Non-Invasive Vagus Nerve Stimulation for PTSD

Overseen By Imanuel R Lerman, MD MSc

Age: 18+

Sex: Male

Trial Phase: Phase 1 & 2

Sponsor: VA Office of Research and Development

Must not be taking: Anti-inflammatories, Chronic pain meds

Disqualifiers: Psychosis, Bipolar, Major depression, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 8

Duration: 1 week

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether a non-invasive device that stimulates the vagus nerve can reduce PTSD symptoms, improve pain response, and enhance life quality for veterans. Participants will use a device on the neck daily, with effects compared to a similar device that does not actively stimulate the nerve. Veterans who have been deployed, experienced trauma, and face PTSD symptoms might be suitable candidates for this study. As a Phase 1/Phase 2 trial, the research aims to understand how the treatment works and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking PTSD treatment advancements.

Will I have to stop taking my current medications?

The trial requires that participants continue taking standard medications used to treat PTSD. However, if you take anti-inflammatory medications for chronic conditions or medications for chronic pain, you will be excluded from the trial.

What prior data suggests that this non-invasive vagus nerve stimulation is safe for PTSD?

Research has shown that cervical transcutaneous vagus nerve stimulation (tcVNS) is generally safe for people with PTSD. In past studies, patients handled the treatment well. One study found that tcVNS reduced certain stress-related inflammation without causing major side effects. Another study demonstrated that it helped lower stress responses in people with PTSD, suggesting its safety. While these studies show promising safety results, it is important to remember that this treatment is still under investigation. Further research could confirm its safety and effectiveness. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for PTSD?

Most treatments for PTSD involve psychotherapy or medications like SSRIs and SNRIs, which work by altering brain chemistry over time. However, cervical transcutaneous vagus nerve stimulation (tVNS) is different because it uses a non-invasive device to directly stimulate the vagus nerve through the skin on the neck. This method is unique because it could potentially modulate brain activity more directly and rapidly than traditional drugs. Researchers are excited about tVNS because it offers a new way to address PTSD symptoms without the side effects associated with medications, and it may provide faster relief than current therapeutic options.

What evidence suggests that this device is effective for PTSD?

Research has shown that cervical transcutaneous vagus nerve stimulation (tcVNS), a treatment participants in this trial may receive, might help people with PTSD by reducing stress. One study found that tcVNS lowered heart rates in people with PTSD, suggesting it helps calm stress. Another study indicated that tcVNS might improve attention and memory, potentially enhancing quality of life. Additionally, tcVNS has reduced the body's inflammatory response to stress. These findings suggest that tcVNS could help lessen PTSD symptoms and improve daily life. ^{1 2 3 6 7}

Who Is on the Research Team?

Imanuel R Lerman, MD MSc

Principal Investigator

VA San Diego Healthcare System, San Diego, CA

Are You a Good Fit for This Trial?

This trial is for male veterans aged 21-65 who have PTSD from deployment, with specific symptom severity scores. They must speak English and be able to follow the study schedule. Excluded are those with certain mental illnesses, recent evidence-based PTSD treatment, chronic pain management, risky alcohol/drug use, or conditions worsened by the treatment.

Inclusion Criteria

You have experienced a traumatic event, but your symptoms do not meet the severity criteria for a diagnosis of PTSD.

For PTSD: Previously deployed, experienced a traumatic event, and meets Clinician-Administered PTSD Scale for DSM-5(CAPS-5) symptom cluster severity criteria for PTSD diagnosis, as well as CAPS total cut-off score > 33

I am a man aged between 21 and 65.

Exclusion Criteria

You have taken part in another drug study or have been given experimental drugs within the last month.

I have not had major heart, artery, or neck issues, nor seizures or fainting in the past year.

I've had a head injury with unconsciousness over a minute and symptoms afterwards.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either active or sham transcutaneous vagus nerve stimulation daily for 7 days

1 week

7 visits (in-person)

Follow-up

Participants are monitored for changes in PTSD symptoms, functional life quality, and inflammatory biomarkers

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cervical Transcutaneous Vagus Nerve Stimulation

Trial Overview The study tests if non-invasive vagus nerve stimulation (nVNS) can change inflammation markers, brain response to pain stimuli in PTSD patients, and improve their symptoms and life quality. Participants will receive either active nVNS or a sham (fake) version as a comparison.

How Is the Trial Designed?

Group I: Transcutaneous Vagus Nerve Stimulation Active Control 1 Intervention

Cervical Transcutaneous vagus nerve stimulation. Participants will undergo once daily cervical transcutaneous vagus nerve stimulation.

Group II: Sham Vagus Nerve Stimulation Placebo Group 1 Intervention

Sham Cervical Transcutaneous Vagus Nerve Stimulation. Participants will undergo once daily sham cervical transcutaneous vagus nerve stimulation.

Cervical Transcutaneous Vagus Nerve Stimulation is already approved in United States for the following indications:

Approved in United States as VNS Therapy System for:

• Treatment-resistant depression
• Epilepsy

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Published Research Related to This Trial

Transcutaneous Vagus Nerve Stimulation (tcVNS) significantly reduced PTSD symptoms by 31% compared to sham treatment over three months, indicating its potential efficacy as a therapeutic intervention.

tcVNS effectively blocked stress-induced increases in the inflammatory marker IL-6, suggesting that its mechanism of action may involve reducing inflammation associated with PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress. Bremner, JD., Wittbrodt, MT., Gurel, NZ., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Transcutaneous cervical VNS (tcVNS) significantly reduces sympathetic responses to acute stress in patients with PTSD, as evidenced by decreased heart rate and improved vascular function during stress exposure.

The study involved 25 participants and demonstrated that tcVNS not only helps with stress related to traumatic memories but also has positive effects during mental stress, indicating its potential as a therapeutic intervention for PTSD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial. Gurel, NZ., Wittbrodt, MT., Jung, H., et al.[2023]

In a study involving 15 PTSD patients, active transcutaneous cervical Vagus Nerve Stimulation (tcVNS) significantly improved paragraph recall performance after two months, indicating potential benefits for memory function in PTSD (p < 0.05).

While active tcVNS showed trends of improved accuracy and recall in working memory tasks, these results were not statistically significant, suggesting that further research is needed to confirm the efficacy of tcVNS in enhancing cognitive functions in PTSD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of transcutaneous cervical vagus nerve stimulation on declarative and working memory in patients with Posttraumatic Stress Disorder (PTSD): A pilot study. Choudhary, T., Elliott, M., Euliano, NR., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive and cost-effective method for modulating the vagus nerve, making it a promising alternative to traditional surgical vagus nerve stimulation.

taVNS allows for easy and safe administration, with considerations for proper electrode placement and individual dosing based on perception thresholds, which enhances its potential for treating various central and peripheral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. Badran, BW., Yu, AB., Adair, D., et al.[2020]

Transcutaneous vagus nerve stimulation (tVNS) shows promise for treating various conditions in pediatric patients, but current studies lack specific protocols and justification for its use in this age group, as none of the 15 identified studies focused exclusively on children.

There are no dedicated tVNS devices for pediatric use, and existing studies do not adequately address neurodevelopmental considerations, highlighting the need for more research on age-appropriate stimulation parameters and protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation in Pediatric Patients: A Systematic Review of Clinical Treatment Protocols and Stimulation Parameters. Sigrist, C., Torki, B., Bolz, LO., et al.[2023]

Transcutaneous cervical vagal nerve stimulation (tcVNS) was shown to enhance brain activation in areas associated with trauma processing, such as the anterior cingulate and hippocampus, during exposure to traumatic stress reminders in a study of 22 participants.

Compared to sham stimulation, tcVNS resulted in significant changes in brain activity, suggesting it may help reverse neurobiological alterations linked to PTSD, potentially improving autonomic control and offering a new treatment avenue for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Cervical Vagal Nerve Stimulation Alters Brain Activity During Traumatic Stress in Individuals With Posttraumatic Stress Disorder. Wittbrodt, MT., Gurel, NZ., Nye, JA., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7739181/

Transcutaneous cervical vagal nerve stimulation reduces ... The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD.

2. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0165032723008625

Effect of transcutaneous cervical vagus nerve stimulation ... These preliminary results suggest that tcVNS improves attention, declarative and working memory, which may improve quality of life and productivity for ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05517304

Transcutaneous Vagal Nerve Stimulation in Veterans With ... This study effects the effects of transcutaneous cervical vagal nerve stimulation (tcVNS) or a sham control on brain, physiology, and PTSD symptoms in Veterans ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8580056/

A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 ... We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of ...

5. frontiersin.org frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1456662/full

Accrued reductions in heart rate following transcutaneous ... tcVNS induces accrued reductions in heart rate for participants with PTSD, potentially suggesting a temporary reduction of chronic cardiac arousal associated ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1935861X25000609

Vagus nerve stimulation therapy for treatment-resistant PTSD VNS therapy was safe and feasible to deliver. •. After therapy, all participants no longer met the criteria for PTSD diagnosis. •.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03858985

Vagal Nerve Stimulation to Probe Inflammation and Brain ... Such outcomes may provide additional evidence of potential treatment efficacy, thus ultimately provide therapies that enhance VA clinical practice guidelines.