I have been reading some of the fascinating posts by Angela Stanton PhD concerning her research in migraine headaches. I regard the substance of her discussions as somewhat like dots on a chart that need to be connected. I learned a great deal about the chemistry involved in migraine. One of her comments that involves ion homeostasis in brain metabolism is fascinating. She noted that “serotonin is created by a normally functioning brain. Why it decreases or increases in the brains of migraineurs has always puzzled me. Should we not try to find out why?” That simple three letter word is the heart and soul of research and I believe that I may be able to add some information that might provide an answer.
Ehlers Danlos and Migraine
In one of Angela’s posts she discusses a subject which has been of interest to me for many years, the overlap of symptoms in disease. She noted that 60% of migraineurs have one type of Ehlers Danlos syndrome (EDS) and 43% of EDS have minor changes in DNA (SNPs) found in migraineurs. She concludes that they must be related. Over 70% of migraineurs have Raynaud’s disease and there is an overlap with EDS and Raynaud’s. Therefore, she concludes that these three diseases are variants. In fact, there is an association between EDS, Postural Othostatic Tachycardia Syndrome (POTS) and a group of conditions known as mast cell disorders. EDS-HT, (one of the manifestations of this disease), is considered to be a multisystemic disorder, involving cardiovascular, autonomic nervous system, gastrointestinal, hematologic, ocular, gynecologic, neurologic and psychiatric manifestations, including joint hypermobility. Many non-musculoskeletal complaints in EDS-HT appear to be related to dysautonomia, consisting of cardiovascular and sudomotor dysfunction. Many of the clinical features of patients with mitral valve prolapse can logically be attributed to abnormal autonomic function. Myxomatous degeneration of valve leaflets with varying degree of severity is reported in the common condition of mitral valve prolapse.
A woman, with what was described as a “new” type of EDS, died after rupture of a thoracic aortic aneurysm. Autopsy revealed myxomatous degeneration and elongation of the mitral and tricuspid valves. Patients with POTS, a relatively common autonomic disorder, may have EDS, mitral valve prolapse, or chronic fatigue syndrome and are sensitive to various forms of stress, as depicted in the clinical treatment of a dental patient affected by the syndrome. Dysautonomia has been described in the pathogenesis of migraine, featured by nausea, vomiting, diarrhea, polyuria, eyelid edema, conjunctival injection, lacrimation, nasal congestion and ptosis. In general, there is an imbalance between sympathetic and parasympathetic tone.
Energy Metabolism and Migraine
Technological studies have confirmed the presence of deficient energy production together with an increment of energy consumption in migraine patients. An energy demand over a certain threshold creates metabolic and biochemical preconditions for the onset of the migraine attack. Common migraine triggers are capable of generating oxidative stress and its association with thiamine homeostasis suggests that thiamine may act as a site-directed antioxidant. It strongly suggests that migraine is a reflection of an inefficient use of brain oxygen. An intermediate consumption of oxygen between deficiency and excess appears to be a necessity at all times. In fact,” moderation in all things” is an important proverb
Backing up energy deficiency, two cases of chronic migraine responded clinically to intravenous administration of thiamine. However, the authors are in error when they state in the abstract that “nausea, vomiting and anorexia of migraine may lead to mild to moderate thiamine deficiency”. An otherwise healthy 30-year-old male acquired gastrointestinal beriberi after one session of heavy drinking. Nausea, vomiting and anorexia relentlessly progressed. He had undergone 11 emergency room visits, 3 hospital admissions and laparoscopy within 2 months but the gastrointestinal symptoms continued to progress, unrecognized for what these symptoms represented. When he eventually developed external ophthalmoplegia (eye divergence), he received an intravenous injection of thiamine which reversed both the neurologic and gastrointestinal symptoms within hours.
In other words it is important to be aware that nausea, vomiting and anorexia are primary symptoms of beriberi due to pseudohypoxia in the brainstem where the vomiting center is located. Chronic migraine has a well documented association with insulin resistance and metabolic syndrome. The hypothalamus may play a role. One of Angela’s comments concerns ion homeostasis in migraines. Thiamine triphosphate (TTP) can be found in most tissues at very low levels. However, organs and muscles that generate electrical impulses are particularly rich in this compound. Furthermore, TTP increases chloride (ion) uptake in membrane vesicles prepared from rat brain, suggesting that it could play an important role in the regulation of chloride permeability. Although this research was published in 1991, the exact role of TTP is still unknown. It has been hypothesized that thiamine and magnesium deficiency are keys to disease.
Angela wondered why serotonin might be increased or decreased in migraineurs. I strongly suspect that it is due to brain thiamine deficiency as the ultimate underlying cause of the migraine. In a review of thiamine metabolism, it was pointed out that metabolites could be high or low according to the degree of the deficiency. Victims of beriberi were found to have either a low or a high potassium according to the stage of the disease. If they were found to have a low acid content in the stomach, treatment with thiamine resulted in a high acid content before it became normal. If the stomach acid was high it would become low before it became normal. Since low and/or high potassium levels may be found in the blood of critically ill patients, thiamine deficiency should be a serious consideration in the emergency room or ICU Thiamine deficiency may be the answer for the fluctuations of serotonin observed in migraine.
Redefining Disease Models
According to the present medical model, each disease is described as a constellation of symptoms, physical signs and laboratory studies, each with a separate etiology. The overlap discussed by Angela suggests that the various conditions nominated have a common cause and that they are indeed nothing more than variations. If energy metabolism is the culprit, it would make sense of the infinite variations according to the degree and distribution of cellular energy deficiency. EDS-HT, described above is reported as a multi-system disease, exhibiting cardiovascular, autonomic gastrointestinal, hematologic, ocular, gynecological and psychiatric symptoms as well as the joint mobility. It seems to be impossible to explain this multiplicity without invoking energy deficiency as the cause. People with prolapsed mitral valve and a patient with a “new” form of EDS, reportedly have myxomatous degeneration as part of their pathology and it is tempting to suggest that such an important loss of structure might well be because of energy deficit.
The controls of the autonomic nervous system are located in the lower part of the brain that is particularly sensitive to thiamine deficiency and beriberi is a prototype for thiamine deficiency in its early stages. Dysautonomia is frequently reported as part of many different diseases, offering energy deficiency as the etiology in common. Yes, it is true that thiamine is not the only substance that enables the production of ATP. Nevertheless, it seems to dominate the overall picture of energy metabolism. It has long been considered the essential focus in the cause of beriberi, even though all the B complex vitamins are found in the rice polishings. Milling and the consumption of white rice was the prime etiology of the disease when it was common in rice consuming cultures.
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Dear Dr Lonsdale,
The relationship with thiamine and potassium seems to be quite complex, and I am wondering how to navigate potassium supplementation during thiamine megadosing.
I have been taking allithiamine (1000 mg/day) together with magnesium and multivitamin-mineral. For a long time that went well, but then I started getting bloating, red and itchy skin, as well as very dry and wrinkly skin and lightheadedness.
I then added B complex and potassium, based on what I have read on this site and Dr Overton’s site.
For a while this improved things, but then worse again. Then I stopped potassium, and it improved, but now it’s getting worse again, and if I add the potassium back in, it becomes even worse.
So I am really quite unsure now as to whether I should supplement potassium, or keep it out, especially since there are also articles about the danger of hyperkalemia.
Many thanks for your work!
Sounds like the dose of thiamine is too high. It also governs potassium metabolism. This is a new type of treatment and obviously we dont have all the answers. My usual advice is to find the ideal dose of thiamine by gradual escalation,. Then add magnesium and a multivitamin.
Thank you for your answer. I will for now stop all thiamine and potassium, in the hope that my skin becomes normal again!
Interesting, I acquired polyarthritis, and myocarditis from a persistent infection (lyme), i was in a good state with the infection for a long time but before the collapse my b12 levels were over 3000, low igm levels, high IGG levels, profound fatige and sleep issues with profuse sweating at night time. I was taking lipothiamin at the time of 100mg per day, but i have problems absorbing the enteric coated tablet considering It comes out the same way it goes in. I started antibiotic therapy and it has worked for a good portion of the time and seems to have reduced bacterial load but relapse keeps occurring. I suffered side effects from one of the antibiotic combinations, amoxicillin and doxycycline, which helped but left me with some pretty bad neuropathy that also radiated to the back of my head. I started higher dose thiamin and magnesium taurate. I started 50 mg allithiamin, and recieved within an hour an immideate heavy increase in neuropathy, dizzyness and depression. Blood pressure reads 150/60 The next day i could tolerate 100 mg before the effects, the next day 300, and now today im at 400 mg allithiamin with b complex multivitamin and magnesium taurate 250-375 mg. i still have profound fatigue but ive been sleeping well, and my neuropathy is nearly gone. I get flares of my arthritis usually after taking it as well, though luckily it has not progressed like it previously has. The last two nights i have not needed pain medication to sleep as well, which is fantastic. So there is some improvement. I’m going to keep the allithiamin dose at 400-500mg, and see where it gets me in the next coming weeks. I’m thinking that my previous dose was nowhere near where it needed to be for improvement. I feel that once my energy levels rise my body will finally be able to do its job correctly. My body is genetically predisposed to producing a low amount of antibodies to lyme disease as demonstrated by HLA-DRB04, but i don’t believe that everybody with the gene gets refractory arthritis, its just a risk factor, because i had the disease once before and recovered quickly with antibiotic treatment. The second time i was infected i was in a much more compromised state due to my diet and lifestyle choices (I was a bodybuilder and ate terribly, with absolutely massive carb binges that would leave me vomiting 4-5000 calories plus)
James, that is very good news.
Would you be interested in sharing your story as a post published on this website? I have had little success convincing folks with Lyme to consider thiamine and your story might help.
will do! when I’m in a place where i can say i’m almost normal, i will definitely be writing a piece. I’ve helped 2 of my friends with anxiety, curing them almost immediately with the use of allithiamin and magnesium. One of them was having issues for 3 months at the time, better in 2 days. His diet and lifestyle pointed me to that direction. You guys are doing amazing work, thank you!
Well, this is “food for thought”. I would guess that you are both suffering from mitochondrial gene effects and we know very little about thiamine treatment that is not acquired. My experience with TTFD has been completely without toxicity in surprisingly large doses, but that does not say that you can NOT experience it. I presume that you are also taking magnesium. I certainly have given thought, not so much to dephosphorylation as to phosphorylation, but no-one to my knowledge has reported it. I am amazed at the instant relief from health collapse to improvement that you report when you renew taking TTFD.
This article is timely — my daughter and I are being worked up for a mitochondrial dz with a thiamine transport/metabolism issue (whole exome and mitochondrial DNA pending). At age 6 my daughter began having thunderclap-onset migraines that were severe and included cyclic emesis, loss of vision, and motor impairment & ataxia that would go on for several days. This past year she began having proximal LE weakness, apathy, intermittent neuropathy and muscle pain (previously she had been very athletic). I am a pediatrician with a longstanding complex disease pattern (IDDM, non-diabetic renal failure, intermittent inflammatory episodes – pericarditis, pleuritis, iritis, proximal LE muscle weakness). Several years ago I stopped thiamine supplementation for 2 weeks and had a severe multi-day ataxia, hyperemesis, and difficulty standing. I restarted the thiamine and the symptoms quickly resided. More recently I was given furosemide, and the resulting low thiamine state caused a similar acute emesis and decompenstion picture — improved by d/cc’ing lasix and taking TTFD. My daughter’s apathy disappeared instantly with the start of TTFD, but the most interesting aspect of the disease is that any thiamine/Benfotiamine/TTFD dose >50-100mg results in pstosis and muscle weakness within 1 hour (especially in my daughter). I too have had “thiamine toxicity” symptoms (mainly pstosis and acute neuropathy) — I use quotes because it is my understanding that there is no such thing as thiamine toxicity. We have many features of a mitochondrial d/o, but all of it centers around thiamine metabolism and a hyper-excitability neuro state with phosphorus supplementation. Wondering if you have any thoughts on the possibility of a defect on the dephosphorylation side…e.g. difficulty with dephosphorylation from TPP to TMP or TMP to Thiamine (perhaps TPP) resulting in both a deficiency and toxicity picture? We do very very poorly with sublingual TPP. We are figuring out how to find a thiamine dose within a very narrow therapeutic range. Thank you for all your research and publications, they have been extraordinarily helpful as we navigate this diagnostic odyssey.
Have you considered a possible potassium deficiency to be causing the muscle weakness? This happened to me after being on B1 for a while, it increased my use of potassium, and my potassium stores were already low to begin with, and the resulting deficiency caused me severe muscle weakness, as well as eventually causing depression, constipation, low adrenal function, insomnia, and salt-retention/Edema. These symptoms resolved quickly once I added a good amount of potassium to my diet (I ate potassium-rich foods, took potassium powder in “Adrenal cocktail” and also added potassium bicarb to my foot-baths).
Thiamine causes low or high potassium at different stages of the disease. This is a reflection of energy metabolism affecting the energy dependent Na/K membrane pump. This pumps sodium out of cells and pumps potassium in.