Nutrient Therapy For The Improvement Of Fatigue Symptoms Part 1

Abstract: Fatigue, characterized by lack of energy, mental exhaustion, and poor muscle endurance which do not recover following a period of rest, is a common characteristic symptom of several conditions and negatively impacts the quality of life of those affected. Fatigue is often a symptom of concern for people suffering from conditions such as fibromyalgia, chronic fatigue syndrome,  cancer, and multiple sclerosis. Vitamins and minerals, playing essential roles in a variety of basic metabolic pathways that support fundamental cellular functions, may be important in mitigating physical and mental fatigue. Several studies have examined the potential benefits of nutrients on fatigue in various populations. The current review aimed to gather the existing literature exploring different nutrients’ effects on fatigue. From the searches of the literature conducted in PubMed, Ovid, Web of Science, and Google Scholar, 60 articles met the inclusion criteria and were included in the review. Among the included studies, 50 showed significant beneficial effects (p < 0.05) of vitamin and mineral supplementation on fatigue. Altogether, the included studies investigated oral or parenteral administration of nutrients including Coenzyme Q10, L-carnitine, zinc, methionine, nicotinamide adenine dinucleotide (NAD), and vitamins C, D, and B. In conclusion, the results of the literature review suggest that these nutrients have potentially significant benefits in reducing fatigue in healthy individuals as well as those with chronic illness, both when taken orally and parenterally. Further studies should explore these novel therapies, both as adjunctive treatments and as sole interventions.

Cistanche can act as an anti-fatigue and stamina enhancer, and experimental studies have shown that the decoction of Cistanche tubulosa could effectively protect the liver hepatocytes and endothelial cells damaged in weight-bearing swimming mice, upregulate the expression of NOS3, and promote hepatic glycogen synthesis, thus exerting anti-fatigue efficacy. Phenylethanoid glycoside-rich Cistanche tubulosa extract could significantly reduce the serum creatine kinase, lactate dehydrogenase, and lactate levels, and increase the hemoglobin (HB) and glucose levels in ICR mice, and this could play an anti-fatigue role by decreasing the muscle damage and delaying the lactic acid enrichment for energy storage in mice. Compound Cistanche Tubulosa Tablets significantly prolonged the weight-bearing swimming time, increased the hepatic glycogen reserve, and decreased the serum urea level after exercise in mice, showing its anti-fatigue effect. The decoction of Cistanchis can improve endurance and accelerate the elimination of fatigue in exercising mice, and can also reduce the elevation of serum creatine kinase after load exercise and keep the ultrastructure of skeletal muscle of mice normal after exercise, which indicates that it has the effects of enhancing physical strength and anti-fatigue. Cistanchis also significantly prolonged the survival time of nitrite-poisoned mice and enhanced the tolerance against hypoxia and fatigue.

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Keywords: vitamin supplementation; fatigue; fatigue symptoms; nutrient therapy; nootropic; supplementation

1. Introduction

Fatigue is among the common complaints in daily life, negatively impacting work performance, family life, and social relationships. Fatigue can be conceptualized as a  sensation of exhaustion or difficulty performing intellectual or physical activities, which is often not recovered after a period of rest [1]. Patients with fatigue typically report a lack of energy, mental exhaustion, poor muscle endurance, delayed recovery after physical exertion, and nonrestorative sleep [2]. Mood scales which include fatigue measures such as the Bond-Lader Visual Analogue Scale (BL-VAS) and Profile of Mood Scale (POMS) are typically used for measuring fatigue states. Moreover, several fatigue scales including the Fatigue Assessment Scale (FAS), the Fatigue Severity Scale (FSS), and the Chalder Fatigue Scale (CFQ 11) are often used for measuring the nature and severity of fatigue.

While no pathology can be identified in one-third of fatigue cases [2], several conditions including depression, viral illness, upper respiratory tract infection, anemia, cancer,  and lung disease, are among the common causes of fatigue. Therefore, fatigue can be classified as secondary to other medical conditions, which might last for a month or longer, in cases of physiologic and chronic fatigue, respectively [2]. Physiologic fatigue, characterized by an imbalance in the routines of exercise, sleep, diet, or other activities unrelated to an underlying medical condition, is most common in adolescents and the elderly and is relieved with rest [3]. However, chronic fatigue, characterized by intense physical and mental fatigue of unknown causes, is not relieved with rest and lasts longer than six months [2]. Accordingly, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling clinical condition, characterized by persistent post-exertional fatigue which produces various degrees of disability by limiting the patient’s functional capacity and is accompanied by a variety of symptoms associated with cognitive, immunological, endocrinological, and autonomous dysfunction [4]. Chronic Fatigue Syndrome (CFS), characterized by prolonged and relapsing fatigue, is a serious and extremely debilitating chronic illness that results in significant disability, lasting from 6 months to several years [5]. Moreover, CFS is associated with a wide range of physical and behavioral symptoms, including joint and muscle pain, headache, intolerance to physical exertion, anxiety, depression cognitive impairment, and sleep disorders [3]. Several common medical conditions are known to cause fatigue symptoms. Fatigue is amongst the major side effects of cancer and its treatment, disrupting the quality of life of cancer patients and may be a risk factor in reduced survival [6]. Fatigue is also described by patients with multiple sclerosis as their most disturbing symptom [7]. Furthermore, fibromyalgia, a common chronic pain syndrome, associated with widespread pain at multiple tender points, is characterized by fatigue and sleep disruption [8]. Severe fatigue is reported by all fibromyalgia patients, with as many as 80% of patients with this condition also fulfilling the criteria for CFS [9].

Management of fatigue is complex and requires a multimodal therapeutic approach. Gradual physical exercise together with cognitive behavior therapy, remain the most common approaches [2,3]. Vitamins and minerals, playing essential roles in a variety of basic metabolic pathways that support fundamental cellular functions, affect cognitive and psychological processes including mental and physical fatigue [10]. Therefore, several micronutrients, enzymes, and amino acids have been suggested to have a role in fatigue,  cognition, or psychological functions [10]. Efficient and safe vitamin and mineral supplementation for individuals suffering from fatigue may provide a beneficial treatment option. The current review hence gathers studies investigating vitamin C, vitamin D, B  vitamins, Coenzyme Q10 (CoQ10), L-carnitine, zinc, nicotinamide adenine dinucleotide (NADH), and methionine, all of which have been suggested as having impacts on physical and mental fatigue, in the management of fatigue symptoms in different conditions.

2. Methods

Searches of the literature were conducted in PubMed, Ovid (including Journals from Ovid, AMED (Allied and Complementary Medicine), Embase, Global Health, and Ovid MEDLINE), Web of Science, and Google Scholar. The search was conducted without any geographical or time restrictions using the following keywords: “vitamin”, “vitamin supplementation”, “IV therapy”, “intravenous therapy”, “IM therapy”, “Intramuscular therapy”, “oral supplementation”, “supplementation”, “nutrient therapy”, “vitamin therapy”, “micronutrient therapy”, “fatigue”, and “fatigue symptoms”. To achieve comprehensive review of the literature, these keywords were used in combination with the following vitamins and minerals: vitamins B, C, and D; glutathione, N-acetyl cysteine,  alpha lipoic acid, manganese, copper, selenium, chromium, magnesium, zinc, methionine,  inositol, leucine, L-carnitine, choline, L-taurine, CoQ10, and NAD. Studies employing both single nutrients as well as combinations of the mentioned micronutrients were included in the literature review. In addition, the most common intravenous nutritional intervention, Myer’s cocktail, has also been included. The included micronutrients in this literature search are amongst the most widely used nutrients in the management of health conditions [11] as well as fatigue symptoms [10] and are also available for both oral and parenteral administration [12]. A manual search of all included bibliographies was carried out to identify any omitted articles. From the combinations of the keywords and relevant articles found in review references, 651 articles were identified. Studies that satisfied the inclusion criteria were retrieved for full-text assessment. Articles were considered for inclusion if they reported data from an original study examining the effects of nutrient supplementation on fatigue status, performed the statistical analysis, were accessible in their full text, and were published in the English language. The exclusion criteria were as follows:  conference proceedings, case reports, letters, summaries, expert opinions and comments, and articles published in a language other than English. Therefore, following a full-text analysis of the 124 retrieved articles, 60 studies met the inclusion criteria and were included for analysis (Figure 1).

3. Search Results 

From the 60 studies included in this review, a total of 35 studies investigated the efficacy of L-carnitine and CoQ10 administration for the management of fatigue symptoms, accounting for 28% and 27% of the studies, respectively. Vitamins C and D are the next most studied nutrients, accounting for 12% of the studies each. The remaining 21% of the studies investigated different nutrients including NADH, thiamine, methionine, zinc, and Myers' cocktail (Figure 2A). Furthermore, it can be seen from (Figure 2B) that most of the included studies investigated oral administration of nutrients, with only 10 and 3 of the studies employing intravenous (IV) and intramuscular (IM) administration routes, respectively. As depicted in (Figure 2C), studies were also sorted based on the effects of each nutrient on measures of fatigue. In most cases, studies reported statistically significant positive outcomes after a period of nutrient therapy. Nevertheless, several studies investigating nutrients such as CoQ10, L-carnitine, vitamin C, and vitamin D, also reported no significant improvements in fatigue symptoms. In terms of statistically significant negative outcomes, only one study reported worsening symptoms as a result of L-carnitine administration in cancer patients undergoing chemotherapy [13].

Differentiating the studies with regards to the population they were studied, revealed that cancer [14], CFS [15], fibromyalgia [16], and MS patients [17] are the most studied populations (Figure 3). The remaining studies investigated the effects of nutrient therapy in the elderly and healthy subjects and those suffering from other medical conditions such as Metabolic syndrome (MetS) [18], end-stage heart failure [19], kidney transplant recipients (KTRs) [20], post-stroke fatigue (PSF) patients with vitamin D deficiency [21], etc. Additionally, it can be postulated from (Figure 3) that L-carnitine [22] and vitamin C [14] are the most employed nutrients for the management of fatigue symptoms in cancer patients. Similarly, CoQ10 is amongst the most administered nutrients in FM  patients [16] as well as healthy subjects [23]. Patients with CFS might also benefit from CoQ10 administration [15].

4. Oral Supplementation

4.1. Clinical Populations 

4.1.1. Vitamins and Minerals 

Several studies have suggested the effects of oral supplementation with vitamins and minerals on fatigue among individuals suffering from different medical conditions (Table 1) [17]. Fatigue is the most common symptom of Multiple Sclerosis (MS), affecting up to 90% of those with MS, and is often reported as the first symptom noted by patients before diagnosis [7]. Moreover, fatigue is suggested to be more severe and disabling among MS patients than in healthy controls and others with chronic illness [7]. The administration of thiamine in MS patients for the management of fatigue has been investigated by Sevim et al. [24]. Daily oral administration of 400 mg sulbutiamine, a synthetic compound that constitutes two thiamine molecules, for two months, was found to be effective in treating fatigue in MS. However, the effect was only observed in patients who were on disease-modifying treatment, but not in those who were not [24]. Moreover, the effect of Alfacalcidol (1 a-hydroxycholecalciferol), a synthetic analog of vitamin D, on MS-related fatigue has been investigated [25]. The intervention group received vitamin D3 alfacalcidol (1 µg or 40 IU) daily. Alfacalcidol lowered the mean Fatigue Impact Scale (FIS) score as compared with a placebo and improved the quality of life in patients with MS [25]. Moreover, Bager et al. have demonstrated the significant beneficial effect of high-dose oral thiamine (600–1800 mg/d) on chronic fatigue in patients with inflammatory bowel disease (IBD),  following 4 weeks of treatment [26].

Vitamin D administration has been also reported to be associated with the improvement of fatigue in various populations. Weekly administration of 50,000 IU oral cholecalciferol in patients with juvenile-onset systemic lupus erythematosus (SLE) improved many aspects of fatigue, including measures of 'fatigue easily', 'fatigue during exercise’, ‘fatigue to medium efforts’, and ‘fatigue considered a problem’ [58]. Furthermore, oxidative stress is thought to underlie fatigue, with serum markers of oxidative stress being associated with symptoms of CFS [14]. Since Vitamin C is a well-known antioxidant, vitamin C treatment for the management of fatigue symptoms has been investigated. Namely, in obese adults on a weight loss program with exercise, 500mg/day of oral vitamin C for four weeks was reported to be better than placebo in reducing the rate of perceived exertion and lowering fatigue scores [14]. The majority of studies, however, have investigated the effects of intravenous vitamin C on fatigue, which is further elaborated in Section 5.

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