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Thanks to Dr. Craig for providing more insights into diets and supplements that may be able to support people with chronic fatigue syndrome (ME/CFS), long COVID, and allied diseases. Creatine – long known to sports nutritionists – begs the question why the ME/CFS and long-COVID fields haven’t looked more closely at compounds athletes use to increase athletic performance. Happily in Dr. Craig, we have someone well acquainted with this compound – she did her Master’s Thesis on it. With a spate of recent studies coming out on it, it was a good time to dig deeper into it.
THE GIST
- Creatine has been used for decades to provide more energy for athletes but is not being explored as a possible treatment option in diseases like ME/CFS, fibromyalgia, and long COVID, as well as neurological diseases. Dr. Craig did her Master’s Thesis on creatine, and with a spate of recent studies coming out on it, it was a good time to dig deeper into it. Thanks to Dr. Craig for the blog.
- Creatine is particularly interesting for energy-depleting diseases like ME/CFS, FM and long COVID because it serves as an alternative energy source for mitochondria, the cell’s powerhouse, offering both enhancing and protective effects.
- Creatine plays a key role by helping recycle ADP back into ATP and acts like a sensor of the cell’s energy state. It also helps to stabilize the mitochondria, helps plug “leaks” in the mitochondria, regulates calcium levels in the mitochondria, and functions as an antioxidant.
- Altered creatine levels have been found in the brains, blood, and urine of ME/CFS and/or FM patients. One study suggested that creatine was being used up more rapidly than usual in ME/CFS.
- Treatment trials have used from 4-20 grams of creatine a day in ME/CFS and/or long COVID. In general, higher levels appear to have had better results. Some improvements have included reduced body aches, breathing problems, concentration problems, headaches, and general malaise as well as an increase in brain creatine levels.
- Creatine monohydrate usually comes as a powder that is mixed into a liquid. It poorly dissolves in water so is often mixed with a small amount of juice – and the addition of this glucose source also helps absorption in the intestine.
- Side effects are rarely reported, but taking large amounts all at once can lead to gastrointestinal stress, nausea, or stomach ache, so care should be taken to titrate up as tolerated. Dr. Craig recommends that people with ME/CFS, FM, and long COVID start very low and go slow.
- According to the International Society of Sports Nutrition, creatine supplementation of up to 30 grams per day for 5 years is considered safe and well-tolerated in both healthy individuals and various patient groups, from infants to the elderly.
- Athletes use creatine with protein powder, branched-chain amino acids, and beta-alanine.
Creatine Monohydrate
Creatine has been used to improve athletic performance for years.
Creatine monohydrate has long been popular among athletes as a go-to supplement for enhancing strength, performance, and recovery. Decades of research back its effectiveness in these areas. However, recent studies are shedding light on creatine’s broader potential. Beyond athletic performance, creatine supplementation may offer promising benefits for conditions linked to mitochondrial dysfunction and also neurodegenerative diseases like ALS and Parkinson’s.
This is because creatine serves as an alternative energy source for mitochondria, the cell’s powerhouse, offering both enhancing and protective effects. Given the many studies that have found mitochondrial problems in diseases like chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and long COVID, this makes creatine an interesting compound indeed.
Creatine – Indirect Mitochondrial Energy Source
Adenosine triphosphate (ATP) is the main energy source in cells, but only a small amount is stored at a time. Energy is created from this molecule when ATP breaks down into adenosine diphosphate (ADP) and inorganic phosphate (Pi). Creatine plays a key role by helping recycle ADP back into ATP and acts like a sensor of the cell’s energy state.
Creatine can also be stored. Inside the mitochondria, the enzyme creatine kinase converts creatine into phosphocreatine (PCr), which can be stored and used to replenish cellular energy (ATP) as needed. Around 95% of the body’s creatine is stored in muscle cells, with the remaining amount distributed in the brain, and heart. These are cell types with high energy demands. Storing creatine here ensures rapid energy availability when needed. High-energy immune cells like macrophages and neutrophils also heavily rely on this stored creatine for quick energy.
Creatine – Mitochondrial Stabilizer
Creatine helps protect the mitochondria by boosting cardiolipin, a specialized fat molecule found in the inner membrane of mitochondria. Cardiolipin acts like a structural scaffold that keeps components in the mitochondrial membrane in place for proper function. By raising cardiolipin levels, creatine helps enhance mitochondrial function and stability.
Cardiolipin is also essential for oxidative phosphorylation (the process by which cells produce ATP) because it supports the structure and function of key protein complexes involved in the mitochondria’s electron transport chain (ETC). Cardiolipin stabilizes these complexes, allowing efficient transfer of electrons through the ETC. This process creates an electrical gradient across the mitochondrial membrane, which drives ATP production.
Without proper cardiolipin levels, the ETC function becomes impaired, reducing the efficiency of ATP production and compromising overall cellular energy. Higher cardiolipin levels contribute to improved mitochondrial health and can boost energy metabolism, making creatine useful in conditions that involve energy deficits, such as ME/CFS.
While it’s not clear exactly what’s happening in the ETC in ME/CFS, problems with two of the five complexes have been found.
Creatine – “Leaky” Mitochondria Supporter
Creatine may be able to tighten up leaky mitochondria.
Creatine also works closely with a protein called the mitochondrial permeability transition pore (MPTP). The MPTP generally should remain closed because its opening can disrupt energy production and lead to cell death. However, in certain controlled situations, temporary MPTP opening can help release excess calcium or remove damaged mitochondria components necessary for cell survival. Prolonged or excessive opening, though, is harmful, as it causes the mitochondria to lose their ability to produce ATP, leading to oxidative stress, energy failure, and, ultimately, cell death.
The MPTP acts like a calcium sensor. Typically, there is more calcium outside the mitochondria than inside. When calcium levels in the mitochondria become too high, it can trigger the opening of the pore. This opening allows molecules to leak out, disrupting the mitochondria’s ability to produce energy. Opening also allows too much calcium to come in, which can damage mitochondria and cause cell death. By stabilizing this pore, creatine helps keep the mitochondria structurally healthy and in calcium balance.
Here again we see a potential ME/CFS link. Klaus Wirth and Mathew Lohn have proposed that overly high calcium levels are playing a major role in the mitochondrial problems found, and a Stanford study recently found significantly increased calcium levels that were associated with reduced ATP production and antioxidant levels.
The MPTP also senses oxidative stress and opens when levels of reactive oxygen species (ROS) become too high. As an indirect antioxidant, creatine helps stabilize this pore by preventing it from opening.
A recent review asserted that high levels of free radicals (reactive oxygen species (ROS)) are responsible for the shift from aerobic energy to anaerobic energy production, and for an immune shift that emphasizes the inflammatory side of the immune system while inhibiting its pathogen-hunting side.
Lastly, the MPTP is also sensitive to changes in lactate, an acidic byproduct of metabolism. Lactate is produced in the cell during glycolysis when oxygen levels are low or energy demand is high, such as during intense exercise. In healthy cells with adequate oxygen, the end product of glycolysis is pyruvate, which is shuttled into the mitochondria to make ATP. In ME/CFS, this process seems to be impaired and more lactate is produced instead of pyruvate. The excess lactate can trigger the MPTP to open.
With all of the ways creatine helps with energy production and mitochondrial function, it is safe to say that those with ME/CFS would have a high demand for creatine.
Creatine Abnormalities in ME/CFS
Brain imaging studies show that individuals with ME/CFS have abnormal brain metabolism. Specifically, they have altered creatine levels in certain brain regions. For example, ME/CFS patients have lower creatine in the parietal cortex but higher creatine in the putamen compared to healthy individuals. These changes and higher brain temperatures suggest location-specific neuroinflammation and mitochondrial dysfunction.
Lower creatine levels in the brain were associated with neuroinflammation in a fibromyalgia study.
Creatine abnormalities are also seen in fibromyalgia, where increased creatine breakdown and higher creatine loss in urine (as creatinine) are linked to fatigue and pain. A positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) study in fibromyalgia found that lower levels of creatine in the brain were associated with higher degrees of neuroinflammation.
Nacul and his team reviewed lab tests from 272 ME/CFS patients and found that those with severe ME/CFS had significantly lower blood creatine kinase (CK) levels compared to healthy controls and milder ME/CFS patients. This finding held true even after adjusting for factors like age and muscle mass.
These findings were also seen in microRNA profiles in the following study: The drop in CK levels could indicate an impaired ability to use creatine, pointing to problems in cellular energy production and mitochondrial dysfunction.
Since creatinine is the end product of creatine metabolism, higher levels of creatinine in the urine may suggest that the body is breaking down and using creatine at a faster rate. Elevated urinary creatinine serves as a marker of increased creatine turnover and energy metabolism issues. A study finding increased 24-hour urinary creatinine clearance in ME/CFS patients suggested that creatine may be being used up at a higher rate than usual – suggesting that creatine supplementation might be helpful.
ME/CFS and Long-COVID Treatment Trials
ME/CFS and long-COVID treatment trials have used from 4-20 grams/day. In general, more has been better, but Dr. Craig recommends that people with ME/CFS start very low and go slow.
Creatine has been the subject of several treatment trials. A 6-week study using 16 grams of creatine monohydrate in 14 ME/CFS patients (CDC criteria) measured subjective factors as well as brain imaging (MRS, magnetic resonance spectroscopy). Supplementation increased brain creatine levels and improved fatigue and some aspects of cognition without producing any side effects. However, this study lacked a comparative placebo group.
More treatment trials have been conducted in long-haul COVID that show promise. An 8-week randomized, controlled trial (RCT) supplementing long-haul patients with 8 g of creatine monohydrate per day (in combination with glucose to improve absorption) resulted in improvements in symptoms including body aches, breathing problems, concentration problems, headaches, and general malaise. Brain imaging also showed increased creatine levels in the treatment group versus the placebo group.
Another small RCT showed improvements in time to exhaustion using a smaller dose (4 gm creatine/day) for 3 months combined with respiratory therapy. No changes, however, were found in fatigue symptoms.
The same group expanded on this study, though, by giving 4 gm of creatine/day for 6 months to long-haul patients. This time the researchers found a significant reduction in general fatigue and improvements in typical long-haul COVID symptoms, including improvements in loss of taste, interestingly enough(!).
Studies using a metabolic precursor of creatine precursor guadinioacteic acid (GAA) have also shown up. Guadinioacteic acid (GAA) is not widely available as a supplement as of yet, but a small randomized control, 3-month ME/CFS trial (with a two-month wash-out) period found no significant changes in fatigue levels but significant increases in muscle creatine stores and increases in muscular strength and aerobic power.
A creatine fibromyalgia randomized controlled trial (RCT) produced similar results. After 16 weeks, creatine supplementation increased the level of phosphocreatine in muscles and enhanced both lower and upper-body muscle function.
An open-label study assessed 16 weeks of supplemental creatine monohydrate (20 grams for 5 days, followed by 5 grams/day for the rest of the trial) in 20 fibromyalgia patients who also received their usual treatments. Significant improvements in fibromyalgia severity, quality of life, sleep, disability, and pain were found. These improvements faded within 4 weeks after stopping creatine supplementation. The study’s conclusions were limited, though, by the small sample size and high dropout rate.
How to Take Creatine Monohydrate
The body produces half of our daily creatine naturally, while dietary sources such as meat, fish, and dairy can contribute to the other half. For instance, a pound of uncooked fish or beef contains about 1-2 grams of creatine. There are no plant-based sources of creatine. This provides yet another reason why plant-based diets are not a good idea for those with ME/CFS.
Creatine monohydrate usually comes as a powder that is mixed into a liquid. It poorly dissolves in water so is often mixed with a small amount of juice – and the addition of this glucose source also helps absorption in the intestine. There are other forms of creatine available but none have been reported to be better than traditional monohydrate. Supplementing with creatine can increase body stores significantly with just a week of use. Taking 4-5 grams/day can increase muscle creatine content by 20–40% and brain creatine content by 5–15%.
Some people may experience water retention when taking creatine. This happens because creatine increases glycogen storage in muscles, which draws in water. Taking large amounts all at once can lead to gastrointestinal stress, nausea, or stomach ache, so care should be used to titrate up as tolerated. However, in the studies referenced, side effects were rarely or never reported.
According to the International Society of Sports Nutrition, creatine supplementation of up to 30 grams per day for 5 years is considered safe and well-tolerated in both healthy individuals and various patient groups, from infants to the elderly.
Athletes use creatine with protein powder, branched-chain amino acids, and beta-alanine.
Can Creatine Trigger a Herx Response?
Yes! Generally any supplement that has immune system effects can potentially trigger a Herxheimer reaction. Creatine has been shown to affect macrophage function via its ability to increase ATP levels. The enhanced energy availability to these immune cells contributes to stronger anti-tumor immunity, primarily driven by the activity of CD8+ T cells. In other cell studies, exposure to creatine seems to affect the production of cytokines and toll-like receptors (TLRs), Because of this, some patients may experience a Herx reaction when supplementing with creatine and should take great care to start very low and slow.
Courtney Craig
Courtney Craig D.C. was first diagnosed with CFS as a teen in 1998 and recovered in 2010 utilizing both conventional and integrative medicine techniques.
Trained as a doctor of chiropractic and nutritionist, she now provides nutrition consulting and blogs about what she’s learned at www.drCourtneyCraig.com/blog.
- Check out her YouTube Channel here.
- Learn more about creatine from Dr. Craig
- Check out more of Dr. Craig’s Health Rising blogs here
Thanks Cort, interesting.
It would be interesting to hear if anyone on this forum has benefited from creatine. The trials sound somewhat promising but certainly not clearcut.
How long do you think amino acids need taking to judge whether or not they might be beneficial? Given how they work, I would have thought 2-3 weeks would be sufficient to know.
My daughter is nearly two weeks in to branched chain amino acids. The rationale behind us trying that relates to kynurenine pathway. No noticeable benefit yet.
I see the Oxford study suggested creatine might need to be taken for 2 months to see benefits, and at a fairly high dose
I agree. More others to weigh into the chat with information/actual experience would be great.
My daughter became unwell at 13. Now 28. We tried BCAA long ago. Who knows if they made a difference …she was given so many other supplements at the same time.
But there are all the indicators that her AAcids are depleted. She prev tested very high for lactate and low for pyruvate … argh.. the human body is far toooo complicated! Very low iron… despite supplementation, no energy and a very warm head! (There’s the brain on fire portion!).
So difficult to deal with… as a patient or a parent!
Thank you Cort!
Apparently, there is some discussion in the body builder scene that Creatine hydrochloride was better absorbable than Creatine monohydrate… Maybe Dr. Craig wants to drop a comment?
It is possible. I haven’t found any literature that one form is better than the other. And the studies highlighted above show that monohydrate is quite effective at increasing muscle and brain creatine stores. Somewhat less effective in the brain since it does not cross the blood-brain barrier as well.
Hi guys,
As a former athlete I have used it. I was also prescribed creatine monohydrate after a back injury at the beginning of my sports career. However I suffered stomach pain from it so stopped taking it.
Since living with ME/CFS and other illnesses (incl. Non hogkin lymphoma in remission) that has resulted in loss of body weight and muscle mass I tried supplementing it on/off in a smaller dosis.
Even weeks and months a time in hope of increasing my energy levels to function.
However unfortunately I didn’t feel any change.
I do believe the mitochondria play a significant role in ME/CFS, fibromyalgia etc. as well as wide spread low grade inflammation throughout the body including the brain.
If the supply or the energy factory (mitochondria) does not function properly, it does not matter which substance you put into the pipeline. Even if creatine helps somewhat at a very high dose, it will only provide some energy in your muscles for a few seconds during exercise. In addition, it causes weight gain because your body retains fluid. Gastrointestinal complaints are also common at high doses.
I took creatine monohydrates for a few months this summer because I had an unexplained weight loss and my fat stores disappeared so I looked awful. This has been thoroughly investigated but no real answer though my stool elastase has dropped from >500 to 241 in 4 years so I think I have a pancreatic issue. They did find I have a 11 mm cyst in my pancreas but they weren’t bothered by its appearance at all or where it was in my pancreas.
I have helped this problem by taking quite a high dose of digestive enzymes and a bile supplement with every meal and a strong digestive enzyme with a snack and have managed to put some weight back on so I don’t look as bad as I did.
The creatine caused fluid retention in my legs and ankles, even at only 2 gms a day or sometimes I took only a quarter of a teaspoon so I stopped taking it. I didn’t feel any benefit in energy or ability to do more physical activity for longer periods of time unfortunately.
I disolved the creatine very easily in my mug of tea first thing in the morning.
Very interesting you took digestive enzymes . I suspect his could help many ME patiënts because there is problem with absorption of fats.
They were very high dose around 12,000,units of lipase with each meal and 4000 lipase with a snack plus high doses of amylase 100,000 units,plus protease 100,000 with a meal (NOW pancreatic enzymes). I had been taking just a typical digestive enzyme for years but they are a tiny dose which obviously did nothing,
I also took 600 mg betaine hcl which I had been taking for years.
I was disappointed the creatine did nothing after I had read such good reports in athletes but as you say if the mitochondrial pathways are broken that would explain it.
I started taking 1 scoop (5 g) of Thorne Creatine (monohydrate) in Nov. 2023 at the age of 72. I started taking it because I noticed that I had less oomph for my daily long walks, and I couldn’t do as many reps of my exercises as I had done before. Yes, aging has its drawbacks. It was three months before I noticed the benefit of easier walks and the ability to do more reps of my exercises, but it did happen, and I’m still taking the creatine. However, taking creatine did NOT prevent me from getting a CFS flare when I unwisely joined a gym in March 2024 and overexercised. I rested as much as I could for 4.5 months before I returned to my normal baseline. If you try creatine and benefit from it as I did, please don’t make the mistake of thinking that you’re now all better! Nevertheless, I’m going to try increasing my daily creatine dose to see what happens.
Very helpful comment, thank you. I’m sorry you had to experience that, but I’m glad you’re back to baseline.
I’ve been taking 5mg daily for many months – no improvement at all.
I was moderate. Creatine def moved the needle for me more that anything i’ve tried for 8 years. i started with two scoops (10g) for about a month, and when i noticed sustained benefits, dropped it down to 5g. It took a few weeks to work. Been on it for 5 months with no side affects. Also take 1.25 mg of LDN but have been on/ff that for years with not great effects on fatigue, just mainly for allergies.
What symptom/s did it help with Joseph?
I’ve tried 5mg of creatinine for 3 months, no change. I’ve tried BCAA for about two months, no change. I’ve tried AXA1125 for
2 and half months, no change.
Tried NAC for many months, no change,
Protein powder shakes, no change
Currently trying LoLa so can’t comment yet.
To me, and reading on forums people with ME/CFS who have tried the amino acids and similar, we had no improvement. So It could be just expensive urine.
However that said, I still would recommend trying it because I have also heard some people claim benefits. And there’s several studies showing benefits. So give it a go for a couple months.
Just don’t buy from Amazon as lots of counterfeit and fake or contaminated products on there as reported several times by Consumer Labs an independent supplement testing company.
Be careful with any supplements due to the lack of regulation and dodgy fillers they put in them.
iHerb have brands that regularly pass testing standards (not all but most) Plus have an independent testing program on selected products
I subscribe to Consumer Labs and often check the test results. There’s so many recalls and warnings of bad products being sold to unwitting customers.
The safest brands are:
NOW,
Dr’s Best,
Lake Avenue,
Pure Encapsulations
Thorne
Blue Bonnet
California Gold
Deva
but be aware they still get caught with incorrect concentrations. Although are pretty good
(Thorne is the safest as is all pharmaceutical grade but you pay for it as is the most expensive)
On creatine see this video
https://www.youtube.com/watch?v=2Wn_1WqQhz0
Dr Paul saladino in his book carnivore code and Dr shawn Baker in his book Carnivore diet both make the point that a carnivore/animal based diet is an excellent way to top up your creatine!
Any thoughts on the Carnivore diet Courtney?
Not a carnivore fan. Too low in fiber and micronutrients. It may have some role on a short-term basis for those with serious gut issues–a bit like a reset. Cannot recommend.
Thanks for responding. What about combining eating bone marrow with a carnivore diet?
https://discover.texasrealfood.com/carnivore-diet/bone-marrow-benefits
Dr Georgia Ede in her new book Change your Diet, change your mind compares the Paleo,Keto, and Carnivore diets and judges the Carnivore diet more positively
For what its worth…Dr Sarah Myhill endorses creatin
I have added creatinine, LOLA and a full range of liposomal amino acids and did notice a difference in my energy and endurance. Unfortunately I started taking all of them around the same time and so didn’t know which was giving me the most advantage. Lately however, I have stopped mainly because all my health ‘routines’ plus house maintenance was becoming a bit too much. I think I’ll start them again. I have to say, the improvement was subtle but noticeable when I discontinued.
Since there is no standardized treatment, stacking supplements to get tiny improvements is the only way I have found to get closer to normal functioning. Meanwhile I have developed additional health issues (like MGUS) so it’s like one step forward and two steps back. Also my POTS has morphed into tachycardia with high rather than low blood pressure. Ah, the joys of getting older!
By the way Cort, I remember you saying you took a tilt table test and ‘failed.’ Me too. I got Peter Rowes book recently and according to him, sometimes it can take up to 29 minutes to show up on a TTT. I don’t know about you, but my test was only about 10 minutes yet I know something is wrong with my autonomic system.
Correction; creatine monohydrate, not creatinine.
I’ve been supplementing with amino acids and cofactors for over a decade now in an effort to combat ME + FMS.
I was formally diagnosed with ME + FMS (Holmes + Wolfe criteria) decades ago.
I’ve found significant success supplementing with amino acids, however; no individual amino acid, by itself, improved my symptoms significantly.
I am not a medical doctor.
My recommendations are purely based in my own anecdotal experience.
I’ve player alchemist while under medical supervision for a very long time now. 🧪 🧫
I’ve had to experiment (still experimenting) with a plethora of amino acid “cocktail blends.”
Creatine is one of the supplements I use.
I use it as a cell volumizer.
There is an “amino acid therapy” image I’d recommend all of you to download via Google images. Source: Dr David Gersten. 🔑
Understanding how to maximize APSORPTION of amino acids is paramount to receiving optimal benefits.
Understanding which systems and organs to target via AA supplementation is pivotal. 🎯
We are comprised of trillions of cells. 🌌
Each micro level individual cell needs mitochondrial energy for the macro level component to function properly. 💯
Amino acids just don’t targets cells, organs, and systems.
Neurotransmitters such as dopamine, serotonin, GABA, and a few others NTs can be significantly affected by amino acid supplementation. 🧠
It is very important that you understand the contraindications that exist between medication 💊 your doctor prescribes for you and amino acids. ⚠️
Amino Acid therapy has improved my QOL tenfold. ✅
Creatine absolutely resolved post exceptional pain. It is the only clear supplement outcome I have ever found, despite being quite cynical when recommended it.
I don’t get it because I have a healthy diet.
However I haven’t tried it for fatigue and am not supplementing on that basis. I might experiment, b it I worry about being supplement dependent.
and creatine causes severe hair loss by elevating DHT level by 30-44%. If balding is an issue, do not use creatine !
I recently started taking creatine monohydrate at a low dose (around 4 grams a day) to help with fatigue from a particularly demanding yard project. I’d heard that creatine could support energy levels, so I added it to my morning shake. After a few days, I noticed a small but clear boost in energy, which was surprising given how ME/CFS usually leaves me wiped out from exertion. Since then, I’ve been slowly increasing the dose (now at about 7 grams daily) with the goal of gradually working up to around 20 grams to see if the effects become even more noticeable.
So far, it seems to help with general fatigue, and I plan to keep taking it and adjusting the dose slowly.
Does anyone know if the study participants (the creatine studies referenced in this article) took all the creatine as one big dose per day, or several smaller doses? I looked up each study, but they just say things like, “8 grams per day,” they don’t talk about dosing. Or any other information about taking large doses of creatine vs. taking smaller doses 2 to 3 x/day? Thanks!