Review Imbalance of Excitatory and Inhibitory Neurotransmitter Systems in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2026, Wirth & Scheibenbogen

[John Mac]

Abstract​

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and post-COVID-19 syndrome share a symptom profile, including severe fatigue, cognitive dysfunction, exertional intolerance, sleep disturbances, hypervigilance, and the paradoxical state of being “wired but tired.”

A well-established finding is sympathetic hyperactivity with reduced vagal tone, typically interpreted as autonomic nervous system dysfunction. Emerging evidence, however, suggests a broader disturbance across multiple neurotransmitter systems.

This paper reviews current knowledge on neurotransmitter systems implicated in ME/CFS and Long COVID, focusing on potential mechanisms of dysregulation and their roles in disease pathology and symptom generation, as well as implications for treatment.

In addition to abnormalities of the noradrenergic system, disturbances in serotonergic, GABAergic, and glutamatergic signaling have been reported. Contributing factors may include autoimmunity, neuroinflammation, gut dysbiosis, epigenetic influences, and stressors such as orthostatic intolerance, metabolic strain, and pain.

A shift toward excitatory over inhibitory neurotransmission may cause brain overactivation, autonomic dysfunction, sensory hypersensitivity, sleep–wake disruption, and cognitive impairment.

Reduced GABAergic tone combined with increased glutamatergic and noradrenergic activity may elevate skeletal muscle tone, contributing to calcium overload, mitochondrial dysfunction, exertional intolerance, and post-exertional malaise.

Various pharmacological treatments may partially rebalance these neurotransmitter systems, but limited efficacy highlights the need for systematic investigation and individualized strategies.

https://www.preprints.org/manuscript/202601.2170

 

[Dude]

"Reduced GABAergic tone"
This may explain why some patients report significant benefit from lorazepam (benzos). I personally notice a clear effect. I am unsure whether the benefit is equally strong in moderately affected patients.

 

[neophyte32]

Along with Ron Davis, Carmen Scheibenbogen is probably the most well-known researcher... Has she ever proven anything or made a major discovery in MECFS? Do you think her antibody theory is viable? The same goes for Wirth... it's all pure speculation, at least that's my impression.

 

[Haveyoutriedyoga]

"Reduced GABAergic tone"
This may explain why some patients report significant benefit from lorazepam (benzos). I personally notice a clear effect. I am unsure whether the benefit is equally strong in moderately affected patients.

I find myself sitting with my feet on the floor rather than having them rest on the sofa, and walk about a bit more, when I occasionally take it. It has been discussed in more detail on other threads too - not sure under what headings.

 

[neophyte32]

I find myself sitting with my feet on the floor rather than having them rest on the sofa, and walk about a bit more, when I occasionally take it. It has been discussed in more detail on other threads too - not sure under what headings.

For me too. Benzo is a huge help for my MECFS. It helps all my symptoms.

 

[Creekside]

In addition to abnormalities of the noradrenergic system, disturbances in serotonergic, GABAergic, and glutamatergic signaling have been reported.

Have been reported, but what about verification of those claims?

Contributing factors may include autoimmunity, neuroinflammation, gut dysbiosis, epigenetic influences, and stressors such as orthostatic intolerance, metabolic strain, and pain.

May, and may not. There's no real evidence supporting or contradicting their involvement in ME.

While some of those things may be involved in ME, or may be involved with symptom severity (but not directly part of ME) in a percentage of PWME, to me it reads as pure speculation. I think if you gave an AI a request to create theories based on all available papers on ME, it could create hundreds, some quite ridiculous, but with as much supporting evidence--or lack thereof. Also with as much or as little clinical testability (the basis of science).