Sadly, in 2020, Dr. Costantini contracted COVID-19 and died. While his work is finished, his legacy of exploring the therapeutic benefits of high-dose thiamine endures. In the past year, several important studies on high-dose thiamine have been released. This review briefly describes two of these studies and several related resources.
High-Dose Thiamine for IBD Fatigue
In the January 2021 issue of Alimentary Pharmacology & Therapeutics, Palle Bager and colleagues published a randomized controlled trial examining whether oral high-dose thiamine helped relieve fatigue in patients with quiescent inflammatory bowel disease (IBD) and severe chronic fatigue. Following a regimen adapted from Costantini’s earlier pilot study and other Costantini studies, the patients in Bager’s trial received 600 to 1,800 mg of oral thiamine hydrochloride daily, based on weight and gender. The 40 patients in the study were randomized to either receive high-dose thiamine or a placebo for four weeks. Following a four-week washout period, the control and treatment groups switched for another four weeks of treatment/placebo, so that everyone in the study received both high-dose thiamine and a placebo. The trial found that high-dose thiamine produced large reductions in self-reported fatigue on the validated IBD fatigue scale that were both clinically and statistically significant. No statistically significant relationship was observed between the impact of high-dose thiamine and patients’ baseline thiamine deficiency status.
This study is significant for its use of a very rigorous evaluation method: a double-blind cross-over randomized controlled trial. Using this gold standard evaluation method, Bager and colleagues largely confirmed the findings of Costantini’s earlier pilot study. While the Bager study focused only on people with IBD, it provides reason to be optimistic that high-dose thiamine may be helpful for the other populations studied by Costantini and possibly for people with other neurological and inflammatory conditions.
Bager and colleagues suggest that the impact of thiamine in reducing fatigue among patients with IBD and chronic fatigue may be related to problems the patients experience with the active transport mechanism for thiamine:
While the effect of high-dose oral thiamine was highly significant in our study, 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 normalise, and a reduction of fatigue is likely to follow.
The inhibition of carbonic anhydrase isoenzymes by high-dose thiamine and the resulting production of carbon dioxide could lead to reductions in fatigue and other symptomatic improvement through one or more of four potential pathways: (a) by reducing intracranial hypertension and/or ventral brainstem compression; (b) by increasing blood flow to the brain; (c) by facilitating aerobic cellular respiration and lactate clearance through the Bohr effect; or (d) by dampening the pro-inflammatory Th-17 pathway, again through the Bohr effect, potentially mediated by reductions in hypoxia-inducible factor 1.
More background on my hypotheses on the potential mechanisms for the impact of high-dose thiamine, with full citations, may be found here. The authors’ thoughtful reply to my letter may be found here.
High-Dose Thiamine for COVID-19
Another important recent study on high-dose thiamine has been released on a preprint server and is currently under consideration at the journal Critical Care. The study found that administration of high-dose thiamine to 83 patients in Saudi Arabia who were critically ill with COVID-19 was associated with a 55% reduction in 30-day ICU mortality and a 51% reduction in in-hospital mortality, as well as a reduction of 81% in the incidence of thrombosis during their ICU stay. The patients received a median of 100 mg of thiamine (presumably intravenously) for a median of 7 days.
Unlike the Bager study, the COVID-19 study by Al Sulaiman and colleagues was a retrospective study using a case matching approach, rather than a prospective study using random assignment. The authors matched the patients treated with high-dose thiamine to other critically ill COVID-19 patients using propensity scores based on baseline characteristics and controlling for the use of systemic corticosteroids. Based on correspondence with the authors, I understand that the patients’ baseline thiamine levels were not measured and thus unavailable as a matching variable.
This study is significant for providing evidence of the potential of high-dose thiamine to help treat critically ill patients with COVID-19. As I noted in an earlier Hormones Matter blog post, a prior study had found that high-dose thiamine damped down the pro-inflammatory th-17 pathway associated with the COVID-19 cytokine storm, but that study did not involve the treatment of actual COVID-19 patients. Outcome data from the Front Line COVID-19 Critical Care Alliance suggests that the combined use of Methylprednisolone, Ascorbic Acid (Vitamin C), Thiamine and Heparin (the so-called MATH+ protocol) may be helpful for COVID-19, but those data do not isolate the impact of high-dose thiamine and do not compare outcomes for treated households to those of a comparison group.
A randomized controlled trial is needed to verify the results found by Al Sulaiman and colleagues and assess whether high-dose thiamine can reduce mortality from COVID-19 among critically ill patients. It would also be valuable to rigorously evaluate whether oral high-dose thiamine could help early stage COVID-19 outpatients avoid hospitalization by reducing the incidence of the COVID-19 cytokine storm. This could help reduce the burdens of hospitals in India, Brazil, and other countries with high COVID-19 caseloads.
I am hopeful that additional rigorous research will be conducted to assess the potential of high-dose thiamine to treat a range of neurological and inflammatory conditions. It is hard to imagine a better tribute to Costantini’s work than a series of additional randomized controlled trials evaluating whether the observations he made in his pilot and case studies hold up when tested with larger samples using rigorous methods.
In addition to the conditions studied by Costantini, I would also encourage research into whether high-dose thiamine could be helpful for people with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and the neurological complications of Ehlers-Danlos Syndrome (EDS) (such as those experienced by my daughter). In this Medium post (more technical discussion) and Health Rising post (less technical discussion), I explain why I think these populations could benefit from high-dose thiamine.
More recently, I documented the retrospective self-reported outcomes for 55 individuals with ME/CFS, EDS or Fibromyalgia who reported taking 200 mg of more daily of high-dose thiamine. Nearly two-thirds of the participants in this retrospective survey reported large benefits, most commonly in reducing fatigue, post-exertional malaise, and brain fog. Interestingly, benefits were reported across a range of doses, including doses below those used by Costantini and Bager. Several study participants described high-dose thiamine as a game-changer that brought them substantial relief. The study has many limitations. For example, it was a small non-representative sample and based on self-reports only, but it is consistent with the potential of high-dose thiamine to provide large therapeutic benefits. I am hopeful it will help make the case for conducting more rigorous research in the future.
To the extent that Long COVID is similar to ME/CFS, I would also encourage the study of high-dose thiamine for people with this debilitating condition.
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