thiamine Archives - Page 7 of 13

ASD, Seizures, and Eosinophilic Esophagitis: Could They Be Thiamine Related?

Published on January 2, 2024

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My 18 year old son has ASD and has had a seizure disorder since he was 6 years old. He has tried virtually all anti-epileptic drugs. Either the side effects were unbearable, they made his seizures worse, or had no effect on his seizures. He was diagnosed with Eosinophilic Esophagitis. He is underweight and of short stature, and always has been. Mitochondrial tests show that complex II is working at 26% capacity. He is also autistic. He has tested positive for folate receptor antibody.

Over the years he has done several rounds of antibiotics, including Flagyl, which I have since learned that it significantly depletes the body of thiamine. He has also taken several rounds of Diflucan, Azithromycin, Vancomycin, Augmentin, Amox for various issues including candida, clostridia, gram negative gut bacteria, etc.

He is currently on Lamictal and just started Briviact for seizures. The Briviact causes anger and aggression issues. He currently deals with OCD tendencies. He was recently found to have bone density of 2.8 standard deviations below normal. This falls in the range of osteoporosis, but he has not been diagnosed with it because of his age.

He eats fresh and a lot of dried fruit, meats, raw and cooked greens, white rice, lots of cooked veggies, eggs. He also takes Lipothiamine 100 mg/day, Magnesium 550 mg, a multi-vitamin, calcium, vitamin D, and K, all at the direction of his doctors.

Childbirth and Infancy

M was born on July 9th 2005 7lbs 9oz. He was full-term. I had high blood pressure at 41 weeks and labor was induced. He would not drop into position and he became distressed and so was delivered via cesarean while I was under general anesthesia.

He spent 4 days in the NICU because he aspirated meconium and would not latch to feed. While in the NICU, he was administered antibiotics. He was formula-fed, not breast-fed.

As an infant, the large size of his head was somewhat of a concern for the pediatrician. He was administered vaccinations according to the CDC guidelines for the first 12 months. He had infantile spasms off and on. He spiked a fever for every vaccination. Tylenol was administered. He received 3 doses of flu vaccine, accidentally, within 3 months.

He did not sleep well, and still doesn’t.

Initially, he was very precocious. As an infant, he would put puzzles together that were for much older children. He would complete sorting activities that were well beyond his age range. He did not babble and eye-contact was fleeting.

After his 18 month vaccination, he lost just about everything within 2 weeks. After these vaccinations, he couldn’t do his puzzles, bring food to his mouth, smile, couldn’t stand to be read to when he previously loved to be read to. He also developed a sensitivity to light and sound and cried a lot.

At 24 months, he was diagnosed with profound autism.

PANDAS/PANS and Eosinophilic Esophagitis

At age 10 years, he abruptly lost skills again and it was thought he had PANDAS/PANS as he had several strep infections treated with antibiotics. He did a several month long courses of Augmentin or Azithromycin to treat PANDAS/PANS. He had a severe trauma at age 11. He was horrifically abused by a school employee.

He has always been of short-stature nearing 5th percentile for height, and slightly overweight for his age, until age 14 when he started having symptoms of Eosinophilic Esophagitis. He was diagnosed with EoE at 15 and has struggled to keep his weight high enough as he dealt with the intense pain, fatigue, and esophagus issues with this condition. He is currently taking Dupixent for his Eosinophilic Esophagitis as the PPI and Budesonide slurry were not addressing the issues. So far Dupixent is allowing him to eat. His diet remains very restricted due to having so many trigger foods and he has almost no appetite.

He eats a lot of dried and fresh fruit. He loves greens, raw and cooked. He also eats meat, white rice noodles. He eats mostly an organic diet. He does occasionally enjoy candy.

Seizures

He developed seizures at age 6. These were controlled for a while on Depakote, but the side effects of Depakote were too much for him and so we had to stop. His seizures are now not controlled. He has 1-2 tonic-clonic seizures per week, plus several staring spells all throughout the day. Recent EEG showed abnormal spikes and discharges in the frontal and temporal lobes. It indicated his seizures involved many places on his brain. Brain surgery was being considered for seizures at this time, but ruled out as an option due to the nature of his seizures.

He has failed several other seizure meds including Vimpat, Zonegran, Aptiom, Topamax, Onfi, and others. He is currently on Lamotrigine and Epidiolex for his seizures. He also takes trazadone and gabapentin for sleep, although these do not consistently help him sleep. He is so consumed by fatigue and can hardly get out of bed even to walk across the room. With tons of encouragement he can do brief periods of school work. The meds cause him to lose focus and become frustrated. He seems to almost always be lost in a fog and unable to participate in basic conversations without losing focus or becoming too exhausted to continue. Each seizure will cause him to be in bed for 2-3 days. He has fallen many times going into a seizure and is now afraid to leave the safety of his bedroom. He will come out, but rarely.

He has intermittent issues with nystagmus. He had a bad case of COVID 2 years ago, which caused clusters of seizures and constant nystagmus.

He has an exaggerated startle response.

Despite It All

M is a sweet young man. He is brilliant. He loves animals. He tells everyone he sees that he is so happy to see them. He is working with a local legislator on how to improve rights for non-speaking people, especially in the court room. He is completing all of his high school courses at home with straight A’s and he is a published poet.

He does not speak, but he communicates by pointing to letters on an alphabet board. This is a skill that took him years to learn. He communicates at an age-appropriate level or higher. He is working, slowly, toward a standard high school diploma.

Postscript

Based upon what I have learned from this website, I discussed thiamine with our physician. It turns out, she heard Dr. Lonsdale speak years ago. She recommended 50mg of Lipothiamine. The entire time he was taking it, he had no seizures. I was not sure that it was thiamine or the meds until we ran out for about a week. The seizures returned, but as soon as we resumed the Lipothiamine, they disappeared again. He has been taking it again and now it has been 2 weeks without seizures. I don’t want to get my hopes up, but it could definitely be a piece of the puzzle. Are there others out there with similar experiences?

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It All Comes Down to Energy

by Derrick Lonsdale MD, FACN, CNS

Published on August 10, 2023

22102 views

The Threat Around Us

Animals, including Homo Sapiens, survive in an essentially toxic environment, surrounded by microorganisms, potential poisons, the risk of trauma, and adverse weather conditions. Evolutionary development has equipped us with complex machinery that provides defensive mechanisms when any one of these factors has to be faced. Before the discovery of microorganisms, medical treatment had no rhyme or reason, but killing the microorganisms became the methodology. The research concentrated on ways and means of “killing the enemy”, the bacteria, the virus, the cancer cell. The discovery of penicillin reinforced this approach. We are now facing a period of potential impotence because of bacterial resistance, failure of attempts to kill viruses, and the resistance to chemotherapeutic agents in cancer. Louis Pasteur is purported to have said on his deathbed, “I was wrong, it is the terrain that matters”, meaning body defenses.

Hans Selye, whose research into how animals defend themselves when attacked by any form of stress, led to his description of the General Adaptation Syndrome (GAS). He recognized the necessity of energy in initiating the GAS and its failure in an animal that succumbed to stress. He labeled human disease as “the diseases of adaptation”. In Selye’s time, there was little information about energy metabolism but today, its details are fairly well-known. The suggestion of a new approach depends on the fact that our defenses are metabolic in character and require an increase in energy production over and above that required for homeostasis. If the GAS applies to human physiology and that we are facing the “diseases of adaptation”, it is hypothesized that research should be applied to methods by which energy metabolism can be stimulated and mobilized to meet the stress.

Energy Deficiency, Defective Immunity, and COVID-19

There is evidence that energy deficiency applies to each of the diseases described here. It may be the unrecognized cause of defective immunity in Covid-19 disease. Although in coronavirus disease the clinical manifestations are mainly respiratory, major cardiac complications are being reported involving hypoxia, hypotension, enhanced inflammatory status, and arrhythmic events that are not uncommon. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes may accompany acute viral infections or may follow infection by weeks, months, or longer in viral recovered patients. Electrocardiographic changes have been reported in Covid-19 patients. The authors suggest that it may be attributed to hypoxia as one possibility. Because the total body stores of thiamine are low, acute metabolic stress can initiate deficiency. Thiamine deficiency has a clinical expression similar to that observed in hypoxic stress and the authors referred to it as pseudo-hypoxia. It is therefore not surprising that defective energy metabolism can express itself clinically in many different ways.

The present medical model regards each disease as having a separate cause, but the large variety of symptoms induced by thiamine deficiency suggest the ubiquitous nature of energy deficiency as a cause in common. Obesity, a reflection of high calorie malnutrition, has been published as a risk factor for patients admitted to intensive care with Covid-19. Thiamine deficiency was reported in 15.5-29% of obese patients seeking bariatric surgery. Hannah Ferenchick M.D. an emergency room physician commented online that many of her patients with Covid-19 had what she called “silent hypoxemia”. These patients had an arterial oxygen saturation of only 85% but “looked comfortable” and their chest x-rays “looked more like edema” It has long been known that patients with beriberi had low arterial oxygen and a high venous oxygen saturation. All that would be needed to support the hypothesis of thiamine deficiency in some Covid victims would be finding a high venous oxygen saturation at the same time as a low arterial saturation. Also, edema is a very important sign of beriberi, and thiamine deficiency has been noted in critical illness.

Disrupted Autonomic Function

There have been many articles in medical journals describing dysautonomia, mysteriously in association with a named disease, but with no suggestion that the dysautonomia is part of that disease. More recently, there is increasing evidence that dysautonomia is a feature of chronic fatigue syndrome (CFS), manifested primarily as disordered regulation of cardiovascular responses to stress. Manipulating the autonomic nervous system (ANS) may be effective in the treatment of CFS. Dysautonomia is also a characteristic of thiamine deficiency. Patients with Parkinson’s disease begin to lose weight several years before diagnosis and a study was undertaken to investigate this association with the ANS. Costantini and associates have shown that high dose thiamine treatment improves the symptoms of Parkinson’s disease, although the plasma thiamine concentration was normal. They have also shown that high dose thiamine treatment decreases fatigue in inflammatory bowel disease, Hashimoto’s disease, after stroke, and multiple sclerosis. As already noted, it is also an important consideration in critically ill patients.

Multiple System Atrophy is a devastating and fatal neurodegenerative disorder. The clinical presentation is highly variable and autonomic failure is one of its most common problems. Dysautonomia was found to be a clinical entity in Ehlers-Danlos syndrome, a musculoskeletal disease, and this syndrome frequently coexists with Postural Orthostatic Tachycardia Syndrome (POTS), a disease that is included in the group of diseases under the heading of dysautonomia. Some cases of POTS have been reported to be thiamine deficient. This common condition often involves chronic unexplained symptoms such as inappropriate fast heart rate, chronic fatigue, dizziness, or unexplained “spells” in otherwise healthy young individuals. Many of these patients have gastrointestinal or bladder disorders, chronic headaches, fibromyalgia, and sleep disturbances. Anxiety and depression are relatively common. Not surprisingly the many symptoms are often unrecognized for what they represent and the patient may have a diagnosis of psychosomatic disease.

Immune-Mediated Inflammatory Diseases (IMIDs) is a descriptive term coined for a group of conditions that share common inflammatory pathways and for which there is no definite etiology. These diseases affect the elderly most severely with many of the patients having two or more IMIDs. They include type I diabetes, obesity, hypertension, chronic pulmonary disease, coronary heart disease, inflammatory bowel disease, rheumatoid arthritis, Sjogren’s syndrome, systemic lupus, psoriasis, psoriatic arthritis, and multiple sclerosis. The recent recognition of small fiber neuropathy in a large subgroup of fibromyalgia patients reinforces the dysautonomia-neuropathic hypothesis and validates fibromyalgia pain. These new findings support the disease as a primary neurological entity.

Energy Deficiency During Pregnancy: The Cause of Many Complications

Irwin emphasized the energy requirements of pregnancy in which the maternal diet and genetics have to be capable of producing energy for both mother and fetus. He found that preventive megadose thiamine, started in the third trimester, completely prevented all the common complications of pregnancy. Hyperemesis gravidarum is the most common cause of hospitalization during the first half of pregnancy and is second only to preterm labor for hospitalization in pregnancy overall. This disease has been associated with Wernicke’s encephalopathy, well known to be due to brain thiamine deficiency. The traditional explanation is that vomiting is the cause, but since vomiting is a symptom of thiamine deficiency, it could just as easily be the cause rather than the effect. In spite of the fact that migraines are one of the major problems seen by primary care physicians, many patients do not obtain appropriate diagnoses or treatment. Migraine occurs in about 18% of women and is often aggravated by hormonal shifts. A complex neurological disorder involving multiple brain areas that regulate autonomic, affective, cognitive, and sensory functions, it occurs also in pregnancy. Features of the migraine attack that are indicative of altered autonomic function include nausea, vomiting, diarrhea, polyuria, eyelid edema, conjunctival injection, lacrimation, nasal congestion, and ptosis.

The Proteopathies: Disorders Involving Critical Enzymes

The earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine. Multiple similarities exist between classical thiamine deficiency and Alzheimer’s disease (AD), in that both are associated with cognitive deficits and reductions in brain glucose metabolism. Thiamine-dependent enzymes are critical components of glucose metabolism that are reduced in the brains of AD patients. Senile plaques and neurofibrillary tangles are the principal histopathological marks of AD and other proteopathies. The essential constituents of these lesions are structurally abnormal variants of normally generated proteins (enzymes). The crucial event in the development of transmissible spongiform encephalopathies is the conformational change of a host-encoded membrane protein into a disease associated, fibril forming isoform. A huge number of proteins that occur in the body have to be folded into a specific shape in order to become functional. When this folding process is inhibited, the respective protein is referred to as being mis-folded, nonfunctional, and causatively related to a disease process. These diseases are termed proteopathies and there are at least 50 different conditions in which the mechanism is importantly related to a mis-folded protein. Energy is required for this folding process. Because of their reported relationship with thiamine, it has been hypothesized that mis-folding might be related to its deficiency on an energy deficiency basis.

It All Comes Down to Energy

A hypothesis has been presented that the overlap of symptoms in different disease conditions represents cellular energy failure, particularly in the brain. If this should prove to be true, the present medical model would become outdated. An attack by bacteria, viruses or an oncogene might be referred to as “the enemy”. The defensive action, organized and controlled by the brain, may be thought of as “a declaration of war” and the illness that follows the evidence that “a war is being fought”. This concept is completely compatible with the research reported by Selye. It underlines his concept that human diseases are “the diseases of adaptation”, dependent on energy for a successful outcome in a “war” between an attacking agent and the complex defensive actions of the body. Killing the enemy is a valid approach to treatment if it can be done safely. Unfortunately, the side effects of most medications sometimes makes things worse and that is offensive to the Hippocratic Oath. We badly need to create an approach to research that explores ways and means of supporting and stimulating the normal mechanisms of defense.

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This article was published originally on May 11, 2020.

Is TTFD Toxic?

by Elliot Overton, DipCNM CFMP

Published on July 31, 2023

18521 views

I regularly receive correspondence from people asking whether thiamine tetrahydrofurfuryl disulfide (abbreviated TTFD), a thiamine (vitamin B1) derivative, is toxic or not. Most people following this line of inquiry base the assumptions of “toxicity” on statements previously made by the famous (and now deceased) Andrew Cutler, PhD. Cutler is most well-known for his work on mercury chelation and detoxification protocols and has amassed thousands of followers over the years. He was strongly opposed to the application of TTFD therapeutically and explicitly advised people against using this molecule as a nutritional supplement for thiamine repletion or heavy metal detoxification. Much of what he said on this topic was documented in the archives of the Onibasu website which can be found here. Cutler’s statements were speculative in nature, based on anecdotes, and to my knowledge, were never backed by any scientific evidence. In this article, I would like to address his claim that TTFD is toxic. I should note, based upon all of the available research, which is substantial, TTFD is not toxic, even at supra-physiological dosages. A version of this article was published on my website.

Is TTFD Toxic?

To understand whether TTFD or any compound may be considered toxic, it is important to recognize how toxicity is determined in pharmacology. Here toxicity is represented by something called a therapeutic index (TI). In animals, where much of the research is conducted initially, the TI is determined between by ratio of the lethal dose 50 (LD50), a dose at which 50% of the animals die, and the effective dose 50 (ED50), the dose at which a therapeutic response is noticed in 50% of the animals. This is represented as TI = LD50/ED50. In humans, instead of lethal dose, toxic dose is used (TD50). Here, the TD50 represents negative or adverse reactions in 50% of the population tested. The equation is basically the same, TI = TD50/ED50.

In both cases, higher therapeutic dosing windows relative to efficacy confers greater drug safety. Compounds where there is little wiggle room between the TD50 and LD50 – a small TI – are considered the most toxic. See Figure 1.

Therapeutic Index — Figure 1. Therapeutic index.

By way of example, alcohol/ethanol has a TI of 10, whereas LSD and cannabis have TI’s of greater than 1000. This means that one has to consume far less alcohol to achieve toxicity and lethality than either LSD or cannabis. Indeed, it is virtually impossible to overdose (OD) with LSD or marijuana compared to the ease at which one can OD on alcohol. Figure 2.

Lethal doses for common drugs — Figure 2. Lethal dose of common drugs.

Similarly, the TI for many common drugs is quite low. Figure 3. from a pharmacology lecture on SlideShare, shows the TI of common medications.

Figure 3. Therapeutic index of medications.

What Does Any of This Mean for TTFD?

In mice studies, the LD50 for TTFD has been calculated at 450mg/kg when given intravenously (IV) while the LD50 for an oral dose is 2200mg/kg. Since the conversion from mice to human dosage is not calculated directly based upon on weight, but accounts for interspecies differences in metabolism, an equivalent LD50 for a 70 kg (154 lb) human would be 2.5 grams of TTFD when administered via IV and 12.5 grams if taken orally. Whilst 2.5 (IV)-12.5 (oral) grams may seem low, no one realistically takes that amount of TTFD per day for therapeutic reasons. The highest oral doses I have observed are around ~1-2 grams per day. These are individuals with chronic thiamine deficiency, usually accompanied by underlying genetic issues. More commonly, observation and clinical research suggest between 100-300 mg/day is used for most treatment/research protocols (see the ‘What about Research in Humans’ section below).

Back to the math, the RDA for thiamine, not TTFD, but thiamine consumed from food naturally, from food fortification and/or via supplementation using the most common formulations of thiamine mononitrate or hydrochloride (HCL) is 1.1 and 1.2 mg per day for adult females and males respectively. Assuming that the RDA values represent an effective dose (there are no actual data on the ED50 for thiamine), and for simplicity, that TTFD is as effective as the other two formulations, when we calculate the TI for humans (TI= ED50/TD50) for humans, we get a huge range between effective dose and toxic or lethal dose. For IV administered TTFD the ratio would be ~2,500:1, while oral dosing, it would be ~12,500: 1. If we assume, based upon its bioactivity that TTFD is more potent than the other two formulations, the TI would increase even more.

Based just upon standard toxicology parameters, it is clear that TTFD is not toxic. An individual would have to take ~12,000 times the effective dose to approximate lethality. I say approximate, because there are no documented cases of TTFD overdose. Lethality, however, is just one component of toxicology. Adverse reactions are an important consideration. That is why, in human research, instead of LD50, TD50 is used. Here though, the work becomes a little murky, partly because animals are used and partly because the chemistry of TTFD metabolism is complicated.

Toxicity Studies Using High Dose TTFD

Consistently, the animal data show that excessive doses for extended periods of time, even during pregnancy and across multiple generations, TTFD is not toxic.

Research performed on the reproductive effects of TTFD in monkeys showed that massive doses of 500mg/kg, close to supposed LD50 for that species, found no deaths. To put this in context, it would be the human equivalent of taking 10-11 grams per day for MONTHS.
That same study also looked at massive doses in rabbits and found no significant increase in incidence of fetal malformations in either group was observed, even in groups treated with high doses and no significant teratogenic effects or developmental abnormalities in pregnancy occurred.
As referenced in this document, Takeda’s research by Mizutani demonstrated that administration of 100, 300 and 500mg/kg in rats for two generations from the time of maturation to the time of reproduction showed no abnormalities. The average human equivalent (70Kg) of these doses would be 570mg, 1.7 grams and 2.8 grams per day for life.
The results of another study showed that long-term oral administration of 30-300mg/kg to pregnant animals failed to produce any significant developmental abnormality. Intraperitoneal administration of 1000mg/kg also showed no sign of chromosome aberration, damage to sex organs or spermatogenesis.

TTFD Metabolism

If TTFD is not toxic via the traditional measures, is there something about the molecule itself that may be problematic and cause unwanted effects? Cutler speculated that the mercaptan part of TTFD was responsible for toxicity, and that this primarily affected the liver. The word “mercaptan” refers to the thiol group that breaks away from thiamine after its absorption into the cell. This mercaptan group essentially accounts for the “TFD” of the abbreviation TTFD. After TTFD is absorbed, it gets “broken apart” (the disulfide bond is chemically reduced) by glutathione, cysteine, or hemoglobin to release the free thiamine molecule, which will become trapped inside the cell and ultimately used by the body.

mercaptan metabolism — Figure 4. Mercaptan metabolism phase 1.

In more technical terms, the prosthetic mercaptan is released and then rapidly metabolized by the liver through methylation and later sulfoxidation by liver mono-oxygenase enzymes into breakdown products which are then excreted in urine. Is mercaptan toxic as Cutler suggested? The original series of studies on the enzymatic breakdown of TTFD and mercaptan show that it is not toxic and is rapidly excreted from urine.

If mercaptan itself is not toxic, perhaps it metabolizes into something else and one of its by-products are problematic. From Figure 5., we see that mercaptan is metabolized into a sulfate that is then eliminated via urinary excretion and a few other compounds that are processed by the liver first before being eliminated via urinary excretion as well. The breakdown products are shown below in Figure 5.

TTFD - mercaptan metabolism — Figure 5. TTFD – Mercaptan metabolism.

A study titled “Pharmacological study of S-alkyl side chain metabolites of thiamine alkyl disulfides” sought to determine the acute and sub-acute toxicity levels of each metabolite. They concluded that toxicity of these breakdown products was low. Remember the LD50, the dose that causes death in 50% of the study animals, research shows that the LD50 each of these breakdown products is enormous, far more than would be clinical relevant in humans. The results of this study showed:

Inorganic sulfate: non-toxic
Delta-methylsulfonyl-gamma-valerolactone: also non-toxic.
- Intravenously, the LD50 in mice was in excess of 5 grams/kg body weight. For comparison, the LD50 estimate for a 70KG human: 5 grams intravenously.
- Orally the LD50 in mice was 6 grams/kg body weight, which, for a 70 kg human would translate to approximately.
4-Hydroxy-5-(methylsulfonyl) valeric acid
- Intravenous LD50 in mice: 1.5 grams/kg body weight
- LD50 estimate for a 70KG human: 3 grams intravenously

Once again, it appears that none of these compounds is toxic. In humans, approximately 82-90% of these metabolites are excreted within 24hrs and 100% are excreted within 48hrs. What this tells us is that by themselves, these metabolites are not toxic except in supra-physiologic doses, which are not relevant from a clinical perspective.

What About Liver Damage?

Cutler speculated that metabolism of TTFD resulted in liver damage. To quote Cutler:

My guess is the tetrahydrofurfuryl mercaptan part kills your liver.

Here too, however, the data suggest otherwise. In animals with artificially induced liver damage by carbon tetrachloride and/or hepatic dysfunction due to choline deficiency, the breakdown products of TTFD were assessed. They showed that the quantity of excreted metabolites in the hepatotoxic group were equal to the control, and in choline deficiency the quantity of excreted metabolites was only slightly reduced. In the hepatotoxic group, a qualitative difference was found with a lower proportion of methyl metabolites (MTHFSO, MTHFS02). This suggests, even in with pre-existing or induced hepatotoxicity, TTFD can be excreted albeit slightly differently.

A peer-reviewed study published in 2018 entitled “The Effects of Thiamine Tetrahydrofurfuryl Disulfide on Physiological Adaption and Exercise Performance Improvement” studied the effects of different doses of TTFD in 30 animals for a period of 6 weeks. The highest oral dose used was 500mg/kg in 10 test subjects, which is the human equivalent to 40mg/kg which, in a 70KG human, is 2.8 GRAMS per day for 6 weeks. Remarkably, they showed that this highest dose produced significant improvement in endurance capacity and lactate homeostasis.

More importantly, this study also performed comprehensive measures of sub-acute toxicity with the aim of evaluating the safety of high doses in humans. Even at the highest dose taken for 6 whole weeks, no changes in behavior, diet, growth curve, or organ weight (liver, kidney, muscle, heart, lung etc.) was observed. Furthermore, to assess liver function, they performed comprehensive metabolic analysis including liver enzymes (ALT, AST), creatine, uric acid, total cholesterol, triglycerides, albumin, total protein, ammonia, creatine kinase, and total protein. The only significant changes were a slight reduction in total cholesterol and significant reduction in lactate, creatine kinase and blood urea nitrogen (all of which are considered positive changes). Every other liver marker was perfectly in range. To gain further insight into the liver function and the health of other tissues, they performed histopathological analysis of the tissue under microscope and showed that massive doses caused no pathological changes in any tissue whatsoever. The authors conclude:

In the current study, we proposed that the higher thiamine derivative, TTFD, could significantly improve physical activities and physiological adaption with evidence-based safety validation. For practical application, we recommend that athletes should consume a daily intake of 40 mg/kg TTFD (equivalently converted from mouse 500 mg/kg dose based on body surface area between mice and humans by formula from the US Food and Drug Administration [36]) to improve energy regulation for higher performance in a combined nutritional strategy, including carbohydrate loading for efficient energy demand during extended exercise.

They were so convinced of the supplement’s safety that they recommended athletes take the equivalent of 2.8 GRAMS per day LONG-TERM to improve athletic performance.

What About Research in Humans?

To those who complain that these are “animal studies”, the comparative metabolic studies have found that the metabolism of TTFD is essentially the same in animals and humans. This means that humans are likely to respond similarly. As one of the first medical doctors to use TTFD as a clinical intervention in the Western world, Dr. Derrick Lonsdale obtained a special license from the FDA to import this molecule and studied its effects in his pediatric patients. In his own words:

I was able to study the value of this incredible substance in literally hundreds, if not thousands of patients. Far from being toxic, as this person claims, I never saw a single item that suggested toxicity.

Some reports published by Lonsdale and other authors include:

22 children with Down’s Syndrome, 12 of which were administered TTFD for 12 months and 12 of which were administered TTFD for 6 months. No serious adverse events noted.
Brainstem dysfunction – three infants saw symptomatic improvement with thiamine disulfide treatment.
Abnormal brainstem auditory evoked potentials, one infant was administered intravenous TTFD and displayed normalization of brainstem function
21 patients subacute necrotizing encephalomyelopathy treated with thiamine derivatives TPD/TTFD 10 Children – no serious adverse events – 1 experienced worsening of behavior/symptoms, 2 with rash
44 polyneuropathy patients treated with 50mg TTFD injection, no adverse effects reported.
Prosultiamine (TPD) at 300mg per day for 12 weeks (TPD, a very similar molecule to TTFD) used to treat spinal cord injury in human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (2013). Significant improvement in motor functions and bladder control, as well as reducing viral numbers in blood. Only adverse symptom was mild epigastric discomfort. No safety concerns.

For a comprehensive look at thiamine research, refer to Drs. Lonsdale and Marrs’ book: Thiamine Deficiency Disease, Dysautonomia and High Calorie Malnutrition

TTFD Used in Other Countries

It is worth noting that TTFD is not well known in Western medicine. The regions of the world in which it is used extensively include Japan, China, and other countries in the Far East.

Japanese Cases

Unfortunately, much of the Japanese literature is not published in English, so it can be difficult to find. I use a translator application called DeepL to read these articles. Furthermore, TTFD is so regularly prescribed for treating thiamine deficiency that much of the literature refers to TTFD simply as “thiamine” or “vitamin B1”, using the terms interchangeably. This means that finding research papers without TTFD in the actual title is very difficult. Below are 33 case reports from the Japanese literature, including some in children, which document the benefits of TTFD clinically. In all of the papers I have read, I have not once seen mention of safety concerns using this. In several reports, hundreds of milligrams are maintained indefinitely with no apparent issues.

267 cases of sudden-onset deafness was treated with 150mg TTFD orally, with most therapeutic effect seen after 2-3 months of treatment
20 cases of perceptive deafness, 20 cases of laryngeal disease, 7 cases of facial nerve palsy and 3 cases of anosmia injected with TTFD 50mg once per day for 5-20 days. 60% effective and no side effects.
24 subjects without nutritional deficiency, 20 cases of alcoholism, and 48 cases of alcoholism with signs of deficiency and/or liver disease were given either TTFD, Thiamine propyldisulfide (a similar disulfide derivative), or thiamine HCL. They showed no toxic effects at 3-6 months in any group, and demonstrated that oral TTFD/TPD increased whole blood, erythrocyte, and cerebrospinal fluid thiamine levels at an equivalent level to intravenous thiamine HCL.
Beriberi treated with 150mg IV one week, followed by 100mg oral long-term (2014)
Cardiac failure 100mg IV (1987)
Heart and circulatory failure (2008)
TTFD administered to 15 year old boy to treat beriberi, remained on the therapy long-term
18 patients with non-diabetic peripheral neuropathy 1-3 months, no serious side effects
Wernicke encephalopathy in hemodialysis – 100mg/iv, later oral continued for 2 months until improvement (2009)
Diabetic lactic acidosis – 100mg/day IV for 7 days resolution in symptoms, followed by 75mg indefinitely (2008)
Beriberi w/ pulmonary hypotension – 50mg long-term (2019)
E/beriberi after intestinal resection – 150mg IV three days, 75mg long-term (2018):
E/Shoshin beriberi – 150mg/IV, 75mg oral long-term (2013)
A case of Wernicke’s encephalopathy with severe cardiac sympathetic dysfunction – 100mg (2012)
Marked anasarca with impaired consciousness, which was thought to be caused by shoshin beriberi due to impaired vitamin B1 utilization. – TTFD 40mg +400mg HCL, followed by 2 months+ TTFD 100mg (2015)
Beriberi neuropathy and shoshin beriberi that developed 6 years after gastrectomy on the cardia side – 100mg TTFD long term (2013)
Chemotherapy induced W.E – IV thiamine HCL followed by TTFD 75mg long-term (2008)
Postoperative W.E treated with 100mg IV TTFD (1998)
Cardiomyopathy associated with mitochondrial disease that developed heart failure, treated with 100mg long-term (2017)
Mitochondria rescue formula recommended for acute encephalopathy: including TTFD 100mg (2019)
Pediatric acute encephalopathy neuroprotection protocol – cocktail including 200mg TTFD in 15 children (2013)
200mg TTFD x 31 children childhood acute encephalopathy (part of protocol) (2014)
Lactic acidosis caused by low-dose metformin: Thiamine HCL 100mg followed by 75mg TTFD long-term, normalization of all liver values (2014)
Beriberi mimicking Guillain-Barré syndrome – IV TTFD 100mg resolved this
Shoshin beriberi – IV TTFD 150mg for 11 days, indefinite oral dose 150mg TTFD long-term
6 infants (0-1 yrs old) treated with TTFD for childhood congenital lactic acidosis. Doses included 35mg/KG – 50mg/KG. Some cases were unresponsive to thiamine HCL, where TTFD ONLY could reduce lactate significantly “Fursulthiamine hydrochloride was significantly superior to thiamine hydrochloride in reducing lactate.” Only the cases which used TTFD survived. Children were kept on high doses permanently with no adverse effects.
75mg TTFD improved cerebral blood flow in deficiency
75mg TTFD used in mitochondrial myopathy long-term
50mg TTFD used to treat edema and weight gain and marginal thiamine deficiency – authors recommend TTFD instead of thiamine HCL (2021)
Biguanide-induced lactic acidosis treated with 100mg, then 300mg TTFD (2017)
100mg used to treat encephalopathy w/ hyperammonemia (2003)
Subacute spinal degeneration caused by B12 deficiency treated with B12 and 75mg TTFD long-term (2020)
Statement by a Japanese physician: recommendation to use TTFD instead of thiamine HCL due to superior qualities.

Chinese Cases

Like the Japanese research, most (if not all) of the Chinese studies using TTFD are not published in English. However, it is clear that the Chinese medical system uses TTFD frequently and has done so for several decades. Most of the studies below were reported within the last 20-30 years. Once again, I could not find any concern regarding the safety of this molecule and it was demonstrated as remarkably effective for a variety of conditions. Interestingly, the Chinese not only use it for deficiency, but also for non-deficient conditions where it is often injected directly into acupoints (acupuncture meridians) either alone, or in combination with other nutrients/medications. They still use these methods to this day. Here are 32 more articles regarding the safety and efficacy of TTFD from the Chinese literature.

194 cases of infantile beriberi cured with IM/IV thiamine and TTFD (1987)
50 infants treated with TTFD for cardiac beriberi (1997)
70 children with infantile beriberi cured with intravenous TTFD (1990)
48 cases of infantile cerebral beriberi (0-3 years old) treated with TTFD (1997)
35 cases of infantile beriberi cured TTFD (2010)
10 cases of infantile cerebral beriberi cured with B1 HCL and TTFD
10 cases of cerebral beriberi and basal ganglia damage treated with TTFD injections (2003)
125 children with pneumonia treated using TTFD as primary treatment (10mg IM <3 months old, 20mg IM <6 months, 20mg twice per day >6 months old)
283 out of 285 children with rectal prolapse cured by TTFD injection into “changqiang” acupoint (1988)
89 cases of rectal prolapse also treated with TTFD acupoint injection (1998)
50 cases of cerebral hypoplasia improved with acupoint injection of acetyl glutamine and TTFD (1983)
35 patients treated for hyperthyroidism with TTFD as adjunctive treatment (1999)
50 cases of costochondritis cured with Analgin + TTFD injection (1993)
13 children with ocular nerve palsy cured with TTFD (2010)
50 cases of urinary incontinence treated with acupoint injection of combination of acetyl glutamine, TTFD and/or r-aminobutyric acid (1990)
26 cases of delayed peripheral neuropathy due to organophosphate poisoning treated with acupuncture and TTFD injection (2001)
47 cases of lumbar disc protrusion treated with acupoint injection, B12 and TTFD (1994)
38 cases of facial neuritis treated with acupuncture and vitamins including TTFD injection (1999)
60 cases of migraine treated with Chinese medicine, flunarizine, and TTFD (2004)
24 cases of migraine treated with TTFD acupoint injection (1990)
40 patients with cerebrovascular disease addressed using acetyl glutamine and TTFD scalp acupoint injections (2001)
30 cases diabetic neuropathy, 75mg TTFD used as a control in– 60% effective (2002)
69 cases of Bell’s Palsy, TTFD used with acyclovir (1999)
120 cases of Bell’s Palsy treated with oral TTFD, methylb12, and/or electroacupuncture and facial muscle exercise (2019)
65 cases of Meniere’s Diseases treated with TCM, vitamins including TTFD injections
118 cases of herpes zoster treated with TTFD in conjunction with acyclovir and traditional Chinese medicine (2013).
100 cases of senile deafness treated with cocktail including TTFD (2000)
36 cases of cervical spondylotic radiculopathy treated with control of TTFD and naproxen – 75% effective (2009)
60 cases of postherpetic neuralgia treated with cocktail including TTFD
1 case of polerarteritis nodosa w/peripheral neuritis treated with cocktail including TTFD
1 case of central paralytic dysphagia (tuberculosis meningitis) unresponsive to conventional treatment cured by injection of TTFD at meridian acupoint (1974)
1 case of drug-induced diplopia treated with methyl B12 and TTFD

TTFD Is Not Toxic

At this point, it should be clear that TTFD is not toxic at either therapeutic or even supraphyisiological doses. This is supported by in vitro, animal, and human studies. One would have to use ~12,000 times the therapeutic dose to approximate toxicity and even then it is not clear that there would be the problems that Cutler suggested. That is not to say that everyone who takes this supplement responds favorably. Clinically, there are individuals for whom other formulations of thiamine work better. This is generally related to a lack of the necessary nutrient cofactors involved with the detox enzyme glutathione. I have written about that previously here. That perceived intolerance, however, is not the same as toxicity. The toxicity data are clear. TTFD is safe. The clinical data are also clear. TTFD is effective. The molecule has been in use for over half a century and is used extensively in medical practice in Eastern countries. No safety concerns or claims of toxicity have been raised, apart from those made by Cutler.

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This articles was published originally in February 2022.

Thiamine Deficiency, Fatigue, and Erectile Dysfunction

by Kash

Published on July 27, 2023

11159 views

Thiamine deficiency and erectile dysfunction

Hello, I am a 33 year old male who has been experiencing a vast range of symptoms over four years including progressively worsening fatigue, brain fog, muscle weakness, body pain and erectile dysfunction. Only a few months ago, I discovered that there could be a relevance of thiamine in all of my issues. All of my health problems worsened at the age of 29 years old. More context can be found below.

Childhood Problems

I had problems with:

Concentration and focus
Emotionally down
Prone to common cold (infection)
- Unfortunately I was put on antibiotics more often every few months as a kid (amoxicillin)
Brain fog
- My brain is slow at processing things, there is always a latency associated with me to perceive things.

Health Journey

My health journey is complex. In the sections below I have tried my best to capture the sequence of events and diagnostic data we have so far. I began developing fatigue, not feeling refreshed even after sleep in my early 20’s but I continued pushing myself – not knowing how to address this. Irrespective of these limitations, I was an active adult – I was working out regularly, lean and athletic. My food habits were clean i.e., no processed foods, no alcohol, but majority of my calories were from carbs. My macro mix was approximately 50% carbs, 25% fat, 25% protein. Being a South Asian, white rice is part of my staple diet.

Things started to go really bad around 29 years of age when my fatigue, brain fog, muscle weakness, body pain worsened and nocturnal erections started to degrade. I was not able to obtain erection without Viagra. I started my health journey to fix my erectile issues. Because of my appearance (lean and athletic) all the doctors refused to even work with me, saying the issues were psychological. I found an alternative doctor who ordered blood work and we found few biomarkers that were off.

Very low Vitamin-D3 – 12.8
Low Platelets – 60,000 – 80,000 x10E3/uL
Subclinical Hypothyroidism (Elevated TSH – 9.5 uIU/mL and Reverse T3 – 33.8 ng/dl)
Testosterone was low for my age but not below reference range – 525 ng/dl

Unfortunately, this is the first time I had a comprehensive health checkup, so I don’t have any previous data to compare against. Since I was in the Pacific Northwest area where there is not much sun, I was living with low D3 for years. I worked with a hematologist to ensure low platelets were not as a result of any major illness. I started addressing my thyroid using levothyroxine and low vitamin-D3 with a vitamin-D3 supplement.

Subclinical Hypothyroid and Low D3

We developed a plan to address vitamin-D3 deficiency via supplements and also thyroid via levothyroxine. We started with 50 mcg of levothyroxine, which improved some of my symptoms slightly. The fatigue, brain fog and erectile issues improved somewhat. Unfortunately this was short lived and after ~4-6 weeks, my health started deteriorating again. Since I saw initial progress with thyroid, the doctors assumed my health issues were related to thyroid and started treating me with different thyroid formulations, different forms etc., to improve thyroid function.

After looking at my thyroid labs, doctors always mention that my thyroid hormones – FreeT3, FreeT4 were good but my reverseT3 and TSH were always elevated.

Neuropathy and Disc Herniation

In the end of 2020, I began developing burning pain in my lower back, which eventually started flowing to both my feet. MRI confirmed that disc herniation in my L5-S1 layer impacted S1 nerve root. I also took EMG that confirmed there is mild impact on S1 nerve root. The burning pain coincided with worsening erectile dysfunction. I was no longer responding to Viagra and I was in immense burning pain. After a few months of intense pain, the pain has begun to recede, but I am still experiencing a constant burning sensation, except when I sleep.

Disc herniation or burning pain was not as a result of any incident. It seemed to develop gradually, like everything else. A straight leg test or no movement worsened it immediately. One neurologist had an alternate theory that burning pain was not coming from disc herniation but because my D3 was low for a long time my microbiome was affected. Since gut bacteria synthesize B vitamins, she suspected that I was deficient. Her theory was I was deficient in vitamin-B5, which was resulting in burning pain and sleep issues. It is also possible that burning pain is caused by thiamine deficiency. I talk about this in the thiamine supplementation section below.

Neurological Issues

During this time period when I developed burning pain, I was also struggling with temperature regulation issues. When I moved from outside ~90f to inside ~70f, I would get chills. I was feeling cold most of the time, cold hands and feet, and sweating profusely. I used to get pins and needles randomly when out in the sun or while walking.

Gastrointestinal Issues

When I developed burning pain, I also started experiencing bad constipation. I was not able to empty my bowel at all. I had to take herbal laxatives every day for my bowel movement. I have also been experiencing bloating, seeing undigested foods in stool, chronic bad breath – potentially from SIBO. In the last three years, I have lost more than 20 pounds. I look more lean and weak at this point.

Sleep Issues

It has been years since I woke up feeling refreshed. I rarely dream. I have noticed that I am able to easily fall asleep and stay asleep most of the time but my sleep quality is bad, especially the later half of the sleep where REM sleep occurs.

Erectile Dysfunction

I have no nocturnal erections at this point and have not had any over the last several years. I still rely on Viagra and am now taking more than 100 mg, which is the max dosage of Viagra. On some days I don’t respond to Viagra as well. All other obvious issues associated with erectile dysfunction were ruled out including hypertension, heart issues, and hormonal issues. Essentially, I am a ‘healthy’ individual suffering from erectile dysfunction. With all of the other issues, am I really healthy? I don’t think so, but the doctors do.

Toxins and Micronutrient Deficiencies

One of the theories of a doctor who evaluated me was that I was exposed to some toxins. Testing revealed that I had high levels of ochratoxin A, a mycotoxin, which is usually from aspergillus but may be impacted by glyphosate exposures. Based on my blood and urine markers, they confirmed that my detox pathways were impaired and in need of more B-vitamins. I also did a Spectracell testing, which looks at the vitamins and minerals in the cell level, and it did show a deficiency in vitamin-B5, and borderline deficiencies in few other vitamins, which supplementing with a multi-vitamin didn’t appear help.

Thiamine (Benfotiamine) Supplementation

I began supplementing with Life Extension – 250mg of Benfotiamine and many things happened.

My sleep quality improved and I felt slightly refreshed the next morning.
I started getting partial nocturnal erections.
I started responding to the same dosage of Viagra much better than before taking Benfotiamine.
Better energy and mood.
Burning pain in my feet reduced greatly.

The problem, from second day onwards my sleep quality fell apart. I was easily able to fall asleep but was not able to sleep for more than ~5-6 hours and my REM + Deep sleep was less than 90 minutes.

I increased electrolytes

Potassium
- Add 1 litre of coconut water
- Added 1 teaspoon of cream of tartar
Magnesium
- Increased from 250 mg to 375 mg – I am taking Magnesium Malate

This improved my sleep quality slightly, but I still struggled. I couldn’t sustain taking Benfotiamine at the same dosage for a long time. So I had to stop.

Current State

Supplements I take currently:

Vitamin B12 – 1000 mcg
Vitamin D3 – 10,000 IU
Magnesium Malate – 375 mg
Creatine (~3 grams)
Athletic Greens (Multi Vitamins)

I am still suffering with all the issues mentioned above and struggling to incorporate thiamine. How should I proceed here?

Should I try small dosages of TTFD and proceed from there? What cofactors to incorporate?
Should I work with doctors and take thiamine injections or incorporate IV?
Should I try Myer’s IV – which contains below formula once a week for few weeks to see if I can experience any improvement to validate this theory
- 5 mL of magnesium chloride hexahydrate (20%)
- 3 mL of calcium gluconate (10%)
- 1 mL of hydroxocobalamin (1,000 μ/mL)
- 1 mL of pyridoxine hydrochloride (100 mg/mL)
- 1 mL of dexpanthenol (250 mg/mL)
- 5 mL of vitamin C (500 mg/mL)
- 20 mL of sterile water
- 1 mL of B-complex 100 containing:
  - 100 mg of thiamine HCl
  - 2 mg of riboflavin
  - 2 mg of pyridoxine HCl
  - 2 mg of panthenol
  - 100 mg of niacinamide
  - 2% benzyl alcohol

I have been very determined to get myself out of these conditions. Any help or guidance here will be much appreciated?

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Mitochondria Need Nutrients

by Chandler Marrs, PhD

Published on July 20, 2023

23129 views

One of the more common questions I get asked is which nutrients do the mitochondria need to function well? This is really two questions. The first involves which nutrients are involved in the enzymatic processes that allow the mitochondria to convert food to ATP and to manage all of the other tasks that they are responsible for like inflammation, immune function, and steroidogenesis. The second question applies specifically to the individual. It is a question of what he/she needs to be healthy. The answers to both are entirely different. While it is true that there are a set of nutrient co-factors involved in the mitochondrial machinery and these are necessary for mitochondrial function for everyone, which ones and how much of each an individual may need to support his or her health varies significantly. Moreover, although there are baseline minimum nutrient requirements that tell us where insufficiency diseases are likely to develop, what determines an individual’s health or disease is entirely dependent upon genetics, exposures, diet and lifestyle, and even day to day stress. Here, there is no one-size-fits all prescription for nutrient replacement and supplementation or even diet and exercise. This frustrates folks to no end and I think it is one of the reasons both patients and physicians are so reticent to look toward nutrient supplementation seriously as a therapeutic option.

Both the current model of medicine, and to a large degree, the way we approach nutritional therapies, relies very heavily on the silver bullet approach to health. If we’re honest with ourselves, so too do we. It is so much simpler to believe that if we just take X drug or vitamin in Y dose, all of our health issues will disappear and they will disappear at set rate that is linear and predictable. Unfortunately, this is not how the body works. While there is an internal chemistry that requires certain nutrients to function appropriately, that chemistry varies ever so slightly by genetics and is endlessly modified by life itself. There is no one-size-fit-all. There are no magic supplements. There is just your chemistry and your needs.

Since I have written repeatedly on the mitochondria and the reasons why nutrients are required for health, this post will not tackle those topics. Articles on those topics can be found on Hormones Matter with any number of search terms. This information can also be found in the book, Thiamine Deficiency Disease, Dysautonomia, and High Calorie Malnutrition, that I co-authored with Dr. Lonsdale. Here, since many have requested it, I just would like to present a graphic illustrating mitochondrial nutrient requirements. This is from Chapter 3 of our book. Use this as template to understanding your health.

Figure 1. Nutrient requirements for healthy mitochondria.

mitochondrial nutrients A few things should be pointed out. First, while these nutrients are required by everyone for proper mitochondrial functioning, not everyone needs to supplement with each one, or even sometimes any of them, although that is becoming increasingly rare with modern dietary patterns. Secondly, notice how many times and where vitamin B1 (thiamine) appears in this chart. It is at the entry points of the entire system and at various junctures throughout. This suggests that among all of the nutrients required for healthy mitochondria, thiamine is particularly important. Unfortunately, it is the one nutrient that is so often ignored or missed in testing. Indeed, that is why we wrote the book. Thirdly, notice how many vitamins are required to process the food we eat into ATP. Contrary to popular opinion, we need more than simply empty calories. For the foods we eat to be converted into ATP, there are multitude of vitamins and minerals required that may or may not be included in sufficient density with the macronutrients we consume daily. Finally, not discussed in this chart, but discussed in great detail in the book, synthetic chemicals, whether in form of pharmaceuticals, industrial, environmental, or food production, damage the mitochondria. Some deplete nutrients directly, while others damage aspects of mitochondrial functioning that necessitate increased nutrient density for the enzyme machinery to work. Of course, underlying all of this, are the genetic variables that each of us brings to the table. These influence how well or poorly we metabolize any of these nutrients from the get-go. All of this combines to make nutrient therapies complicated.

What is not complicated, however, is that we need nutrients to function and so, no matter what else we do to improve health, if we do not address nutrient concentrations, we can never be well. Mitochondrial functioning demands nutrients, and thus, health demands the same. Nutrient deficiencies are not something we can override with a pharmaceutical. That being said, addressing nutrient deficiencies holds great promise for those seeking health. If you or someone you love experiences chronic and complicated illnesses that have been treatment refractory, consider healing the mitochondria by tackling nutrient deficiencies. You might be surprised at well this works.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

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This article was originally published on November 11, 2019.

From Mother to Daughter: The Legacy of Undiagnosed Vitamin Deficiencies

by B. Figueroa

Published on July 10, 2023

18085 views

This is a story of a mother with undiagnosed vitamin B deficiencies who gave birth to a daughter who was also born with undiagnosed vitamin B deficiencies. In the eyes of conventional doctors and labs, there was not much wrong with us, but we knew that life was harder than it should be. We lived managing debilitating dizziness, daily migraines, fibromyalgia pain, chronic fatigue, allergies, hormonal changes, anxiety, and depression. Until we discovered that we were both hypermobile with histamine issues, hypoglycemic, and had many vitamin B deficiencies. The biggest challenge was for my daughter to start taking thiamine (vitamin B1). Her heart rate was all over the place and she had such a bad paradoxical reaction to thiamine that we believe she had been living with undiagnosed beriberi along with POTS.

Mom’s Health Marked by Asthma, Anxiety, Migraines, and a Difficult Pregnancy

All I remember as a child is being afraid to talk in school even if I knew the answer to a question. I had allergies and could not exercise due to asthma. During college, I had to read over and over the same thing because I could not concentrate. I worked extremely hard because the fear of failure was too much to bear. I started to have hormonal imbalances and missing periods. I successfully finished college and moved away to another state. That is when migraines started. Later, I became pregnant with my first child and started having blood clots. Anxiety and depression would come and go with hormonal changes.

When I was pregnant with my second child, my daughter, I was sick every morning with nausea. After 6 months of pregnancy, I had gained only 6 pounds. Ultrasounds showed that the baby was growing normally, but I was losing weight. At that point, I also could see blood clots on my leg. I was placed on bed rest. By the 8^th month, my water broke and my daughter was born. She was jaundiced and placed under UV light for a week. I also stayed in the hospital for a week dehydrated, with blood clots, and with the “baby blues”. We left the hospital after a week, and she had a “normal” development. However, you could see that she was a baby that would not go with anyone, not even the people close to us, indicating some anxiety.

Daughter’s Early Health Issues: Selective Mutism, Asthma, Concentration Issues

When my daughter turned four years old, we moved out of state and that is when she stopped talking outside the house. I later found out that it is called selective mutism, a form of severe social anxiety. She started seeing a school counselor to try to help with her anxiety and self-esteem issues. I brought a girl scout group to my house so that she could start having friends and talk to others in her area of comfort. She also developed asthma and needed nebulizer/albuterol treatments frequently and daily QVAR for prevention. She was given Singulair, but it made her very depressed. Her grades in all classes were all over, from A to D. She would spend the whole time after school trying to complete homework, but she couldn’t. Her teacher told me that she really did not have that much homework. I would ask her to watch the dog eating and to take her outside as soon as the dog finished but she would be wandering around the kitchen and could not pay attention to the dog. Her neurologist gave her Strattera and that helped a little. Her EGG also showed some abnormal activity. The doctor recommended anti-seizure medicine and said that she was probably having mal-petit seizures. I refused medication based on how she reacted to Singulair and because the doctors were using words like “probably” and “just in case”. I kept an eye on her and noticed when she ate ice cream and got asthma. I had her stop sugars and dairy. Soon after that, a teacher called me, excited to tell me that my daughter was talking at school. She also was able to stop all asthma medication except for 2 weeks every year when seasonal allergies would hit. At this point, it had been already four years since she stopped talking outside our house. She started excelling in all classes and we were able to stop Strattera. However, the continuous anxiety remained.

The Teenage Years: Continuous Migraine, More Medications, and No Answers

At 16 years old, she got a cold that turned into asthma with a continuous headache that just would not go away. She started waking up every day with a migraine, depressed with no energy. We had to wait three months to see a pediatric neurologist. Meanwhile, I would take her to my chiropractor early in the morning, give her an Excedrin, and she would go to school whenever she felt better. She began drinking at least 2 cups of coffee every day to help with the pain. Sometimes she would go to school at 11am, sometimes at 1pm. Even if there was just one class left, she would go to school. At this point, she felt that she wouldn’t have a future.

When we finally went to the neurologist, he recommended amitriptyline. I had been on amitriptyline and woke up one day not knowing which year or season was, but I was told that the issue was the high dose given to me (125mg), after decades of it increasing it every year. I agreed as long as it was a low dose. Amitriptyline lessened the continuous headache, but it was not really gone, and she still needed some Excedrin. She started daily aspirin as well. She was just getting by day to day trying to manage her pain and mood and trying to have a normal teenage life.

Increasing Weakness When Outdoors: Untangling Root Causes

She became very weak whenever we would go to the beach or to a park. We would have to drag her indoors and give her water. On some occasions, she would say that she could not see. Somehow, she successfully managed to graduate from high school. We started seeing functional doctors. We found that she had some variants related to mitochondria dysfunction, but we really didn’t know how to address this. We also found out that she had Hashimoto’s and antibodies against intrinsic factors, which was indicative of pernicious anemia. We knew right there, that she had issues that conventional doctors had missed.

We also did a Dutch test and found that all of her hormones were high. The functional doctors suggested sublingual B12, folinic acid, and a B complex. She said the vitamins made her feel awake for the first time. However, chronic fatigue was still a major struggle for her. Eventually, she had to stop folinic acid because it made her depressed and unmotivated. Meanwhile, she managed her anxiety with herbs, but it was a real struggle. She also continued to have asthma requiring albuterol every fall season. She chose a very challenging career in cell biology with biochemistry. She went through college with many cups of coffee just to control migraines, have energy, and be alert.

Discovering Her POTS Symptoms

The summer of 2019, before her senior year of college, the nurse checked her vitals as part of her new summer internship. The nurse thought the pulse monitor was broken because her heart rate was 120 sitting down. After a few minutes, it went down to 99, so the nurse dismissed it. When she told me that, I started paying attention to her heart rate. We went to her physician and neurologist and in both instances, her heart rate was 100, just sitting down waiting for the doctor. I asked if it was normal, and they said that it was in the upper range but not a concern. I was still concerned and made an appointment with a cardiologist but also bought her an iwatch. She noticed right away how her standing heart rate would be over 100, and by only taking a few steps, her heart rate would go even higher and she would become fatigued and even dizzy. From the heart rate monitor on her iwatch, we could see how quickly her heart rate would climb upon standing and then slow a bit when sitting.

That is when I remember that I have read about POTS and hypermobile people. I remember that when she was a child, the neurologist had said that she was hypermobile, but never said that it could be a problem for her. It just seemed like a fun thing to have. I started asking in health groups and someone mentioned that her medications could also cause high heart rate. I searched and amitriptyline did have that side effect. That is when my daughter showed me that her resting heart rate was in the 90s and it would fluctuate from 29 to 205 without exercising. When we went to the cardiologist and explained all of this, he said that he did not even know how to diagnose POTS because it is rare. He did testing and said that the heart was fine but there was some inefficiency due to some valve leaking but that it usually does not cause symptoms. I asked about amitriptyline and he confirmed that it could raise heart rate. At that point, she stopped amitriptyline and her maximum heart rate was 180 instead of 205.

She went back to her last year of college when Covid hit. She came back home and we could see the lack of energy and how much doing any little thing or stress would crash her for days. Since I needed glutathione for chemical sensitivities, I decided to see if it would help her. Glutathione with co-factors helped her recover, instead of crashing for days, she would recover the next day. That is when she told me that every time she walked to school, she felt that she would pass out. When she gets up in the morning, she ends up lying on the floor because of dizziness. Despite her dizziness, daily muscle pain, daily migraines, and chronic fatigue, she had big dreams. She just kept pushing through day by day, with coffee, herbs, and whatever it took, but she knew that something had to change. She successfully graduated in May, Magna Cum Laude, and she had a couple of months to deal with her health before she would leave to start her graduate studies and research job. That is when I found people that knew about Dr. Marrs’ work and thiamine, and her life finally changed.

Introducing Thiamine and Other Micronutrients: Navigating the Paradox

A functional doctor recommended magnesium and niacin for her migraines and they significantly helped. This gave the functional doctor the idea to try tocotrienols. High doses of tocotrienols worked better for reducing her migraine pain than amitriptyline and aspirin combined. Then she started taking high doses of B6. This helped her muscle pain and improved her mobility. Despite being hypermobile, easy stretches gave her intense muscle cramps prior to starting B6. Guided by very knowledgeable researchers belonging to Dr. Marrs’ Facebook group, Understanding Mitochondrial Nutrients, we started Allithiamine. The first thing she said was “wait, the sun does not hurt?”. I asked her what she meant. She explained that all her life, being in the sun gave her pain in her eyes and forehead and that she couldn’t understand why people wanted to be outside. No wonder she never wanted to go outside. She also said her migraines were gone. We have waited 4 years to hear that!

After just a couple of days, she started having a lot of nausea and lower-intensity migraines returned. The researchers knew right away that she needed more potassium. She started to eat apricots, coconut water, or orange juice every time she had nausea and it helped. However, it was happening every hour so we decided to try a different Thiamine. We tried half Lipothiamine and Benfotiamine but she didn’t feel as much benefit and still gave her issues. We went back to 1/10 of Allithiamine. Chatting with the researchers, one asked if she also experienced blinding episodes. Yes! Finally, someone that knew about that! They recommended B2 and we started it. That’s when we discovered that her pain in the sun and dizziness were caused by a B2 deficiency. She continued waking up with crashes needing potassium every hour. She did not sleep that week. The researchers suggested taking cofactors including the rest of the B vitamins, phosphate salts, phospholipids, and beef organs. Beef organs and phospholipids helped with energy and bloating, phosphate salts helped with nausea and irritability.

Then researchers suggested that she needed to stabilize sugars and have more meat. That is when we realized that she had some type of hypoglycemia. We had noticed that she would get very tired and got shaky hands if she didn’t eat. Functional doctors had mentioned that she may have reactive hypoglycemia since she had a fasting glucose of 70. She started having more meat to stabilize her sugars and removed all packaged foods, sugars, grains, and starches. She started having just fresh meat, veggies, rice, beans, nuts, and berries. She felt that she was so much better with beef that she started using it for potassium between meals and bedtime.

She was able to increase allithiamine little by little. She would mix a little bit with orange juice since it tasted so awful. Little by little, she started having fewer crashes and feeling better. It took a month for her to be able to tolerate one capsule of Allithiamine. She was sleeping more but not the whole night. That is when our functional doctor suggested supporting adrenals. That really helped but then she began having stomach pain and nausea after eating beef and developed frequent diarrhea. Chicken always increased her hunger and reduced her energy compared to beef and but now she was afraid of having beef. She stopped all sources of beef and phospholipids.

We consulted a very good functional doctor. She did Nutraeval and confirmed that all her B vitamins were low or deficient and recommended TUDCA and Calcium D Glucarate along with trying lamb and bison first. Both helped in reducing bloating/nausea and she was able to start eating lamb and bison along with reintroducing a minimal amount of carbs. Soon after, she was eating beef again with no pain. After starting TUDCA, her bilirubin levels were normal for the first time in her life. We continued to work with the functional doctor to fix other deficiencies.

Recovery from Multiple Nutrient Deficiencies and the Prospect of a Normal Life

After Allithiamine and vitamin B2, we worked with our functional doctor to balance the remaining B vitamins. She is now able to go out in the sun without bothering her eyes and without passing out. She gained weight after starting the B vitamins and began looking healthier, compared to how skinny and underdeveloped she looked before. She also learned how to manage electrolytes. She sometimes needs more sodium, but other times needs more potassium. She feels sick when electrolytes get out of balance. Although she still had some continuous pressure in her head, she no longer needs any amitriptyline, aspirin, or Excedrin for pain. One thing that remained problematic was folate deficiency. She still became depressed with folinic acid, so she tried methylfolate instead. She felt so unmotivated that preferred not to have it, but she realized that it was key to something that she struggled with all her life: anxiety. She figured that she could have methylfolate every other day, so that she could have less anxiety.

Now, for the first time, she began to have a normal life. She can now exercise daily without dizziness and her heart rate skyrocketing. Her heart rate in general is more normal, doesn’t go down to 29 or up to 205. She had not had any asthma requiring albuterol. She started driving without having to deal with anxiety and panic attacks. She was able to walk to her office without fainting. She now can now live alone dealing with the stress of having a full-time job, graduate classes, cooking her food, and exercise every day! She is not cured completely but for a person that once thought she couldn’t have a future, she is doing pretty darned good!

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, and like it, please help support it. Contribute now.

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This article was published originally on July 22, 2021.

Health Requires Energy. Energy Requires Nutrients.

by Derrick Lonsdale MD, FACN, CNS

Published on June 27, 2023

16441 views

A Fundamental Issue

I was horrified to watch the “60 Minutes” program Sunday, April 12th, 2020 on television that dealt with the colossal number of Americans suffering from obesity, chronic fatigue and diabetes, both types I and II. About half of the program dealt with the essential consumption of natural food, reminding us that Hippocrates, 400 BCE said “let food be your medicine and let medicine be your food”. This must have been said thousands of times but everything in our modern civilization is totally destructive to the whole idea. I have seen so many hundreds, if not thousands, of people whose illness was caused by themselves. It was treatable by making sure that each individual understood the fundamental issue. So before I illustrate a typical illness situation within my experience, I will try to state what I mean by describing what I consider to be the “fundamental issue”.

We behave according to what we eat.

I have stated this so many times but unfortunately the American medical profession is the major inhibitor to its clinical success. When a suffering patient with many symptoms arising from what I call “dietary mayhem”, goes to his or her physician, they simply do not recognize the clinical expression of the popular high calorie malnutrition. The many symptoms are usually referred to as psychosomatic and the unfortunate patient is told that “it is all in your head”. I have witnessed this so many times; I cannot understand why the physicians don’t pay a little more attention to what the patient is trying to tell them. Often the patient has discovered the real cause of the problem but find that her words are considered to be the voice of ignorance and delusion.

Food and Energy

Our food consists of fuel that must be burned (oxidized) to liberate energy. In any text this element of the food is described as “calories”. The energy quality of our food intake is measured in kilocalories and a single one is defined as “the energy needed to raise the temperature of 1 kg of water through 1°C”. Notice the use of the word energy, the result of oxidation. Now, as everyone knows, vitamins and minerals, known as non-caloric nutrients, are vital to the release of energy from the caloric elements. To understand how this combination of chemicals works, there must be a ratio of calories to the noncaloric elements. That is why high calorie foods without vitamins or minerals are known as empty calories. It is the consumption of empty calories across America that has given rise to the idea of high calorie malnutrition. I have actually seen a written statement that this is an oxymoron. “How can excess of calories be considered a form of malnutrition?” It seems that few people understand this vital ratio and they seem to think that as long as you are consuming calories, you will flourish. Also, the food industry fills the grocery store with cartons of temptation and seems to have no regard for the well-being of its consumers. They keep using the term “all natural” so much, it becomes meaningless.

A Typical Case of Energy Deficiency

I was a pediatrician at Cleveland Clinic and one of my interests was sudden infant death (SIDS). So one day I was having lunch with one of the surgeons who practiced ear nose and throat surgery. He told me that he had been called to the medical ICU because a woman had stopped breathing and he had performed a tracheostomy. He was intrigued by the reason for this disaster and, knowing my interest, he suggested that I should take a look. Pediatricians are assumed to be familiar with diseases of children but ignorant of adult disease and I knew that I was not welcome. I found a 50-year-old woman who was grossly edematous and unconscious. Without considering the technical details, I proved that she had the vitamin B1 deficiency disease beriberi. With injections of thiamine she became conscious and the edema disappeared. During her recovery she developed a progressive anemia, thought to be evidence of internal bleeding, but all the tests were negative. I took some urine from her and subjected it to a special type of test. It showed that she was deficient in folate, another B vitamin. It is important to note that she did not develop folate deficiency until she began her recovery from thiamine, it was masked by cellular energy deficiency. When she began to receive folate there was an immediate recovery from the anemia but she had been given at least one injection of thiamine by then.

She was discharged from hospital, wheelchair bound, taking both thiamine and folate. When she returned as an outpatient, I found that she had a skin rash and that her legs were, if anything, weaker. It had long been known that anemia would develop from either folate or B12 deficiency, but the folate deficient variety required B12 supplementation as well as folate. If B12 was not provided, the patient would develop paralysis of the legs and I had forgotten this. Also, it is not well-known that vitamin B12 deficiency can cause a skin rash. I gave her an injection of B12 and the rash disappeared. However, for a few days she had muscle aches and fever that I did not understand at that time. Looking back I would now assume that this was what we call “paradox” on Hormones Matter. To those that may not have read about this it is the temporary worsening effect by introducing an essential nutrient to someone who has long been deficient in that nutrient. One of the things that had probably been a serious indictment on self cause was that she was a chronic cigarette smoker, a well-known habit that damages oxidation.

Energy Metabolism

Can we extrapolate from this case any general ideas about how medical treatment should advance? Perhaps the general opinion would be that this is a rare and unusual case, an outlier from the “usual and customary diagnosis”. But if we consider the facts; long-term cigarette smoking, dietary indiscretion and genetic risks appear to be quite common. I treated a 12-year old girl with a conventional diagnosis of Juvenile Rheumatoid Arthritis, using a nutritional supplement. Without discussing the technicalities of laboratory evidence, it was clear that defective energy metabolism was the underlying cause. The combination of genetic risk, failure to adapt to any form of stress (infection, trauma, chronic useless brain activity etc.) and inadequate energy metabolism are the three factors that either collectively or singly lead to breakdown of health. As Selye predicted, energy for adaptation is the essential ingredient.

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More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

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This article was published originally on April 22, 2020.

Rest in peace Dr. Lonsdale, May 2024.

Medication and Vaccine Adverse Reactions and the Orexin – Hypocretin Neurons

by Chandler Marrs, PhD

Published on June 1, 2023

15545 views

A paper published in Science Translational Medicine, provides preliminary evidence that the H1N1 Flu Vaccine Pandemrix can evoke immune system mediated damage to the orexin – hypocretin neurons and induce narcolepsy in individuals with a particular genetic variant. The orexin – hypocretin neurons were only recently discovered in the mid 1990s, by two separate research groups, hence, the two names for the same molecule. For this paper, we’ll be utilizing the orexin nomenclature.

Initially, the orexin neurons were thought to be involved only in feeding behavior, as damage elicited hypophagia in animals. Soon it was learned that more severe damage to the orexin neurons induced narcolepsy and the orexin system became a key focus in narcolepsy related research. With time, however, it became quite clear that these neurons were involved in regulating a myriad of hormone and neurotransmitter systems and their consequent behaviors. Narcolepsy or rather the ability to sustain wakefulness, is but one of the many functions regulated by the orexin system.

In a previous paper, I touched briefly on the possibility that the orexin neurons might be damaged and have diminished functionality in individuals suffering from post Gardasil side effects. In particular, I suspected these neurons were indicated in post-Gardasil hypersomnia, a derivative of narcolepsy. That may be only the tip of the iceberg. As I soon learned, the hypocretin/orexin neurons are brain energy sensors and may be involved in array of post medication or vaccine adverse reactions. Indeed, they may be central to the ensuing state of sickness behaviors that emanate once an organism becomes overwhelmed.

The Orexin – Hypocretin Basics

Orexin nuclei are located in the lateral hypothalamus, the section of the hypothalamus that is most known for regulating feeding, arousal and motivation. The hypothalamus is the master regulator for all hormone systems and hormone related activity including feeding, sleeping, reproduction, fight, flight, energy usage – basically every aspect of human and animal survival. It sits at the interface between the central nervous system functioning and the endocrine system functioning.

From the lateral hypothalamus, orexin neurons project across the entire brain with its two receptors (OXA and OXB) differentially distributed throughout the central nervous system and even in the body, including in the kidney, adrenals, thyroid, testis, ovaries and small intestine. The orexin neurons also modulate local networks of adjacent neurons within the hypothalamus that in turn influence a myriad of behaviors.

The most densely innervated brain regions include the thalamus, the locus coeruleus, dorsal raphe nucleus, accounting for the hormone’s role in arousal, feeding and energy management. At the most basic level, release of the orexin induces wakefulness. When orexin neurons are turned on and firing appropriately, arousal is maintained. When orexin neurons are turned off, diminished or dysfunctional, melatonin, the sleep promoting hormone, is turned on. The two work in concert to manage wakefulness and sleep.

Orexin receptors are also located in the amygdala, the ventral tegmental area (VTA) and throughout the limbic system, accounting for its role in emotion and the reward system. Orexin directly activates dopamine in the VTA. The VTA is the reward, addiction, and in many ways, the pleasure center of the brain. All drugs of addiction, all pleasurable activities, activate dopamine in the VTA. Through the release of dopamine, here and elsewhere, orexin modulates the motivation to sustain pleasurable activities. When orexin is diminished, not only does dopamine diminish, but the motivation to sustain behaviors decreases and dysphoria increases.

That’s not all. Orexin influences the release of many other neurotransmitters and hormones, several of which are co-located on the orexin neurons themselves. For example, the neuropeptide dynorphin is co-located on orexin neurons. Dynorphin is an endogenous opioid involved in the perception of pain and analgesia. It has dual actions that can both elicit analgesia or pain depending upon dose and length of exposure. Stress activates dynorphin. Dynorphin then inhibits orexin firing by as much as 50%. Illness is a stressor, a vaccine is a stressor, either could activate dynorphin and inhibit orexin. After the initial activation of dynorphin, and the ensuing decrease in orexin, the presence of chronic stressors and chronic pain could begin a continuous feedback loop of diminished arousal, and increasing pain.

Other Neurochemical Connections

Consistent with orexin’s role in arousal, orexin neurons contain glutamate vesicles. Glutamate is the brain’s primary excitatory neurotransmitter. Drugs that increase glutamate, also increase orexin. Drugs that block glutamate, via its NMDA receptor, decrease orexin. Common migraine medications block glutamate and thereby may also diminish orexin.
Serotonin and norepinephrine decrease hypocretin/orexin firing (suggesting if one is concerned with hypersomnia, anti-depressants might not be a good option).
As one might expect, orexin neurons are inhibited by GABAα agonists – sedatives. From a women’s health perspective, consider that cycling hormones would also affect orexin neurons through the GABAα pathway. Progesterone is a GABAα agonist – a sedative, while DHEA and its sulfated partner DHEAS are GABAα antagonists, anxiolytics that block GABAα, reduce sedation, and thereby increase anxiety and wakefulness. There may be a cyclical nature to orexin firing that has yet to be investigated.
The hypocretin/orexin neurons also influence galanin, a GI and CNS hormone that seems to inhibit the activity of a variety of other neurons in those regions.

These are but a few of the brain systems that the orexin neurons touch in some way or another. Damage to this system would have serious health consequences by initiating a cascade of biochemical changes within the brain and body. Many of which, we have yet to fully understand.

How Might the Orexin Neurons Become Inhibited?

Quite easily, apparently. In addition to the orexin’s vast interconnected pathways with a myriad of neurotransmitters and neuropeptides, the orexin neurons act as energy and activity sensors with some unique intracellular mechanics that make them especially sensitive to the changing dynamics of the extracellular milieu. Disruptions in ATP, glucose and temperature, elicit reactions in orexin functioning.

Orexin neurons require as much as 5-6X the amount of intracellular ATP to maintain firing, and to maintain a state of wakefulness or arousal. This extreme sensitivity to reduced ATP makes the orexin neurons uniquely positioned to sense and monitor brain energy resources, early, before ATP levels become critical in other areas of the brain. The orexin neurons cease firing when ATP stores become low, thereby allowing the reallocation energy, perhaps to those cells required for survival, breathing and heart rate. As Hans Selye observed many decades ago, one of the first, and indeed, most consistent of the sickness behaviors, no matter the disease, is lethargy, fatigue and sleepiness. Orexin is at the center of this behavior.

Orexin neurons react to extracellular glucose levels, though perhaps not as one might expect. When extracellular glucose levels are high, orexin neurons stop firing via what is called an inward rectifying potassium (K+) channel that is ATP dependent. That means that when extracellular glucose is high, intracellular ATP is allocated to open K+ channels and flood the cell with the inhibitory K+ ions. K+ hyperpolarizes the cell, prohibiting it from firing. This mechanism reminds me of Dr. Peter Attia’s talk about the nature of Type 2 Diabetes and our approach to treatment. He proposes that the body’s metabolic response – the conservation of energy – to Type 2 Diabetes is not something aberrant but is exactly as it should be with a disease state. We’re just not treating the correct disease state.

Another way we can shut down the orexin neurons is via increased temperature. The orexin neurons are very sensitive thermosensors. Increased temperatures shut down orexin firing via the inward K+ flow. Again, this is consistent with sickness behaviors and the reallocation of resources.

Orexin – Hypocretin Neurons in Migraine and Seizures

Diminished orexin has been linked to migraine and seizure activity. With migraines specifically, orexin may contribute to the early warning, hours to days, of impending cortical disruption via changes in feeding and sleep patterns that often precede migraine onset. Orexin may also be linked to the pre-migraine aura mediated by changes in brain electrical activity that prelude the migraine pain itself by minutes, called cortical spreading depression or more appropriately, cortical spreading depolarization – the massive spreading change in ion balance of the neurons. Initially the wave is excitatory, neurons are firing, but that is soon followed by a period of neural silence. Finally, orexin is also connected to the vasodilation of the trigeminal nerve, the nerve responsible for migraine pain. These findings have led some to call orexin a migraine generator.

Diminished cerebral spinal concentrations of oxerin have been found in patients generalized tonic-clonic seizures. Conversely, in rodent studies, injections of orexin elicit seizure activity. Despite the somewhat contradictory findings in seizure activity versus migraine activity, it is likely that the orexin system is involved both disease processes.

Pulling it all Together: Orexins Monitor and Mark Disruptions in Brain Homeostasis

Here’s where it gets really interesting. Although some have argued orexin, particularly diminished orexin functioning, is the cause and culprit of disruptions in brain homeostasis, leading to narcolepsy, excessive sleepiness, migraine, seizures and other diseases, I think this system represents merely a marker of a disease process. I think the orexin system is the stopgap, the final barrier of disrupted cellular energetics, of mitochondrial function. Mitochondrial ATP is the key.

When we consider orexin’s role in migraine, in particular, we see clearly how environmental changes (diet, stress, illness, medication/toxin exposure) can lead to changes in the extracellular milieu where orexins reside. The orexin sensors adjust to these changes, mostly by reducing neural firing in attempt to counteract damages. The reduction in orexin then elicits the premonitory phases of the impending brain disruptions, sleep and hypophagia – the sickness behaviors. If it progresses, the massive waves of electrical disruption ensue, and migraine, perhaps even seizures are evoked. When the extracellular environment become chronically disrupted, so too does the diminishment of orexin activity, thereby initiating a perpetuating loop of dysregulated brain activity. We can hypothesize that similar progressions exist with disease processes marked by aberrant electrical activity, such as epilepsy.

We know that mitochondrial dysfunction is often generated by genetic polymorphisms and can predispose individuals to an array of seemingly unrelated conditions like migraine and fibromyalgia, dysautonomias and cognitive deficits. At the root of the dysfunction is a error of some sort in mitochondrial energy processing – ATP.

What has become increasingly clear, is that the production of cellular energy, can be disrupted environmentally, by diet, illness and exposures, if co-factors necessary for the production ATP like thiamine are diminished. It is via diminished ATP production, that I think some medications and vaccines evoke adverse reactions in some individuals. The orexin system, because it is so exquisitely sensitive to changes in cellular energy, is our warning system; first by subtle changes in neurochemistry, then by changes in arousal and feeding behavior, and finally, by an all-out reallocation of resources – excessive sleeping. If ATP remains deficient chronically, and an individual is so disposed, then the cortical misfiring we see in migraine and seizure ensues, along with autonomic dysregulation and the syndromes associated therewith. It is not the orexin – hypocretin system that is at root of many of these diseases, but rather, the causes are deeper yet and reside with mitochondrial health.

We Need Your Help

More people than ever are reading Hormones Matter, a testament to the need for independent voices in health and medicine. We are not funded and accept limited advertising. Unlike many health sites, we don’t force you to purchase a subscription. We believe health information should be open to all. If you read Hormones Matter, like it, please help support it. Contribute now.

Yes, I would like to support Hormones Matter.

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This article was published originally on January 29, 2014.

thiamine - Page 7

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