Chemistry and Forms

In 1926, thiamine was the first B vitamin isolated, as a crystalline, water-soluble, yellowish white powder with a salty, slightly nutty taste. By 1936 it had been synthesized and its chemical structure determined. This substance is heat and oxygen stable in its dry form, heat and alkali reactive in solution, and stabilized by acid.

Physiology and Function

Thiamine uptake by active transport is highest in the jejunum and ileum, with both passive diffusion and active, carrier-mediated transport. Throughout the small intestine, and generally by cells in various organs, absorption is mediated by a saturable, high-affinity transport system, and once absorbed, thiamine is primarily transported in the serum bound to albumin. In humans, thiamine can be synthesized in the large intestine as thiamine pyrophosphate (TPP). Too large a molecule to be absorbed across the intestinal mucosa, TPP requires the use of an enzyme to cleave the smaller thiamine molecule out of the compound. Skeletal muscle, heart, liver, kidneys, and the brain are sites of particularly high concentrations, although only small amounts of thiamine (30-70 mg) are typically stored in the body.

Thiamine is required for all tissues as a coenzyme in the metabolism of carbohydrates and branched-chain amino acids, particularly in the tricarboxylic acid (TCA) cycle and pentose phosphate shunt. Thiamine needs to be phosphorylated to become metabolically active, and thiamine diphosphate is its active form. Thiamine diphosphate is a cofactor for several important enzymes involved in the biosynthesis of neurotransmitters and various cell constituents, for the production of reducing equivalents used in oxidative stress responses, and for the biosyntheses of pentoses (e.g., ribose, deoxyribose) used as nucleic acid precursors. When it combines with two molecules of phosphoric acid, thiamine will form TPP. Functioning as a co-carboxylase, TPP is required for the oxidative decarboxylation of pyruvate to form active acetate and acetyl coenzyme A. It is also required for the oxidative decarboxylation of other alpha keto acids such as α-ketoglutaric acid and the 2-keto-carboxylates derived from the amino acids methionine, threonine, leucine, isoleucine, and valine. TPP is also involved as a coenzyme for the transketolase reaction, which functions for the pentose monophosphate shunt pathway. With a specific role in neurophysiology separate from its coenzyme function, TPP works at the nerve cell membrane to allow displacement so that sodium ions can freely cross the membrane. Although thiamine is needed for the metabolism of carbohydrates, fat, and protein, it is especially central to carbohydrate metabolism in the brain. In addition to providing TPP, thiamine becomes part of thiamine triphosphate, which appears to have an important function in brain cell viability. Thiamine is also required in acetylcholine and fatty acid synthesis.

Research is ongoing into the genetic and biochemical factors contributing to interindividual differences in susceptibility to development of disorders related to thiamine deficiency, as well as the differential vulnerabilities of various tissues and cell types.

Known or Potential Therapeutic Uses

Thiamine deficiency manifests primarily as disorders of the nervous, cardiovascular, muscular, and gastrointestinal systems. Deficiency symptoms include: fatigue, weight loss, depression, irritability, memory loss, mental confusion, heart palpitations, tachycardia, anorexia, indigestion, edema, neuritis, neuropathies, paresthesia, hyporeflexia (especially of legs), defective muscular coordination, muscular weakness, and sore muscles (especially calves).

Historical/Ethnomedicine Precedent

Beriberi, the classic thiamine deficiency disease.

Possible Uses

Alcoholism, Alzheimer's disease, anxiety, atherosclerosis, canker sores, chronic dieting, congestive heart failure (CHF), Crohn's disease, depression, diabetes mellitus, dysmenorrhea, fibromyalgia, glaucoma, hepatitis, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) support, insomnia, Kearns-Sayre syndrome, Leigh's disease, minor injuries, mosquito repellant, multiple sclerosis, neuropathy (especially benfotiamine), roundworms, sciatica, sensory neuropathy (diabetic), trigeminal neuralgia, Wernicke-Korsakoff syndrome; diets consisting primarily of highly processed, refined foods; treatment of thiamine deficiency–related disorders, including cardiovascular (wet) beriberi, nervous (dry) beriberi, Wernicke's encephalopathy syndrome, and peripheral neuritis associated with pellagra (vitamin B3deficiency); alcoholic patients with altered sensorium; various genetic metabolic disorders, such as thiamine-responsive megaloblastic anemia.

Dietary Sources

Pork, liver, chicken, fish, beef, wheat germ, dried yeast, cereal products, lentils, potatoes, brewer's yeast, rice polishings, most whole-grain cereals (especially wheat, oats, and rice), all seeds and nuts, beans (especially soybeans), milk and milk products, vegetables such as beets, green leafy vegetables.

Most plant and animal foods contain some thiamine, but the richest dietary sources are brewer's yeast and organ meats.

Thiamine deficiency is one of the most common nutritional deficiency patterns in modernized societies. Almost half the U.S. population consumes less than half the recommended daily allowance (RDA) of thiamine, according to the U.S. Department of Agriculture. Although whole grains may be rich in thiamine, processing of grains significantly reduces their thiamine content. Likewise, because thiamine is water soluble and heat sensitive, cooking largely results in the loss or destruction of this vitamin, especially when chlorinated water is used.

Clinical signs of thiamine deficiency primarily involve the nervous, cardiovascular, muscular, and gastrointestinal systems. Adults have the following symptoms:

• Mental confusion, anorexia, muscle weakness, calf muscle tenderness, ataxia, indigestion, constipation, tachycardia with palpitations.
• Wet beriberi: edema starting in the feet and progressing upward into the legs, trunk, and face, eventually resulting in death from cardiac enlargement and CHF.
• Dry beriberi: worsened polyneuritis in early stages (particularly peripheral neuritis), difficulty walking, and muscle wasting, especially atrophy of the legs.

The distinction between wet (cardiovascular) and dry (neuritic) manifestations of beriberi usually relates to the duration and severity of the deficiency, the degree of physical exertion, and the caloric intake. The wet or edematous condition results from severe physical exertion and high carbohydrate intake. The dry or polyneuritic form stems from relative inactivity with caloric restrictions during the chronic deficiency.

Wernicke-Korsakoff syndrome is the classical manifestation of central nervous system (CNS) deficiency of thiamine caused by alcoholism. Patients present with impaired memory and cognitive function, irritability, and nystagmus caused by weakness in the sixth cranial nerve; coma is a common end state. Vitamin B1is necessary for the metabolism of alcohol, but alcohol interferes with its absorption, making malnourished alcoholics often severely thiamine deficient. Alcoholics given intravenous (IV) glucose without thiamine are at high risk of developing Wernicke-Korsakoff syndrome and sustain permanent neurological damage, because the glucose, which also requires thiamine for its metabolism, rapidly depletes remaining tissue levels of brain thiamine. For this reason, an IV “cocktail” of glucose, thiamine, and a narcotic antagonist is typically administered in emergency rooms to unconscious patients who present with unconsciousness of unknown etiology.

Infant symptoms appear suddenly and severely, involving cardiac failure and cyanosis.

The etiology of thiamine deficiency can be traced to an exclusive diet of milled, nonenriched rice or wheat, raw fish consumption (microbial thiaminases), large amounts of tea, alcoholism (impaired absorption and storage, poor nutrition, increased thiamine utilization), use of loop diuretics, and several inborn errors of metabolism.

Special Populations

Individuals with alcoholism, anorexia, CHF, Crohn's disease, folate deficiency, malabsorption syndrome, and multiple sclerosis are at increased risk of developing thiamine deficiency, as are those undergoing long-term diuretic therapy, hemodialysis, or peritoneal dialysis.

Alcoholic individuals frequently develop a deficiency of thiamine because the vitamin is a necessary cofactor in the metabolism of alcohol. Because many alcoholics tend to eat less and drink more, and usually their alcohol-based drinks are low in thiamine, they frequently develop a thiamine deficiency. In hospitals it is routine for alcoholics to receive intramuscular (IM) injections of thiamine on admission.

Elderly persons demonstrate a general decline in thiamine levels that is apparently related more to age than to coexisting illness or health status. This increased susceptibility enhances the risk for adverse effects of drug-induced depletion, especially in regard to cardiovascular health and cognitive stability. ¹

Nutrient Preparations Available

Thiamine, water soluble. Thiamine hydrochloride is generally considered the preferred supplemental form of thiamine. Thiamine mononitrate is also available. Thiamine supplementation is usually provided in vitamin B–complex formulations, in most multivitamin preparations, and in vitamin-enriched foods, such as breakfast cereals.

Benfotiamine is a lipid-soluble form of thiamine developed and patented in Japan, now widely used in neuropathy therapies.

Dosage Forms Available

Capsule, liquid, tablet, effervescent tablet; liposomal spray. Parenteral form may be administered by IM or slow IV injection.

Source Materials for Nutrient Preparations

Synthesized.

Dosage Range

The RDA for thiamine varies slightly with gender and life stage.

• Men (>19 years): 1.2 mg/day
• Women (>19 years): 1.1 mg/day
• Pregnancy and breastfeeding (any age): 1.4 mg/day

Adults

• Supplemental/Maintenance:   Dependent on dietary intake, usually 1 to 2 mg/day. A paper on the “ideal” daily thiamine intake reported that the healthiest people consumed more than 9 mg/day. ²
• Pharmacological/Therapeutic:   1.5 to 200 mg/day. In research studies, therapeutic dosage for most conditions ranges from 10 to 100 mg/day, in divided doses. In clinical practice, 200 to 600 mg/day may be given, and some clinicians have used oral dosages as high as 8 g/day, in divided doses, for a variety of metabolic disorders.
• Thiamine deficiency (beriberi):   5 to 30 mg per dose, intramuscularly (IM) or intravenously (IV), three times daily (if critically ill); then orally 5 to 30 mg/day in single or divided doses, three times daily for 1 month.
• Wernicke's encephalopathy:   100 mg IV initially, then 50 to 100 mg/day IM or IV until consuming a consistently balanced and nutritious diet.
• Toxic:   There is no defined upper limit (UL) for thiamine because of its relative safety.

Pediatric (<18 years)

Supplemental/Maintenance:

• Infants: 0.3 to 0.5 mg/day
• Children: 0.5 to 1 mg/day

• Toxic:   No toxic intake level known to date.

Overview

Thiamine is generally considered virtually nontoxic, even in very high doses orally. Being water soluble, thiamine excretion is rapid; the vitamin is not stored in the body, and accumulation to toxic levels is highly improbable using oral intake. No adverse effects associated with thiamine intake from food sources or nutritional supplements have been reported. Rare occurrences of adverse effects of thiamine have been documented, although they appear to be largely associated with allergic reactions to thiamine injections.

Nutrient Adverse Effects

General Adverse Effects

Adverse effects are theoretically possible but rare with oral supplemental thiamine intake. Oral doses greater than 200 mg have been reported to cause drowsiness in some individuals. In a study of 989 patients, 100 mg/day IV thiamine hydrochloride resulted in a burning effect at the injection site in 11 subjects and pruritus in one. ³

Large doses of vitamin B1over an extended period may cause imbalance among various B vitamins.

Administration of IV or IM thiamine warrants caution because anaphylactic or allergic reaction infrequently occurs. Allergic reactions to thiamine injections are rare (<1%) but can be severe and include cardiovascular collapse and death, angioedema, paresthesia, warmth, and rash.

Adverse Effects Among Specific Populations

High oral intakes might have some unknown potential for adverse reactions in select, metabolically compromised populations because of pharmacogenomic susceptibility, but such data are only recently under consideration.

Pregnancy and Nursing

A review of the medical literature reveals no substantial reports of adverse effects related to fetal development during pregnancy or to breast-fed infants.

Infants and Children

A review of the medical literature reveals no substantial reports of adverse effects specifically related to the use of thiamine in infants and children.

Contraindications

No contraindications are known to date, except hypersensitivity to thiamine or to any component of any compound formulation. Some clinicians and researchers are proposing that cancer patients undergoing chemotherapy may benefit from restricted thiamine intake during treatment.

Precautions and Warnings

Use with caution with parenteral administration, especially with IV administration.

Laboratory Values

Whole-blood thiamine: Level less than 70 nmol/L indicates deficiency.

Erythrocyte transketolase (EKTA): Low activity of EKTA (<5 U/mmol hemoglobin) indicates deficiency, as does increase in EKTA (>16 U/mmol) after stimulation by the addition of TPP.

Therapeutic reference range: 1.6-4.0 mg/dL.

Strategic Considerations

Thiamine plays a critical role in a range of metabolic processes, especially the Krebs cycle and adenosine triphosphate (ATP) synthesis. Vitamin B1depletion by diet, lifestyle, or medications increases several risk factors, especially for the cardiovascular and nervous systems. Although thiamine is central to metabolic vitality and cardiovascular health, the use of loop diuretics increases the risk of clinically significant thiamine depletion. However, adverse effects caused by drug depletion can be safely and effectively treated with thiamine supplementation, while further supporting healthy cardiac function. Thiamine intake during chemotherapy is challenging, and personalized integrative care may clarify paradoxical data. In other, simpler situations, the potential for adverse effects from unintentional depletion of thiamine by pharmacological agents can be corrected through supplementation at typical therapeutic levels.

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