Is Vagus Nerve Stimulation Safe? What 177 Studies Tell Us

Introduction: Why Safety Matters in Neuromodulation

Any therapy that modulates the nervous system — whether pharmacological or device-based — demands rigorous safety evaluation. For vagus nerve stimulation (VNS), this is particularly important because the vagus nerve influences heart rate, respiration, digestion, and immune function. Understanding the safety profile of VNS is not merely an academic exercise; it is essential for clinicians, researchers, and individuals seeking evidence-based information.

Fortunately, VNS has been studied extensively. With more than three decades of clinical use for invasive VNS (iVNS) and a rapidly growing evidence base for non-invasive approaches — particularly transcutaneous auricular vagus nerve stimulation (taVNS) — there is now a substantial body of data on which to assess safety and tolerability.

This article examines what the peer-reviewed literature tells us about the safety of VNS, with particular focus on a landmark systematic review and meta-analysis by Kim et al. (2022) that analysed 177 studies involving 6,322 participants.

The Kim et al. 2022 Systematic Review: A Landmark Analysis

Published in Frontiers in Neurology, the systematic review by Kim and colleagues represents the most comprehensive analysis of taVNS safety and tolerability to date. The review encompassed 177 peer-reviewed studies with a combined total of 6,322 participants, spanning research conducted from the early 2010s through 2022.

The key findings of this analysis were reassuring:

- taVNS was generally well-tolerated across the included studies
- The most commonly reported side effects were mild and transient
- Serious adverse events were rare and were not clearly attributable to taVNS
- Dropout rates in taVNS studies were comparable to those in sham stimulation groups, suggesting that the intervention itself was not a primary cause of study withdrawal

This meta-analysis provides a robust foundation for evaluating the safety of non-invasive vagus nerve stimulation. However, to fully understand the safety landscape, it is important to consider each modality of VNS separately.

Safety Profile of Invasive VNS (iVNS)

Invasive VNS has the longest clinical track record, with FDA approval for epilepsy dating to 1997. Because iVNS involves surgical implantation of a pulse generator and electrode lead, its side effect profile includes both stimulation-related and procedure-related effects.

Common Side Effects of iVNS

The most frequently reported side effects of iVNS are related to the electrical stimulation of the cervical vagus nerve and surrounding tissues:

- Voice alteration or hoarseness — reported in approximately 30–65% of patients, typically occurring during stimulation "on" periods and resolving during "off" periods (Ben-Menachem, 2002)
- Cough — experienced by approximately 12–45% of patients
- Dyspnoea (shortness of breath) — reported in some patients, particularly during initial parameter adjustment
- Paraesthesia (tingling sensation) in the throat or neck
- Dysphagia (difficulty swallowing) — generally mild

These effects are directly related to stimulation parameters and can often be managed by adjusting the pulse width, frequency, or intensity of stimulation. Importantly, most stimulation-related side effects diminish over time as patients habituate to the therapy (Morris & Mueller, 1999).

Surgical Risks

As with any implantable device, iVNS carries procedure-related risks:

- Infection at the implant or incision site (approximately 3–6%)
- Lead displacement or fracture (rare, but may require revision surgery)
- Postoperative pain at the surgical site
- Rare cardiac effects — bradycardia during intraoperative lead testing has been reported but is uncommon with proper surgical technique (Ardesch et al., 2007)

Long-term surveillance data from the manufacturer's registry and independent studies have not identified significant delayed safety concerns. A review by Elliott et al. (2011) following 436 patients with drug-resistant epilepsy found that iVNS maintained an acceptable safety profile over years of continuous use.

Safety Profile of Transcutaneous Auricular VNS (taVNS)

The safety profile of taVNS is considerably more favourable than that of iVNS, which is expected given its non-invasive nature. The Kim et al. (2022) meta-analysis provides the most comprehensive picture of taVNS safety across diverse study populations and protocols.

Mild and Transient Side Effects

The most commonly reported side effects of taVNS include:

- Tingling or prickling sensation at the electrode site — this is the most frequently reported effect and is an expected consequence of transcutaneous electrical stimulation. In most studies, it is considered a feature of the stimulation rather than an adverse event, as subjects are typically asked to report when they feel tingling to confirm adequate electrode contact.

- Local skin irritation or redness — mild erythema at the electrode application site has been reported in some studies, particularly with prolonged stimulation sessions. This typically resolves within minutes to hours after electrode removal.

- Ear pain or discomfort — a small proportion of participants report mild discomfort at the stimulation site. This is generally associated with higher stimulation intensities and resolves when parameters are adjusted.

- Headache — reported infrequently and typically mild. It is often difficult to distinguish from pre-existing headache in study populations.

- Dizziness — reported rarely. When present, it is usually transient and resolves spontaneously.

Serious Adverse Events

The Kim et al. (2022) review found that serious adverse events in taVNS studies were rare. Where serious adverse events were reported, they were generally not attributable to the stimulation itself. The reviewers noted that the incidence of adverse events in active taVNS groups was often comparable to that in sham stimulation control groups — an important finding suggesting that many reported effects may be related to the experience of wearing an ear electrode rather than to vagal stimulation specifically.

No deaths attributable to taVNS have been reported in the published literature.

Cardiac Safety

Given the vagus nerve's role in cardiac regulation, cardiac safety is a primary concern in VNS research. The evidence is reassuring:

- Stimulation of the left ear (targeting the cymba conchae or tragus) has not been associated with clinically significant cardiac effects in the vast majority of studies
- Badran et al. (2018) specifically investigated the cardiac effects of taVNS and found no significant changes in heart rate, blood pressure, or cardiac rhythm during stimulation at standard parameters
- The auricular branch of the vagus nerve (ABVN) is a sensory branch, and its stimulation does not directly activate the cardiac efferent fibres responsible for heart rate modulation

However, researchers have generally recommended avoiding stimulation of the right ear as a precaution, since right-sided vagal fibres have a preferential innervation to the sinoatrial node of the heart (Kreuzer et al., 2012). This convention is followed in the majority of clinical protocols.

Safety Profile of Transcutaneous Cervical VNS (tcVNS)

Transcutaneous cervical VNS (gammaCore) has been evaluated in multiple clinical trials for headache disorders. The safety data from these trials indicate a favourable profile:

- Application site discomfort — the most common side effect, typically described as a pulling or tingling sensation on the neck
- Facial muscle contraction — can occur if stimulation intensity is too high
- Lip or facial drooping — reported rarely and transiently
- No significant cardiac adverse events in controlled trials (Silberstein et al., 2016)

The FDA clearance of gammaCore for cluster headache and migraine was based on clinical trial data demonstrating an acceptable safety profile for self-administered use.

Contraindications and Precautions

While VNS — particularly taVNS — has a favourable safety profile, several contraindications and precautions have been identified in the literature:

Absolute Contraindications

- Active implantable devices — Individuals with cardiac pacemakers, implantable cardioverter-defibrillators (ICDs), or other active implantable medical devices should not use VNS without specific medical guidance, due to the theoretical risk of electromagnetic interference
- Carotid atherosclerosis (for tcVNS) — Stimulation over the carotid artery area is contraindicated in patients with known carotid artery disease

Relative Contraindications and Precautions

- Cardiac arrhythmias — While taVNS has not been shown to cause arrhythmias in healthy populations, individuals with pre-existing cardiac conduction disorders should exercise caution
- Pregnancy — Insufficient safety data exist for VNS during pregnancy. Most clinical trials have excluded pregnant individuals as a precaution
- Active ear pathology — Skin lesions, infections, or dermatological conditions affecting the outer ear may contraindicate electrode placement at that site
- Epilepsy (for non-prescribed use) — While iVNS is an approved therapy for epilepsy, self-administered taVNS in individuals with uncontrolled seizure disorders should only be undertaken with medical supervision

Comparison of Safety Across Stimulation Types

The three modalities of VNS differ substantially in their safety profiles, reflecting their respective levels of invasiveness:

Invasive VNS (iVNS):
- Highest risk profile due to surgical implantation
- Well-characterised side effects (voice alteration, cough)
- Long-term safety data available (25+ years)
- Requires specialist management

Transcutaneous Auricular VNS (taVNS):
- Lowest risk profile
- Most side effects mild and transient
- No surgical risks
- Growing but shorter-term evidence base
- Suitable for self-administration

Transcutaneous Cervical VNS (tcVNS):
- Intermediate risk profile
- Local application site effects
- FDA-cleared for self-use in headache
- Moderate evidence base

Special Populations

Children and Adolescents

iVNS is approved for patients aged 12 and older with drug-resistant epilepsy. Paediatric studies have generally shown a safety profile comparable to that observed in adults (Orosz et al., 2014). taVNS research in paediatric populations is limited but emerging, with initial studies reporting good tolerability (Badran et al., 2020).

Older Adults

Bretherton et al. (2019) specifically studied the effects of taVNS in individuals aged 55 years and older. The study reported that taVNS was well-tolerated in this population, with no serious adverse events. Notably, the researchers observed improvements in autonomic function and quality of life, suggesting potential benefits of taVNS for age-related autonomic decline.

Pregnancy

There is currently insufficient evidence to establish the safety of VNS during pregnancy. Because the vagus nerve influences uterine contractility and autonomic regulation, most clinical protocols and device manufacturers recommend avoiding VNS during pregnancy unless the potential benefits clearly outweigh the unknown risks (Ben-Menachem et al., 2015).

What Dropout Rates Tell Us About Tolerability

One of the most informative — and often overlooked — indicators of tolerability in clinical research is the dropout rate. If a therapy causes significant discomfort or adverse effects, participants are more likely to withdraw from a study.

The Kim et al. (2022) meta-analysis found that dropout rates in taVNS studies were generally low and comparable to those in sham (placebo) stimulation groups. This finding is significant because it suggests that taVNS is not causing sufficient discomfort or adverse effects to drive study withdrawal beyond what would be expected from the general demands of clinical trial participation.

A review of randomised controlled trials on taVNS for various conditions found average completion rates exceeding 90% in most studies (Burger et al., 2020), further supporting the tolerability of the intervention.

Additionally, studies that have assessed participant satisfaction and willingness to continue have generally reported positive results. In the Bretherton et al. (2019) study of older adults, the majority of participants indicated they would be willing to continue daily taVNS, and several reported subjective improvements in wellbeing.

Summary: What the Evidence Tells Us About Safety

The safety of vagus nerve stimulation is supported by a substantial and growing body of evidence:

For invasive VNS (iVNS):
- More than 25 years of clinical data support an acceptable safety profile for approved indications
- Side effects are well-characterised, predictable, and often manageable through parameter adjustment
- Surgical risks exist but are comparable to other implantable neuromodulation devices

For transcutaneous auricular VNS (taVNS):
- The Kim et al. (2022) meta-analysis of 177 studies and 6,322 subjects confirms that taVNS is generally well-tolerated
- Most side effects are mild, transient, and localised (tingling, skin irritation)
- Serious adverse events are rare and not clearly attributable to stimulation
- Dropout rates are comparable to sham stimulation, indicating good tolerability
- No deaths attributable to taVNS have been reported

For transcutaneous cervical VNS (tcVNS):
- FDA clearance for self-administered use in headache disorders supports an acceptable safety profile
- Side effects are primarily local and manageable

While the overall safety data are encouraging, it is important to acknowledge certain limitations. The majority of taVNS studies have been relatively short in duration (days to weeks), and long-term safety data from extended daily use remain limited. Additionally, there is substantial variability in stimulation parameters and protocols across studies, making direct comparisons difficult.

As with any therapeutic intervention, individuals considering VNS should consult with a qualified healthcare professional, particularly those with pre-existing cardiac conditions, implantable devices, or other medical considerations.

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References

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Badran, B.W. et al. (2020). Transcutaneous auricular vagus nerve stimulation-paired rehabilitation for oromotor feeding problems in newborns: an open-label pilot study. Frontiers in Human Neuroscience, 14, 77.

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