Sham control importance and trial blinding

The vagus nerve, also known as the Great Nerve, connects the brain to all parts of the body, like an internet (Figure below). Every week we’re learning more about its importance for health and disease. Until recent years the brain and immune system were thought to be in separate “firewalled” compartments. But that turned out to be far from the truth.

Dr. Kevin Tracey, who directs the Feinstein Institute at Northwell Health, has been studying the vagus nerve for more than 3 decades. In the early 1990’s he made the seminal observation that stimulating the vagus reduces the inflammatory cytokine known as tumor necrosis factor (TNF), what he described at the time as a “holy s**t” moment. In 2025 he published the book THE GREAT NERVE with many rich patient anecdotes and the history for how this field developed.

I wrote about the brain-immune axis previously on Ground Truths, spotlighting the vagus nerve’s role. That included much more on depth of the pathways if you are interested.

We discussed the recent FDA July approval for refractory rheumatoid arthritis (RA)(unresponsive to medications or intolerance to medical therapy) based on a sham-controlled randomized trial published in December 2025 in Nature Medicine. It is striking that the benefits were derived from 1 minute of vagal stimulation per day. That stimulation is barely perceived (tingling, many not at all) by device recipients. The surgery takes one hour to implant the tiny stimulator device along side the vagus nerve in the neck.

But this is much bigger than a treatment for RA. It is now being tested for lupus, Crohn’s disease, and other autoimmune conditions. That’s beyond the role vagus nerve stimulation (VNS) has played for epilepsy and depression, independent of VNS’s anti-inflammatory impact (Tracey named it “the inflammatory reflex”).

We also discussed handheld VNS devices, potential use for Long Covid and POTS, cold plunges, heart rate variability, stress, and other topics related to the vagus nerve and parasympathetic nervous system (the brakes, “rest and digest” as opposed to the sympathetic nervous system (the gas, “fight or flight”).

Most people are not aware of this device approved treatment for an autoimmune disease. Our treatments are so drug-centric but they are immunosuppressive, have important side-effects, and are expensive. It’s good to see a non-drug approach get compelling data as an alternative. Moreover, as I recently wrote about, there’s a shift ongoing from treatment to cures vs autoimmune diseases that will be adding to the mix.

Here are some very recent papers about the vagus nerve to give you a sense about how its prominence is getting appreciated more all the time

Gut-brain-vagus axis for reward circuit and addiction, 30 Jan 2026, Science Advances

Randomized trial of VNS for depression , Int J of Neuropsychopharm 2026

The vagus nerve role in heart function after a heart attack, Cell, February 2026

Vagus receptors and hemorrhage, blood volume, Nature, 28 Jan 2026

A Quick Poll

Thank you Harshi Peiris, Ph.D., Tay MacIntyre, David Dansereau, MSPT, Max Manwaring-Mueller, RJ, and over 600 others for tuning into my live video with Kevin J. Tracey, MD! Join me for my next live video with Robert Wachter Feb 4th, 12:30 PM PT in the app.

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