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Nutritional treatment of fatigue.

Fatigue is one of the most common health complaints. It can be caused by a wide range of medical conditions and by various medications. In many cases, treatment of the underlying disorder results in an improvement in fatigue. However, in a large proportion of patients evaluated for fatigue, no underlying cause is identified. Conventional medicine has little to offer patients with unexplained fatigue, other than "reassurance" that their symptoms are not being caused by a serious illness.


Nutritional medicine, on the other hand, is frequently beneficial for patients with chronic, unexplained fatigue. In my experience, approximately 70% to 80% of these patients experience substantial improvement with nutritional therapy. The astute practitioner, relying on a combination of clinical history, physical examination, and appropriate laboratory tests, can usually develop a nutritional program for chronic fatigue that has a high probability of success.

The evaluation and management of fatigue is discussed in greater detail in my recently published textbook, Nutritional Medicine.1

Dietary Factors

Published reports and clinical observations by numerous practitioners indicate that reactive hypoglycemia and hidden food allergy are important contributing factors to chronic fatigue in some patients. Patients with reactive hypoglycemia may experience a worsening of symptoms in the late morning or late afternoon (before mealtime) and an improvement after eating. They tend to crave sweets and may note that consumption of refined sugar relieves their symptoms transiently, only to be followed by an exacerbation. In my experience, a program that includes avoidance of refined sugar and other refined carbohydrates; consumption of small, frequent meals; and supplementation with nutrients that help stabilize blood glucose levels (e.g., chromium, magnesium, and B vitamins) often relieves fatigue in patients whose clinical picture is suggestive of reactive hypoglycemia.

Allergic fatigue may be associated with other symptoms of allergy, such as nasal congestion, abdominal pain, headache, body aches, hyperactivity, hyperirritability, and edema. Some patients with allergic fatigue note that they feel better while fasting and worse after eating a meal. However, in other cases, fatigue improves after a meal containing a regularly ingested hidden food allergen, presumably because the patient is addicted to that food. Patients with allergic fatigue are frequently unaware that dietary factors are contributing to their symptoms. Hidden food allergies can usually be identified by means of an elimination diet followed by individual food testing.

Potassium Magnesium Aspartate

It has been hypothesized that fatigue is caused in some cases by inefficient energy production at the cellular level, and that substances which improve energy production might ameliorate fatigue. In the 1960s, the potassium and magnesium salts of aspartic acid (potassium magnesium aspartate) were investigated as a treatment for fatigue, because of their potential to improve metabolic efficiency. Potassium regulates basic aspects of cellular functioning (i.e., transmembrane electrical potential and intracellular ionic strength) and is also involved in muscle contraction. Magnesium is required for the synthesis of the energy-yielding compound adenosine triphosphate (ATP), and also enhances potassium transport into cells. Aspartic acid is converted in vivo to oxaloacetate, which is a substrate for the Krebs cycle.

In several uncontrolled and double-blind trials, 75% to 94% of patients experienced an improvement in fatigue after treatment with potassium magnesium aspartate. In contrast, only 5% to 27% of patients given placebo improved.2-9 In most studies, 2 g per day of potassium magnesium aspartate was administered, although one study used 4 g per day. These dosages refer to total weight: 2 g of potassium magnesium aspartate provides about 240 mg of potassium, 170 mg of magnesium, and 1.6 g of aspartate. Symptom relief was usually seen after 3 to 14 days. Fatigue of diverse etiologies (i.e., postoperative, postviral, postpartum, menopausal, and nonspecific) responded to potassium magnesium aspartate. Adverse effects were uncommon and consisted mainly of mild gastrointestinal symptoms.

In my experience, some patients who respond to potassium magnesium aspartate are able to discontinue treatment after about 6 weeks without experiencing a recurrence of symptoms, but they may need to resume supplementation during periods of increased activity or stress. Other patients require continuous treatment (with 50%-100% of the initial dose) to maintain their improvement.

Vitamin B12

Since shortly after its discovery in 1948, vitamin B12 given by intramuscular injection has had a reputation of being a "tonic," capable of improving fatigue, mood, and overall well-being in certain people who are not deficient in the vitamin. Although this use of vitamin B12 remains controversial, a double-blind trial provided some support for the empirical use of vitamin B12 injections.

In that study, 48 subjects with fatigue, all of whom had normal hemoglobin concentrations and serum vitamin B12 levels, were randomly assigned to receive, in double-blind fashion, vitamin B12 (hydroxocobalamin, 5 mg intramuscularly twice a week for 2 weeks) or placebo. After a 2-week washout period, each person received the alternate treatment for an additional 2 weeks. Twenty-eight subjects completed the trial. The outcome measure was the proportion of participants who preferred one treatment over the other for various subjective symptoms. Among subjects who received placebo before vitamin B12, 12 preferred vitamin B12 and preferred placebo with respect to "general well-being" (p = 0.006). For "happiness," 9 preferred vitamin B12 and 2 preferred placebo (p = 0.03). For "fatigue," 10 preferred vitamin B12 and 4 preferred placebo (p = 0.09). Among subjects who received vitamin B12 before placebo, there was no difference in response to the two treatments, apparently because the effect of vitamin B12 carried over to the second treatment period (serum vitamin B12 levels were still well above normal in 10 of 13 subjects 4 weeks after the last vitamin B12 injection).10

One possible explanation for the beneficial effect of vitamin B12 injections is that some people need to maintain unusually high serum concentrations of the vitamin in order to function normally. Some individuals appear to have either a defect in the transport of vitamin B12 across the blood-brain barrier or accelerated breakdown of the vitamin in the central nervous system.11 Effective therapy for patients with presumed vitamin B12 dependency usually consists of 1000, ug intramuscularly every 4 days to 2 weeks, depending on how long the treatment lasts. While the interval between injections varies from one patient to another, it is usually fairly consistent for any particular patient. To maintain the beneficial effect of vitamin B12, injections may have to be continued indefinitely, unless another method of relieving the fatigue can be identified.

Because of its potential to produce substantial clinical improvement, intramuscular vitamin B12 is one of my first-line therapies for patients with unexplained fatigue. It is often tried first in patients who have associated neuropsychiatric symptoms such as anxiety, depression, insomnia, or decreased memory. In patients who do not have neuropsychiatric symptoms, potassium magnesium aspartate is often tried first.


Anemia due to iron deficiency can cause fatigue, which is reversible with iron therapy. In addition to being a component of hemoglobin, iron is a cofactor for enzymes involved the electron-transport chain (which plays a role in energy production) and in the synthesis of dopamine (which appears to modulate fatigue). In cases of mild iron deficiency, the activity of iron-dependent enzymes may be decreased before a reduction in hemoglobin levels occurs. Consequently, iron deficiency could contribute to fatigue even in patients who are not anemic.

Clinical trials have demonstrated that iron supplementation can improve fatigue in nonanemic iron-deficient patients.12-14 Most of the improvement is probably due to an increase in the activity of iron-dependent enzymes, although some of the benefit might be due to an increase in hemoglobin levels within the normal range.12

Administration of iron to patients who are not iron deficient may increase the risk of developing certain chronic illnesses, and it can harm people who carry an iron-overload gene. Therefore, iron supplementation should be reserved for patients with documented iron deficiency or borderline-low iron status.


Carnitine facilitates the transport of fatty acids into mitochondria, where they are metabolized to produce energy. Carnitine deficiency or suboptimal carnitine status would presumably lead to decreased energy production, potentially resulting in fatigue. Relative carnitine deficiency, resulting from decreased carnitine absorption, decreased endogenous carnitine synthesis, increased urinary carnitine loss, or an increased carnitine requirement could occur in various disease states, with the use of certain medications, or with advancing age. In clinical trials, administration of 2 g per day of L-carnitine for 6 months decreased fatigue in patients with celiac disease who were on a gluten-free diet, and also improved fatigue in a group of centenarians (> 100 years old).15,16

Other Nutritional Treatments

Other treatments that I have found to be effective in selected cases include thyroid hormone (for patients with clinical evidence of hypothyroidism), intravenous nutrient therapy (Myers cocktail), dehydroepiandrosterone (DHEA; usually in patients with low or borderline-low serum concentrations of DHEA-sulfate), and B vitamins or a multivitamin-multimineral preparation.


(1.) Gaby AR. Nutritional Medicine. Chapter 329.Concord NH; 2011.

(2.) Oliver S. Relationship of fatigue to gastrointestinal inadequacy. Curr Ther Res.1963; 5:62-625.

(3.) Hicks JT. Treatment of fatigue in general practice: a double-blind study. Clin Med.1964; 71:85-90.

(4.) Agersborg HPK Jr, Shaw DL Jr. Physiologic approach to the problem of fatigue. J Sports Med Phys Fitness.1962; 2:217.

(5.) Formica PE. The housewife syndrome: treatment with the potassium and magnesium salts of aspartic acid. Curr Ther Res.1962; 4:98-106.

(6.) Shaw DL Jr et al. Management of fatigue: a physiologic approach.Am I Med Sci. 1962; 243:758-769.

(7.) Crescenie FJ. Treatment of fatigue in a surgical practice.J Abdom Surg.1962; 4:73-76.

(8.) Friedlander HS. Fatigue as a presenting symptom.Curr Ther Res.1962; 4:441-449.

(9.) Kruse CA. Treatment of fatigue with aspartic acid salts. Northwest Med.1961; 60:597-603.

(10.) Ellis FR, Nasser S.A pilot study of vitamin B 12 in the treatment of tiredness.Br J Nutr.1973; 30:277-283.

(11.) van Tiggelen CJM et al. Assessment of vitamin B12 status in CSF.Am I Psychiatry.1984; 141:136-137.

(12.) Beutler E et al. Iron therapy in chronically fatigued, nonanemic women: a double-blind study. Ann Intern Med.1960; 52:378-394.

(13.) Verdon F et al. Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial. BMj. 2003; 326: 1124.

(14.) Balltn A et al.Iron state in female adolescents. Am J Dis Child.1992; 146:803-805.

(15.) Ciacci C et al. L-Carnitine in the treatment of fatigue in adult celiac disease patients A pilot study. Dig Liver Dis. 2007; 39:922-928.

(16.) Malaguarnera M el al. L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial. Am I Clin Nutr.2007; 86:1738-1744.
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Author:Gaby, Alan R.
Publication:Townsend Letter
Article Type:Editorial
Geographic Code:1USA
Date:Dec 1, 2011
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