Vitamin B1

Vitamin B1 (Thiamine): A Comprehensive Reference

1. Identity: Chemical Names, Natural Sources, and Preparation Forms

Nomenclature and Chemical Structure

Thiamine, also known as thiamin and vitamin B1, is a vitamin — an essential micronutrient for humans and animals. It was the first B vitamin to have been identified, thus its designation B1. It is also known historically as aneurin or antineuritic factor.

The chemical name of thiamine is 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-5-(2-hydroxyethyl)-4-methylthiazolium; its coenzyme form is thiamine pyrophosphate (TPP). The chemical structure consists of an aminopyrimidine and a thiazolium ring linked by a methylene bridge. The thiazole is substituted with methyl and hydroxyethyl side chains. Thiamine is a colorless organosulfur compound with a chemical formula C₁₂H₁₇N₄OS. Thiamine was named by the Williams team as a portmanteau of "thio" (meaning sulfur-containing) and "vitamin."

Thiamine is stable at acidic pH, but it is unstable in alkaline solutions and from exposure to heat. Thiamine is soluble in water, methanol, and glycerol, and practically insoluble in less polar organic solvents.

Phosphorylated Forms and Vitamers

Thiamine occurs in the free form and as an array of interconvertible phosphorylated vitamers, such as thiamine monophosphate (TMP), thiamine diphosphate (also called pyrophosphate, TDP), and thiamine triphosphate (TTP). The predominant vitamer (80%) is thiamine diphosphate, which is also biologically active. Adults store approximately 30 mg thiamine, mainly found in the liver, kidneys, brain, heart, and skeletal muscle.

Natural Sources

Food sources of thiamine include whole grains, legumes, and some meats and fish. Grain processing removes much of the vitamin content, so in many countries cereals and flours are enriched with thiamine. The richest sources are yeasts (e.g., dried brewer's and baker's yeasts), liver (especially pork liver), and pork meat. In plant-based foods, thiamine predominantly occurs in the free form, while in animal-based foods, it is bound to proteins.

Plants and microorganisms synthesize thiamine, but humans and other animals must rely on exogenous dietary sources. Only small amounts are stored in the liver, so a daily intake of thiamin-rich foods is needed.

Supplement and Pharmaceutical Forms

Thiamin is found in multivitamin/mineral supplements, in B-complex dietary supplements, and in supplements containing only thiamin. Common forms of thiamin in dietary supplements are thiamin mononitrate and thiamin hydrochloride. Some supplements use a synthetic form of thiamin called benfotiamine.

Many vitamin B1 analogues, such as benfotiamine, fursultiamine, and sulbutiamine, are synthetic derivatives of thiamine. Most were developed in Japan in the 1950s and 1960s as forms intended to improve absorption compared to thiamine. Some are approved for use in some countries as a drug or non-prescription dietary supplement for treatment of diabetic neuropathy or other health conditions.

Supplements and medications are typically taken by mouth, but may also be given by intravenous or intramuscular injection.

2. Historical and Traditional Use

Ancient Observations

Although symptoms of thiamin deficiency were first recorded in ancient texts of Chinese medicine, the symptoms were not connected with diet until the late 19th century. A Vitamin B Research Committee in Japan provided detailed information on the history of beriberi, now known to be associated with deficiency of thiamine. The disease has been known since antiquity and its original name of 'Kakke' can be found in documents as early as 808.

Beriberi in East Asia

Before the discovery of thiamine, beriberi was a major health problem in East Asian countries, where polished rice (thiamine is mainly present in the husk) was the staple food. This dietary shift contributed to the rising prevalence of beriberi, particularly in major cities such as Kyoto, Nagoya, Edo (modern Tokyo), and Osaka by the late 17th century. In contrast, rural populations and farmers, who relied on mixed grains and less refined brown rice with higher thiamine content, were largely spared from the disease.

It gradually became evident that polished rice ingestion caused beriberi and that rice bran germ, barley and red beans, when taken together with polished rice, would prevent the disease. This represents one of the earliest recorded examples of dietary intervention to prevent a deficiency disease.

The Japanese Navy and the Discovery of Dietary Prevention

The first successful preventive measure against beriberi was discovered by Takaki Kanehiro, a British-trained Japanese medical doctor of the Imperial Japanese Navy, in the mid-1880s. Beriberi was a serious problem in the Japanese navy; sailors fell ill an average of four times a year in the period 1878 to 1881, and 35% were cases of beriberi. Switching diets on a navy ship, he discovered that replacing a diet of white rice only with one also containing barley, meat, milk, bread, and vegetables nearly eliminated beriberi on a nine-month sea voyage.

Scientific Milestones: Isolation, Identification, and Synthesis

Christiaan Eijkman observed that chickens fed white rice developed a leg paralysis or 'polyneuritis', whereas chickens fed brown (unpolished) rice did not. Gerrit Grijns succeeded Eijkman in the beriberi studies in Java and concluded correctly that there were unknown substances in foods that were needed for the peripheral nervous system. In 1929, Eijkman and Hopkins were awarded the Nobel Prize for Physiology or Medicine for their discoveries.

In 1911, a Polish biochemist Casimir Funk isolated the antineuritic substance from rice bran (the modern thiamine) that he called a "vitamine" (on account of its containing an amino group). However, Funk did not completely characterize its chemical structure. Dutch chemists Barend Coenraad Petrus Jansen and his closest collaborator Willem Frederik Donath went on to isolate and crystallize the active agent in 1926, whose structure was determined by Robert Runnels Williams in 1934. Robert Williams synthesized thiamin in 1936.

3. Key Constituents and Mechanisms of Action

The Active Coenzyme: Thiamine Diphosphate (ThDP/TPP)

Thiamine (vitamin B1) is an essential molecule for all living organisms. It is the precursor for several phosphorylated derivatives, the most important being the coenzyme thiamine diphosphate (ThDP). Thiamine is transported into cells by specific transporters and pyrophosphorylated to ThDP in the cytosol. ThDP is a cofactor for important catabolic reactions — pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase (a limiting step in the Krebs cycle), branched-chain 2-oxo acid dehydrogenase, and transketolase (a key enzyme in the pentose phosphate pathway). Therefore, ThDP is indispensable for oxidative energy metabolism.

In its diphosphate form (also known as TDP, thiamine pyrophosphate, TPP, or cocarboxylase), it serves as a cofactor for enzymes involved in carbohydrate metabolism, including transketolase, α-ketoglutarate dehydrogenase, pyruvate dehydrogenase, and branched chain α-keto acid dehydrogenase. These enzymes are involved in pathways that allow for the production of ATP, NADPH, and ribose-5-phosphate, which are critical for generating cellular energy and downstream production of amino acids, nucleic acids, and fatty acids.

Thiamine pyrophosphate is synthesized in the cytosol and is required in the cytosol for the activity of transketolase, and in the mitochondria for the activity of pyruvate-, oxoglutarate- and branched chain keto acid dehydrogenases.

Role in Carbohydrate and Energy Metabolism

Thiamin (vitamin B1) helps the body's cells change carbohydrates into energy. The main role of carbohydrates is to provide energy for the body, especially the brain and nervous system. In thiamine deficiency, pyruvate cannot be metabolized and accumulates in the blood. Thiamine TPP is also an essential cofactor for transketolase in the pentose-phosphate pathway.

Neurological and Non-Coenzyme Roles

Thiamin also plays a role in muscle contraction and conduction of nerve signals. It is needed to ensure the proper functioning of the central and peripheral nervous system, where it is involved in neurotransmitter synthesis. Other reputed non-cofactor roles of thiamine compounds include the oxidative stress response, gene regulation, the cholinergic system, immune function, chloride channels, and neurotransmission.

Thiamin (vitamin B1) is a pharmacological agent boosting central metabolism through the action of the coenzyme thiamin diphosphate (ThDP). However, positive effects including improved cognition of high thiamin doses in neurodegeneration may be observed without increased ThDP or ThDP-dependent enzymes in brain. Thiamin is not only a coenzyme for acetyl-CoA production, but also an allosteric regulator of acetyl-CoA metabolism including regulatory acetylation of proteins and acetylcholine biosynthesis.

Absorption, Transport, and Storage

Ingested thiamine from food and dietary supplements is absorbed by the small intestine through active transport at nutritional doses and by passive diffusion at high concentrations. Thiamine absorption in the jejunum involves both passive diffusion and active transport, with thiamine being converted into thiamine pyrophosphate (TPP). At high concentrations, thiamine can pass through the intestinal membranes by spontaneous diffusion. The total amount of vitamin B1 in the body is 30 mg, 40% of which is in the muscles.

The brain requires much more thiamine than other tissues of the body. Much of ingested thiamine never reaches the brain because of passive diffusion and the blood–brain barrier.

4. Scientific Evidence by Area of Use

4.1 Thiamine Deficiency, Beriberi, and Prevention

The most common effect of thiamin deficiency is beriberi, which is characterized mainly by peripheral neuropathy and wasting. People with this condition have impaired sensory, motor, and reflex functions. There are two clinical types of avitaminosis: wet and dry. The former is accompanied by extensive edema, resulting in an abnormal cardiovascular system, circulatory failure and heart attack, while the latter is associated with abnormal functioning of the nervous system and the development of polyneuropathy. In the acute form of beriberi disease, called Shoshin syndrome, cardiovascular failure, metabolic acidosis, and pulmonary edema may occur.

The incidence of beriberi in Asia has markedly decreased because an improved standard of living has allowed a more varied diet and partly because of the gradual popular acceptance of partially dehusked, parboiled, and enriched rice — forms that contain higher concentrations of thiamin. The clinical evidence base for thiamine supplementation in frank deficiency and beriberi is considered well-established, grounded in decades of observational and interventional data, and thiamine repletion is universally recommended for confirmed deficiency.

4.2 Wernicke–Korsakoff Syndrome (WKS)

Korsakoff syndrome is a chronic amnesia resulting from unrecognized or undertreated Wernicke encephalopathy and is caused by thiamine (vitamin B1) deficiency. The combination of Wernicke encephalopathy and Korsakoff syndrome is also called Wernicke-Korsakoff syndrome. The triad signs of Wernicke encephalopathy are described as ocular motility abnormalities (external ophthalmoplegia and/or nystagmus), ataxia affecting primarily the gait, and confusion or delirium. Caine and colleagues proposed four specific criteria for the clinical identification of Wernicke encephalopathy: the presence of dietary deficiencies, oculomotor abnormalities, cerebellar dysfunction, and either an altered mental state or mild memory impairment.

While chronic alcohol misuse remains the classic risk factor, thiamine deficiency is increasingly documented in malnutrition, hyperemesis gravidarum, post-bariatric surgery, chronic gastrointestinal disease, and malignancy. Whether the tools were magnetic resonance imaging, diffusion tensor imaging, positron emission tomography, autopsy, or memory testing, the narrative stayed consistent: the mammillary bodies, thalamus, hippocampus, and cerebellum take the greatest hit. Imaging reveals symmetrical atrophy, micro-hemorrhages, and fraying white-matter tracts deeper in alcohol-related WKS, while non-alcoholic cases show extracortical or cerebellar lesions.

Despite universal clinical acceptance of thiamine for WKS treatment, the formal randomized trial evidence base is limited. There is insufficient evidence from randomized controlled clinical trials to guide clinicians in the dose, frequency, route or duration of thiamine treatment for prophylaxis against or treatment of WKS due to alcohol abuse. Nevertheless, prompt treatment is universally advocated: the best scanner cannot outmatch a timely intravenous dose of thiamine. Hours separate reversible Wernicke's encephalopathy from lifelong Korsakoff syndrome.

4.3 Heart Failure and Cardiac Function

The rates of poor thiamin status in patients with heart failure have ranged in studies from 21% to 98%. Most studies assessing body thiamine status have reported variable degrees of thiamine deficiency in patients with heart failure, particularly those treated chronically with high doses of furosemide. Thiamine deficiency in patients with heart failure seems predominantly to be due to increased urine volume and urinary flow rate. There is also evidence that furosemide may directly inhibit thiamine uptake at the cellular level.

An early clinical study examined 23 patients with chronic CHF receiving furosemide (80–240 mg/day for 3–14 months). Researchers assessed the effect of thiamine repletion on thiamine status, functional capacity, and left ventricular ejection fraction (LVEF). Thirty patients were randomized to one week of double-blind inpatient therapy with either IV thiamine 200 mg/day or placebo (n=15 each). All previous drugs were continued. Following discharge, all 30 patients received oral thiamine 200 mg/day as outpatients for 6 weeks. Thiamine repletion can improve left ventricular function and biochemical evidence of thiamine deficiency in some patients with moderate-to-severe CHF who are receiving long-term furosemide therapy. These studies are small and exploratory; larger-scale confirmatory RCTs are lacking, and the evidence is regarded as preliminary.

4.4 Diabetes Mellitus and Diabetic Complications

Some small studies have shown that oral supplementation with 150–300 mg/day thiamin can decrease glucose levels in patients with type 2 diabetes or impaired glucose tolerance. However, the authors of these studies did not assess the potential clinical significance of these findings.

A few small randomized studies have assessed the effects of benfotiamine supplements on diabetic neuropathy. Three studies found that, compared to placebo, 120–900 mg/day benfotiamine with or without other B-vitamins decreased the severity of neuropathy symptoms and lowered urinary albumin excretion (a marker of early-stage diabetic nephropathy). However, another study found no effect of 900 mg/day benfotiamine on urinary excretion of albumin or kidney injury molecule-1, a marker of kidney injury. Well-designed studies with larger sample sizes and longer durations are required to determine whether thiamin supplements can reduce glucose levels in patients with diabetes or decrease diabetic complications. The evidence in this area is therefore mixed and insufficient to support routine supplementation for diabetes management.

4.5 Alzheimer's Disease and Cognitive Decline

The role of thiamine in memory/cognition and as the cause of the brain and memory disorder Wernicke-Korsakoff syndrome (WKS) has been well known since the 1930s, and data support a role in AD. Multiple batteries of memory tests demonstrate clinical similarities of AD and WKS. The activities of thiamine-dependent enzymes are reduced in the brains of WKS patients and in patients with AD.

Animal studies suggest that a lack of thiamin may cause oxidative stress or the death of nerve cells, memory loss, formation of plaque, and reduced glucose metabolism, which are all risk factors for Alzheimer's disease. Post-translational modifications have been identified on tau and amyloid-beta with effects that have been shown to promote plaque and tangle formation, neuroinflammation, neurodegeneration, and increased advanced glycation end products (AGE), which are regulated by thiamine. AGE are toxic modifications that form by the chemical addition of glucose and its byproducts to proteins, lipids and nucleotides when glucose is not tightly controlled in the cell, as is seen with the abnormal glucose metabolism in AD. High concentrations of AGE are predictive of long-term decline in cognition-related daily living performance in patients with AD.

Benfotiamine, a prodrug of thiamine, provides a novel therapeutic direction in AD that has potential for additive or synergistic effects beyond current mainstream approaches. It is a first-in-class small molecule with a unique mechanism of action, raising blood thiamine (vitamin B1) 50–100 times to pharmacological levels. In this way, it addresses and treats a well-characterized tissue thiamine action deficiency in AD that is associated with changes in glucose metabolism and thiamine-dependent post-translational modifications linked to AD pathology. Clinical trial evaluation is ongoing; the evidence in this area is currently preliminary and does not yet support clinical recommendations.

4.6 Sepsis and Critical Illness

A randomized, double-blind, placebo-controlled trial was conducted to determine if intravenous thiamine would reduce lactate in patients with septic shock, conducted at two US hospitals, enrolling adult patients with septic shock and elevated lactate (>3 mmol/L). The intervention was thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge. The observation that thiamine would decrease lactate in deficiency states is consistent with the expected pathophysiology, and suggests that a sub-clinical form of beriberi may exist in patients with septic shock.

An exploratory subgroup analysis with a limited sample size revealed supplementation of thiamine reduced mortality in thiamine-deficient patients; however, the sample size included in this outcome analysis was excessively small (a total of 51 cases). As such, the results have significant limitations and should only be regarded as hypotheses for future research, rather than a basis for clinical practice. Overall, current evidence does not support pharmacological use of single thiamine supplementation in septic shock patients, and future trials will probably focus on an early multi-micronutrient approach.

4.7 Bariatric Surgery

Bariatric surgery for weight loss is known to interfere with vitamin absorption. A meta-analysis reported that 27% of people who underwent bariatric surgeries experience vitamin B1 deficiency. A 2008 literature review identified 84 cases of Wernicke's encephalopathy after bariatric surgery (primarily gastric bypass surgery) between 1991 and 2008. About half of these patients experienced long-lasting neurologic impairments. Micronutrient supplements that include thiamin are almost always recommended for patients following bariatric surgery to avoid deficiencies.

4.8 Refeeding Syndrome

Although all vitamin deficiencies may occur at variable rates with inadequate intake, thiamine is of most importance in complications of refeeding. Thiamine is an essential coenzyme in carbohydrate metabolism. Its deficiency results in Wernicke's encephalopathy (ocular abnormalities, ataxia, confusional state, hypothermia, coma) or Korsakoff's syndrome (retrograde and anterograde amnesia, confabulation). Supplementation of thiamine is commonly provided to patients at risk for refeeding syndrome to prevent exacerbation of an underlying thiamine deficiency when nutrition is reintroduced.

5. Body Systems and Health Areas of Association

• Central and Peripheral Nervous System: Thiamine deficiency leads to mitochondrial dysfunction, lactate and pyruvate accumulation, and consequently to focal thalamic degeneration, manifested as Wernicke's encephalopathy or Wernicke–Korsakoff syndrome.
• Cardiovascular System: Beriberi disease may result in skeletal muscle atrophy, weakening of the contractile strength of the heart muscle, reduced blood pressure and paralysis of the nervous system.
• Metabolic System / Energy Production: Thiamine plays a special role in the body as a coenzyme necessary for the metabolism of carbohydrates, fats and proteins. In addition, it participates in cellular respiration and oxidation of fatty acids. It also participates in energy production in the mitochondria and protein synthesis.
• Musculoskeletal System: Thiamin plays a role in muscle contraction and conduction of nerve signals.
• Brain and Cognition: Thiamine deficiencies are also associated with aging-related disorders such as Parkinson's, Alzheimer's, kidney disease, cancer, mental disorders, and other diseases of the cardiovascular and nervous systems.
• Gastrointestinal System: Ingested thiamine from food and dietary supplements is absorbed by the small intestine through active transport at nutritional doses and by passive diffusion at high concentrations.

6. Recommended Intakes and Dosages Reported in Studies

Dietary Reference Intakes (United States)

The current Estimated Average Requirements (EARs) for thiamine for women and men ages 14 and up are 0.9 mg/day and 1.0 mg/day, respectively; the RDAs are 1.1 and 1.2 mg/day. The RDA for pregnancy equals 1.4 mg/day. The RDA for lactation also equals 1.4 mg/day. For infants up to 12 months, the Adequate Intake (AI) is 0.2–0.3 mg/day, and for children ages 1–13 years the RDA increases with age from 0.5 to 0.9 mg/day.

A Tolerable Upper Intake Level (UL) is the maximum daily dose unlikely to cause adverse side effects in the general population. There is no UL for thiamin due to a lack of reports showing negative effects from high thiamin intakes.

Dosages Used in Clinical Studies

• Type 2 diabetes / impaired glucose tolerance: Oral supplementation with 150–300 mg/day thiamin has been studied for decreasing glucose levels in patients with type 2 diabetes or impaired glucose tolerance.
• Diabetic neuropathy (benfotiamine): 120–900 mg/day benfotiamine with or without other B-vitamins has been used in small randomized studies.
• Congestive heart failure / furosemide-related deficiency: Thirty patients were randomized to one week of double-blind inpatient therapy with either IV thiamine 200 mg/day or placebo, followed by oral thiamine 200 mg/day for 6 weeks as outpatients.
• Septic shock: Adult patients with septic shock and elevated lactate received thiamine 200 mg or matching placebo twice daily for 7 days or until hospital discharge.
• Wernicke-Korsakoff syndrome (non-alcoholic, single case report): The patient received high-dose thiamine (300 mg three times daily).

7. Safety Considerations and Notable Interactions

General Safety Profile

Like all water-soluble vitamins, thiamine is rapidly expelled through the urinary system, does not accumulate in the body, and has no toxic effects. Thiamine supplements are generally well tolerated. The Food and Nutrition Board of the U.S. Institute of Medicine sets Tolerable Upper Intake Levels (ULs) for vitamins and minerals when evidence is sufficient. In the case of thiamine there is no UL, as there is no human data for adverse effects from high doses.

Hypersensitivity reactions have been reported following repeated parenteral doses. Parenteral preparations may contain aluminum; use caution in patients with impaired renal function.

Drug Interactions: Loop Diuretics (Furosemide)

Furosemide (Lasix) is a loop diuretic used to treat edema and hypertension by increasing urinary output. Research has linked the use of furosemide to decreases in thiamin concentrations, possibly to deficient levels, as a result of urinary thiamin loss. In patients taking loop diuretics, thiamine excretion has been observed to double compared to patients not taking diuretics. Biochemical evidence of severe thiamine deficiency was found in 98% (24 of 25) patients receiving at least 80 mg/day of furosemide and in 57% (four of seven) of patients taking 40 mg furosemide daily.

Alcohol Use Disorder

Alcohol alone can decrease thiamine absorption by approximately 50% in healthy patients. When coupled with malnutrition, thiamine absorption is decreased to 70%. The absorption of thiamine and pyridoxine may commonly be decreased in alcoholics and in patients with cirrhosis.

Drug-Nutrient Interactions: Transporter Inhibition

A clinical trial involving fedratinib raised awareness in the drug development and regulatory communities about the potential for transporter-mediated drug-nutrient interactions. Although thiamine deficiency has been primarily associated with alcoholism, malnutrition, and various disease states such as HIV infection, this event brought to light a new mechanism for thiamine deficiency — drug-induced deficiency through inhibition of thiamine transporters.

Populations at Elevated Risk of Deficiency

Vitamin B1 deficiency is a common, underrecognized cause of multisystem illness spanning cardiovascular, neurologic, and metabolic complications. Populations at highest risk include individuals with chronic alcohol use disorder, malnutrition, bariatric surgery, diuretic use, and increased metabolic demand. Thiamine deficiency is increasingly documented in malnutrition, hyperemesis gravidarum, post-bariatric surgery, chronic gastrointestinal disease, and malignancy.

Refeeding Syndrome and Thiamine

The body stores of thiamine (vitamin B1) are sufficient for up to 7 days. It is a co-factor in aerobic glucose consumption. In thiamine deficiency, a combined enzyme defect results in aerobic metabolism impairment and insufficient ATP generation. Furthermore, pyruvate is converted into lactate, resulting in hyperlactaemia and lactic acidosis. As thiamine-dependent metabolic pathways are present in almost all human cells, deficiency can affect many organ systems. Adequate thiamine status must therefore be ensured before or alongside reintroduction of nutrition in malnourished patients.

Magnesium as a Cofactor

Patients with hypomagnesemia may fail to respond to thiamine. This may especially be the case in the context of alcohol withdrawal or in adverse side effects of proton pump inhibitors combined with diuretics. Magnesium is an important cofactor for thiamine-dependent enzymes, and concurrent deficiency can impair thiamine's effectiveness.

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