Treating illness through the vagus nerve

How far is vagus nerve stimulation from wider use beyond epilepsy and depression?

Implanted vagus nerve stimulation is FDA-approved for epilepsy (1997), for adjunctive long-term treatment of chronic or recurrent depression (2005), for upper-limb motor deficits after chronic ischaemic stroke (2021) and for moderately to severely active rheumatoid arthritis (2025). A non-invasive handheld device is cleared for acute migraine pain. For several of the newer approvals the public evidence is limited. The FDA depression supplement record does not describe its supporting trial, and a later one-year trial with inactive-device controls (RECOVER) did not meet its primary endpoint. The rheumatoid arthritis evidence reported so far comes from one sham-controlled trial, with a 3-month primary result and open-label follow-up.

AI illustration · Illustrative scene, not a photograph of the specific device or experiment.
WHERE WE AREPilots

Close. Early pilots are running in the real world.

Implanted devices are approved for several indications, so the approval step is no longer open. Use outside epilepsy is recent or limited. The stroke and rheumatoid arthritis approvals are new, and for depression the controlled evidence is mixed: the 2005 supplement record does not describe its supporting trial, and the later RECOVER trial missed its primary endpoint. The stage is pilot rather than scaling because wide routine use beyond epilepsy has not been shown in the sources reviewed.

The tech tree

Everything recorded on Vrulum that this future needs, oldest foundations at the top and the goal at the bottom. Lines show what each step requires.

What it takes: Treating illness through the vagus nerve Unlocked Being researched Locked
  1. 1997Vagus nerve stimulationCommercial Unlocked.
  1. 1997Implanted vagus nerve stimulation approved for epilepsyDone Unlocked.
  2. 2005Implanted vagus nerve stimulation approved for depressionDone Unlocked.
  3. 2018Non-invasive vagus nerve stimulation cleared for acute migraineDone Unlocked.
  4. 2021Implanted vagus nerve stimulation approved for stroke rehabilitationDone Unlocked.
  5. 2024Controlled evidence for depression beyond the approvalDone Unlocked.
  6. 2025Implanted vagus nerve stimulation approved for rheumatoid arthritisDone Unlocked.
  7. Date not recordedSham-controlled proof for non-invasive use across headache endpointsIn progress Being researched.
  8. Date not recordedControlled evidence beyond rheumatoid arthritis and strokeNot started Locked.
  1. GoalTreating illness through the vagus nerveGoalRequires: Vagus nerve stimulation, Implanted vagus nerve stimulation approved for epilepsy, Implanted vagus nerve stimulation approved for depression, Controlled evidence for depression beyond the approval, Implanted vagus nerve stimulation approved for stroke rehabilitation, Implanted vagus nerve stimulation approved for rheumatoid arthritis, Non-invasive vagus nerve stimulation cleared for acute migraine, Sham-controlled proof for non-invasive use across headache endpoints, Controlled evidence beyond rheumatoid arthritis and stroke. Locked.

The road so far

6 of 8 steps done, 1 in progress.

  1. Done · 16 Jul 1997Implanted vagus nerve stimulation approved for epilepsy

    The FDA premarket approval record for the VNS Therapy System (PMA P970003) shows a decision date of 16 July 1997, with the generic device name 'stimulator, autonomic nerve, implanted for epilepsy'. [1]

  2. Done · 15 Jul 2005Implanted vagus nerve stimulation approved for depression

    FDA supplement S050 to PMA P970003 shows approval on 15 July 2005 for 'adjunctive long-term treatment of chronic or recurrent depression' in adults aged 18 and over with a major depressive episode who have not had an adequate response to four or more antidepressant treatments. The supplement record does not describe the trial that supported it, and it does not say that the device description changed. [2][1]

  3. Done · 18 Dec 2024Controlled evidence for depression beyond the approval

    The one-year RECOVER trial enrolled 493 adults at 84 US sites in its treatment-resistant depression arm, with about half randomised to active devices and half to devices that were not stimulating. Its primary measure, the share of time with relief of depressive symptoms, showed no significant difference between the groups. Researchers said the inactive group improved more than expected, and that all participants knew devices would be switched on at the end of the year, which may have affected the control group's responses. Many secondary measures, including quality of life, showed significant benefit with active stimulation. [8]

  4. Done · 27 Aug 2021Implanted vagus nerve stimulation approved for stroke rehabilitation

    The FDA approved the Vivistim Paired VNS System on 27 August 2021 for moderate to severe upper-limb motor deficits associated with chronic ischaemic stroke. The News-Medical article describes a trial of 108 patients (53 treated, 55 control) at 19 clinical sites in the US and UK. The device went through the premarket approval pathway and received Breakthrough Device designation. The trial's main results are not restated here, as the full paper was not opened. [5]

  5. Done · 30 Jul 2025Implanted vagus nerve stimulation approved for rheumatoid arthritis

    The FDA record for the SetPoint System (PMA P240039) shows approval on 30 July 2025 for adults with moderately to severely active rheumatoid arthritis and an inadequate response, loss of response or intolerance to one or more biological or targeted synthetic DMARDs. The FDA page does not name the trial. Healio reports the RESET-RA trial of 242 patients, which used a sham control, with an ACR20 response at 3 months of 35.2% with active stimulation against 24.2% with sham (P = .0209). [3][4]

  6. Done · 29 Jan 2018Non-invasive vagus nerve stimulation cleared for acute migraine

    The FDA cleared an expanded label for the gammaCore handheld device for acute treatment of pain associated with migraine in adults, according to the manufacturer's press release dated 29 January 2018. The company reports that the pivotal PRESTO trial met some secondary endpoints, but not the 2-hour pain-free primary endpoint (30.4% vs 19.7%, P = .067). The clearance is for symptom treatment, not prevention. [6]

  7. In progressSham-controlled proof for non-invasive use across headache endpoints

    Results for non-invasive stimulation are mixed. A post hoc analysis of the PRESTO trial reported that 46.8% of patients on active stimulation had at least a 1-point pain reduction at 120 minutes, against 26.2% with sham (P = 0.002). The authors state that these end points are not the previously reported primary or key secondary end points. Preventive use has been studied in sham-controlled trials, but those results were not verified in this review, so the sources reviewed do not show that this use is established. [7][6]

  8. Not startedControlled evidence beyond rheumatoid arthritis and stroke

    The sources reviewed include no approved use or controlled trial of vagus nerve stimulation for other inflammatory diseases, and none for mood outside the depression indication. Trials of this kind would be needed before routine use. [3][4]

Why it matters

If stimulating the vagus nerve can treat conditions with few good options, such as drug-resistant depression or inflammatory disease, it could offer treatment that does not rely on drugs. Whether it does depends on controlled trials that separate the device's effect from expectation and from the sham response, which is the part of the evidence that is still unsettled.

What stands in the way

  • The depression evidence is mixed: the RECOVER trial missed its primary endpoint, with researchers pointing to a larger than expected improvement in the inactive group, and the 2005 supplement record does not describe its supporting trial.
  • The rheumatoid arthritis evidence reported so far comes from one sham-controlled trial (RESET-RA). The 3-month difference from sham was about 11 percentage points, and the 6- and 12-month results come from open-label follow-up without a control group.
  • The stroke rehabilitation evidence reported so far is a single trial of 108 patients, and the sources reviewed do not report its long-term outcomes.
  • The non-invasive device's trial results are mixed. Its pivotal acute migraine trial did not meet its 2-hour primary endpoint, according to the manufacturer's press release.

Signals to watch

  • A controlled trial of the rheumatoid arthritis device that reports results beyond 3 months with a sham or randomised comparison.
  • Independent replication of the stroke rehabilitation benefit in a larger or later trial.
  • Replication of the RECOVER result, or a new controlled depression trial with a clearer sham arm.
  • Non-invasive device trials that prespecify and meet a preventive endpoint in a sham-controlled design.
  • Trials of vagus nerve stimulation in another inflammatory disease with a control group.

Sources

  1. government report
    VNS Therapy System, PMA P970003
    US Food and Drug Administration, 16 Jul 1997.
  2. government report
    VNS Therapy System, PMA P970003, supplement S050 (depression)
    US Food and Drug Administration, 15 Jul 2005.
  3. government report
    SetPoint System, PMA P240039
    US Food and Drug Administration, 30 Jul 2025.
  4. news
    Vagus nerve stimulator shows ongoing efficacy in rheumatoid arthritis
    Rob Volansky. Healio, 4 Feb 2026.
  5. news
    FDA approves drug-free stroke rehabilitation system to treat upper extremity motor deficits
    News-Medical, 27 Aug 2021.
  6. company announcement
    gammaCore receives FDA clearance for the acute treatment of pain associated with migraine headache in adult patients
    electroCore, LLC (company press release), 29 Jan 2018.
  7. peer reviewed paper
    Practical and clinical utility of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: a post hoc analysis of the randomized, sham-controlled, double-blind PRESTO trial
    Licia Grazzi, Cristina Tassorelli, Marina de Tommaso. The Journal of Headache and Pain, 19 Oct 2018.
  8. university press release
    Vagus nerve stimulation relieves severe depression
    Washington University in St. Louis (Source), 18 Dec 2024.

Last reviewed 21 Oct 2026.