Today let’s decode creatine. Not the creatine of gym lore, the stuff that makes you look slightly more inflated after a week and causes everyone to drink three extra litres of water. The creatine that is starting to appear in peer reviewed research on ME/CFS, Long COVID and post-exertional malaise. It turns out the mechanism behind why creatine helps athletes recover from exercise is directly relevant to why people with these conditions struggle to recover from, well, existing.
I should say upfront that I go to the gym (though mainly to walk on the treadmill and write these articles). My partner, who has PoTS, does not currently go to the gym in the way I do. The irony of creatine being the supplement most associated with people who want to lift heavy things, turning out to be potentially relevant to people who crash after lifting a cup of tea, is not lost on me.
Why creatine matters at a cellular level
Creatine’s job in the body is to help maintain energy supply during periods of high demand. It does this by replenishing phosphocreatine, a rapidly available energy reserve that the cell uses to regenerate ATP, the molecule that powers essentially everything the body does. When you exercise, phosphocreatine stores get depleted. In healthy people, they replenish relatively quickly. Supplementing with creatine increases the pool of phosphocreatine available, which is why it became a staple of sports nutrition.
In ME/CFS and Long COVID, something goes wrong with this energy system at a much more fundamental level. Studies consistently show that patients have lower creatine and phosphocreatine levels in both skeletal muscle and the brain compared to healthy controls. The mitochondria, which are supposed to produce ATP efficiently through oxidative phosphorylation, are not functioning properly. The body falls back on less efficient anaerobic pathways, which deplete energy faster and produce lactic acid as a byproduct. This is part of why even minor exertion triggers the cascade we decoded in our PEM piece: the system is running on empty before the activity even starts, and the crash afterwards reflects a body that has genuinely run out of the cellular currency it needs to function.
If the problem is partly a depleted phosphocreatine pool and impaired energy metabolism, supplementing with creatine is at least a biologically plausible intervention. It’s not a cure. It’s not addressing the underlying immune dysregulation or mitochondrial damage. But it might help the cell cope better with the energy crisis that exertion triggers.
What the studies actually show
A 2024 feasibility study published in Nutrients gave 14 ME/CFS patients 16g of creatine monohydrate daily for six weeks and used brain MRI spectroscopy to measure creatine levels in two regions of the brain before and after supplementation. Creatine levels in the brain increased measurably. Participants also reported improvements in fatigue, cognitive function and grip strength, though this was a small study without a placebo control, which limits how much we can conclude from the symptom data.
A separate 2024 randomised controlled trial took a more targeted approach, combining 8g creatine with 3g of glucose, the rationale being that glucose helps transport creatine into cells more efficiently. The creatine-glucose combination produced large effect sizes for reducing difficulties concentrating and body aches in Long COVID patients, with an effect size of 0.80 for concentration and 1.33 for body aches, which are genuinely substantial numbers. Adding glucose outperformed creatine alone for elevating brain creatine levels, which is an interesting finding given that brain fog is one of the most consistent and debilitating features of these conditions.
Most recently, a 2025 trial found that just four weeks of 6g per day creatine supplementation significantly reduced fatigue scores and increased peripheral grip strength in Long COVID patients. A June 2025 review specifically on creatine and post-viral fatigue syndrome concluded that impaired creatine metabolism is a key contributor to the bioenergetic disruption seen in these conditions, and that supplementation shows genuine promise.
What we still do not know
The ME Association reviewed the 2024 MRS study and made a fair point: it was a small study without a placebo control, which means we cannot rule out placebo effect for the symptom improvements, even if the brain creatine changes were objectively measured. No large, properly powered, double-blind randomised controlled trial of creatine in ME/CFS has yet been conducted. The optimal dose, duration, and whether combining with glucose is necessary are all open questions. And crucially, we do not know whether creatine helps with PEM specifically, or whether it simply reduces baseline fatigue without affecting how the body responds to exertion.
There is also a practical concern specific to this patient population: some people with ME/CFS and Long COVID report that high doses of creatine initially worsen symptoms, possibly because any intervention that shifts cellular metabolism can be destabilising in an already dysregulated system. Starting low and increasing slowly, under clinical supervision, seems to be the sensible approach if anyone is considering it.
What this means practically
Creatine monohydrate is one of the most studied and safest supplements available. It is inexpensive, widely accessible, and has a well established safety profile across decades of sports science research. The emerging evidence for its role in ME/CFS and Long COVID is genuinely interesting and mechanistically coherent. It is not yet at the level of a clinical recommendation, but it is at the level of something worth discussing with your clinician, particularly if fatigue and brain fog are prominent features of your presentation.
The cell does not know whether its phosphocreatine stores are depleted because you did deadlifts or because you had a conversation that lasted too long. In both cases, it needs the same thing to recover. The question the research is still answering is whether supplementation actually helps bridge that gap when the underlying energy system is as compromised as it is in these conditions.
The answer so far is: possibly yes, in some people, at the right dose. Which in a field with very few treatment options is not nothing.
The views and opinions expressed in Dysautonomia Decoded are my own and do not represent those of my employer or any affiliated organisation.
References
Holwerda AM, et al. Six-week supplementation with creatine in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a magnetic resonance spectroscopy feasibility study at 3 Tesla. Nutrients. 2024;16(19):3308. https://doi.org/10.3390/nu16193308
Kakagia D, et al. Eight-week creatine-glucose supplementation alleviates clinical features of long COVID. Journal of Nutritional Science and Vitaminology. 2024;70(2):174–178. https://doi.org/10.3177/jnsv.70.174
Twomey R, et al. Creatine and post-viral fatigue syndrome: an update. Journal of the International Society of Sports Nutrition. 2025. https://doi.org/10.1080/15502783.2025.2517278
Santos et al. Creatine supplementation reduces fatigue and increases grip strength in Long COVID patients. 2025.
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