Creatine for MECFS, Fibromyalgia, & Long COVID

Historically, creatine supplementation has been reserved for athletes. For many decades, professional and amateur athletes have supplemented with creatine to improve strength gains and augment performance and recovery. Countless studies have supported the supplement for these purposes for more than 150 years. New research illustrates the many other properties of creatine, suggesting supplementation may be beneficial in ME/CFS, depression, long COVID, and fibromyalgia.

Creatine is found abundantly in skeletal muscle but also in the brain. Dietary sources of creatine can contribute to body stores with regular milk, meat, and fish consumption. A pound of uncooked fish or beef contains 1-2 g of creatine but is partially degraded with cooking. Creatine is metabolized to creatinine and excreted in the urine.

*As an aside, serum creatinine is a common laboratory measurement predictive of kidney function. Do not confuse creatine with creatinine. Those with a high meat intake, strenuous weight lifting, or creatine supplementation may have elevated levels of serum creatinine. This, however, is not completely indicative of kidney damage and one must also consider the rate of kidney filtration. Creatinine may increase with certain medications, fever, or inflammatory conditions. There is a large body of evidence and a long history of safety surrounding creatine supplementation and kidney health. Routine kidney function testing may be warranted in those with a renal disease history.

Creatine is Good for the Mitochondria  

Creatine is a good supplement option for conditions characterized by mitochondrial dysfunction. Creatine is an excellent alternate energy source for the cell’s powerhouse, the mitochondria. Its effects on the mitochondria are two-fold; protective and enhancing. It acts as an antioxidant, quenching free radicals and lactic acid. Creatine is converted to phosphocreatine (PCr) by the enzyme creatine kinase, which is found in the inner mitochondrial membrane. This PCr can be stored and contributes to a cellular energy (ATP) pool.

Creatine also helps stabilize the mitochondrial membrane by increasing cardiolipin—a protein that acts as scaffolding for the delicate mitochondrial membrane. It also interacts with a protein associated with mitochondrial permeability—the mitochondrial permeability transition pore (MPTP). This pore controls influxes of calcium into the mitochondria. Excess calcium influx leads to mitochondrial dysfunction and death. Creatine inhibits this pore to preserve mitochondria. The MPTP is implicated in several neurological conditions—brain injury, Parkinson’s, stroke, etc. In these conditions, the MPTP is stimulated to promote mitochondrial dysfunction and death. Individuals with traumatic brain injury who received creatine for 6 months and showed significant improvement in communication, cognition, personality/behavior, and self-care as compared to individuals who did not receive creatine.

Creatine Problems in ME/CFS

A 2019 study from Dr. Nacul’s group found reduced serum creatine kinase (CK) concentrations in severe ME/CFS compared to less severe cases. This enzyme is typically increased in serum due to skeletal muscle injury (CK-MM) or cardiac muscle injury (CK-MB). It is no surprise that there would be more muscle injury (more CK-MM in serum) due to rapid muscle loss of bed rest in severe ME/CFS. Here, measured levels of this important enzyme were markedly reduced in skeletal muscle but not cardiac muscle. A 2010 study of 14 ME/CFS patients found plasma creatine kinase levels (measured from muscle biopsy), before and after an exercise challenge, to be low in patients. These two studies suggest insufficiency of the important energy system enzyme. Supplemental creatine does raise tissue creatine levels in muscle as well as in the brain.

Creatine for Pain in Fibromyalgia  

Creatine may lessen muscle pain and soreness in fibromyalgia by scavenging lactic acid. Lactic acid build-up also occurs in some subsets of ME/CFS as a consequence of post-exertion. This happens to me! Since creatine can be stored, it also may provide a boost in energy for those with chronic fatigue syndrome. A 16-week double-blind, randomized control study in fibromyalgia patients showed creatine supplementation increased intramuscular phosphocreatine content by ~80% (more ATP available) and improved lower- and upper-body muscle function, with some additional effects in general symptoms.

Creatine May Benefit Long COVID

Creatine is suggested in those with long COVID to improve mitochondrial function, reduce oxidative stress, and provide alternate energy sources. A small study showed improved respiratory function following 3 months of creatine supplementation. It also helped reduce fatigue in another study from the same group. Clinical trials are summarized below…

Creatine & Severe ME/CFS 

The muscle atrophy that occurs with prolonged bed rest and immobility of ME/CFS, may be mitigated with creatine supplementation. Studies in those immobilized due to fractures show a reduced amount of muscle atrophy and better insulin sensitivity with supplementation. Another interesting study showed increases in peak oxygen uptake following creatine supplementation in those immobilized due to spinal cord injury. Meta-analyses of creatine supplementation in the elderly show consistent improvement in muscle mass, strength, and bone mineral density when combined with some degree of resistance training. Those with severe ME/CFS who struggle with mobility may consider supplementation with gentle stretching or isometric exercises as mentioned in an earlier post.

Creatine & Depression

Perhaps most fascinating about creatine is that it also has neuroprotective properties. Creatine can be synthesized in the brain, and it can cross the blood-brain barrier via specific creatine transporters. In the brain, it plays a major role in ATP/ADP balance by providing a steady phosphorous group to ADP to replenish ATP. In addition to an energy substrate, creatine can be released from neurons and function as a neurotransmitter.

In animal studies and human clinical studies of depression, there have been detectable changes in creatine and its enzymes and metabolites. Most, but not all, studies show lower levels of creatine in depressed individuals. Those taking tricyclic or selective serotonin reuptake inhibitors (SSRIs) may positively influence creatine levels in the brain. These medications seem to affect the action of the enzyme creatine kinase. The anti-depressive effects of these medications are enhanced by creatine supplementation in some studies.  

Animal studies have shown that creatine can interact with dopamine and serotonin systems in the brain. It also seems to inhibit NMDA receptors, resulting in lower levels of the highly excitatory glutamate. In this way, creatine may reduce neuroinflammation by blocking excess glutamate from producing nitrosative and oxidative stress.  

Consider these clinical studies: 

• A small parallel‐group, randomized placebo‐controlled double‐blind trial of those 12 individuals with long COVID were given creatine monohydrate (4g per day) for 6 months. Tissue sampling showed increases in creatine and this correlated with improvements in symptoms. (Slankamenac J et al., 2023)

• A case study of a 52-year-old woman who suffered from post-traumatic stress disorder, depression, and fibromyalgia who was not responsive to treatment with citalopram experienced improvement in depressive symptoms and fibromyalgia lasting up to 8 weeks after the end of supplementation (Amital et al., 2006). 

• 8 unipolar and 2 bipolar patients with treatment-resistant depression treated for 4 weeks with creatine significantly improved their symptoms, and 1 patient had improvement after just 1 week (Roitman et al., 2007). 

• 5 female adolescents with continued depression despite fluoxetine, used creatine as an adjunct for 8 weeks and exhibited increased brain creatine and significant depression improvement (Kondo et al., 2011).

• Improvement in depressive symptoms in a group of 52 women who received creatine and escitalopram for 8 weeks. These effects were seen as early as week 2 into treatment and were maintained at weeks 4 and 8 when compared to the placebo group (Lyooet al., 2012).

Bottom Line:

There’s no question that more study is needed. But these small studies are all promising! No study I reviewed while writing this showed adverse effects of creatine supplementation or kidney insult. Let’s summarize the potential benefits of creatine:

• Potent antioxidant in the brain and the periphery

• Source of ATP

• Protective to mitochondria

• Reduces neuroinflammation

• Improved memory and cognition

How to Take

Many forms of creatine are on the market (visit the FullScript Store for a selection). Yet, there is no consensus that any form is better than the traditional, inexpensive creatine monohydrate. Some may experience water retention with creatine supplementation. This is because it acts in the muscle to increase glycogen, which harbors water. In general, alkaline creatine supplements should not cause water retention.

The International Society of Sports Nutrition has stated that creatine supplementation up to 30 g/day for 5 years is safe and well-tolerated in healthy individuals and several patient populations ranging from infants to the elderly. For those with chronic disease, 10–30 g per day is suggested to offset deficiencies or provide therapeutic benefit. The highest range is also suggested for severe post-viral conditions to facilitate muscle health.

References

Wallimann T, Tokarska-Schlattner M, Schlattner U. (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids.40(5):1271-96. doi: 10.1007/s00726-011-0877-3. Epub 2011 Mar 30.

Pazini, F. L., Cunha, M. P., & Rodrigues, A. L. S. (2018). The possible beneficial effects of creatine for the management of depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry.

Alves CR, et al. (2013) Creatine supplementation in fibromyalgia: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res (Hoboken). 65(9):1449-59.

Ostojic SM. Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome. Nutrients. 2021;13(2):503. Published 2021 Feb 4. doi:10.3390/nu13020503

Kreider, R. B. et al. (2017). International Society of Sports Nutrition position stand: safety and efficacy of creatine supplementation in exercise, sport, and medicine. Journal of the International Society of Sports Nutrition, 14(1).

Slankamenac J, Ranisavljev M, Todorovic N, Ostojic J, Stajer V, Ostojic SM. Effects of six-month creatine supplementation on patient- and clinician-reported outcomes, and tissue creatine levels in patients with post-COVID-19 fatigue syndrome. Food Sci Nutr. 2023;11(11):6899-6906. Published 2023 Sep 20. doi:10.1002/fsn3.3597

Slankamenac J, Ranisavljev M, Todorovic N, Ostojic J, Stajer V, Ostojic SM. Creatine supplementation combined with breathing exercises reduces respiratory discomfort and improves creatine status in patients with long-COVID. J Postgrad Med. Published online December 7, 2023. doi:10.4103/jpgm.jpgm_650_23