Could High-Dose Thiamine Improve Post-Exertional Malaise and Brain Fog in Individuals with ME/CFS and Ehlers-Danlos Syndrome? — A Call for Research

by Jeffrey Lubell[1]

As discussed more fully in an accompanying working paper, researchers have found that high-dose thiamine reduces fatigue for individuals with a wide range of conditions, including Inflammatory Bowel Disease (IBD), Fibromyalgia, Multiple Sclerosis, and Parkinson’s disease. Most of these studies were uncontrolled case studies, but the results for IBD fatigue were recently confirmed through a randomized controlled trial. (Bager et al. 2021). Given the promising findings for other conditions, I believe research is warranted to explore whether high-dose thiamine might benefit individuals with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and Ehlers-Danlos Syndrome (EDS).

Why Does High-Dose Thiamine Relieve Fatigue?

Efforts to determine whether patients with ME/CFS or EDS might benefit from high-dose thiamine are complicated by a lack of clarity about the mechanism through which thiamine produces these effects. In my accompanying paper examining why high-dose thiamine relieves fatigue, I review the explanations offered by thiamine researchers, which include a hypothesis that large concentrations of thiamine induce the passive transport of thiamine to compensate for “dysfunction in thiamine transport from blood to mitochondria” (Bager et al. 2021). I also explore the alternative hypothesis that the results can be explained, in whole or in part, by thiamine’s inhibition of carbonic anhydrase isoenzymes (Özdemir et al. 2013). I hypothesize that the benefits accrue 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 by (d) tamping down the pro-inflammatory Th-17 pathway (Vatsalya et al. 2020), again through the Bohr effect, possibly mediated through a reduction in hypoxia-inducible factor 1.

One caution to consider and explore more fully relates to the diuretic properties of carbonic anhydrase inhibitors, which could potentially aggravate lipedema or lymphedema in individuals susceptible to these conditions by concentrating protein in the lymphatic fluid, leading to fibrosis that further obstructs the flow. More research is needed to determine what level of high-dose thiamine, if any, is safe for people with these conditions and whether the potential risks can be mitigated through the regular use of manual lymphatic drainage or other similar approaches.

Could High-Dose Thiamine Help Individuals with ME/CFS?

While the population of individuals with Chronic Fatigue Syndrome is quite heterogeneous, there are a number of reasons to believe that high-dose thiamine could benefit a significant subset of individuals with CFS in light of the mechanisms through which I hypothesize that high-dose thiamine may relieve fatigue. Specifically:

— Many individuals with ME/CFS have intracranial hypertension. In a study of 229 individuals with ME/CFS, Bragée et al. (2020) found that “171 (83%) had signs of possible [intracranial hypertension,] including 65 (32%) who had values indicating more severe states” of intracranial hypertension.

— Many individuals with ME/CFS have reduced blood flow to the brain. In a study of 429 ME/CFS patients, van Campen et. al. (2020) found that 100 percent of patients with POTS, 92 percent of patients with delayed orthostatic hypotension and 82 percent of the other patients exhibited an abnormally low rate of cerebral blood flow during a tilt table test.

— The Th-17 pro-inflammatory process appears to play a role in ME/CFS, as discussed in Metzger et al. (2008).

As discussed in Booth et al. (2012) and Vink (2015), individuals with ME/CFS also have an impaired ability to engage in aerobic respiration, which may lead to an increased reliance on anaerobic respiration, which produces less energy. This appears to be due to mitochondrial defects, however, and it is not clear to me how carbonic anhydrase inhibition could help with this, though perhaps the passive thiamine transport hypothesis offered by Costantini and Pala (2013) and Bager et al. (2021) could provide an explanation for benefits in these circumstances. On the other hand, the production of carbon dioxide through carbonic anhydrase inhibition could help to improve lactate clearance, which Vink (2015) identifies as a problem in ME/CFS. Weyne et al. (1970) found that reductions in carbon dioxide were associated with increases in lactate levels.

Could High-Dose Thiamine Help Individuals with Neurological Complications of EDS?

A subset of individuals with EDS experience neurological complications. My daughter, for example, has Craniocervical instability and Chiari malformation. Henderson et al. (2019) describe how a combination of Craniocervical instability and Chiari malformation, also known as complex Chiari, causes a range of adverse symptoms. They call the overall cluster of problems the Cervical Medullary Syndrome (Henderson et al. 2018). As Henderson (2016) explains, an acute clivo-axial angle can lead to brainstem deformity and stress of the neuraxis:

The Clivo-Axial Angle (CXA) is that angle formed between a line drawn along the posterior aspect of the lower clivus and the posterior axial line. The angle of less than 135 degrees is pathological. Increasing acuteness of clivo-axial angle creates a fulcrum by which the odontoid deforms the brainstem. The medulla becomes more kinked as the angle becomes more acute, and this results in deformative stress of the neuraxis.

In complex Chiari, an acute CXA is exacerbated by the presence of a Chiari malformation that together operate to increase the risk of ventral brainstem compression. (Henderson et al. 2019). Henderson et. al. (2017) and Hulens et al. (2018) likewise note an association between EDS and intracranial hypertension. To the extent the carbonic anhydrase inhibition effected by thiamine reduces the production of cerebral spinal fluid, it could lead to reductions in intracranial pressure and possibly ventral brainstem compression as well.

Patient and provider reports in Driscoll et al. (2015) suggest that acetazolamide could lead to symptomatic improvements in EDS patients with cervical instability. If thiamine inhibits carbonic anhydrase isoenzymes in people nearly as well as acetazolamide, as Özdemir et al. 2013 found in vitro, it could have a similar effect. Our daughter’s experience with high-dose thiamine is consistent with the potential of high-dose thiamine to help individuals with complex Chiari, as she has experienced improvements in visual and mental acuity and reductions in post-exertional malaise. Despite these improvements, her condition has deteriorated in other ways that complicate efforts to use her experience as a case study to generate learning.

Research Needed on the Effects of High-Dose Thiamine on Individuals with ME/CFS and the Neurological Manifestations of EDS

Given the emerging evidence of the benefits of high-dose thiamine for treating a range of neurological and autoimmune conditions, research is warranted to study whether people with ME/CFS and certain neurological complications of EDS could similarly benefit. The following are some questions and considerations related to this research.

1. What symptoms should be studied? Both the pioneering Costantini studies (see citations in the accompanying article) and Bager et al. (2021) focus on high-dose thiamine’s role in reducing fatigue, generally. Given the prominence of post-exertional malaise (PEM) in ME/CFS, it would be useful to separately study the effects on PEM. It may also be useful to try to break-out other components of the more general concept of fatigue — for example, distinguishing overall tiredness from the state of becoming rapidly exhausted with exertion. Headaches should also be studied, given its association with intracranial hypertension. Based on my daughter’s experience with high-dose thiamine, I would also recommend studying the effects on brain fog (or mental acuity) and visual field and perception (both subjectively and objectively measured). My daughter described the visual improvements as being more easily able to see objects distinguished from the background.

2. Interactions between high-dose thiamine and other medications and supplements. One complication I see with research into the effects of high-dose thiamine (and ongoing management of its administration) is the potential for interaction between high-dose thiamine and the many supplements and medications that ME/CFS patients and EDS patients take daily. For example, there are warnings about combining acetazolamide and aspirin, which is used as a mast cell stabilizer, due to concerns about salicylate toxicity.[2] To take another example, hypokalemia is a known risk factor of the co-administration of acetazolamide and certain diuretics. Some patients with ME/CFS and EDS take supplements with diuretic properties, such as dandelion root, that could potentially interact with thiamine to produce hypokalemia. While taking high-dose thiamine, my daughter tested mildly low for potassium without any obvious use of another diuretic. Could one of her other supplements have had diuretic effects without us being aware of it?

More broadly, to ensure an effective study and provide guidance for ingoing administration, it would be useful to examine whether there are interactions between high-dose thiamine (or acetazolamide) and mast cell stabilizers such as Cromolyn Sodium and Quercetin that may not have been studied to the same extent as other more common medications. The bioflavonoids Quercetin and Luteolin, for example, also have carbonic anhydrase inhibitory properties (Ekinci 2013), raising the question of whether there is a cumulative effect that may lead to overdosing; these supplements appear to be poorly absorbed, however, so it would be important to study them in a real-world context and not just in vivo.

3. Will high-dose thiamine stop working after a period of time?

Driscoll et al. (2015) warn that acetazolamide can stop being effective after a period of time in addressing the symptoms of craniocervical instability in EDS patients due to increased acidity, at which point sodium bicarbonate may be needed to restore functionality by improving the acid-base balance. I reviewed the articles on acetazolamide and intracranial hypertension in Up to Date and did not find any reference to this phenomenon. But it is discussed in the older literature on acetazolamide. For example, Campbell et al. (1957) note that the diminished effectiveness over time of acetazolamide was a core problem with the drug; they found potassium bicarbonate helpful in restoring its functionality in patients that have seen diminished effectiveness. Epstein and Grant (1977) write about patients experiencing “malaise” that prevents continued therapy with acetazolamide. These patients, on the whole, were more acidotic than those without malaise and no more likely to be deficient in potassium. Sodium bicarbonate was effective in restoring acetazolamide’s functionality for many of these patients.

It is unclear whether individuals with EDS and CFS are more likely than others to struggle with maintaining an acid-base homeostasis, leading carbonic anhydrase inhibitors like thiamine to grow less effective after a period of time, but it would be worth considering this possibility. If this is a problem, it would be useful to examine whether this is related to their illness or to an interaction with other medications or supplements. It would also be useful to formulate guidance on how to restore acid-base balance (for example, with potassium or sodium bicarbonate) if and when patients start to experience a loss of effectiveness from high-dose thiamine or a malaise. Acetazolamide comes with a warning against its co-administration with sodium bicarbonate, due to the risk of kidney stones, so presumably the routine ongoing use of sodium bicarbonate in the absence of this type of malaise or a temporary loss of effectiveness would be inadvisable.

Practical guidance for patients and practitioners on how to avoid kidney stones related to ongoing carbonic anhydrase inhibition would also be helpful. One easy place to start would be increased water intake.

4. What dosage is optimal and can the dosage be lowered over time while maintaining effectiveness?

As described in the literature cited in my accompanying paper, researchers have explored two different approaches to dosing. Under one approach, patient were started at 600 mg of oral thiamine HCL daily, and then increased in steps up to a maximum of 1,800 mg daily until the desired benefits were achieved. The other approach is a common dosage formula based on gender and weight. This was the approach taken in the RCT conducted by Bager et al. (2021), based on Costantini and Pala (2013). Bager et al. (2021) used 300 mg tablets, describing the dosage as follows:

The daily dose depended on gender and body weight (BW) according to the following scheme: 1) 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); 2) 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).

Driscoll et al. (2015) note that some of their patients have found that the dose they need to benefit from acetazolamide decreases with time. Costantini et al. (2018) report a similar effect for high-dose thiamine, and this appears to have been the case for our daughter as well. If this is verified through research, reducing the dosage after an initial period of effectiveness may prove to be a useful strategy for reducing the extent of acidosis and its attendant side effects and decreasing the likelihood that the treatment becomes less effective over time.

In an informal and non-representative survey I conducted on the retrospective use of high-dose thiamine by people with ME/CFS, EDS, and Fibromyalgia, one of the strinking findings was that people reported strong benefits in all of the dosage ranges. Indeed, some respondents to the survey and commentators on the article even reported notable benefits at doses below the 200 mg per day cut-off used to define the survey analysis sample. Further research is needed to confirm whether substantially lower doses of high-dose thiamine than used by Costantini and Bager could provide meaningful effects.

5. Could higher doses of thiamine exacerbate lipedema or lymphedema in susceptible individuals?

One reason to explore the benefits of dosages that fall below those studied by Costantini and Bager is the potential for the diuretic effect of a carbonic anhydrase inhibitor to interfere with lymphatic flow and exacerbate Lipedema (Herbst 2012). The extent of the overlap between Lipedema and EDS, ME/CFS, and Fibromyalgia is not clear, but hypermobility is common among people with Lipedema, suggesting the overlap may be substantial. Lower doses of thiamine would presumably have less of a diuretic effect and thus less potential to interfere in this way.

Further research is needed to better understand what levels of high-dose thiamine, if any, are safe in people susceptible to lipedema or lymphedema. It would also be useful to better understand whether the regular use of manual lymphatic drainage, or other similar mechanisms, could help reduce the risks associated with a carbonic anhydrase inhibitor in people who would otherwise benefit from high-dose thiamine through other mechanisms.

Conclusion

In sum, research is needed and warranted into the potential of high-dose thiamine to help individuals with ME/CFS and certain neurological complications of Ehlers-Danlos syndrome.

References

Bager P, Hvas CL, Rud CL, Dahlerup JF. Randomised clinical trial: high-dose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease. Aliment Pharmacol Ther. 2021;53(1):79–86. doi:10.1111/apt.16166.

Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208–220.

Bragée B, Michos A, Drum B, Fahlgren M, Szulkin R and Bertilson BC (2020) Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurol. 11:828. doi: 10.3389/fneur.2020.00828

Campbell, D.A., Jones, M., Renner, N.E.A. et al. Combined Action of Diamox and Potassium Bicarbonate in the Treatment of Chronic Glaucoma. Brit. J. Ophthal. (1957) 41, 746.

Costantini A., Pala M.I. Thiamine and fatigue in inflammatory bowel diseases. An open label pilot study. J Altern Complement Med. Published Online First: 4 Feb 2013.

Costantini, A., Tiberi, M., Zarletti, G., et al. Oral High-Dose Thiamine Improves the Symptoms of Chronic Cluster Headache. Case Reports in Neurological Medicine Volume (2018)

Driscoll, D, De A., Doherty, C. et al. The Driscoll Theory® Newly Revised: The Cause of POTS in Ehlers-Danlos Syndrome and How to Reverse the Process. Warnick Publishing (2015).

Ekinci D, Karagoz L, Ekinci D, Senturk M, Supuran CT. Carbonic anhydrase inhibitors: in vitro inhibition of α isoforms (hCA I, hCA II, bCA III, hCA IV) by flavonoids. J Enzyme Inhib Med Chem. 2013 Apr;28(2):283–8. doi: 10.3109/14756366.2011.643303. Epub 2011 Dec 14. PMID: 22168126.

Epstein DL, Grant WM. Carbonic anhydrase inhibitor side effects. Serum chemical analysis. Arch Ophthalmol. 1977 Aug;95(8):1378–82. doi: 10.1001/archopht.1977.04450080088009. PMID: 889513.

Henderson, F.C. Sr., Cranio-cervical Instability in Patients with Hypermobility Connective Disorders. J Spine 2016, 5:2.

Henderson FC Sr, Austin C, Benzel E, et al. Neurological and spinal manifestations of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):195–211. doi:10.1002/ajmg.c.31549

Henderson FC Sr, Henderson FC Jr, Wilson WA 4th, Mark AS, Koby M. Utility of the clivo-axial angle in assessing brainstem deformity: pilot study and literature review. Neurosurg Rev. 2018;41(1):149–163. doi:10.1007/s10143–017–0830–3

Henderson FC Sr, Francomano CA, Koby M, Tuchman K, Adcock J, Patel S. Cervical medullary syndrome secondary to Craniocervical instability and ventral brainstem compression in hereditary hypermobility connective tissue disorders: 5-year follow-up after Craniocervical reduction, fusion, and stabilization. Neurosurg Rev. 2019;42(4):915–936. doi:10.1007/s10143–018–01070–4 (2019)

Herbst KL. Rare adipose disorders (RADs) masquerading as obesity. Acta Pharmacol Sin. 2012;33(2):155–172. doi:10.1038/aps.2011.153

Hulens M, Rasschaert R, Vansant G, Stalmans I, Bruyninckx F, Dankaerts W. The link between idiopathic intracranial hypertension, fibromyalgia, and chronic fatigue syndrome: exploration of a shared pathophysiology. J Pain Res. 2018;11:3129–3140. Published 2018 Dec 10. doi:10.2147/JPR.S186878

Metzger, K., Frémont, M., Roelant, C., & De Meirleir, K. (2008). Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients. Biochemical and Biophysical Research Communications, 376(1), 231–233. doi:10.1016/j.bbrc.2008.08.135

Özdemir, Z.O., Şentürk, M. & Ekinci, D. Inhibition of mammalian carbonic anhydrase isoforms I, II and VI with thiamine and thiamine-like molecules, Journal of Enzyme Inhibition and Medicinal Chemistry (2013), 28:2, 316–319.

van Campen CLMC, Verheugt FWA, Rowe PC, Visser FC. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract. 2020;5:50–58. Published 2020 Feb 8. doi:10.1016/j.cnp.2020.01.003

Vatsalya, V. Li, F., Frimodig JC. et. al. Repurposing Treatment of Wernicke–Korsakoff Syndrome for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-Vitro Evidence and Pharmacokinetic Profile. Frontiers in Pharmacology, Vol. 11 p. 2312 (2021). DOI=10.3389/fphar.2020.598128

Vink M (2015). The Aerobic Energy Production and the Lactic Acid Excretion are both Impeded in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Neurol Neurobiol 1(4): doi http://dx.doi.org/10.16966/2379-7150.112

Weyne, J., Demeester, G., & Leusen, I. (1970). Effects of carbon dioxide, bicarbonate and pH on lactate and pyruvate in the brain of rats. Pflügers Archiv European Journal of Physiology, 314(4), 292–311. doi:10.1007/bf00592288

Endnotes

[1] I am the parent of a child with Ehlers-Danlos Syndrome and a series of related conditions. I offer this analysis to encourage and facilitate future research. I am not a doctor and have no medical training. I would welcome constructive feedback on the hypotheses explored in this paper.

[2] The studies cited in the Drugs.com interaction checker all involved high doses of aspirin. One question to examine is whether low-dose aspirin is safe to use with high-dose thiamine.