Taking creatine as a supplement for 6 months appears to significantly improve clinical features of post–COVID-19 fatigue syndrome (PVFS or long COVID), a small randomized, placebo-controlled, double-blinded study suggests.
Researchers, led by Jelena Slankamenac, with Applied Bioenergetics Lab, Faculty of Sport and PE, University of Novi Sad, Serbia, published their findings in Food, Science & Nutrition .
“This is the first human study known to the authors that evaluated the efficacy and safety of supplemental creatine for fatigue, tissue bioenergetics, and patient-reported outcomes in patients with post–COVID-19 fatigue syndrome,” the authors write.
They say the findings may be attributed to creatine’s “energy-replenishing and neuroprotective activity.”
Significant reductions in symptoms
Researchers randomized the 12 participants into two groups of 6 each. The creatine group received 4 g creatine monohydrate per day, while the placebo group received the same amount of inulin.
At 3 months, dietary creatine supplements produced a significant reduction in fatigue, compared with baseline values ( P = .04) and significantly improved scores for several long COVID–related symptoms, including loss of taste, breathing difficulties, body aches, headache, and difficulties concentrating) ( P < .05), the researchers report.
Intervention effect sizes were assessed by Cohen statistics, with a d of at least 0.8 indicating a large effect.
Among highlights of the results were that patients reported a significant 77.8% drop in scores for concentration difficulties at the 3-month follow-up (Cohen’s effect, d = 1.19) and no concentration difficulties at the 6-month follow-up (Cohen’s effect, d = 2.46).
Total creatine levels increased in several locations across the brain (as much as 33% for right parietal white matter). No changes in tissue creatine levels were found in the placebo group during the trial.
“Since PVFS is characterized by impaired tissue bioenergetics ..., supplemental creatine might be an effective dietary intervention to uphold brain creatine in post–COVID-19 fatigue syndrome,” the authors write.
The authors add that creatine supplements for long COVID patients could benefit organs beyond the brain as participants saw “a significant drop in lung and body pain after the intervention.”
Unanswered questions
Some experts said the results should be interpreted with caution.
“This research paper is very interesting,” says Nisha Viswanathan, MD, director of the long COVID program at University of California, Los Angeles, “but the limited number of patients makes the results difficult to generalize.”
Dr. Viswanathan, who was not part of the study, pointed out that the patients included in this study had a recent COVID infection (under 3 months).
“Acute COVID infection can take up to 3 months to resolve,” she says. “We define patients with long COVID as those with symptoms lasting greater than 3 months. Therefore, these patients could have had improvements in their fatigue due to the natural course of the illness rather than creatine supplementation.”
Alba Azola, MD, assistant professor in the department of physical medicine and rehabilitation at Johns Hopkins University, Baltimore, said she also was troubled by the window of 3 months for recent COVID infection.
She said she would like to see results for patients who have ongoing symptoms for at least 6 months after infection, especially given creatine supplements’ history in research.
Creatine supplements for other conditions, such as fibromyalgia and chronic fatigue syndrome, have been tested for nearly 2 decades, she pointed out, with conflicting findings, something the authors acknowledge in the paper.
“I think it’s premature to say (creatine) is the key,” she says. She added that the small sample size is important to consider given the heterogeneity of patients with long COVID.
That said, Dr. Azola says, she applauds all efforts to find treatments for long COVID, especially randomized, controlled studies like this one.
No major side effects
No major side effects were reported for either intervention, except for transient mild nausea reported by one patient after taking creatine.
Compliance with the intervention was 90.6% ± 3.5% in the creatine group and 95.3% ± 5.0% in the control group (P = .04).
Participants were eligible for inclusion if they were 18-65 years old, had a positive COVID test within the last 3 months (documented by a valid polymerase chain reaction [PCR] or antigen test performed in a COVID-19–certified lab); had moderate to severe fatigue; and at least one additional COVID-related symptom, including loss of taste or smell, breathing trouble, lung pain, body aches, headaches, or difficulties concentrating.
The authors acknowledge that they selected a sample of young to middle-aged adults experiencing moderate long COVID symptoms, and it’s unknown whether creatine is equally effective in other PVFS populations, such as elderly people, children, or patients with less or more severe disease.
Senior author Dr. Sergei Ostojic serves as a member of the Scientific Advisory Board on creatine in health and medicine (AlzChem LLC). He co-owns a patent for “Supplements Based on Liquid Creatine” at the European Patent Office. He has received research support related to creatine during the past 36 months from the Serbian Ministry of Education, Science, and Technological Development; Provincial Secretariat for Higher Education and Scientific Research; Alzchem GmbH; ThermoLife International; and Hueston Hennigan LLP. He does not own stocks and shares in any organization. Other authors declare no known relevant financial interests. Dr. Viswanathan and Dr. Azola report no relevant financial relationships.