Tiredness and fatigue are common symptoms in the primary health care system – approximately one-fifth of patients present with fatigue, and one-third of adolescent’s report having fatigue at least four days per week.2bThe clinical presentation of fatigue may vary between individuals. Men often describe fatigue as tiredness whereas women are more likely to describe feeling anxious or depressed.2c

Fatigue is one of the first and most common symptoms associated with an activated immune system

These symptoms are often initiated by inadequate rest, physical effort, or mental strain unrelated to an underlying medical condition (physiological fatigue) and may be quickly relieved by rest or lifestyle changes.

On the other hand, fatigue may be associated with an underlying medical condition (pathological fatigue) and is often persistent, lasting longer than four months and not ameliorated by rest.2d,3a In a French study of 24 healthy men and women, poor sleep followed by family and professional worries was the main reason for a feeling of fatigue, reported as a lack of motivation in 75% of subjects and a lack of vitality in 50% of patients.1b,c

Medical conditions associated with fatigue include physical and/or chronic ailments such as HIV infection and other viral illnesses (infectious mononucleosis and post Covid-19 infection), autoimmune disorders, chronic heart, liver or kidney disease, cancer, endocrine diseases (hypothyroidism, Addison’s Disease), neurological diseases (multiple sclerosis) and mental illness such as depression and anxiety. Medications used to treat disorders may also cause fatigue.2e,f

Muscle fatigue is a commonly experienced phenomenon that limits athletic performance and other strenuous or prolonged activities. It is also increasing and restricts daily life under various pathological conditions, including neurological muscular and cardiovascular disorders, as well as ageing and frailty.3b

Physical examination and laboratory investigations may identify underlying medical conditions which explain fatigue. Tiredness cannot generally be completely explained as a consequence of a single disease or pathological mechanism.4a No aetiology is found in approximately one-third of patients who present with fatigue.2g

Research exploring mechanisms of fatigue in different disease states is limited. To date, cancer research has proposed biological mechanisms of fatigue. Inflammation, dysregulation of the hypothalamic-pituitary–adrenal (HPA) axis, and activation of the autonomic nervous system may be involved in the development of fatigue in disease.5a

Recently, studies have explored the notion that certain biological compounds involved in energy homeostasis, may play a role in physical and mental fatigue. Inadequate nutritional intake (low protein diet, vitamin and mineral deficiencies), underlying inflammatory mechanisms and immune system activation, may contribute to the feeling of tiredness through disturbances in energy production, production of cytokines and oxidative stress.1,6,9

Researchers propose that low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy and increases reactive oxygen species. These effects result in reduced glucose availability and, therefore, reduced cellular energy. Inflammation can also affect circadian rhythms and sleep (and vice versa), which can further exacerbate the effects on energy availability and expenditure. 7a,b

Fatigue is, interestingly, one of the first and most common symptoms associated with an activated immune system. Activation of the immune system produces pro-and anti-inflammatory cytokines. The cytokine signal reaches the brain via several immune-to-brain pathways and induce modifications in neurotransmitter and neuroendocrine systems, along with modifications in brain functions, which lead to behavioural changes. During cancer treatment, the increase in circulating concentrations of inflammatory markers, such as C-reactive protein (CRP) and interleukin (IL-6), was related to the development of an overall feeling of fatigue. 8a,b,c,d

Subclinical or inadequate intake of vitamins and minerals can lead to a significant proportion of the population not meeting their optimum delivery needs in emerging and developed countries. These insufficiencies may subsequently result in a higher risk of pathologies. The majority of Americans consume sufficient amounts of most nutrients to offset clinical symptoms, but in many individuals, intake falls below adequate Intake levels. In these situations, supplementation may be of value. An improvement in cognition and psychological function, a reduction in mental and physical fatigue and a general feeling of well-being are commonly reported motivations for taking supplements.1d,e,f,g,m

Amino Acids and Fatigue

  • Essential Amino acids – dependent on dietary intake.
  • Non-essential Amino Acids – made within the body and not dependent on diet.
  • Conditionally Essential Amino Acids – amino acids that become essential during pathological states where demand>supply.

In the human body, cells and organs require energy to maintain life. Amino acids are the building blocks for tissue proteins and essential substrates for important physiological functions. These are functionally classified as essential and non-essential amino acids.

Essential amino acids are dependent on dietary intake whereas non-essential amino acids are synthesised within cells and therefore referred to as nutritionally non-essential. In certain conditions (pregnancy, lactation, injury, burns and disease), the rate of amino acid utilisation in the body is greater than the supply of nutrients from the diet. Under these conditions, certain amino may become ‘conditionally essential’.6a,b,c

Therefore, in certain pathophysiological states, accompanied by decreased protein supply from dietary sources, the overall result is a loss of muscle mass, impaired immunity, and improper functioning of organs with subsequent fatigue. There is increasing evidence that regular essential amino acid intake as part of an oral diet is effective in reversing muscle catabolism, promoting muscle anabolism, and restoring immunological function. Therefore, the use of amino acids as supplements to diet would be expanding into the near future.9a

Measuring protein intake

Protein intake is measured by measuring nitrogen balance. Nitrogen balance is measured by a collection of nitrogen losses in urine, faeces, skin, and miscellaneous losses (sweat, secretions, etc) and subtracting these losses from the measured nitrogen content of protein intake.

The amount of protein required to maintain nitrogen balance is dependent on amino acids, which further supports the claim that supplementation may be useful in maintaining energy homeostasis in persons with a protein-deficient diet. 10

Nitrogen balance = Nitrogen Intake – Nitrogen Losses

Evidence for specific amino acids and their benefits in fighting fatigue

  • L-lycine and L-arginine normalise hormonal stress response in humans with high trait anxiety.11
  • Novel administration of glycine improves sleep quality in humans who have repeated complaints of sleep. 12
  • The anti-fatigue role of glutamine has also been described in athletes to delay the onset of fatigue and improve athletic performance. Glutamine supplementation also improves fatigue markers such as increased glycogen synthesis and reduces ammonia accumulation during physical exercise.13a
  • The combination of L-glutamine and L-arginine as ‘immuno-nutrients’ provide support duration exercise and improve muscle fatigue.14
  • L-ornithine supplements have been shown to relieve stress and improve sleep quality related to fatigue.15

Vitamins and Minerals can improve physical and mental fatigue

Enzymes break down ingested carbohydrates into monomeric sugars, lipids into fatty acids and proteins into amino acids. Acetyl CoA that is derived from glucose, fatty acids and amino acids, enter the Citric Acid Cycle in the mitochondria of cells. Through oxidative phosphorylation, there are billions of molecules of adenosine triphosphate (ATP) produced, the cell’s energy source. Macronutrients, vitamins and minerals are necessary to drive this highly efficient system. All the B vitamins, except for folate, are involved in at least one, or several steps in the energy production system (figure 1).1h

B vitamins

amino acids

Figure 1: B Vitamins in the Citric Acid Cycle


The active forms of thiamine (vitamin B1), riboflavin (vitamin B2), niacin (vitamin B3) and pantothenic acid (vitamin B5) are essential co-enzymes in mitochondrial aerobic respiration and cellular energy production via their direct roles in the citric acid cycle, the electron transport chain, and the resultant formation of ATP via Acetyl-CoA.16a In addition, thiamine and biotin (vitamin B8) play unique and essential roles in the mitochondrial metabolism of glucose and fatty acids and amino acids, respectively, thereby contributing substrates to the citric acid cycle.16b

Pyridoxine (vitamin B6) act as a cofactor of enzymes involved in amino acid metabolism, glycogenolysis and gluconeogenesis.1i It also has a direct effect on immune function and plays a role in brain glucose regulation.16e Biotin (vitamin B8) plays a critical role in the synthesis of fatty acids and plays a key role in glucose metabolism and haemostasis.16f

Beyond their role as cofactors in the production of energy, B vitamins also play a vital role in the metabolic functioning of the brain. Thiamine plays a neuro-modulatory role in the acetylcholine neurotransmitter system.16c Pantothenic acid contributes to the structure and function of brain cells via its involvement in the synthesis of cholesterol, amino acids, phospholipids and fatty acids, and is also involved in the synthesis of multiple neurotransmitters and steroid hormones.16d


Magnesium is essential for energy generation as it is involved in over 300 generation enzymatic reactions in metabolic pathways. In the Western world, recommended daily allowances of magnesium are not achieved in two-thirds of the population. Magnesium deficiency has been shown to impair physical performance. Several cross-sectional surveys have reported a positive association between magnesium intake and muscle strength, muscle performance and muscle power. Magnesium by virtue of its GABA agonist properties can also restore sleep and thereby improve fatigue.17a,b,c,d

Alpha Lipoic Acid

Oxidative stress plays an important role in the pathogenesis of Chronic Fatigue Syndrome.18a Alpha lipoic acid is thought to increase intracellular glutathione, which also is a potent antioxidant thereby leading to an improvement in chronic fatigue.18b Additionally, alpha-lipoic acid is an essential co-factor for mitochondrial metabolism19a and possesses anti-inflammatory cognitive, cardiovascular, and neuroprotective effects. 20a

Vitamin C, Vitamin D and Zinc

Vitamin C provides antioxidant protection where free radicals are encountered. It is also involved in the biosynthesis of carnitine, an essential co-factor in the transport of long-chain fatty acids into the mitochondria.1j A study in the UK in 15 000 healthy men and women revealed that poor physical function was related to lower vitamin C levels.1k Zinc has an anti-inflammatory activity which results in the downregulation of the production of reactive oxygen species.1 Vitamin D deficiency is frequent and has been associated with fatigue and other non-specific symptoms including headache, musculoskeletal pain and weakness, depression and impaired cognitive performance. Studies have shown that Vitamin D treatment significantly improved fatigue in otherwise healthy persons with vitamin D deficiency.21a,b


The incomplete knowledge of pathophysiological mechanisms of fatigue and the lack of a gold standard tool for its assessment contribute to the poor appreciation of fatigue in clinical practice.4b Dietary support with enhanced nutritional therapies have been tested in various patient populations with fatigue, although studies are of inconsistent quality. Invulnerable individuals with subclinical deficiencies or inadequate dietary intake, a nutrient supplement that addresses energy demands and maintains nitrogen homeostasis needs, with added anti-inflammatory and immunomodulatory effects, may assist in treating fatigue.

This may be particularly relevant in patients who have had a severe Covid-19 infection. Supplementation may benefit patients who are likely to struggle to consume adequate amounts of protein-rich foods and also in older patients, those with chronic conditions and patients who have been discharged from intensive care who are likely to have muscle wasting or feel weak.22

Author: Dr Ilhaam Mohamed


  1. Tardy A, Pouteau E, Marquez D, Yilmaz C,  Scholey . A Vitamins and Minerals for Energy, Fatigue and Cognition: A Narrative Review of the Biochemical and Clinical Evidence. Nutrients. 2020 Jan; 12(1): 228.
  2. Rosenthal TC, MajeroniBA, Pretorius R, MPH, Malik K. Fatigue. An Overview. Am Fam Physician. 2008 Nov 15;78(10):1173-1179.
  3. Wan J, Qin Z, Wang P, Sun Y, Liu X. Muscle fatigue: general understanding and treatment. Experimental & Molecular Medicine2017 49:384
  4. Azzolino D, Arosio B, Marzetti E, Riccardo Calvani R Cesari M. Nutritional Status as a Mediator of Fatigue and Its Underlying Mechanisms in Older People. Nutrients 2020, 12, 444
  5. Matura LA, Malone S, Jaime-Lara R, Riegel B. A Systematic Review of Biological Mechanisms of Fatigue in Chronic Illness. Biological Research for Nursing 2018, Vol. 20(4) 410-421Stadje R, Dornieden K, Baum E, Becker A, Biroga T, Bösner S, Haasenritter J, Keunecke C, Viniol A ,Donner-Banzhoff N. The differential diagnosis of tiredness: a systematic review. Stadje et al. BMC Family Practice (2016) 17:147
  6. Wu G. Functional amino acids in nutrition and health. Amino Acids (2013) 45:407–411.
  7. Lacourt TE, Vichaya EG, Chiu GS, Dantzer R, Heijnen C. The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Front Behav Neurosci. 2018; 12: 78.
  8. Karshikoff B, Sundelin T, Lasselin J. Role of Inflammation in Human Fatigue: Relevance of Multidimensional Assessments and Potential Neuronal Mechanisms. Front Immunol. 2017; 8: 21
  9. Dioguardi FS. Clinical use of amino acids as a dietary supplement: pros and cons. J Cachexia Sarcopenia Muscle (2011) 2:75–80
  10. Kondrup J. Basic concepts in nutrition: Energy and protein balance. e-SPEN the European e-Journal of Clinical Nutrition and Metabolism.2008
  11. Smriga M, Ando T, Akutsu M, Furukawa Y, Miwa K, Morinaga Y. Oral treatment with L-lycine and L-arginine reduce anxiety and basal cortisol levels in healthy humans. Biomedical Research 2007 28(2)85-90.
  12. Bannai M , Kawai N.New therapeutic strategy for amino acid medicine: glycine improves the quality of sleep J Pharmacol Sci. 2012;118(2):145-8.
  13. Coqueiro AY , Rogero MM , Tirapegui J. Glutamine as an Anti-Fatigue Amino Acid in Sports Nutrition. Nutrients 2019 Apr 17;11(4):863.
  14. Cruzat VF, Krause M, Newsholme P. Amino acid supplementation and impact on immune function in the context of exercise. Journal of the International Society of Sports Nutrition 2014, 11:61
  15. Miyake M, Kirisako T, Kokubo T, Miura Y, Morishita K, Okamura H and Tsuda A. Randomised controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers. Nutrition Journal 2014, 13:53
  16. Kennedy D. B Vitamins and the Brain: Mechanisms, Dose and Efficacy—A Review. Nutrients. 2016 Feb; 8(2): 68
  17. Schwalfenberg GK, Genuis SJ. The Importance of Magnesium in Clinical Healthcare. Scientifica (Cairo) 2017;2017:4179326
  18. Logan AC, Wong C Chronic fatigue syndrome: oxidative stress and dietary modifications. Altern Med Rev. 2001 Oct;6(5):450-9.
  19. Solmonson A, DeBerardinis RJ. Lipoic acid metabolism and mitochondrial redox regulation. J Biol Chem 2018 May 18;293(20):7522-7530
  20. El Barky AR, Hussein SA, Mohamed TM. The Potent Antioxidant Alpha Lipoic Acid.J Plant Chem and Ecophysiol. 2017; 2(1): 1016
  21. Nowak et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial. Medicine (Baltimore) 2016 Dec;95(52):e5353.
  22. Holdoway A. Nutritional management of patients during and after COVID-19 illness.Br J Community Nurs 2020 Aug 1;25(Sup8): S6-S10.