Lipid Replacement Therapy with a Glycophospholipid Formulation, NADH, and CoQ10 Significantly Reduces Fatigue and Improves Mood and Cognition in Intractable Fatiguing Illnesses

and Chronic Lyme Disease

by Garth L. Nicolson, PhD; Robert Settineri, MS; and Rita Ellithorpe, MD, ND

Chronic fatigue is the most common complaint of patients seeking general medical care.^1,2 It occurs naturally during aging, and it is also an important symptom in many chronic diseases.^1–3 In the last few years, natural supplements have been used to reduce fatigue in patients with chronic fatigue and other chronic medical conditions with fatigue; however, few of these natural supplements are considered effective. ^3,4 One approach that has proved effective in reducing fatigue in aging and chronic illnesses is lipid replacement therapy (LRT), or the natural replacement of damaged, mainly oxidized, membrane lipids in mitochondria and other cellular organelles.^3,5

Fatigue has been described as a multidimensional sensation, and clinical studies have determined the extent of fatigue in aging and various medical conditions (neurological, respiratory, coronary, musculoskeletal, metabolic, autoimmune and gastrointestinal diseases, cancer, infections).^3,5–7 Most patients consider fatigue to be a loss of overall energy and inability to perform even simple tasks without exertion. At the cellular level, fatigue is related to energy systems found primarily in the mitochondria and specifically in the inner mitochondrial membrane electron transport system.⁸ Damage to mitochondrial membranes occurs in various diseases, mainly by oxidation, and this can result in loss of mitochondrial inner membrane potential and impairment in the ability of mitochondria to produce high-energy molecules.^3,6,9

In fatiguing illnesses, such as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), patients have intractable fatigue for at least six months and show increased susceptibility to oxidative stress and peroxidation of membrane lipids.^10,11 To some degree, this excess oxidative stress can be reduced with antioxidant supplements, but these antioxidants cannot repair the oxidative damage to cells.^12,13

Lipid Replacement Therapy

Recent clinical trials have shown the effectiveness of LRT plus antioxidants in the treatment of certain clinical disorders and conditions, such as chronic fatigue.^3,5,14–16 LRT results in the actual replacement of damaged cellular phospholipids with undamaged (unoxidized) lipids to ensure proper function of cellular and organelle membranes. Combined with antioxidant supplements, LTR has proved to be an effective method to prevent oxidative damage to cellular activities and functions and for use in the treatment of various clinical conditions.^5–7

LRT can repair mitochondrial membranes, increase function, and decrease fatigue in various chronic conditions, including aging, chronic fatigue syndrome, fibromyalgia syndrome, and obesity (Table 1). When mitochondrial function was followed in parallel with fatigue in a crossover clinical trial, there was a close correspondence between loss of fatigue and gains in mitochondrial function.¹⁵

Table 1:

Effects of Dietary LRT Supplementation on Fatigue Scores^a

________________________________________________________________________________

Av.

Time Piper Fatigue Scale (PFS)

Subjects/patients n age on LRT fatigue reduction (%) Reference

________________________________________________________________________________

Chronic fatigue^b 34 50.3 8 wks 40.5** Ellithorpe et al.¹⁴

Aging, chronic fatigue^c 20 68.9 12 wks 35.5* Agadjanyan et al.¹⁵

Chronic fatigue syndrome

(and/or fibromyalgia

syndrome)^b 15 44.8 8 wks 43.1* Nicolson & Ellithorpe⁵

Obesity, fatigue^d 35 42 8 wks 24* Ellithorpe et al.¹⁶

Aging, fatigue^e 67 57.3 1 wk 36.8* Nicolson et al.¹⁷

______________________________________________________________________________

^aModified from Nicolson and Settineri⁷

^bPropax with NT Factor

^cNT Factor

^dHealthy Curb with NT Factor

^eAdvanced Physician’s Formula with NT Factor

**p < 0.0001, *p < 0.001 compared to without LRT

LRT with Glycophospholipids, CoQ10, and NADH

Recently we tested the results of using an oral formulation of glycophospholipids (polyunsaturated phosphatidylcholine, phosphatidylglyerol, phosphatidylserine, phosphatidylinositol, and other membrane phospholipids), CoQ10 plus microencapsulated NADH and other nutrients (Table 2) on suppression of intractable fatigue during a two-month trial.¹⁸ The 58 participants in this study had moderate to severe intractable fatigue (30 females, 51.8 ± 1.7 years, and 28 males, 58.5 ± 2.1 years, respectively). They were long-term chronic-illness patients (30 CFS/ME; 17 chronic Lyme disease; 16 other fatiguing illnesses, including fibromyalgia syndrome and Gulf War illness; 4 autoimmune disease, including rheumatoid arthritis; 2 cancer; and 2 diabetes) who had tried unsuccessfully many drugs and supplements (average >35) to reduce their fatigue. The participants had been fatigued an average of >17 years and had been to an average of over 15 practitioners without resolution of their fatigue.¹⁸

Participants took the suggested daily test supplement dose (5 capsules in the morning and 5 at night) for 8 weeks.¹⁸ Fatigue was scored using the Piper Fatigue Scale (PFS).^19,20 The PFS is a validated instrument that measures four dimensions of subjective fatigue: behavioral/severity, affective/meaning, sensory, and cognitive/mood. These were used to calculate the four subscale/dimensional scores and the total fatigue scores.^19,20 The standardized alpha (Cronbach’s alpha) coefficient of reliability was at least 0.960 for any of the subscale data, and the standard alpha for the entire scale was 0.979, indicating excellent reliability and internal consistency. The study participants took the PFS survey at days 0, 7, 30, and 60.¹⁸

Table 2.

Test Supplement (ATP Fuel with NT Factor, NADH, and CoQ10)^a

__________________________________________________________________________________

Amount

%

Per Daily

Component Serving Value^b

__________________________________________________________________________________

Vitamin E (as alpha-D-tocopherol) 20 IU 67

Krebs Energy Foundation 35 mg *

NADH, Coenzyme Q10

Mitochondria Pro Regulator 260 mg *

Calcium (as calcium pyruvate, calcium ascorbate

dicalcium phosphate), phosphate/sulfate/pyruvate;

Phosphorus (as dicalcium phosphate);

Magnesium (as magnesium oxide)

Krebs Cycle Glucose Absorb 180 mg *

Alpha-ketoglutaric acid, L-tyrosine

RN Fatty Acid Metabolizer 160 mg *

L-carnitine L-tartrate, pantethine

NT Factor^c Maximum Potency 2,000 mg *

__________________________________________________________________________________

^aATP Fuel is a registered trademark of Researched Nutritionals Inc., Los Olivos, CA.

^bDaily values are based on a 2000 calorie per day diet

*Daily values not established

^cNT Factor is a nutrient complex containing membrane polyunsaturated phospholipids extracted from soy lipids and purified using proprietary processes, Bifido and Lactobacillus bacteria with supportive essential growth media and phytonutrients for optimal absorption and performance, by Nutritional Therapeutics Inc., Commack, NY.

The initial PFS mean total fatigue score ± SD was 7.51 ± 0.29, and after 8 weeks of supplement this improved to 5.21 ± 0.28, or a 30.7% reduction in fatigue in these patients with intractable chronic fatigue. The mean decrease in fatigue scores was significant by t-test (p < 0.0001) and Wilcoxon signed-rank (p < 0.0001) analyses. The PFS fatigue scores can be further dissected into subcategories (Table 3). All of these subcategories showed significant reductions by the end of the 8-week trial (p < 0.0001), indicating that there were significant improvements in all subcategories of fatigue. For example, there was a 30.7% reduction (p < 0.0001) in severity/behavior of fatigue, indicating that there was a significant reduction in the intensity of fatigue, and a significant increase in the ability to complete tasks, socialize, and engage in sexual and other activities. Also, there was a 28.0% improvement (p < 0.0001) in mood and cognitive ability, such as the ability to concentrate, remember, and think clearly (Table 3).¹⁸

Table 3.

Results From Overall Fatigue and Subcategories of the Piper Fatigue Scale

__________________________________________________________________________________

Mean Fatigue Level ± SD Percent-test

Category Day 0 Day 60

Reduction

p

__________________________________________________________________________________

Overall Fatigue 7.51 ± 0.29 5.21 ± 0.28 30.7 <0.0001

Behavior/Severity^a 7.43 ± 0.26 5.15 ± 0.12 30.7 <0.0001

Affective/Meaning^b 8.36 ± 0.14 5.90 ± 0.16 29.4 <0.0001

Sensory^c 7.75 ± 0.22 5.49 ± 0.17 29.2 <0.0001

Cognitive/Mood^d 6.40 ± 0.24 4.61 ± 0.21 28.0 <0.0001

__________________________________________________________________________________

^aBehavior/Severity subcategory deals with completing tasks, socializing, engaging in sexual activity and other activities, and intensity or degree of fatigue.

^bAffective/Meaning subcategory determines whether fatigue/tiredness is pleasant/unpleasant, patient is agreeable/disagreeable, protective/destructive, or feels normal/abnormal.

^cSensory subcategory determines whether patient is strong/weak, awake/sleepy, refreshed/tired, or energetic/unenergetic.

^dCognitive/Mood subcategory assesses whether patient feels relaxed/tense, exhilarated/depressed, able/unable to concentrate, remember, and think clearly.

Analysis of Fatigue Data

To see if the trends in fatigue reduction over time during the trial were consistent, occurred with a high degree of confidence, and could predict further reductions in fatigue, we conducted regression analyses of the data. The regression analysis of overall fatigue and in each of the subcategories of fatigue (behavior/severity, affective meaning, sensory, and cognitive/mood) indicated significant and consistent downward trends in the fatigue data, suggesting that further reductions in fatigue would have been likely if the trial had been continued. The regression R² values for the various subgroups were: behavior/severity, 0.956; affective meaning, 0.960; sensory, 0.950; and cognitive/mood, 0.980. Regression analysis of the overall fatigue yielded a R² = 0.960. This indicates a high level of confidence and reproducibility in the downward trends in all fatigue data.¹⁸

We also examined the data to see if there was a difference in response to the test supplement that depended on fatigue severity. As expected from previously trials that used NT Factor alone, the most severely fatigued subjects showed the greatest reductions in fatigue scores.^14,15 For example, subjects with initial overall fatigue scores above 8 in the PFS scale showed greater reductions in fatigue scores on day 60 (35.3% improvement in overall fatigue) than subjects with lower scores (initial PFS score 4–8, 25% improvement) by day 60. Examination of scores from patients with CFS/ME, Lyme disease, or other diagnosis categories did not reveal major differences in overall fatigue or its reduction by the test supplement. For example, the CFS/ME, Lyme disease and other fatiguing illness groups total fatigue was reduced on day 60 by 29.6%, 26% and 34.6%, respectively.¹⁸

Effects of CoQ10 and NADH Alone

Prior studies reported that microencapsulated NADH alone had a positive effect on fatigue. Analysis of those studies, however, indicated that a subset of patients responded or the response was for a limited time. In a study on CFS/ME patients 8 of 26 (30.7%) responded to microencapsulated NADH compared with 2 of 26 (8%) on placebo (p < 0.05).²¹ However, these results were not considered significant by others.²² Santaella et al. compared the effectiveness of 24 months of oral NADH versus psychological/nutritional therapy for 31 CFS/ME and found that NADH only reduced fatigue in the first trimester of the trial.²³ After the first trimester, symptom scores were similar in NADH and psychological/nutritional arms of the trial. In another study, oral NADH was given for two months to CFS/ME patients and showed a decrease in anxiety and maximum heart rate after a stress test, but little difference in the functional impact of fatigue, quality of life, sleep quality, exercise capacity, or functional reserve between the test and placebo groups.²⁴

CoQ10 is an important cellular antioxidant and an essential electron carrier in the mitochondrial respiratory chain as well as a molecule involved in gene regulation.²⁵ CoQ10 has been used as a dietary supplement in a variety of chronic illnesses and age-related conditions.^25,26 CoQ10 was used here to improve energy transduction and combat oxidative stress.²⁶

Chronic fatigue is related to loss of mitochondrial function.^15,27 The patients here are considered as having intractable fatigue, yet they responded quite well to the combination supplement containing NT Factor, CoQ10, and NADH.¹⁸ Regression analysis indicated that the data were consistent with a high degree of confidence and also suggested that the peak benefits on fatigue were yet to be realized. The supplement was safe, and only two participants experienced minor symptoms that resolved after the supplement was discontinued and could not be directly attributed to the test supplement. The clinical trial here demonstrated that the test supplement was effective and safe for long-term chronic illness patients, such as those with CFS/ME, fibromyalgia syndrome, chronic Lyme disease, Gulf War illness, and other chronic conditions.

Summary

Fatigue is the most common complaint of chronic illness patients. A combination oral supplement containing a mixture of phosphoglycolipids, CoQ10, and microencapsulated NADH significantly (p < 0.001) reduced intractable fatigue in a group (n = 58) of patients with chronic fatigue syndrome, fibromyalgia syndrome, Gulf War illness, chronic Lyme disease, and other conditions. These patients had been symptomatic for an average of over 17 years, had been seen by multiple practitioners (>15), and had used many other supplements and drugs (>35) without apparent reductions in their fatigue. Analysis of subcategories of fatigue indicated significant improvements in the ability to complete tasks and activities as well as in mood and cognitive abilities. Regression analysis of the data indicated that reductions in fatigue were gradual and consistent, and occurred with a high degree of confidence (R² = 0.960). The combination supplement was a safe and effective method to significantly reduce fatigue in patients with intractable chronic fatigue.²⁸

Notes

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14. Ellithorpe RR, Settineri R, Nicolson GL. Reduction of fatigue by use of a dietary supplement containing glycophospholipids. J Am Nutraceutical Assoc. 2003; 6(1):23–28.

15. Agadjanyan M, Vasilevko V, Ghochikyan A, et al. Nutritional supplement (NTFactor) restores mitochondrial function and reduces moderately severe fatigue in aged subjects. J Chronic Fatigue Syndr. 2003; 11(3):23–26.

16. Ellithorpe RA, Settineri R, Jacques B, Nicolson GL. Lipid Replacement Therapy functional food with NT Factor for reducing weight, girth, body mass, appetite, cravings for foods and fatigue while improving blood lipid profiles. Funct Food Health Dis. 2012; 2(1):11–24.

17. Nicolson GL, Ellithorpe RR, Ayson-Mitchell C, Jacques B, Settineri R. Lipid Replacement Therapy with a glycophospholipid-antioxidant-vitamin formulation significantly reduces fatigue within one week. J Am Nutraceutical Assoc. 2010; 13(1): 11–15.

18. Nicolson GL, Settineri R, Ellithorpe E. Lipid Replacement Therapy with a glycophospholipid formulation with NADH and CoQ10 significantly reduces fatigue in intractable chronic fatiguing illnesses and chronic Lyme disease. Intern J Clin Med. 2012; in press.

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21. Forsyth LM, Preuss HG, MacDowell AL, et al. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1999; 82:185–191.

22. Colquhoun D, Senn S. Is NADH effective in the treatment of chronic fatigue syndrome? Ann Allergy Asthma Immunol. 2000; 84:639–640.

23. Santaella ML, Font I, Disdier OM. Comparison of oral nicotinamide adenine dinucleotide (NADH) versus conventional therapy for chronic fatigue syndrome. Puerto Rico Health Sci J. 2004; 23(2):89–93.

24. Alegre J, Rosés JM, Javierre C, et al. Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome. Rev Clin España. 2010; 210(6):284–288.

25. Littarru GP, Tiano L. Clinical aspects of coenzyme Q10: an update. Nutr. 2010; 26:250–254.

26. Orsucci D, Filosto M, Siciliano G, et al. Electron transfer mediators and other metabolites and cofactors in the treatment of mitochondrial dysfunction. Nutr Rev. 2009; 67:427–438.

27. Myhill S, Booth NE, McLaren-Howard J. Chronic fatigue syndrome and mitochondrial dysfunction. Intern J Clin Exp Med. 2009; 2(1):1–16.

28. The authors have no conflicts of interest or ownership in any products or companies discussed in this contribution. This study was supported in part by a grant from Researched Nutritionals Inc.

Correspondence should be addressed to: Garth L. Nicolson; PhD; Department of Molecular Pathology, Institute for Molecular Medicine, Huntington Beach, California 92647; gnicolson@immed.org

Robert Settineri, MS; Sierra Research, Irvine, California 92606

Rita Ellithorpe, MD, ND; Tustin Longevity Center, Tustin, California 92780