Wirth & Scheibenbogen (2026)
- Authors: Klaus J. Wirth, Carmen Scheibenbogen
- Institutes: Mitodicure GmbH, Kriftel, Germany, Institute of Medical Immunology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Publisher: Preprints.org
- Link: DOI
Summary
This paper provides a comprehensive neurobiological framework that connects neurological symptoms and physical exhaustion to a fundamental imbalance in neurotransmitter regulation. By viewing ME/CFS as a state of brain and muscle overstimulation, it offers a scientific rationale for why treatments like low-dose naltrexone 💊 or pyridostigmine 💊 can be beneficial. This model helps move the clinical understanding of the disease from subjective complaints to a measurable disturbance of the central and autonomic nervous systems.
What was researched?
This review investigates how an imbalance between excitatory and inhibitory neurotransmitter systems contributes to the complex symptoms of ME/CFS and Long COVID.
Why was it researched?
The research aims to explain the paradoxical “wired but tired” state, sensory hypersensitivities, and skeletal muscle dysfunction by moving beyond the simple sympathetic-parasympathetic model.
How was it researched?
The authors synthesized evidence from neuroimaging, autoantibody studies, and metabolomics to evaluate dysregulation in noradrenaline, glutamate, GABA, and serotonin systems. They also analyzed the mechanisms of drugs such as clonidine 💊, aripiprazole 💊, and SSRIs 💊 to assess their potential for rebalancing these systems.
What has been found?
The study identifies a shift toward excitatory neurotransmission (glutamate, noradrenaline) over inhibitory signaling (GABA, serotonin), which promotes brain overactivation and sensory hypersensitivity. In muscles, this imbalance leads to hyperexcitability, calcium overload, and mitochondrial dysfunction, contributing to cramps and post-exertional malaise. Pharmacological agents like dextromethorphan 💊, memantine 💊, or lorazepam 💊 may partially address these issues by restoring the neurotransmitter equilibrium.
Discussion
Evidence for some systems, such as histamine and glycine, remains hypothetical and requires further research. The high interindividual variability in neurotransmitter profiles likely explains why single-drug therapies often show inconsistent efficacy across the patient population.
Conclusion & Future Work
Targeted investigation into individual neurotransmitter abnormalities is necessary for future care. The authors propose that ME/CFS management should evolve toward personalized “rebalancing” strategies that address the specific neurobiological profile of each patient.