Thiamine-Dependent Dysfunction in ME/CFS: A Clinical Hypothesis and Practical Therapeutic Trial

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystem illness distinguished not simply by fatigue, but by post-exertional malaise (PEM), prolonged recovery after physical or cognitive demand, unrefreshing sleep, cognitive dysfunction, and frequent autonomic or orthostatic manifestations. Its cause remains unresolved, no confirmatory diagnostic biomarker exists, and no specific curative treatment is established. This perspective proposes that clinically important thiamine-dependent dysfunction may account for an unrecognized subset of patients currently diagnosed with ME/CFS. This hypothesis is supported by convergence among the dynamic physiology of ME/CFS, abnormalities reported in energy-related and post-exertional metabolism, the central metabolic roles of thiamine pyrophosphate (TPP), and the broad multisystem phenotype of thiamine-deficiency disorders; symptom overlap alone is insufficient. A non-low whole-blood TPP concentration should not automatically be interpreted as excluding clinically important thiamine-dependent dysfunction. Where the clinical phenotype generates sufficient suspicion, a meaningful clinician-directed therapeutic trial of intramuscular thiamine may be more informative than a modest oral trial or isolated low-intensity parenteral exposure. This paper therefore proposes a practical IM approach and the use of reproducible "target symptoms" to interpret response. The hypothesis is deliberately bounded: ME/CFS is not asserted to be a single disease, all cases are not presumed thiamine-dependent, and therapeutic response alone does not establish etiology.