions to answer about aVNS. We do not yet know the optimal stimulation pattern for every condition, why some people respond more strongly than others or how much benefit every individual will experience. 

But uncertainty does not mean that there is no basis for treatment. 

aVNS already combines several features that are rarely found together in an emerging therapy: 

 a well-established biological pathway · measurable effects on the brain and body · encouraging human clinical findings · the ability to use treatment repeatedly at home · no surgery · no implanted device · and a favourable safety and tolerability profile. 

A 2024 clinical review encompassing more than 3,200 active and comparison participants across 109 studies similarly concluded that aVNS appeared safe and tolerable while showing favourable therapeutic effects across a wide range of clinical populations.  

For many people, particularly when existing approaches have produced incomplete results or when there is a desire to add a non-drug strategy, this combination makes a carefully selected trial of aVNS a reasonable option to explore. 

The response may be obvious for some people and more gradual or modest for others. Some people will not respond. 

But the practical advantages of aVNS mean that it is often possible to find out whether it is helpful without surgery, implantation or a major treatment burden. 

Making Informed Decisions About Your Care 

InnateSignal™ is intended to give people another evidence-informed option, not to take control of treatment decisions away from them. 

We believe that patients should have a meaningful say in the direction of their healthcare. That requires access to understandable information about what is known, what remains uncertain, the potential benefits, the limitations and the available alternatives. Once properly informed, a person’s own priorities, treatment goals, tolerance of risk and preferences should form an important part of decisions about their care. 

At the same time, exploring aVNS should not inadvertently delay investigation or treatment of a condition where delay could cause harm. Prescribed medication or other medically necessary treatment should also not be stopped or reduced without appropriate discussion with the treating clinician, particularly where sudden withdrawal or inadequate treatment could be dangerous. 

This does not mean that existing treatment can never change. If a person improves and wishes to reconsider medication or another therapy, that is a perfectly reasonable discussion to have. The aim should be informed, shared decision-making—allowing the patient and clinician to consider the response to aVNS, the benefits and disadvantages of existing treatments, objective findings where available, and the patient’s own goals before deciding together what should come next. 

Ultimately, Luminnova InnateSignal™ is about expanding treatment possibilities: using the emerging science of vagal neuromodulation to provide another practical, non-invasive and evidence-informed way of helping the body regulate, adapt and recover. 

REFERENCES

The studies below represent selected key publications supporting the clinical and scientific evidence discussed throughout this Guide. They include systematic reviews, randomized clinical trials and important supporting human studies. Where relevant, preclinical research or studies using implanted VNS rather than non-invasive auricular VNS are clearly identified.

Foundational Evidence & Safety

Gerges ANH, Williams EER, Hillier S, et al. Clinical application of transcutaneous auricular vagus nerve stimulation: a scoping review. Disability and Rehabilitation. 2024;46(24):5730–5760. doi:10.1080/09638288.2024.2313123. PMID: 38362860.
Scoping review — 109 studies across 21 clinical populations.

Kim AY, Marduy A, de Melo PS, et al. Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Scientific Reports. 2022;12:22055. doi:10.1038/s41598-022-25864-1. PMID: 36543841.
Systematic review and meta-analysis — 177 studies involving 6,322 participants.

Sleep & Recovery

de Oliveira HM, Gallo Ruelas M, Viana Diaz CA, et al. Transcutaneous Auricular Vagus Nerve Stimulation in Insomnia: A Systematic Review and Meta-Analysis. Neuromodulation. 2025;28(8):1332–1340. doi:10.1016/j.neurom.2025.04.001. PMID: 40323248.

Zhang S, Zhao Y, Qin Z, et al. Transcutaneous Auricular Vagus Nerve Stimulation for Chronic Insomnia Disorder: A Randomized Clinical Trial. JAMA Network Open. 2024;7(12):e2451217. doi:10.1001/jamanetworkopen.2024.51217. PMID: 39680406.
Randomized clinical trial with post-treatment follow-up.

Do M, Evancho A, Tyler WJ. Bilateral transcutaneous auricular vagus nerve stimulation for the treatment of insomnia in breast cancer. Scientific Reports. 2026;16:1081. doi:10.1038/s41598-025-30600-6. PMID: 41345210.
Human pilot study — improvements in insomnia, sleep quality, sleep efficiency, fatigue, depression and HRV.

Autonomic Health

Stavrakis S, Chakraborty P, Farhat K, et al. Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. JACC: Clinical Electrophysiology. 2024;10(2):346–355. doi:10.1016/j.jacep.2023.10.015. PMID: 37999672.
Randomized human trial — heart-rate response, HRV, inflammatory markers and adrenergic autoantibodies.

Maestri R, et al. Impact of optimized transcutaneous auricular vagus nerve stimulation on cardiac autonomic profile in healthy subjects and heart failure patients. Physiological Measurement. 2024. doi:10.1088/1361-6579/ad5ef6. PMID: 39016202.
Randomized crossover human studies examining HRV and cardiac autonomic responses.

Pain Regulation

Chen J, Kuang H, Chen A, et al. Transcutaneous Auricular Vagus Nerve Stimulation for Managing Pain: A Scoping Review. Pain Management Nursing. 2025;26(1):33–39. doi:10.1016/j.pmn.2024.11.006. PMID: 39690039.

Akkurt MF, Özden AV, Akkurt HE, Akkurt B, Bildik C. Effects of left and bilateral transcutaneous auricular vagus nerve stimulation on pain, mood, and autonomic nervous system in female patients with fibromyalgia: a randomized controlled trial. Physiotherapy Theory and Practice. 2026;42(5):657–667. doi:10.1080/09593985.2025.2594572. PMID: 41332177.
Randomized human fibromyalgia trial — pain, function, mood and HRV outcomes.

Demircioğlu G, et al. Comparison of the efficacy of auricular vagus nerve stimulation and conventional low back rehabilitation in patients with chronic low back pain. Complementary Therapies in Clinical Practice. 2024. PMID: 38815433.
Randomized human study.

Tavares-Figueiredo I, Pers YM, Duflos C, et al. Effect of Transcutaneous Auricular Vagus Nerve Stimulation in Chronic Low Back Pain: A Pilot Study. Journal of Clinical Medicine. 2024;13(24):7601. doi:10.3390/jcm13247601. PMID: 39768526.
Three-month human pilot — pain, disability and quality-of-life outcomes.

Prott LS, Kaldenhoven V, Hugger A, et al. Transcutaneous Auricular Vagus Nerve Stimulation for the Treatment of Myoarthropathic Symptoms Associated With Temporomandibular Disorders—A Pilot Randomised Controlled Trial. Journal of Oral Rehabilitation. 2025;52(12):2351–2360. doi:10.1111/joor.70039. PMID: 40814998.
Randomized human TMD pilot study.

Migraine Headaches

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: a randomized, monocentric clinical trial. Journal of Headache and Pain. 2015;16:63. doi:10.1186/s10194-015-0543-3. PMID: 26156114.
Randomized human trial.

Acute Inflammation | COVID-19

COVID-19

Transcutaneous Auricular Vagus Nerve Stimulation Improves Inflammation but Does Not Interfere with Cardiac Modulation and Clinical Symptoms of Individuals with COVID-19: A Randomized Clinical Trial. 2022. PMID: 36295080.
Randomized human aVNS trial — including IL-6 and CRP outcomes.

Acute Pancreatitis

Feng J, Chen L, Lou L, et al. Transcutaneous Auricular Vagal Nerve Stimulation Alleviates Symptoms of Mild Acute Pancreatitis: A Multicenter Randomized Double-Blind Controlled Study. American Journal of Gastroenterology. 2026. doi:10.14309/ajg.0000000000004060. PMID: 42153655.
Multicenter randomized human trial.

Sepsis

Wu Z, Zhang X, Cai T, et al. Transcutaneous auricular vagus nerve stimulation reduces cytokine production in sepsis: An open double-blind, sham-controlled, pilot study. Brain Stimulation. 2023;16(2):507–514. doi:10.1016/j.brs.2023.02.008. PMID: 36801260.
Randomized human pilot — significant reductions in pro-inflammatory cytokines and increases in anti-inflammatory cytokines.

Wu Z, Zhang X, Li Y, et al. Transcutaneous auricular vagus nerve stimulation is associated with higher gastric antral motility in septic patients with acute gastrointestinal injury: A randomized, sham-controlled pilot trial with blinded outcome assessment. Brain Stimulation. 2026;19(4):103154. doi:10.1016/j.brs.2026.103154. PMID: 42392443.
Randomized human pilot — objective gastrointestinal motility and physiological outcomes in sepsis.

Long COVID & Post-Viral Recovery

Badran BW, Huffman SM, Dancy M, et al. A pilot randomized controlled trial of supervised, at-home, self-administered transcutaneous auricular vagus nerve stimulation to manage long COVID symptoms. Bioelectronic Medicine. 2022;8:13. doi:10.1186/s42234-022-00094-y. PMID: 36002874.

Transcutaneous auricular vagus nerve stimulation improves dysautonomia, post-traumatic stress disorder and cognitive impairment in long COVID patients: a pilot study. 2026. PMID: 42106490.
Prospective human pilot — autonomic symptoms and objective cognitive outcomes.

Gierthmuehlen M, Schmieder K, Thon N, Gierthmuehlen PC. Transcutaneous Auricular Vagal Nerve Stimulation Against Fatigue Syndrome in Patients with Long COVID: Results of the Randomized, Placebo-Controlled Clinical Pilot Trial COVIVA. Neurology and Therapy. 2026;15(3):1327–1343. doi:10.1007/s40120-026-00928-w. PMID: 41926033.
Randomized evidence with mixed/negative primary findings — included for balance.

Chronic Inflammatory & Autoimmune Conditions

Systemic Lupus Erythematosus

Aranow C, Atish-Fregoso Y, Lesser M, et al. Transcutaneous auricular vagus nerve stimulation reduces pain and fatigue in patients with systemic lupus erythematosus: a randomised, double-blind, controlled pilot trial. Annals of the Rheumatic Diseases. 2021;80(2):203–208. doi:10.1136/annrheumdis-2020-217872. PMID: 33144299.
Randomized human aVNS trial.

Systemic Sclerosis

Bellocchi C, Carandina A, Della Torre A, et al. Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis. RMD Open. 2023;9:e003265. doi:10.1136/rmdopen-2023-003265. PMID: 37536947.
Randomized human study — pain, autonomic and inflammatory outcomes.

Rheumatoid Arthritis

Koopman FA, Chavan SS, Miljko S, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proceedings of the National Academy of Sciences USA. 2016;113(29):8284–8289. doi:10.1073/pnas.1605635113. PMID: 27382171.
Implanted VNS — human evidence.

Inflammatory Bowel Disease

Sahn B, Pascuma K, Kohn N, Tracey KJ, Markowitz JF. Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial. Bioelectronic Medicine. 2023;9:23. doi:10.1186/s42234-023-00124-3. PMID: 37849000.
Human Crohn’s disease/ulcerative colitis study including objective inflammatory-marker outcomes.

Multiple Sclerosis

Herr T, Gamain J, Strauss S, et al. Effect of non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) on non-motor symptoms in multiple sclerosis: study protocol for a randomised, controlled trial. BMJ Open. 2025;15:e103998. doi:10.1136/bmjopen-2025-103998. PMID: 41213698.
Randomized controlled study programme examining cognition, fatigue and depression in relapsing-remitting MS; publication of clinical outcome data awaited.

Skin Health

Rosacea

Li J, Wei J, Zhang M, et al. Transcutaneous Auricular Vagus Nerve Stimulation Treatment for Erythematotelangiectatic Rosacea: A Randomized Clinical Trial. JAMA Dermatology. 2025;161(12):1229–1237. doi:10.1001/jamadermatol.2025.3796. PMID: 41060641.
Randomized human clinical trial.

Psoriasis

Transcutaneous auricular vagus nerve stimulation inhibits mental stress-induced cortisol release—Potential implications for inflammatory conditions. PMID: 39936474.
Human physiological study with additional preliminary psoriasis observations.

Atopic Dermatitis — Preclinical

Lee CM, Shin JH, Song JJ. Efficacy of atopic dermatitis alleviation through transcutaneous auricular vagus nerve stimulation in 2,4-dinitrochlorobenzene (DNCB)-induced mouse model. Annals of Medicine. 2026;58(1):2680845. doi:10.1080/07853890.2026.2680845. PMID: 42263156.
Preclinical aVNS study — improvements in skin pathology and inflammatory markers.

Psoriasis & Atopic Dermatitis — Preclinical

Nahm WJ, Kim KJ, et al. Vagus Nerve Stimulation Reduces Cutaneous Inflammation and Proinflammatory Cytokines in Murine Models of Psoriasis and Atopic Dermatitis. Experimental Dermatology. 2026;35(6):e70297. doi:10.1111/exd.70297. PMID: 42281200.
Preclinical implanted-VNS study — substantial reductions in cutaneous TNF-α, IL-1β and IL-6.

Vitiligo — Preclinical

Luo S, Meng X, Ai J, et al. Transcutaneous Auricular Vagus Nerve Stimulation Alleviates Monobenzone-Induced Vitiligo in Mice. International Journal of Molecular Sciences. 2024;25(6):3411. doi:10.3390/ijms25063411. PMID: 38542385.
Preclinical aVNS mouse model.

Inflammation – Substantial Objective Evidence

The objective anti-inflammatory evidence discussed in this section is drawn from multiple clinical and preclinical areas rather than from a single disease category. Key studies include:

Aranow C, et al. Annals of the Rheumatic Diseases. 2021;80(2):203–208. PMID: 33144299.
Systemic lupus erythematosus — randomized human aVNS study.

Bellocchi C, et al. RMD Open. 2023;9:e003265. PMID: 37536947.
Systemic sclerosis — inflammatory and autonomic outcomes.

Transcutaneous Auricular Vagus Nerve Stimulation Improves Inflammation…in Individuals with COVID-19. PMID: 36295080.
COVID-19 — randomized human trial including IL-6 and CRP.

Wu Z, et al. Brain Stimulation. 2023;16(2):507–514. PMID: 36801260.
Sepsis — randomized human pilot demonstrating changes in pro- and anti-inflammatory cytokines.

Sahn B, et al. Bioelectronic Medicine. 2023;9:23. PMID: 37849000.
Inflammatory bowel disease — objective intestinal inflammatory-marker outcomes.

Koopman FA, et al. PNAS. 2016;113(29):8284–8289. PMID: 27382171.
Rheumatoid arthritis — implanted VNS human evidence demonstrating suppression of cytokine production.

Nahm WJ, Kim KJ, et al. Experimental Dermatology. 2026;35(6):e70297. PMID: 42281200.
Preclinical psoriasis/atopic dermatitis — direct measurement of substantial reductions in inflammatory cytokines within skin.

Cardiovascular Health

Atrial Fibrillation

Stavrakis S, Stoner JA, Humphrey MB, et al. TREAT AF (Transcutaneous Electrical Vagus Nerve Stimulation to Suppress Atrial Fibrillation): A Randomized Clinical Trial. JACC: Clinical Electrophysiology. 2020;6(3):282–291. doi:10.1016/j.jacep.2019.11.008. PMID: 32192678.
Randomized human trial — AF burden and inflammatory outcomes.

Cardiac Autonomic Regulation / Heart Failure

Maestri R, et al. Impact of optimized transcutaneous auricular vagus nerve stimulation on cardiac autonomic profile in healthy subjects and heart failure patients. Physiological Measurement. 2024. doi:10.1088/1361-6579/ad5ef6. PMID: 39016202.
Randomized crossover studies — HRV and autonomic regulation in healthy participants and heart-failure patients.

Clinical outcome of electrical transcutaneous auricular vagal stimulation in patients with stable symptomatic chronic heart failure — A pilot study. PMID: 40819769.
Randomized human heart-failure pilot study.

Gastrointestinal Health

Functional Dyspepsia

Lee B, Kwon CY, Jeong YK, Sclocco R, Kuo B, Napadow V, Lee JH, Kim H. Transcutaneous auricular vagus nerve stimulation for functional dyspepsia: A systematic review and meta-analysis. Complementary Therapies in Medicine. 2025;94:103243. doi:10.1016/j.ctim.2025.103243. PMID: 40967422.

Shi X, Zhao L, Luo H, et al. Transcutaneous Auricular Vagal Nerve Stimulation Is Effective for the Treatment of Functional Dyspepsia: A Multicenter, Randomized Controlled Study. American Journal of Gastroenterology. 2024;119(3):521–531. doi:10.14309/ajg.0000000000002548. PMID: 37787432.

Irritable Bowel Syndrome / Constipation

Liu J, Lv C, Yin M, et al. Efficacy and Safety of Transcutaneous Auricular Vagus Nerve Stimulation in Patients With Constipation-Predominant Irritable Bowel Syndrome: A Single-Center, Single-Blind, Randomized Controlled Trial. American Journal of Gastroenterology. 2025;120(9):2139–2153. doi:10.14309/ajg.0000000000003257. PMID: 39689011.

Inflammatory Bowel Disease

Sahn B, Pascuma K, Kohn N, Tracey KJ, Markowitz JF. Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial. Bioelectronic Medicine. 2023;9:23. doi:10.1186/s42234-023-00124-3. PMID: 37849000.

Neurological Health & Rehabilitation

Parkinson’s Disease

Liu C, Jin Y, Lin H, et al. Effects of transcutaneous auricular vagus nerve stimulation on motor and gait performance in Parkinson’s disease: a meta-analysis of randomized controlled trials. Journal of Neurology. 2026;273(3):196. doi:10.1007/s00415-026-13738-9. PMID: 41805933.

Wang R, Liu M, Liu Q, et al. Home-based transcutaneous auricular vagus nerve stimulation improves motor and non-motor symptoms by improving autonomic and brain functions in patients with Parkinson’s disease: A randomized clinical trial. Neurotherapeutics. 2026;23(1):e00832. doi:10.1016/j.neurot.2026.e00832. PMID: 41549029.

Epilepsy

Moro P, Rocha Dos Santos MA, de Souza ALB, 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 & Behavior. 2025;167:110394. doi:10.1016/j.yebeh.2025.110394. PMID: 40158411.

Stroke Rehabilitation

Wan S, Liu X, Jiang W, et al. Effectiveness of transcutaneous auricular vagus nerve stimulation in stroke rehabilitation: a systematic review and meta-analysis of randomized clinical trials. Frontiers in Neurology. 2026;17:1786103. doi:10.3389/fneur.2026.1786103. PMID: 42222529.

Gao L, Fan Y, Zhang N, Chen L. Transcutaneous Auricular Vagus Nerve Stimulation Paired With Exercise Training for Upper Limb Motor Function and Activities of Daily Living After Stroke: A Systematic Review and Meta-analysis. Archives of Physical Medicine and Rehabilitation. 2026;107(10):2951–2962. doi:10.1016/j.apmr.2026.03.008. PMID: 41865861.

Cognitive Health

Liu F, Li Y. Sorting the mind: cognitive enhancement through transcutaneous auricular vagus nerve stimulation: a systematic review and meta-analysis. Psychological Medicine. 2026;56:e207. doi:10.1017/S0033291726105017. PMID: 42339645.

Wang L, Zhang J, Guo C, et al. The efficacy and safety of transcutaneous auricular vagus nerve stimulation in patients with mild cognitive impairment: A double blinded randomized clinical trial. Brain Stimulation. 2022;15(6):1405–1414. doi:10.1016/j.brs.2022.09.003. PMID: 36150665.
Randomized human MCI trial.

Autism Spectrum Disorder — Preclinical

Zhang W, Mou Z, Zhong Q, et al. Transcutaneous auricular vagus nerve stimulation improves social deficits through the inhibition of IL-17a signaling in a mouse model of autism. Frontiers in Psychiatry. 2024;15:1393549. doi:10.3389/fpsyt.2024.1393549. PMID: 38993386.
Preclinical aVNS study — social behavior, anxiety, microglial activation and IL-17A outcomes.

Anxiety & Depression

Tan C, Qiao M, Ma Y, Luo Y, Fang J, Yang Y. 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. Journal of Affective Disorders. 2023;337:37–49. doi:10.1016/j.jad.2023.05.048. PMID: 37230264.

Transcutaneous auricular vagus nerve stimulation inhibits mental stress-induced cortisol release—Potential implications for inflammatory conditions. PMID: 39936474.
Human experimental study — objective cortisol response to psychological stress.

Women’s Health

Endometriosis & Adenomyosis

Nie J, Yi Y, Liu X, Koninckx PR, Guo SW. A pilot study on the use of transcutaneous auricular vagus nerve stimulation to relieve dysmenorrhea in patients with adenomyosis and endometriosis. Reproduction and Fertility. 2026;7(2):RAF260052. doi:10.1530/RAF-26-0052. PMID: 42189961.
Human pilot study.

Primary Dysmenorrhea

Yıldız Kızkın Z, Yıldız R, Özden AV. Effects of Transcutaneous Auricular Vagus Nerve Stimulation in Individuals with Primary Dysmenorrhea: A Randomized Controlled Trial. Neuromodulation. 2026;29(4):576–587. doi:10.1016/j.neurom.2025.09.306. PMID: 41108303.

Wang C, Xia J, Li P, et al. Electroencephalography Microstates Reveal Variability in Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation in Primary Dysmenorrhea. Annals of the New York Academy of Sciences. 2026;1557(1):e70244. doi:10.1111/nyas.70244. PMID: 41824790.
Randomized human study with follow-up through the sixth menstrual period.

Polycystic Ovary Syndrome

Zhang S, He H, Wang Y, Wang X, Liu X. Transcutaneous auricular vagus nerve stimulation as a potential novel treatment for polycystic ovary syndrome. Scientific Reports. 2023;13:7721. doi:10.1038/s41598-023-34746-z. PMID: 37173458.
PCOS-focused scientific review — autonomic balance, insulin resistance, metabolic regulation, inflammation and reproductive-endocrine rationale.

Metabolic Health

Zou N, Zhou P, Zhou Q, Ma J, Feng S, Rong P, Li S. Brain-gut interaction for holistic regulation: Transcutaneous auricular vagus nerve stimulation in modulating glucose and lipid metabolic disorders. Clinical Nutrition. 2026;56:106544. doi:10.1016/j.clnu.2025.12.003. PMID: 41483489.
Current review of human and preclinical metabolic evidence.

Huang F, Dong J, Kong J, et al. Effect of transcutaneous auricular vagus nerve stimulation on impaired glucose tolerance: a pilot randomized study. BMC Complementary and Alternative Medicine. 2014;14:203. doi:10.1186/1472-6882-14-203. PMID: 24968966.
Randomized human study.

Selected Preclinical Metabolic Evidence

Li S, Zhai X, Rong P, et al. Therapeutic effect of vagus nerve stimulation on depressive-like behavior, hyperglycemia and insulin receptor expression in Zucker fatty rats. PLoS ONE. 2014;9(11):e112066. doi:10.1371/journal.pone.0112066. PMID: 25365428.
Preclinical — diabetic animal model.

Wang S, Zhai X, Li S, et al. Transcutaneous vagus nerve stimulation induces tidal melatonin secretion and has an antidiabetic effect in Zucker fatty rats. PLoS ONE. 2015;10(4):e0124195. doi:10.1371/journal.pone.0124195. PMID: 25880500.
Preclinical — diabetic animal model.

Zhang Y, Zou N, Xin C, et al. Transcutaneous auricular vagal nerve stimulation modulates blood glucose in ZDF rats via intestinal melatonin receptors and melatonin secretion. Frontiers in Neuroscience. 2024;18:1471387. doi:10.3389/fnins.2024.1471387. PMID: 39564526.
Preclinical — diabetic animal model.

Kaushik AS, Agarwal V, Kumar N, et al. Stimulation of auricular vagus nerve ameliorates chronic stress induced metabolic syndrome via activation of Sirtuin-6. Biochemical and Biophysical Research Communications. 2025;756:151567. doi:10.1016/j.bbrc.2025.151567. PMID: 40056501.
Preclinical — chronic stress-induced metabolic syndrome.

Cancer Support & Recovery

Cancer-Related Pain & Fatigue

Zuo X, Xu Y, Li S, et al. Efficacy and safety of transcutaneous auricular vagus nerve stimulation plus pregabalin for radiotherapy-related neuropathic pain in patients with head and neck cancer (RELAX): a phase 2 randomised trial. EClinicalMedicine. 2025;86:103345. doi:10.1016/j.eclinm.2025.103345. PMID: 40697962.
Phase 2 randomized human trial — significantly greater pain relief, with improvements in fatigue and quality-of-life measures during treatment.

Do M, Evancho A, Tyler WJ. Bilateral transcutaneous auricular vagus nerve stimulation for the treatment of insomnia in breast cancer. Scientific Reports. 2026;16:1081. doi:10.1038/s41598-025-30600-6. PMID: 41345210.
Human breast-cancer study — insomnia, sleep quality, cancer-related fatigue, depression and HRV.

Post-Surgical Recovery

Ouyang R, Jin X, Qu L, et al. Low-intensity transcutaneous auricular vagus nerve stimulation reduces postoperative ileus after laparoscopic radical resection of colorectal cancer: a randomized controlled trial. Minerva Anestesiologica. 2023;89(3):149–156. doi:10.23736/S0375-9393.22.16735-0. PMID: 36326770.
Randomized human trial — lower postoperative ileus and improved return of bowel activity following colorectal cancer surgery.

Yi Y, Li Y, Luo G, et al. Efficacy of Transcutaneous Auricular Vagus Nerve Stimulation for Postoperative Pain Relief in Patients Undergoing Elective Laparoscopic Gastrointestinal Tumor Surgery. Pain and Therapy. 2026;15:681–695. doi:10.1007/s40122-026-00825-y. PMID: 41824217.
Randomized human trial — postoperative pain, analgesic requirements and gastrointestinal recovery.

Ma L, Xia J, Li X, Chen H, Yu B. Transcutaneous auricular vagus nerve stimulation for prevention of postoperative cognitive dysfunction in older adults with gastrointestinal tumors: A randomized controlled trial. Journal of Geriatric Oncology. 2026;17(7):103049. doi:10.1016/j.jgo.2026.103049. PMID: 42456197.
Randomized human trial — postoperative cognitive outcomes with accompanying IL-1β and S100β biomarker changes.

Cancer Recovery & Neuroimmune Regulation

Do M, Tyler WJ. Transcutaneous vagus nerve stimulation in breast cancer: a neuroimmune model to improve quality of life. Frontiers in Oncology. 2026;16:1731999. doi:10.3389/fonc.2026.1731999. PMID: 41717404.
Review integrating emerging clinical and mechanistic evidence for sleep, fatigue, mood, autonomic regulation, inflammation and survivorship.

Cancer Biology — Preclinical Evidence

Preclinical research has also examined whether vagal modulation can influence tumor biology, immune activity and cancer-associated metabolic changes. Findings are biologically interesting but are not yet sufficiently consistent to establish a direct anti-cancer effect of aVNS in humans. For this reason, these studies are best considered separately from the substantially stronger clinical evidence for symptom control and recovery.

A Note About the Evidence

The strength of evidence varies between conditions. Some applications are now supported by systematic reviews, meta-analyses and multiple randomized human clinical trials, while others have smaller clinical studies or are currently supported mainly by preclinical research.

The evidence is particularly important where studies have demonstrated objective biological or functional changes—including inflammatory biomarkers, heart-rhythm burden, heart-rate variability, gastrointestinal motility, brain imaging and connectivity, cognitive testing, motor performance and other measurable physiological outcomes—rather than relying solely on subjective symptom reporting.

Where evidence comes from animal studies or implanted VNS rather than non-invasive auricular VNS, this has been specifically identified. Preclinical findings are included where they provide important biological or translational evidence, but they should not be interpreted as equivalent to demonstrated clinical benefit in humans.