Intervention with Supplemental Creatine Found Effective, Safe for Symptom Reduction After COVID-19 Infection


At a 6-month follow-up, supplemental creatine intervention significantly improved scores for fatigue symptoms and tissue bioenergetics related to COVID-19 infection.

Post-viral fatigue syndrome (PVFS) is a long-term neurological disorder that is known for hindering patients’ abilities to be involved in routine activities after viral infections. PVFS, formerly known as chronic fatigue syndrome or myalgic encephalomyelitis, can last longer than 6 months and is characterized by fatigue, post-exertional malaise, and poor sleep.

Woman experiencing fatigue

Image credit: brizmaker |

During the COVID-19 pandemic, an association was found with PVFS after COVID-19 infection, however, there are few strategies to combat this onset of fatigue. To address this issue, a study published in Food Science & Nutrition evaluated the efficacy and safety of medium-term supplemental creatine when used to treat fatigue and tissue bioenergetics, as well as prevalence and severity of patient- and clinician-outcomes in patients with post-COVID-19 fatigue syndrome.

This parallel-group, placebo-controlled, double-blind trial randomized 12 participants into 2 groups, an experimental group (creatine, 6 participants) and a control group (placebo, 6 participants). The creatine group received a 4g dose of creatine monohydrate per day whereas the placebo group received an equivalent amount of insulin. Treatment lasted 6 months, and patients were asked to stop taking any dietary supplements during the trial’s duration. The primary outcome measured was the change in vastus medialis creatine levels from baseline to the 6-month follow-up. Fatigue was measured by a self-report and 5 aspects of fatigue—general fatigue, physical fatigue, reduced motivation, reduced activity, and mental fatigue—were calculated and scored.

The participants involved were aged 18 to 65 years and tested positive for COVID-19 within 3 months prior to the start of the trial. These patients experienced moderate to severe fatigue and at least 1 additional COVID-19-related symptom (eg, lung pain, difficulty breathing, anosmia, ageusia, body aches, headaches, difficulty concentrating).

When compared to baseline values, the results presented a significant increase in tissue creatine levels in vastus medialis muscle and right parietal white matter at both 3- and 6-month follow-ups (p < .05). Further, no changes in tissue creatine values were present in the placebo group.

Time versus intervention compared by 2-way analysis of variance (ANOVA) showed a significant difference between interventions in tissue creatine levels (p < .05), with the creatine group showing higher creatine levels at vastus medialis muscle, left frontal white matter, and right parietal white matter compared to the placebo group. Further, a non-significant trend for interaction effect between interventions was reported in other areas including right frontal white matter, right paracentral gray matter, left parietal white matter, and left parietal mesial gray matter (p ≤ .20).

In addition, creatine had significantly reduced general fatigue after 3 months of intervention, with the scores for reduced motivation worsening after 6 months in the placebo group. There weren’t any significant interaction effects found between interventions across the 5 subdomains of fatigue during the trial; however, a strong trend interaction was demonstrated for reduced motivation toward creatine improving the fatigue subdomain, whereas placebo did the opposite.

The time to exhaustion had increased after 6 months of creatine administration (baseline, 894 ± 121 s; 6-month follow-up, 959 ± 94 s, p = .10). Although it didn’t significantly influence anosmia and lung pain, creatine had improved visual analogue scale scores for multiple symptoms related to PVFS compared to baseline values. In the placebo cohort, body ache and headache mean scores were lower at the 3- and 6-month follow-ups, respectively.

Further, strong effect sizes of creatine (d ≥ 0.8) had demonstrated increased brain levels in thalamus (3 months, 0.82), right frontal white matter (3 months, 1.25; 6 months, 1.32), right paracentral gray matter (3 months, 0.88), left parietal white matter (3 months, 0.92; 6 months, 1.17), parietal white matter (3 months, 1.99; 6 months, 1.74), left parietal mesial gray matter (6 months, 0.84), and right parietal mesial gray matter (3 months, 1.17; 6 months, 1.06). In addition, creatine had decreased mental fatigue (6 months, 1.02), anosmia (3 months, 0.97; 6 months, 1.02), ageusia (3 months, 1.23; 6 months, 1.29), breathing difficulties (3 months, 0.89; 6 months, 1.25), lung pain (6 months, 0.99), body aches (3 months, 1.77; 6 months, 3.03), headache (3 months, 1.17; 6 months, 1.26), and difficulties concentrating (3 months, 1.19; 6 months, 2.46). Except for 1 patient who experienced nausea, participants who received intervention with creatine did not present any adverse effects.

Limitations include the limited population that was studied, the inability to account creatine intake from a regular diet that could influence the total net exposure to creatine, and the habitual physical activity that can impact tissue uptake of creatine. Further, it is unknown whether creatine is just as effective in other PVFS populations that weren’t evaluated in the study (eg, elderly, children, patients with less or more severe COVID-19 infection). Further research is needed to confirm findings in additional post-COVID-19 cohorts, according to the study authors.


Slankamenac J, Ranisavljev M, Todorovic N, et al. 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;n/a. doi:10.1002/fsn3.3597

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