Research Update articles are produced in order to keep practitioners up to date on impactful research that is relevant to the field of integrative medicine. These articles may contain summaries of recent studies, events, or other industry news that advances current knowledge and standards of care.
The following article summarizes the research conducted by Castro-Marrero et al. titled, “Effect of dietary coenzyme Q10 plus NADH Supplementation on fatigue perception and health-related quality of life in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: A prospective, randomized, double-blind, placebo-controlled trial,” which was published in Nutrients an Open Access Journal from MDPI in 2021. (5)
Myalgic encephalomyelitis, commonly referred to as chronic fatigue syndrome (ME/CFS), is a highly debilitating neurological condition affecting millions of people worldwide. (3)(5) ME/CFS is a multifaceted condition with a wide array of symptoms, including sleep problems, extreme fatigue, muscle pain, orthostatic intolerance, problems with memory, and worsening symptoms after physical or mental activity, amongst many others. (5)(11) Unfortunately, many individuals are left undiagnosed due to the fact that there are no accurate medical tests for diagnosing or universal treatment for the condition. (5)(11) This study was conducted to assist in rectifying the latter by testing the effectiveness of coenzyme Q10 (CoQ10) and NADH on the perceived fatigue, unrefreshing sleep, and quality of life experienced by these patients. CoQ10 and NADH are powerful antioxidants and key components to the electron transport chain responsible for mitochondrial adenosine triphosphate (ATP) production. (5) Mitochondrial dysfunction and increased oxidative stress have been linked to numerous illnesses including ME/CFS, explaining the interest in testing these specific nutraceuticals. (2)
The study included female participants recruited from a single outpatient tertiary referral center from January 2018 to December 2019. To be eligible for this study, participants had to have a confirmed ME/CFS diagnosis according to the 1994 CDC/Fukuda case definition. The Fukuda definition defines chronic fatigue as “self-reported persistent or relapsing fatigue lasting 6 or more consecutive months” and requires a clinical evaluation to identify or rule out medical or psychological conditions that could explain the chronic fatigue’s presence. (6) All participants signed a written consent form and were 18 years of age and older. The trial’s criterion excluded some of the registrants from participation such as those with any medical conditions relating to chronic fatigue, a history of neuropsychiatric disorders, and hypersensitivities to CoQ10 and NADH.
The study was conducted as a 12-week randomized, double-blind, placebo-controlled trial. The participants (n= 207) were divided into two groups, each of which took four enteric-coated tablets a day for eight weeks. The placebo group received 20 mg of phosphatidylserine and 40 mg of vitamin C, while the experimental group received 50 mg of CoQ10 and 5 mg of NADH as well as excipients (20 mg of phosphatidylserine and 40 mg of vitamin C) per tablet.
The primary outcome was to identify any changes in fatigue scores using the Fatigue Impact Scale (FIS-40) from baseline to the final follow-up, which was reassessed three months later. The FIS-40 is a self-reported assessment which comprises 40 items divided into three domains that describe how perceived fatigue impacts cognitive (ten items), physical (ten items), and psychosocial functioning (20 items) over the previous four weeks. (5)
The secondary outcome measured changes in health-related quality of life and changes in sleep disturbances. The health-related quality of life was also self-reported and measured using the 36-item Short Form Health Survey (SF-36) and the HRQoL questionnaires. Meanwhile, changes in sleep disturbances were reported via the Pittsburgh Sleep Quality Index (PSQI), a self-assessment examining changes in the seven domains of sleep quality.
The patient-reported outcomes were assessed at baseline and reassessed at week four and eight in addition to four weeks post treatment.
This study demonstrated that CoQ10, taken in conjunction with NADH, was effective in reducing overall fatigue perception and cognitive fatigue. In addition, demonstrating a positive effect on sleep quality which, in conjunction with perceived fatigue, increases health-related quality of life in patients with ME/CFS.
Changes in cognitive-perceived fatigue outlook improved; however, improvements were clinically insignificant (3.27% and 3.30% FIS-40 reduction) at the four and eight weeks from baseline to follow-up within the active group. On the other hand, the psychosocial domain showed statistically insignificant improvements (2.07% FIS-40 reduction) within the active group at week four. Additionally, the FIS-40 domain scores evolved in a parallel between the groups over the course of the study. (5) This resulted in reductions from baseline but no relevant statistical differences between the groups.
Changes in sleep quality between groups demonstrated a positive difference in the active group at four weeks post treatment (13.45% increase). Additionally, the PSQI domains from baseline over time were not statistically or clinically significant.
Results from the SF-36 questionnaire demonstrated no significant differences between groups, although there were statistically better scores in the active group at both follow-up visits (8.78% and 17.01% increase). Additionally, bodily pain improved at the four-week follow-up (19.91% increase). There was also a reduction in energy and fatigue in the placebo group four weeks post treatment (15.31% decrease). However, in the final analysis, the results were not statistically significant.
This study was one of the first to assess the effectiveness of CoQ10 with NADH on a vast number of ME/CFS patients. The strengths of the study were the number of participants (n = 207), the fact that they were all chosen based on the same definition criteria of ME/CFS (1994 CDC/Fukuda), and the recruitment of age and sex matched participants (considering the mitochondrial function decline within same sex). The age and sex of the participants were considered because there are sex-associated differences in mitochondrial function. More specifically, mitochondrial complexes I, I+II, and IV, as well as uncoupled respiration and electron transport system capacity in peripheral blood mononuclear cells isolated from blood samples of females are higher compared to males. (12)
There are also limitations to the study, such as the subjectiveness of the results through self-reported questionnaires and the biases in the sample (all Caucasian women from the same referral center).
In addition, the results demonstrated that the placebo/excipient (phosphatidylserine and vitamin C) may have been the cause of the lack of statistical differences between the groups. This may be due to the fact that vitamin C functions as a cofactor, enzyme complement, co-substrate, and a potent antioxidant in various reactions and metabolic processes. (1) More specifically, supplementation with vitamin C assists in reducing fatigue and attendant symptoms such as sleep disturbances, depressive symptoms, pain, and cognitive disorders caused by oxidative stress and inflammation. (14) To provide antioxidant protection, the Recommended Dietary Allowance (RDA) for vitamin C in adult women is 75 mg per day; the placebo dose given in the study was 40 mg, which is more than half of the RDA. (10)
Phosphatidylserine is a major phospholipid component found in healthy neuronal tissues, membranes, and myelin sheath. (7) It is especially important in supporting cognitive function by helping to improve concentration and short- and long-term memory, while simultaneously enhancing mood and reducing stress levels. (4)(8) Consequently, it is able to affect the results of the study as supplementation with a phosphatidylserine has been observed to normalize stress induced dysregulations such as those caused by ME/CFS. (8)
Similarly, CoQ10 is also a potent antioxidant that scavenges free radicals and reduces levels of lipid peroxidation via the reduction of pro-oxidative compounds. (13)
The bottom line
This research study is an important step in finding a universal treatment for ME/CFS patients. The study demonstrated the potential to reduce cognitive fatigue and overall fatigue perception with the use of CoQ10 and NADH over a two-month period. In addition, it demonstrated that the use of these supplements in ME/CFS patients is well tolerated at the given dosages. Furthermore, using a placebo such as starch will be useful in future studies because it does not have the same mechanism of action as CoQ10 and NADH. (9)
This study can be used to help propel future related studies to improve patient outcomes by challenging the effectiveness of these supplements with additional objective physiological and biological indicators.
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- Anderson, G., & Maes, M. (2020). Mitochondria and immunity in chronic fatigue syndrome. Progress in neuro-psychopharmacology & biological psychiatry, 103, 109976. https://doi.org/10.1016/j.pnpbp.2020.109976
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- Castro-Marrero, J., Segundo, M. J., Lacasa, M., Martinez-Martinez, A., Sentañes, R. S., & Alegre-Martin, J. (2021). Effect of Dietary Coenzyme Q10 Plus NADH Supplementation on Fatigue Perception and Health-Related Quality of Life in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial. Nutrients, 13(8), 2658. https://doi.org/10.3390/nu13082658
- Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington (DC): National Academies Press (US); 2015 Feb 10. 3, Current Case Definitions and Diagnostic Criteria, Terminology, and Symptom Constructs and Clusters. Available from: https://www.ncbi.nlm.nih.gov/books/NBK284898/
- Glade, M. J., & Smith, K. (2015). Phosphatidylserine and the human brain. Nutrition (Burbank, Los Angeles County, Calif.), 31(6), 781–786. https://doi.org/10.1016/j.nut.2014.10.014
- Hellhammer, J., Vogt, D., Franz, N., Freitas, U., & Rutenberg, D. (2014). A soy-based phosphatidylserine/ phosphatidic acid complex (PAS) normalizes the stress reactivity of hypothalamus-pituitary-adrenal-axis in chronically stressed male subjects: a randomized, placebo-controlled study. Lipids in health and disease, 13, 121. https://doi.org/10.1186/1476-511X-13-121
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- Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington (DC): National Academies Press (US); 2000. 5, Vitamin C. Available from: https://www.ncbi.nlm.nih.gov/books/NBK225480/
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- Silaidos, C., Pilatus, U., Grewal, R. et al. Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain. Biol Sex Differ 9, 34 (2018). https://doi.org/10.1186/s13293-018-0193-7
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- Vollbracht, C., & Kraft, K. (2021). Feasibility of Vitamin C in the Treatment of Post Viral Fatigue with Focus on Long COVID, Based on a Systematic Review of IV Vitamin C on Fatigue. Nutrients, 13(4), 1154. https://doi.org/10.3390/nu13041154