This review examines how creatine—a natural substance in the body that helps muscles produce energy—may be abnormal in people with post-viral fatigue syndrome (PVFS, which includes ME/CFS and long COVID). The authors looked at whether creatine supplements or related compounds might help reduce fatigue and improve function in these conditions. While some studies suggest creatine could be helpful, the review shows we still need more research to know if it actually works.
Why It Matters
ME/CFS and post-COVID fatigue currently lack diagnostic biomarkers and approved treatments. If creatine metabolism abnormalities are confirmed to play a role in these conditions, supplementation could represent a low-cost, accessible therapeutic avenue worth investigating further in rigorous clinical trials.
Observed Findings
Creatine metabolism irregularities are documented in various PVFS populations, including alterations in brain creatine levels, impaired phosphocreatine resynthesis rates in skeletal muscle, and abnormal blood creatine kinase concentrations.
Some patient-reported outcomes and clinician-reported measures have shown improvement in chronic fatigue syndromes following creatine supplementation in select studies.
Creatine analogs and related guanidino compounds appear to modulate fatigue-related outcomes in certain syndromes with chronic fatigue.
Inferred Conclusions
Creatine metabolism disturbances may represent a treatable biomarker or therapeutic target in PVFS and post-COVID-19 fatigue.
Dietary creatine supplementation warrants further investigation as a potential adjunctive therapy, though more rigorous clinical trials are needed before clinical recommendations can be made.
Post-COVID-19 fatigue may share some metabolic features with earlier PVFS presentations, suggesting creatine-focused research could benefit this growing patient population.
Remaining Questions
What is the optimal creatine dose, duration, and formulation (monhydrate vs. analogs) for ME/CFS or PVFS patients?
Do creatine metabolism abnormalities correlate with severity of fatigue or post-exertional malaise, and could they serve as diagnostic or prognostic biomarkers?
What This Study Does Not Prove
This review does not prove that creatine supplementation is an effective treatment for ME/CFS or PVFS—it identifies metabolic abnormalities and summarizes preliminary evidence. The review does not establish causation between creatine metabolism disturbances and fatigue symptoms, nor does it provide definitive dosing or safety recommendations. Results from preliminary studies do not yet demonstrate efficacy in large, well-controlled patient populations.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →