Creatine for Chronic Fatigue Syndrome

In a thought-provoking keynote at the Creatine Conference 2025, Prof. Sergej M. Ostojic, MD, PhD—a leading expert in creatine research and head of the Applied Bioenergetics Lab—delved into the potential of creatine supplementation for managing chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis (ME) or post-viral fatigue syndrome (PVFS). Drawing from emerging research, including his recent narrative review published in the Journal of the International Society of Sports Nutrition, Ostojic highlighted how creatine might address bioenergetic disruptions in this debilitating condition. With over 320 peer-reviewed articles to his name, Ostojic’s presentation updated findings from 2022, emphasizing the surge in studies post-COVID-19. This blog post summarizes the key takeaways from his talk, blending scientific insights with practical implications for those affected by CFS.

 

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Understanding Chronic Fatigue Syndrome: A Persistent Mystery

Chronic fatigue syndrome has puzzled researchers since its first documented outbreak in 1950 on Iceland’s Akureyri island, where 465 cases presented flu-like symptoms without typical infection markers, leading to prolonged fatigue, muscle soreness, and sleep issues. Today, CFS is classified by the World Health Organization (ICD-11 code 8E49) as a neurological condition, affecting up to 7.6% of the population—predominantly women and adults. Diagnosis often relies on patient interviews rather than biomarkers, as no gold-standard tests exist.

Core symptoms include unrelenting fatigue lasting at least six months, post-exertional malaise (worsening symptoms after minimal activity, lasting over 24 hours), cognitive impairment (“brain fog”), unrefreshing sleep, muscle pain, sore throat, and tender lymph nodes. The condition’s economic toll is staggering: estimates from Harvard Business School and JAMA pegged costs at $2.6 trillion in 2020, rising to $3.7 trillion by late 2024, encompassing direct medical expenses and lost productivity. The NIH has invested heavily, with $1.15 billion in 2021 and $515 million in 2024 for the RECOVER initiative to uncover diagnostics and treatments.

Despite over 48,000 published papers—many in the last five years, spurred by long COVID—no cure exists. Patient advocacy groups like the International Association for Chronic Fatigue Syndrome and the American ME/CFS Society play crucial roles in support and awareness.

Unraveling the Causes: From Viruses to Energy Shortfalls

Ostojic outlined multifaceted potential triggers for CFS, including viral infections (linked to coronaviruses long before COVID-19), autoimmune responses, family history, immune abnormalities, sleep disturbances, psychiatric factors, and bioenergetic issues. A key focus was mitochondrial dysfunction—an impairment in cellular energy production—that may underlie the profound fatigue.

Similarities with long COVID are striking, though the latter may include unique symptoms like loss of smell or taste. Overall, CFS remains “mysterious and perplexing,” with no approved treatments, underscoring the need for innovative approaches like creatine supplementation.

The Role of Creatine: Addressing Metabolic Disturbances

Creatine, a natural compound essential for energy homeostasis, emerged as a central theme. Ostojic discussed disturbances in creatine metabolism observed in CFS patients:

• Blood creatine kinase (CK) levels are often normal or slightly elevated, but not diagnostic.
• Magnetic resonance spectroscopy (MRS) reveals lower ATP levels post-exercise, altered phosphocreatine (PCr) during activity, slower PCr resynthesis, and reduced creatine-to-PCr ratios at rest.
• Brain studies show diminished creatine in areas like the pregenual anterior cingulate cortex (pgACC) and dorsolateral prefrontal cortex (DLPFC), linked to cognitive symptoms; choline-to-creatine ratios are also affected in long COVID.
• Heart assessments in small cohorts indicate lower PCr-to-ATP ratios and delayed recovery, suggesting cardiac involvement.
• Urinary biomarkers in related conditions like fibromyalgia show elevated creatine loss, correlating with pain severity.
• Ostojic’s own lab found reduced creatine in muscle, thalamus, and brain matter in 90 long COVID patients, associating lower levels with worse myalgia.

 

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These findings position creatine as a potential diagnostic tool and therapeutic target, as it helps recycle ADP to ATP and acts as an energy buffer in mitochondria. Evidence from Studies: Promising Results in CFS and Related Conditions

Recent trials, many post-2020, support creatine’s benefits:

• A 6-week open-label study with 16g daily creatine monohydrate in 14 ME/CFS patients increased brain creatine in pgACC and DLPFC, reduced fatigue, improved Stroop test reaction times (congruent and incongruent trials), and boosted hand-grip strength—without side effects.
• In long COVID, an 8-week RCT with 8g creatine plus glucose improved body aches, breathing issues, concentration, headaches, and malaise, alongside elevated brain creatine versus placebo.
• A 3-month RCT with 4g creatine in 12 long COVID patients reduced general fatigue and extended walking time to exhaustion.
• Fibromyalgia studies show creatine lessens muscle pain by scavenging lactic acid, which builds up post-exertion in CFS subsets.
• Older research, like a 6-week low-dose (2.3g/day) trial, enhanced fatigue resistance during high-intensity contractions without weight gain.

Ostojic noted these studies, while encouraging, are small and call for larger, placebo-controlled trials. Creatine appears safe, with no major adverse effects reported in these contexts.

Mechanisms, Safety, and Future Directions

Creatine supports mitochondrial function, reduces oxidative stress, and provides an alternative energy source, potentially mitigating PEM and brain fog. It may also protect against muscle atrophy in immobilized patients and improve insulin sensitivity.

Safety profiles from decades of use in sports and health show creatine is well-tolerated, though Ostojic stressed monitoring in chronic conditions. Future research should explore dosages (e.g., 4-16g/day), durations, forms (monohydrate vs. others), and combinations (e.g., with omega-3s or exercise). Long-term efficacy, diverse populations, and impacts on mood, immunity, and cognition need investigation.

Final Thoughts: A Step Toward Hope

Prof. Ostojic’s presentation underscores creatine’s potential as a simple, accessible intervention for CFS, backed by growing evidence of its role in bioenergetics. While not a cure, it offers promise for symptom relief in a field desperate for options. Patients should consult healthcare providers before starting supplementation, and researchers must prioritize robust trials. As Ostojic leads the Creatine Global Initiative, expect more advancements—stay tuned for updates from events like the Creatine Conference.

Disclaimer: This summary is based on the presentation and related research; it’s not medical advice.