Several clinical studies have demonstrated that transcutaneous auricular vagus nerve stimulation (taVNS) can substantially reduce circulating IL-6 and TNF-alpha concentrations, in some cases by more than 40% within only a few weeks.

Human studies showing simultaneous reductions exceeding 40% for both cytokines are relatively uncommon, since many investigations report statistically significant but smaller effects. Nevertheless, several particularly impressive studies deserve attention.

1. Shi et al. (2021) – JCI Insight

Study design

Randomized, sham-controlled clinical trial involving 42 patients with constipation-predominant irritable bowel syndrome (IBS-C).

Treatment protocol

• Four weeks
• Two daily sessions
• Thirty minutes per session
• Stimulation at the cymba conchae

Results

• TNF-alpha: reduced from 6.7 ± 3.0 pg/mL to 3.9 ± 2.1 pg/mL
  • approximately 42% reduction
• IL-6: reduced from 3.4 ± 2.8 pg/mL to 1.9 ± 1.1 pg/mL
  • approximately 44% reduction

The improvements were significantly greater than those observed in the sham group.

2. Seitz et al. (2022) – Frontiers in Physiology

This randomized study included critically ill COVID-19 patients admitted to the intensive care unit.

Patients received either:

• auricular vagus nerve stimulation plus standard care, or
• standard care alone.

Treatment lasted an average of 12 days (range 3–18 days).

Results

• IL-6: approximately 59% reduction
• TNF-alpha: approximately 67% reduction, with an overall reduction of approximately 58% after one week

Although this study used percutaneous auricular electrodes rather than purely transcutaneous stimulation, the underlying neurophysiological mechanism is essentially identical to taVNS.

3. Shin et al. (2024) – Scientific Reports

Animal study using a mouse model of gout-induced arthritis.

After only three days of taVNS:

• IL-6 decreased by 82–84%
• TNF-alpha decreased by 47–89%, depending on stimulation frequency.

These findings illustrate the remarkable anti-inflammatory potential of vagus nerve stimulation under experimental conditions.

Overall Interpretation

Across the literature, reductions in inflammatory cytokines are generally statistically significant, although simultaneous reductions exceeding 40% for both IL-6 and TNF-alpha are less common in chronic diseases.

Numerous review articles, particularly in rheumatoid arthritis and COVID-19, consistently conclude that activation of the cholinergic anti-inflammatory pathway reduces systemic inflammation, although the magnitude of effect varies according to patient population and stimulation protocol.

Additional clinical studies demonstrating reductions in inflammatory biomarkers include investigations by:

• Wu et al. (2023)
• Corrêa et al. (2022)
• Laurido-Soto et al. (2026)
• Uehara et al. (2022)
• Li et al. (2026)
• Shi et al. (2021)
• Seitz et al. (2022)
• Hua et al. (2025)
• Badran et al. (2022)
• Guo et al. (2021)

Collectively, these studies consistently support the concept that vagus nerve stimulation exerts clinically measurable anti-inflammatory effects.

Ancient and Intuitive Methods of Vagal Activation

Long before anyone knew about the vagus nerve, humans intuitively developed behaviors that most likely stimulate the parasympathetic nervous system through vagal pathways.

Examples include:

Humming, Singing and “Om” Meditation

• Vibrations of the larynx, pharynx and thorax stimulate vagal pathways.
• Slow prolonged exhalation additionally calms both heart rate and respiration.

Sucking

Examples include:

• breastfeeding
• pacifiers
• thumb sucking

These behaviors are especially calming in infants because they activate oral, trigeminal and vagal neural circuits.

Slow Deep Exhalation

Found in many forms of:

• prayer
• chanting
• meditation

A prolonged expiration enhances parasympathetic activity.

Gargling

Gargling activates the muscles of the pharynx together with vagally mediated reflexes.

Group Singing and Choir Music

The combination of

• rhythmic breathing
• social safety
• vibration

probably produces a particularly strong polyvagal effect.

Prayer and Rhythmic Recitation

Examples include:

• the Rosary
• mantras
• Psalms
• Sufi chanting

Slow rhythmic breathing synchronizes cardiovascular activity with brainstem autonomic centers.

Rocking and Gentle Swaying

Used instinctively with babies throughout the world, rocking provides vestibular input that calms the brainstem.

Cold Water on the Face

Activation of the diving reflex produces powerful vagal stimulation through brainstem reflex circuits.

Safe Social Contact

Examples include:

• hugging
• gentle stroking
• rhythmic holding

These behaviors combine oxytocin release with activation of vagal safety networks.

Slow Chewing

Chewing activates several cranial nerves while simultaneously initiating parasympathetic digestive programs.

Slow Breathing Meditation

Breathing at approximately 4–6 breaths per minute produces particularly strong coupling between heart rate variability and vagal activity.

Drumming and Rhythmic Dance

Repetitive rhythmic sensory input appears to stabilize autonomic networks and may represent one of humanity’s oldest social regulatory mechanisms.

Yogic “Bee Breathing”

Humming generates powerful resonance within the skull and pharynx and often produces an immediate calming effect.

Laughter

Rhythmic expiration combined with social safety cues measurably activates vagal pathways.

Many of these techniques developed centuries or even millennia before anyone understood vagus nerve physiology. They were likely preserved across cultures simply because they reduced stress, strengthened social bonding, and stabilized the nervous system.

Among the institutions currently using tVNS® are:

• Stanford University
• Technical University of Vienna
• University Hospital Bonn
• Maastricht University
• Inselspital Bern
• Otto-von-Guericke University Magdeburg
• University of Tartu
• University of Salamanca
• University of Marburg
• Friedrich-Alexander University Erlangen-Nuremberg
• University Hospital Regensburg
• Ludwig Maximilian University Munich
• Northwestern University
• University of Illinois
• University of Tübingen
• Karolinska Institute
• University of Ulm
• University of Coimbra
• Leiden University
• Trinity College Dublin
• Korea University
• Max Planck Society

…and many others.

Important Information for Healthcare Professionals

Until the end of 2025, the device officially listed 17 clinical indications.

These were deliberately reduced to four for regulatory reasons.

The decision was not based on reduced efficacy, but rather on international regulatory strategy.

Obtaining approval in countries such as Australia or Singapore becomes considerably easier when the officially marketed indication list remains relatively small.

Otherwise, manufacturers may have to repeat expensive approval procedures separately for every indication in every country.

Regulatory approval obtained in one jurisdiction does not automatically permit marketing in another.

Consequently, physicians frequently encounter legal restrictions even when strong scientific evidence exists.

Importantly, the indications removed from the official label remain supported by the same university-based clinical studies that originally validated their efficacy.

Removing an indication from the official product label does not imply that the therapy suddenly became ineffective.

Instead, treatment simply becomes off-label.

Clinical validation means that efficacy has been demonstrated under scientifically rigorous conditions, usually in randomized placebo-controlled trials.

Such studies are extremely expensive and contribute substantially to the final cost of high-quality medical devices.

Understanding On-Label and Off-Label Therapy

For much of my professional career, these regulatory distinctions played only a minor role.

Medicine was primarily based on:

• physician experience,
• scientific conferences,
• peer-reviewed journals,
• and, above all,
• continuous feedback from patients.

Over approximately the last decade—and particularly since the COVID pandemic—medicine has become increasingly regulated.

Today, physicians are expected to prescribe almost exclusively according to officially approved indications.

Deviation from these rules may carry legal consequences.

On-label

The device or medication has official regulatory approval for the specific disease being treated.

Off-label

The device or medication has regulatory approval, but for a different indication than the one currently being treated.

The regulatory approval confirms that the safety profile has been scientifically evaluated.

Examples include:

• Metformin, officially approved for diabetes but widely investigated in oncology.
• Trazodone, officially approved as an antidepressant but now commonly prescribed as a sleep medication.

No-label

No regulatory approval exists.

Consequently, safety has not been validated according to modern regulatory standards.

Examples might include:

• medical-grade Manuka honey for chronic wounds,
• investigational peptides such as BPC-157.

Why Many Physicians Hesitate to Use Off-Label Therapies

Physicians enjoy the greatest legal protection when prescribing on-label treatments.

With off-label—or especially no-label—therapies, legal liability increases substantially, even when scientific evidence may support their use.

Examples include physicians facing legal proceedings after prescribing:

• intravenous vitamin C,
• phytotherapeutic Lyme disease protocols,
• or other scientifically plausible but non-approved therapies.

Whether one agrees with these regulatory systems or not, they represent today’s legal reality.

Why Genuine Medical Devices Are Expensive

The regulatory requirements imposed on manufacturers of certified medical devices are exceptionally demanding.

One manufacturer described having to perform animal safety studies simply because a transparent PET cover—made from exactly the same plastic used worldwide in beverage bottles—was attached to a small LED device intended for acupuncture point stimulation.

Although the material had already been extensively tested over decades, the mandatory regulatory study alone cost approximately €30,000.

Another manufacturer explained that maintaining CE certification for a medical device requires expenditures of approximately €80,000 every few years, simply to continue marketing the device within the European Union.

If sales volume is insufficient, production of otherwise valuable medical devices often becomes economically impossible.

This explains why genuinely certified medical devices are frequently much more expensive than consumer wellness products.

Similarly, many homeopathic preparations disappeared from the market after regulatory changes required complete re-registration whenever product names were modified—procedures that often cost approximately €30,000 per product.

These examples illustrate that modern regulatory approval for medical devices is rigorous, complex, and extremely costly.