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December 8, 2004

Chronic Fatigue Syndrome and the Cholinergic Hypothesis

Author Affiliations

Letters Section Editor: Robert M. Golub, MD, Senior Editor.

JAMA. 2004;292(22):2723. doi:10.1001/jama.292.22.2723-a

To the Editor: While the study by Dr Blacker and colleagues1 demonstrates that galantamine is not an effective treatment for persons with chronic fatigue syndrome (CFS), I do not believe that this negative outcome represents an appropriate test of the cholinergic hypothesis in the pathogenesis of CFS.

Soreq and Seidman2 and Brenner et al3 have demonstrated in animal models of posttraumatic stress disorder and in Gulf War syndrome (a possible syndromic relative of CFS) that cholinergic neurons produce sustained and excessive amounts of AChE-R, an altered soluble variant of acetylcholinesterase. There is evidence that the sustained production of AChE-R derails the cholinergic neurons from performing their normal “signal-to-noise ratio” determination role in healthy brain function.4 If there is a cholinergic contribution to the pathogenesis of CFS, it would likely be the dysregulated production of AChE-R. The failure of galantamine to favorably influence the outcome of this syndrome could then be predicted because, being a cholinesterase inhibitor, it is likely inducing overproduction of AChE-R.