Longtime readers of the Health Rising blog may remember an article that Cort wrote in 2013 about the promising results of a small study that found marked reductions in fatigue among three individuals with Fibromyalgia who took high doses of thiamine (Vitamin B-1).

Cheap, Effective Relief From Fibromyalgia (and ME/CFS) Found? Early Reports Spark Interest in Little Used Supplement

In the intervening years, several important studies on high-dose thiamine have been published, including a well-designed randomized controlled trial in November 2020. The publication of this landmark study provides a good opportunity to re-examine the evidence on high-dose thiamine and consider whether this supplement might be helpful for some people with ME-CFS, Fibromyalgia and Ehlers-Danlos Syndrome.

Citric Acid Cycle Diagram

Thiamine plays a key role in aerobic energy production.

Thiamine, also known as Vitamin B-1, is an essential nutrient that plays a critical role in aerobic cellular respiration.  A thiamine derivative, thiamine pyrophosphate, is necessary for the citric acid cycle to function properly and produce an adequate amount of the ATP molecules that the body uses for energy.  Thiamine deficiency is a serious health problem, but most people in the western world get all the thiamine they need through a healthy diet.

The recommended daily allowance of thiamine is 1.1-1.2 mg/day.  By contrast, the 2013 study on fibromyalgia used 600 to 1,800 mg of thiamine daily, more than 500 times this amount.  This is the first clue that the study may involve something other than simple supplementation to remedy a vitamin deficiency.

The fibromyalgia study was one of a series of case studies published by the Italian physician, Antonio Costantini, and colleagues in 2013-2018, finding reductions in fatigue from high-dose thiamine among individuals with a range or neurological and inflammatory conditions, including Inflammatory Bowel Disease (IBD), Multiple Sclerosis, Parkinson’s Disease, and chronic cluster headaches.

These studies were all fairly small, and none compared the results against a control group of individuals who did not receive the treatment.  Without the rigor of a randomized controlled trial, it was impossible to know for sure if the benefits were due to thiamine, the placebo effect, or some other explanation.

With the publication in November 2020 of a randomized controlled trial of high-dose thiamine by Palle Bager and colleagues at the Aarhus University Hospital in Denmark, that criticism has largely been addressed.  This randomized trial confirmed the results of one of the earlier Italian studies, finding significant reductions in self-reported fatigue from high-dose oral thiamine hydrochloride over a four-week period among patients with quiescent (i.e., non-active) IBD and long-term fatigue.

In this guest post for Health Rising, I describe the results of this new study, explore potential explanations for why high-dose thiamine might relieve fatigue, and describe why I think some people with ME/CFS, Fibromyalgia, and the neurological complications of Ehlers-Danlos Syndrome (EDS) might benefit from it.

I conclude by asking those of you who have tried high-dose thiamine to complete a survey to help the field better understand whether and for whom high-dose thiamine might be helpful.  If the survey results suggest that at least some people with ME-CFS, Fibromyalgia or EDS might benefit, I hope to use the results to encourage researchers to conduct a more rigorous study of its potential benefits for individuals with these conditions.

Study Results

increased energy

The randomized control study found a significant decrease in fatigue in those taking the high-dose B-1.

Between November 2018 and October 2019, Palle Bager and colleagues in Aarhus, Denmark enrolled 40 individuals (35 female, 5 male) with quiescent IBD and fatigue lasting six months or more in a randomized, double-blind placebo-controlled crossover trial.

Half of the individuals were randomly assigned to received high-dose thiamine for four weeks, followed by a four-week washout period and then four weeks of placebo.  The other half got the placebo first, then the washout, and then high-dose thiamine.  Neither the patients nor the researchers knew who was in which group.

The study used 300 mg tablets of oral thiamine hydrochloride, assigning a daily dose by gender and body weight (BW) as follows:

  • “Females: BW <60 kg: 600 mg (2 tablets), BW 60-70 kg: 900 mg (3 tablets), BW 71-80 kg: 1200 mg (4 tablets), and BW >80 kg: 1500 mg (5 tablets);
  • Males: BW <60 kg: 900 mg (3 tablets), BW 60-70 kg: 1200 mg (4 tablets), BW 71-80 kg: 1500 mg (5 tablets) and BW >80 kg: 1800 mg (6 tablets).”

It is not clear whether the study participants took their pills all at once each day or spread out into divided doses, but they were advised not to take the pills in the evening due to the risk of temporary sleeplessness.

The primary outcome consisted of a measurement based on Section I of the IBD-F fatigue scale. Section I of this validated scale consists of five questions to the patient asking about fatigue over the past two weeks.  To be included in the study, participants needed to have a fatigue score greater than 12, which is about 70 percent higher than the mean fatigue score of 7 in the general population. The researchers defined a reduction of 3 points or more as clinically relevant.

They found the patients’ reported fatigue declined by an average of 4.5 points while taking high-dose thiamine as compared with an increase of an average of 0.75 points while taking the placebo, a statistically significant difference.  The results, after excluding three patients who had a flare-up of IBD or needed an iron infusion during the study, found a net reduction of 4.7 points in the average fatigue scale score attributable to high-dose thiamine.

There was no significant difference in results among those with and without a thiamine deficiency at the time they enrolled in the study.  The finding that reductions in fatigue were not limited to those with a thiamine deficiency accords with the results reported by Costantini and colleagues across a range of conditions.

Why might thiamine reduce fatigue?

If high-dose thiamine does not work by addressing a thiamine deficiency, through what mechanism does it reduce fatigue?  The short answer is we do not know for sure, but several hypotheses have been offered.

Building on a hypothesis first advanced by Costantini, Bager and colleagues suggest the possibility that high-dose thiamine may have helped compensate for a defect in the active transport mechanism through which thiamine is normally absorbed.   “While the effect of high-dose oral thiamine was highly significant in our study,” the authors write, “its exact mechanisms still need to be explored and investigated. The theory of a dysfunction in thiamine transport from blood to mitochondria remains a plausible explanation.

The participants in our study were exposed to high doses of thiamine which induces passive diffusion that will add thiamine to the cells and the mitochondria. Consequently, the carbohydrate metabolism can normalize, and a reduction of fatigue is likely to follow.”

In a recent comment on a blog post, noted thiamine expert Derrick Lonsdale offered an alternative hypothesis to explain what he terms as the “miraculous” clinical effects of high-dose thiamine.

“[T]hiamine, and particularly its derivatives, are being used as ‘drugs’. It is nothing to do with simple vitamin replacement. The enzymes that require thiamine have been deprived of it for so long that it can be expected that they have deteriorated ‘physically’ in their metabolic responsibility. The cofactor has to be used in megadoses in order to stimulate the enzymes back into their normal function.”

As Lonsdale acknowledged, this hypothesis still needs to be evaluated through research.

In a letter to Alimentary Pharmacology and Therapeutics, the medical journal that published Bager’s study (the authors’ reply is here), I offered a different hypothesis that builds on two other recent studies of high-dose thiamine.

In 2013, Özdemir and colleagues found that high-dose thiamine inhibited three carbonic anhydrase isoenzymes nearly as well as acetazolamide (Diamox).  Inn 2021, Vatsalysa and colleagues found that high-dose thiamine tamps down the pro-inflammatory Th-17 pathway believed to play a role in the COVID-19 cytokine storm.

Building on these findings, I propose that the benefits of high-dose thiamine in relieving fatigue and generating other symptomatic improvement in patients with a diverse range of neurological and inflammatory conditions may be due to thiamine’s role as a carbonic anhydrase inhibitor.

I hypothesize that the benefits accrue through one or more of four potential pathways:

  1. by reducing intracranial hypertension and/or ventral brainstem compression;
  2. by increasing blood flow to the brain;
  3. by facilitating aerobic cellular respiration and lactate clearance through the Bohr effect; or by
  4. tamping down the pro-inflammatory Th-17 pathway, again through the Bohr effect, possibly mediated by reductions in hypoxia-inducible factor 1.

This is a lot to unpack, so let me offer this high-level overview, and refer readers interested in the technical details to a blog post I wrote on Medium that explains my theory in more detail, with full citations.

Could high-dose thiamine help with blood flows to the brain, intracranial hypertension and aerobic functioning?

In a nutshell, I am proposing that taking high-dose thiamine is a lot like taking Diamox (the brand name for acetazolamide – the most common treatment for intracranial hypertension, but without many of the worrisome side effects.  Rather than working by addressing a vitamin deficiency, high-dose thiamine operates by reducing intracranial hypertension (and possibly ventral brainstem compression as well) through a reduction in cerebral spinal fluid.

In the process, by inhibiting carbonic anhydrase isoenzymes, high-dose thiamine produces carbon dioxide, which leads to increased blood flow to the brain and an increase in the availability of oxygen at the cellular and tissue levels for aerobic respiration, reducing reliance on anaerobic respiration and helping to clear lactate.  By reducing hypoxic conditions, the increased oxygenation also reduces the levels of a mediator (hypoxia-inducible factor 1) that triggers the pro-inflammatory Th-17 process, helping to counter inflammation.

I will be the first to admit that these ideas need to be carefully evaluated through rigorous research.  My goal in proposing these hypotheses is not to offer them as gospel but rather to stimulate research into the mechanisms through which high-dose thiamine operates.  These mechanisms are important both for predicting the potential conditions that high-dose thiamine could help treat and for clarifying the limitations and cautions that should be applied to its use.

The hypothesized mechanisms I describe above are alternatives in the sense that one or more may be accurate while the others may be inaccurate.  It also may be the case that some individuals benefit through one mechanism while others benefit through another mechanism, which may help explain why people with a wide range of conditions report benefits from high-dose thiamine.  Some individuals may even benefit simultaneously through multiple mechanisms.

Could high-dose thiamine help people with ME/CFS, Fibromyalgia, or EDS?

More research is needed to answer this question definitively, but I believe we know enough to suspect this research would be worth conducting.  The 2013 study by Costantini and colleagues finding benefits among people with fibromyalgia provides a basis for conducting a larger and more rigorous study of the potential applications of high-dose thiamine for people with fibromyalgia.

Similarly, the case reports and discussion included in the Driscoll Theory provide a basis for follow-up research on the potential benefits of a carbonic anhydrase inhibitor like high-dose thiamine for people with certain neurological complications of EDS.  Driscoll’s book argues that people with some neurological complications of EDS can benefit from acetazolamide (Diamox).  She attributes the results to reductions in intracranial hypertension, a known complication of EDS.  I wonder, as well, whether a carbonic anhydrase inhibitor could help with ventral brainstem compression caused by Craniocervical instability and Chiari malformation.

The case for predicting the benefits for people with ME/CFS is more circumstantial.  A 2020 study found signs of possible intracranial hypertension in 83% of 205 individuals with ME/CFS that had an MRI performed.  The reductions in cerebral spinal fluid achieved through a carbonic anhydrase inhibitor like high-dose thiamine might potentially be helpful for individuals with these and other neurological conditions.

Does Intracranial Hypertension Run Rampant in Fibromyalgia, ME/CFS and Migraine?

There is reason to believe that some of the other pathways may also apply.  For example, many individuals with ME/CFS have reduced blood flow to the brain. As Cort has summarized in past blog posts, this might be related to the finding in several studies of reduced levels of CO2 in people with ME/CFS.  The authors of these studies hypothesize that these reduced CO2 levels may be narrowing blood vessels, constricting the flow of blood to the brain.  By producing CO2, high-dose thiamine could potentially remedy this problem and improve blood flow to the brain.

Low Brain Blood Flows and Orthostatic Intolerance Ubiquitous in Chronic Fatigue Syndrome (ME/CFS)


The Gist

  • A randomized-controlled trial of high-dose thiamine found that it reduced fatigue in people with quiescent IBD.
  • The outcomes did not differ for individuals with or without a thiamine deficiency at the start of the study.
  • The exact mechanism for thiamine’s effects on fatigue is not clear. The author of this post hypothesizes that high-dose thiamine’s effects might be due to its role as a carbonic anhydrase inhibitor, which could reduce intracranial hypertension and produce CO2 that increases blood flow to the brain, tamps down the pro-inflammatory Th-17 process, increases aerobic respiration and clears lactate.
  • There are reasons to believe high-dose thiamine could potentially help people with ME/CFS, Fibromyalgia and the neurological complications of Ehlers-Danlos Syndrome. Rigorous research is needed to assess whether this might be the case, and if so, who is most likely to benefit.
  • Carbonic anhydrase inhibitors are powerful medications that have the potential to interact with a number of other medications and supplements.

As discussed in a 2008 article by Metzger and colleagues, there is also evidence that the Th-17 pro-inflammatory process may also play a role in ME/CFS.  If so, the tamping down of this inflammatory process by high-dose thiamine could potentially help to provide relief.

While a preference for anaerobic respiration is apparently common among people with ME/CFS, this is often attributed to mitochondrial issues, and I am not quite sure how a carbonic anhydrase inhibitor could help with this.  (The passive transport theory articulated by Bager and Costantini might potentially be useful, however.)  On the other hand, the production of carbon dioxide through carbonic anhydrase inhibition could potentially help to improve lactate clearance, which Vink identifies as a problem in ME/CFS.

Hopefully, future studies of the potential benefits of high-dose thiamine for people with ME/CFS, fibromyalgia and the neurological complications of EDS will go beyond studying the general concept of “fatigue” to assess a range of more specific outcomes.  Potential benefits could include improvements in mental acuity / brain fog and certain kinds of headaches – due to reductions in intracranial hypertension – and reductions in post-exertional malaise due to increases in aerobic respiration and lactate clearance.

While it is just one case, my daughter, who has EDS, craniocervical instability and chiari malformation, appears to have experienced improvements in brain fog and post-exertional malaise from high-dose thiamine (though at particularly high doses of thiamine, she actually reports an increase in general tiredness).

To help bolster the case for conducting a rigorous study of whether high-dose thiamine benefits individuals with ME/CFS, fibromyalgia, or the neurological complications of EDS, it would be helpful to learn more about whether individuals with these conditions have benefitted from high-dose thiamine.  Please don’t start high-dose thiamine just to participate in this survey, but if you have already tried high-dose thiamine (which I define as a daily dose of 200 mg or more or oral thiamine), and feel comfortable completing this survey, please go ahead and do so.

Please complete the survey whether your experience has been positive or negative.  I will summarize and report out the results in a future column.

Cautions and Limitations

If I am right that high-dose thiamine is a carbonic anhydrase inhibitor with a potency approaching acetazolamide, there are many cautions that should apply to its use.  These include the risk of potassium deficiency (particularly if combined with a diuretic, including herbal diuretics) and the potential to form kidney stones.  The combined use of high doses of aspirin and acetazolamide (another carbonic anhydrase inhibitor) has been reported to lead to salicylate toxicity.  And people with intracranial HYPOtension would likely feel worse from high-dose thiamine, even as people with intracranial HYPERtension potentially feel better.

Driscoll reports a phenomenon in which acetazolamide sometimes stops working after a period of time.  This phenomenon is also reported in the older literature on acetazolamide, which also describes a general malaise that appears to be related to mild acidosis.  The older literature reported the problem resolved with sodium or potassium bicarbonate, though acetazolamide today comes with a warning against the routine co-administration with sodium bicarbonate due to the risk of kidney stones.  In addition to taking sodium bicarbonate, Driscoll also recommends lowering the dose.

Finally, there is some suggestion that thiamine may be a histamine liberator and DAO inhibitor (though in theory, reductions in intracranial hypertension and brainstem compression could potentially lead to improvements in MCAS symptoms).  My daughter seems to have experienced some shifts in food tolerance after starting high-dose thiamine, but no marked improvements or worsening.

This all suggests the importance of clarifying whether high-dose thiamine really is a carbonic anhydrase inhibitor as predicted by Özdemir’s 2013 in vitro study, and providing clear guidance to practitioners and patients on how to avoid or reduce complications.

For more discussion on the potential of high-dose thiamine to help people with ME-CFS and the neurological implications of EDS, including full citations, see my Medium post on this topic.

Jeffery is a father of a daughter with ME/CFS and allied disorders.

About the Author

I am the parent of a teenage daughter who has been diagnosed with Ehlers-Danlos Syndrome, hypermobility type; Postural Orthostatic Tachycardia Syndrome; Mast Cell Activation Syndrome; and Chronic Fatigue.

I have prepared this post to stimulate further research, and not to provide medical advice.  I am not a medical professional and do not have medical training.



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