Thiamine (vitamin B1)

In brief

What thiamine is

Think of the food you eat as fuel waiting at the door of a furnace. Sugar is broken down in the body until it becomes a small molecule called pyruvate, and pyruvate has to be handed through the door into the mitochondria, the small furnaces inside every cell, before most of its energy can be used. Thiamine is the hand that passes it through. Without enough of it, fuel piles up outside the door, and the cells that burn the most, in the brain, the nerves and the heart, are the first to struggle ^1,3.

Chemically, thiamine is two rings tied together by a single carbon. One is a pyrimidine, a six-membered ring with two nitrogens and an amino group, the same family of ring that appears in DNA. The other is a thiazolium, a five-membered ring with a nitrogen, a sulfur and a permanent positive charge, carrying a short arm that ends in an alcohol ¹. The name says as much: thi- for the sulfur and -amine for the amino group.

Thiamine as it arrives in food or in a tablet is not the working form. Once inside a cell, an enzyme called thiamine pyrophosphokinase adds two phosphates to the alcohol arm, making thiamine diphosphate, and that is the molecule the enzymes actually hold ^2,3. Bacteria, yeasts and plants build thiamine from scratch, assembling the two rings separately and joining them; animals lost the pathway and have to take the vitamin in ⁵.

Every form, side by side

Every card below is drawn on the same skeleton, the same way up and at the same scale. The pyrimidine is always on the left, the bridging carbon always in the same place, and the thiazole or what is left of it always to the right of the bridge. What a form adds or changes sits on the copper wash, so the comparison is made by the eye rather than by reading the formulas.

The cards fall into five groups. The first four forms are made by your own cells. The two salts are what tablets and injections contain. The six fat-soluble cousins open the thiazole ring and hang something on the freed sulfur, which lets them cross membranes without a transporter. The three impostors are close enough copies to be mistaken for thiamine. The last card is what thiamine becomes in the laboratory, so that it can be measured ^3,17,19,26.

One distinction matters more than the rest. The disulfides, allithiamine, prosultiamine, fursultiamine and sulbutiamine, are genuinely fat-soluble. Benfotiamine is not: it is an S-acyl compound with a charged phosphate, practically insoluble in both water and oil, and it reaches the blood by a different route ¹⁷. The marketing that groups them together is the most common error made about vitamin B1.

The whole history, including the reversals

Beriberi was named long before anyone knew what caused it, and the first serious explanations were wrong. Each of the reversals below was made by someone working carefully with the evidence of their day, which is the reason to keep them on the page ^6,44.

What it does in the body

Thiamine diphosphate's whole repertoire rests on one carbon. Bound inside an enzyme, the carbon between the thiazolium's nitrogen and sulfur loses its hydrogen and becomes a carbanion, a carbon carrying a negative charge, which attacks the carbonyl carbon of a substrate and holds onto it while the bond beside it breaks ¹. The rest of the molecule is a handle: the phosphates anchor it in the enzyme, and the pyrimidine's amino group helps pull the hydrogen off C2 ¹.

In people, the enzymes that use it sit at the junctions of metabolism. Pyruvate dehydrogenase turns pyruvate into acetyl-CoA, the step that admits sugar into the mitochondria. 2-oxoglutarate dehydrogenase runs a step of the citric acid cycle. Transketolase, in the pentose phosphate pathway, makes the ribose cells need to copy DNA. The branched-chain keto acid dehydrogenase breaks down leucine, isoleucine and valine, and 2-hydroxyacyl-CoA lyase, in the peroxisomes, shortens certain fatty acids ^1,26,50.

The other phosphorylated forms are a puzzle. Thiamine triphosphate occurs in small amounts in most organisms, from bacteria to humans; in bacteria it rises when amino acids run short and is made by the same ATP synthase that makes ATP, and in rat brain membranes its level tracks chloride permeability ^30,31,32. Adenosine thiamine triphosphate appears when bacteria run out of carbon ⁴. Both look more like signals than cofactors, and in people their functions are not known ³.

Getting it in: transporters, drugs and the fat-soluble route

Thiamine is charged, so it does not cross cell membranes on its own. Two transporters do the work: THTR-1, made from the SLC19A2 gene, and THTR-2, from SLC19A3, which carry it across the gut wall and into cells ⁸. In the liver, the organic cation transporter OCT1 turns out to be a high-capacity thiamine carrier as well ⁹. Mutations in each step cause their own disease: SLC19A2 thiamine-responsive megaloblastic anemia with diabetes and deafness, SLC19A3 a basal ganglia disease of children, and TPK1, the enzyme that makes the diphosphate, a childhood encephalopathy with ataxia, dystonia and lactic acidosis ^2,46,52.

Drugs use the same doors. Metformin is both carried by and an inhibitor of THTR-2, and it competitively blocks thiamine entry through OCT1; given to mice, it reduced the thiamine taken up by the gut ^9,28. Phenformin, chloroquine, verapamil, famotidine and amprolium inhibit THTR-2 too ²⁸. Fedratinib, a drug for the blood cancer myelofibrosis, had its development halted after cases of Wernicke's encephalopathy, and the explanation proposed is that it blocks THTR-2; the antibiotic trimethoprim blocks both transporters at concentrations of about 6 micromolar ²⁹. Fedratinib was later approved in the United States, in 2019 ⁵³.

The old teaching that oral thiamine stops being absorbed above a few milligrams does not survive measurement. In healthy adults given 100, 500 and 1,500 mg of thiamine hydrochloride by mouth, blood levels kept rising with the dose, less than proportionally but without a ceiling, because a passive process takes over when the transporters are full ¹⁰.

The fat-soluble derivatives were invented to go around the transporters altogether. A disulfide crosses membranes by diffusion and is reduced back to thiamine inside the cell, which is why these compounds reach higher blood levels than the same dose of the salt ^16,17. An early human study measured the absorption and use of thiamine propyl disulfide in people with alcohol use disorder ³⁵. Benfotiamine reaches the blood by yet another path: given by mouth in healthy volunteers, it produced about eleven times the plasma thiamine and twice the red-cell thiamine diphosphate of an equal dose of thiamine hydrochloride, and left hippuric acid behind from its benzoyl group ^54,55,56.

When it runs out: beriberi and Wernicke's

Deficiency has two classical faces. Dry beriberi is a neuropathy, numbness and weakness spreading up the legs. Wet beriberi is heart failure with fluid retention. In infants breastfed by deficient mothers it is still a cause of death ¹². Wernicke's encephalopathy is the brain's version: confusion, eye-movement problems and an unsteady walk, which can leave the permanent memory loss of Korsakoff syndrome ^12,57.

It is still common where diets depend on polished rice or other staples low in thiamine, and where food is prepared in ways that wash or mill it away. No biomarker is agreed upon, which makes its true prevalence hard to count, and there is evidence that even subclinical deficiency in childhood may have lasting effects on development ¹². In 2003 it appeared in Israel, in infants fed a soy-based formula manufactured without thiamine: several developed encephalopathy and two died of cardiomyopathy ⁴⁷.

In wealthy countries it follows illness and surgery. Of 84 cases of Wernicke's encephalopathy after bariatric surgery, 94 percent began within six months of the operation, 90 percent followed frequent vomiting, and in 18 percent intravenous glucose had been given without thiamine; half of the patients did not fully recover ¹³. In hyperemesis gravidarum, people had vomited for a median of seven weeks before Wernicke's set in, and pregnancy was lost in half of the cases ¹⁴. Long-term furosemide, by washing thiamine out in urine, produced biochemical deficiency in people with heart failure, and replacing it improved heart function in a placebo-controlled study ^18,58.

The diagnosis is easy to miss. In a necropsy series, 80 percent of people with Wernicke-Korsakoff syndrome had never been diagnosed during life, and only 16 percent had shown all three textbook signs ¹⁵. The European guideline's response is to treat on suspicion: parenteral thiamine for every at-risk patient in the emergency department, given before any glucose ⁵⁷.

Treating deficiency, and what the doses rest on

There is no doubt that thiamine treats thiamine deficiency. There is surprisingly little trial evidence about how much to give. A Cochrane review found that randomized trials were insufficient to guide the dose, frequency, route or duration of thiamine for preventing or treating Wernicke-Korsakoff syndrome in people with alcohol use disorder ⁵⁹.

The guidelines therefore rest on physiology and experience. The European Federation of Neurological Societies recommends 200 mg three times a day, preferably intravenously, given before any carbohydrate, and follow-up of thiamine status for at least six months after bariatric surgery ⁵⁷. The Royal College of Physicians set out similar guidance for emergency departments ⁶⁰. In hyperemesis gravidarum, a systematic review recommends 100 mg intravenously or intramuscularly for anyone with persistent or severe late vomiting ¹⁴.

The fear that held back intravenous thiamine was anaphylaxis. In 989 consecutive patients given 1,070 intravenous 100 mg doses, there were eleven cases of local irritation and one generalized itch, and no anaphylaxis ²⁰.

The fat-soluble cousins, one by one

Each derivative was made to deliver more thiamine than the salt, and each has drifted toward a use of its own. The evidence behind those uses is uneven, and the tabs below give each its due, including the trials that came back negative.

How to measure it

No single test settles thiamine status, and there is no agreed biomarker for populations ¹². In practice, laboratories measure the working form directly in whole blood, and research studies add a functional test of a thiamine enzyme in red cells ^19,51. Both methods meet in one place: the standard assays separate the thiamine compounds and convert them to thiochrome, whose fluorescence is what the instrument reads ^19,43.

For Wernicke's encephalopathy none of these is fast enough to wait for. The diagnosis is clinical, supported by MRI, and treatment is given on suspicion ⁵⁷.

• Whole-blood thiamine diphosphate (HPLC)The working form, measured directly in blood, where it is about 90 percent of all the thiamine present ¹⁹.The thiamine test most clinical laboratories offerAgreed with the older enzyme test in 59 of 63 patients suspected of deficiency, and precise enough to run in minutes ^19,43.A normal result does not rule out Wernicke's encephalopathy, which is diagnosed clinically and treated before any result returns ⁵⁷.
• Erythrocyte transketolase activity coefficient (ETKAC)Red cells are tested for transketolase activity with and without added thiamine diphosphate; the bigger the boost from adding it, the more the enzyme was going without ⁵¹.A functional test in use for more than fifty years, mainly in research and nutrition surveysSensitive and specific, but laboratories have never agreed on the cutoffs, because the assay was never harmonized ⁵¹.It depends on how much transketolase the red cells contain, which varies for reasons unrelated to thiamine ⁵¹.
• Brain MRICharacteristic changes around the third ventricle, the aqueduct and the mammillary bodies support a diagnosis of Wernicke's encephalopathy ⁵⁷.Recommended to support the diagnosis in people with and without alcohol use disorderIt found lesions in 14 of 30 people with Wernicke's encephalopathy after bariatric surgery who were scanned ¹³.Half of those scanned had no characteristic lesion, so a normal scan cannot exclude the diagnosis ¹³.
• Blood lactatePyruvate that cannot enter the mitochondria becomes lactate ²⁷.Measured routinely in the critically illIn septic shock, giving thiamine lowered lactate only in the patients who were deficient to begin with ²⁷.It is not specific: lactate rises for many reasons, and most of them have nothing to do with thiamine.

High doses beyond deficiency: sepsis, fatigue and cancer

Septic shock is the clearest case of an idea that rose and fell. A before-and-after study at one hospital reported that intravenous vitamin C, hydrocortisone and thiamine got patients off vasopressors in about 18 hours instead of 55 and reduced deaths ⁴⁸. Randomized trials followed. In VITAMINS, 90-day mortality was 28.6 percent with the combination and 24.5 percent with hydrocortisone alone ²¹; in ACTS the combination did not reduce organ failure against placebo ²²; and in VICTAS it did not increase days alive without a ventilator or vasopressors, although that trial stopped early ⁴⁹. A separate trial of thiamine alone lowered lactate only in the patients who were deficient to begin with ²⁷.

Fatigue is the more promising thread. In a randomized crossover trial in people with inflammatory bowel disease in remission, high-dose oral thiamine reduced a fatigue score by 4.5 points against an increase of 0.75 on placebo ⁶⁸. The star for thiamine in dysautonomia sits on this thread, and this trial is the strongest evidence the thread has.

Cancer cuts both ways. Tumor cells use transketolase, a thiamine enzyme, to make ribose, and in mice with a transplanted tumor, thiamine supplementation that corrected a pre-existing deficiency made the tumor grow faster; at roughly 2,500 times the recommended intake the effect reversed into a small inhibition ⁴¹. In cancer cell lines, very high concentrations reduced growth by reactivating pyruvate dehydrogenase, the same mechanism as the experimental drug dichloroacetate ⁶⁹. None of this has been tested in people, and oxythiamine, the impostor in the figure above, is studied as a cancer drug for the same reason ²⁶.

Where it comes from, and how it is made

In nature, thiamine is made by bacteria, yeasts and plants, which build the pyrimidine and the thiazole on separate branches of a pathway and join them as thiamine phosphate ⁵. Animals eat it. The richest foods are whole grains, legumes, pork and yeast, and in the United States enriched and fortified grain products supply a large share ⁷. Milling grain and washing polished rice remove much of it, which is how polished rice came to cause beriberi ^6,12.

The thiamine in tablets and in fortified flour is synthetic: the same molecule as the natural vitamin, made by chemical synthesis from simple starting materials along routes refined since Williams's synthesis in 1936 ^6,70. Fermentation with engineered microbes is being developed as an alternative but has not replaced chemistry ⁷⁰.

Allithiamine is the only fat-soluble form that occurs naturally: it appears when garlic is crushed and its allicin meets thiamine ³⁴. Every other lipophilic form on this page is synthetic. Natural or synthetic says nothing about which works better here, because the synthetic salts are the natural vitamin once dissolved.

What was believed and is not

Several ideas about vitamin B1 were standard for decades and turned out to be wrong. They are kept here because each was reasonable when it was made.

What is strange about it

The word vitamin exists because of thiamine, and thiamine really is the amine Funk's word promised ¹¹.

The machine that makes ATP can make thiamine triphosphate instead. In starving Escherichia coli, ATP synthase uses the proton gradient across the membrane to add a phosphate to thiamine diphosphate rather than to ADP, and the same reaction was found in mammalian brain mitochondria ³¹.

Thiamine deficiency is turning up in the wild. Wild birds of several declining European species were found paralyzed and dying, with low thiamine in their eggs, livers and brains, and treatment with thiamine reversed the paralysis ⁷¹.

A drug for chickens can do to camels what deficiency does to people. Amprolium starves coccidia of thiamine, and in racing camels on a barley diet it produced the same cerebrocortical necrosis ⁴². Fedratinib, a drug for a blood cancer, did it to people, by blocking the transporter rather than the enzyme ²⁹.

What is still unknown

What thiamine triphosphate and adenosine thiamine triphosphate do in human cells is not known, beyond the fact that they exist ^3,4.

The right dose and route for preventing and treating Wernicke-Korsakoff syndrome have never been tested properly in randomized trials ⁵⁹.

Whether benfotiamine slows Alzheimer's disease is the question the current phase 2 trial is designed to answer ²⁵. Whether any lipophilic derivative does something in people that the same blood level of ordinary thiamine would not do is a question no trial has been designed to answer.

Laboratories still lack agreed cutoffs for the red-cell transketolase test, and populations lack a biomarker that tells them how many people are deficient ^12,51.

Where it connects

Sources

71 sources, numbered as they are cited. Every one was checked against PubMed or its publisher before it was cited here; the note under each says what it shows and what it does not.

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