For the estimated 17–24 million people living with ME/CFS globally — a number swelled by post-COVID long-haulers — the absence of a coherent biological explanation has long frustrated clinicians and patients alike. A new mechanistic review proposes that the condition's most bewildering paradoxes, being simultaneously exhausted yet unable to rest, hypersensitive yet cognitively foggy, may have a unifying neurochemical basis: a systemic tilt toward excitatory over inhibitory neurotransmission.
The review synthesizes evidence implicating at least four neurotransmitter systems in ME/CFS pathology. Beyond the well-documented noradrenergic hyperactivity and reduced vagal tone, the authors map disturbances in serotonergic, GABAergic, and glutamatergic signaling. Crucially, reduced GABAergic inhibitory tone combined with elevated glutamatergic and noradrenergic drive is proposed to create a state of neural overactivation that simultaneously elevates skeletal muscle tension, promotes calcium dysregulation, impairs mitochondrial function, and generates post-exertional intolerance. Upstream contributors identified include autoimmune processes, neuroinflammation, gut dysbiosis, epigenetic modifications, orthostatic stress, and metabolic strain — suggesting the excitatory-inhibitory imbalance is a downstream convergence point rather than a root cause.
This framing carries meaningful implications, though important caveats apply. As a narrative review rather than original experimental data, the paper synthesizes heterogeneous findings across disparate study designs, cohort sizes, and methodologies — a limitation inherent to any field still lacking reliable biomarkers. The proposed glutamate-GABA framework does, however, align with neuroimaging data showing elevated brain glutamate in ME/CFS patients and with the clinical overlap with conditions like fibromyalgia and anxiety disorders that feature similar inhibitory deficits. The direct mechanistic link to Long COVID further elevates relevance, suggesting shared pathophysiology across post-infectious syndromes. For researchers, this review is less paradigm-shifting than it is a useful consolidating framework — one that points toward GABAergic and glutamatergic pathways as underexplored therapeutic targets worth rigorous prospective investigation.
