thiamine alzheimer's Archives

It All Comes Down to Energy

Published on August 10, 2023

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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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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 published originally on May 11, 2020.

Beyond Deficiency: Using Thiamine as a Metabolic Stimulant

by Elliot Overton, DipCNM CFMP

Published on May 23, 2023

17789 views

Throughout the past few years, I have been prescribing thiamine more and more often for individuals with a range of different health conditions. I have witnessed major symptomatic improvement in some people who displayed none of the key risk factors for thiamine deficiency, and many times had been following clean, whole-food dietary regimes which contained levels of thiamine beyond what is suggested by the RDA. I began asking myself:

Why does thiamine, in sustained high doses, work so well for such a wide variety of diseases? Is it merely addressing a deficiency or is there something else going on here?

I have since come to the conclusion that one does not need to be deficient in the nutritional sense to benefit from this type of therapy; that high-dose thiamine is not simply working by correcting nutritional deficiency. Rather, thiamine is functioning as a metabolic stimulant to restore oxidative energy metabolism in cells that have been inhibited by factors unrelated to nutritional status.

Overwhelming toxicity and chronic oxidative stress have the capacity to inactivate thiamine-dependent enzymes involved in the generation of cellular energy, producing biochemical changes which are similar to clinical thiamine deficiency. This could basically be referred to as “functional” thiamine deficiency. In a functional deficiency, dietary thiamine intake is somewhat irrelevant, because the concentrations obtained via the diet are simply not sufficient to overcome enzymatic inactivation.

Instead, high concentrations of thiamine are often necessary to overcome the “metabolic block” and restore the deranged metabolism back to normal. Dr. Derrick Lonsdale has discussed this concept on many occasions and laid out the theory in his various writings. In this article, I will explain the rationale behind high-dose thiamine therapy as a tool for bypassing these metabolic blocks and examine how this can be a useful therapy for chronic health conditions.

Understanding Enzymes

To appreciate thiamine’s potential utility in mega-doses, we should first look at the very basic function of enzymes. Enzymes are a type of protein that the body uses as a catalyst to facilitate or “speed up” the rate of biochemical reactions.

Enzymes are responsible for driving the reactions involved in practically every known function of the human body, including building things up, breaking things down, modifying or changing molecules, and converting one molecule into another. Vitamins and minerals act as necessary cofactors or “helpers” for specific enzymes to work as they should. In the hypothetical diagram below, the enzyme responsible for converting substrate “A” into product “B” can only fulfill the task once it has bound its cofactor/coenzyme.

Enzyme activity

The ability of an enzyme to bind with its respective cofactor is referred to as the coenzyme affinity (km). A simple way to conceptualized this is to think of the enzyme like a magnet. Enzymes with high affinity for their coenzyme/cofactor exert a strong magnetic pull and can bind very readily with their coenzyme.

With high coenzyme affinity and more binding, the activity of the enzyme speeds up and the rate of reaction (A->B) increases. In contrast, enzymes with low coenzyme affinity exert a much weaker “magnetic” pull, meaning that they are less able to bind with the cofactor/coenzyme. Less cofactor binding means that the rate of reaction decreases.

Genetic Enzyme Defects and Nutrients

A variety of inherited, genetic conditions feature the production of defective enzymes with poor cofactor affinity. For these unfortunate individuals, the concentrations of nutrients found in food are simply not sufficient to overcome the genetically determined lack of affinity.

nutrient cofactors enzymes

A successful strategy used for these conditions is the administration of pharmacologic/mega-doses of the nutrient cofactor. By saturating the cell, one can bypass the low affinity and restore enzyme function back to its normal state. Extremely high doses are often required to achieve this effect and this therapy must be maintained lifelong.

Thiamine-responsive maple syrup urine disease: A genetic defect in the branched chain ketoacid dehydrogenase enzyme results in remarkably low affinity for its coenzyme TPP. Continued high doses are necessary restore the function of this enzyme complex.
Thiamine responsive Leigh’s disease: Inherited mutation in the gene encoding Pyruvate Dehydrogenase, with a decreased affinity for its TPP cofactor. Treated with pharmacological doses of thiamine to stimulate defective enzyme activity.
B12-responsive Methylmalonic acidaemia: Genetic defect encoding the methylmalonyl-CoA mutase enzyme, causing low affinity for adenosylcobalamin cofactor and a pathological accumulation of methylmalonic acid. This condition can be treated with megadoses of B12.
Biotin-responsive holocarboxylase synthetase deficiency: Genetic mutation renders biotin-responsive carboxylase enzymes much less able to bind with biotin cofactor due to markedly decreased affinity. Supraphysiologic doses can restore normal enzyme function.
B6-responsive homocysteinuria: A rare defect in the cystathionine-B-synthase enzyme reduces affinity for its coenzyme pyridoxal-5-phosphate. This leads to the toxic buildup of homocysteine. Mega-doses of vitamin B6 can return enzyme activity back to normal.

It is worth noting that these genuine genetic defects are extremely rare and are not applicable to the large majority of people. Nevertheless, similar principles can also be applied when an enzyme has been inactivated by other factors.

Prolonged Oxidative Stress, Inflammation, and Enzyme Activity

The activity of different enzymes is tightly regulated depending on metabolic requirements, energy intake, and numerous other conditions within the cell. In simplified terms, if cells need to break something down, build something up, slow a process down, speed a process up, the activity of the enzymes involved in those pathways will reflect that. Enzyme activation/inhibition is a necessary part of normal cell physiology. However, the activity of specific enzymes can also be affected by other factors including toxins. There are certain enzymes involved in energy metabolism which are particularly susceptible to inactivation by free radicals and oxidative damage. Short-term, this is most likely beneficial, but under conditions of chronic oxidative stress, such as that found in chronic disease, enzyme inactivation can become pathological.

A key enzyme involved in mitochondrial energy metabolism called alpha ketoglutarate dehydrogenase (KGDH). Several nutrients serve as cofactors for this enzyme complex, with thiamine taking center stage. KGDH is a rate-limiting step in in the TCA cycle, meaning that when this enzyme slows down, every other downstream step also slows down. Whilst a deficiency of any of the necessary cofactors will reduce the activity of this enzyme, it is also exquisitely sensitive to oxidative stress. KGDH appears to be more sensitive to disturbed homeostatic factors than other enzymes, playing the role of a metabolic redox sensor, capable of switching oxidative phosphorylation “on” or “off” depending on the cellular redox state and requirement for energy. Reactive oxygen species will selectively inactivate the KGDH complex and slow down oxidative energy metabolism. This inhibition is functionally beneficial for cells in the short-term as an attempt to avoid energy overload and oxidation. Not only is KGDH a target of oxidative inactivation, but it is also a significant generator of oxidative free radicals. Here, it plays a regulatory role which clearly serves essential functions in maintaining cell homeostasis.

Under long-term conditions of oxidative stress, chronic KGDH inhibition is thought to be a driving factor underlying many neurodegenerative diseases. In chronic fatigue syndrome, recent metabolomic analysis found that one of the few metabolites (out of 800+) elevated with statistical significance was alpha-ketoglutarate, which is perhaps also consistent with chronic KGDH inhibition. Several toxic and inflammatory factors have also been shown to inhibit KGDH. Immune cells in the brain called microglial are involved in neuroinflammation and can be activated by a variety of stressors including toxins, trauma, and infectious insult (think Lyme, or lipopolysaccharide coming from a leaky blood brain barrier). Microglia produce myeloperoxidase and downstream products including hypochlorous acid and mono‐N‐chloramine – all of which are powerful inhibitors of KGDH. Heavy metals including aluminum and arsenic, along with fungal mycotoxins inhibit thiamine-dependent enzymes including KGDH and pyruvate dehydrogenase (PDHC).

Activated microglia caused by inflammation in the brain generate excess amounts of nitric oxide and its free radical peroxynitrite, both of which further inactivate KGDH. Polyunsaturated fats lining neuronal membranes are prime targets for oxidative damage in the brain, yielding a toxic byproduct called hydroxynonenal (HNE). Once more, HNE was shown to inactivate both KGDH and PDHC, whereas other mitochondrial enzymes were unaffected.

Endogenous neurotoxins such as and isoquinolone derivatives (breakdown products of catecholamine neurotransmitters) have been associated with Parkinson’s disease, and also inactivate KGDH. These metabolites include oxidized derivatives of dopamine and norepinephrine. Other KDHC and PDHC inhibitors include the breakdown products of halogenated toxic chemicals such as Tetrafluoroethylene (TFEC).

KDGH enzyme modulation
Oxidative stress and chronic inflammation are the hallmarks of chronic disease and both factors appear to inhibit/inactivate KGDH. As the rate-limiting step in oxidative phosphorylation, the chronic inhibition of this enzyme can spell devastating consequences for cellular energy turnover. A person could be obtaining a great amount of thiamine through their diet, but the underlying inhibition of these enzymes will produce the exact same outcomes as a dietary deficiency. In other words, these changes will induce a functional deficiency.

Mega-Dose Thiamine to the Rescue

When enzyme inhibition becomes pathological, we can apply similar principles as outlined above with nutrient-responsive genetic conditions. We can use high doses to bypass or overcome the metabolic blocks caused by enzyme inhibition. This concept was wonderfully illustrated in a study titled: Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex.

For this study, researchers investigated the effects of traumatic brain energy (TBI) on energy metabolism, using several groups of rats who were not deficient in thiamine. They showed that the oxidative stress associated with TBI inactivated the KGDH enzyme, causing great reductions in energy synthesis, which was coupled with brain damage. Administering massive doses of thiamine to the rats before TBI was able to completely protect the KGDH enzyme. The thiamine-treated group maintained normal activity of KGDH, mitochondrial respiration, and ATP despite being exposed to the injury. Furthermore, the restoration/protection of KGDH might have also conferred some degree of cytoprotection by combating inflammation, which was demonstrated by reduced inflammatory gene expression at three days post-TBI.

KDGH and thiamine

What this study demonstrated was that very high doses of the cofactor could provide protection against an insult which was not related to deficiency. In fact, similar results have been shown in several other studies:

Thiamine administration protected neurons against inflammation-induced impairments in neurogenesis caused by exposure to radiation, both in vitro and in vivo. Thiamine treatment also significantly increased lifespan. Attenuation of these inflammatory effects are thought to be due to increased stimulation of KGDH activity.
A more recent study also looked at traumatic brain injury (TBI) with a focus on glutamate neuroexcitoxicity. They showed that excess nitric oxide and peroxynitrite found in neuroinflammation led to the inactivation of KGDH. KGDH inhibition reduced glutamate uptake into the Kreb’s cycle, producing glutamate excitotoxicity and neuronal cell death. Once again, extra levels of thiamine reversed this issue by stimulating KGDH, increasing glutamate clearance and protecting the cells against injury. The authors concluded:

Thus, the impairment of OGDHC [KGDH] plays a key role in the glutamate mediated neurotoxicity in neurons during TBI; pharmacological activation of OGDHC may thus be of neuroprotective potential.

Interesting choice of words, huh? They are basically telling us that the pharmacological use of thiamine might be helpful in conditions where KGDH is inactivated, and enzymatic stimulation can be protective against glutamate neuroexcitoxicity. For the reader’s reference, here are a quick list of conditions which are thought to involve neuroexcitoxicity as part of the disease-process:

Spinal cord injury leads to significant neuroinflammation similar to that found in TBI, with excess nitric oxide production and deficits in brain glutathione levels (an intracellular antioxidant). In one study: thiamine in high doses ameliorated excess nitric oxide levels and maintained brain levels of glutathione. The authors hypothesized that this was related to changes in precursor amino acid availability. However, this is likely also related to the stimulation of transketolase (TKT) activity (a thiamine-dependent enzyme involved in replenishing reduced glutathione). Under conditions of oxidative burden and increased requirement for glutathione recycling, there is a need for increased TKT activity and thiamine.

High doses of thiamine will stimulate the transketolase enzyme to maintain glutathione levels. This was shown in a different study using metabolomic analysis in cardiac ischemia, which found increased levels of ribulose-5-phosphate suggestive of increase TKT activity. Indeed, both thiamine and benfotiamine were found to increase the genetic expression and activity of the transketolase enzyme to counteractive oxidative damage and cell injury in diabetic vascular endothelial dysfunction. High doses of thiamine can also restore activity of the pyruvate dehydrogenase enzyme complex in the face of inactivation. Cardiac arrest was shown to markedly depress PDHC activity through inactivation.

In rats, high-dose thiamine post-cardiac arrest restored pyruvate dehydrogenase activity in brain, mitochondrial respiration, improved neurological function, reduced brain injury, and improved survival at 10 days. The quantity of the enzyme did not change, showing that thiamine worked by stimulating PDHC activity at high doses, thereby preventing injury-induced inactivation of this enzyme complex.

Pre-treatment with thiamine pyrophosphate protected against cardiac ischemia by maintaining mitochondrial function, ATP concentrations, and inhibiting mitochondrial fission.

Furthermore, copper toxicity was shown to inactivate the PDHC , produce mitochondrial dysfunction and neurological damage in rats. High doses of thiamine protected against the inhibition of Pyruvate dehydrogenase, markedly extended life span and protected against neuronal death.

The Use of Mega-Dose Thiamine in Clinical Practice

The late Italian neurologist A. Constantini published several case studies on the use of mega doses of thiamine for different conditions and saw impressive results. In one of the case reports on fibromyalgia, two patients saw an abrupt and immediate improvement only when they reached 1,800mg per day. At lower doses, improvements were negligible. High dose thiamine produced appreciable improvements in fatigue in 15 MS patients. Likewise, high doses were shown to produce remarkable and rapid improvement in the neurological condition essential tremor. Severe chronic fatigue in IBD patients with normal thiamine lab tests was reversed in most patients with megadoses.

Thiamine injections completely reversed gait abnormalities and motor failure in two patients with Freidrick’s Ataxia. Importantly, Constantini and colleagues concluded:

From this clinical observation, it is reasonable to infer that a thiamine deficiency due to enzymatic abnormalities could cause a selective neuronal damage in the centers that are typically affected by this disease.

Furthermore, in a case report of two patients, dystonia was reverse with thiamine administration. I have also seen this occur in several children with autism and/or neurodevelopmental abnormalities. Another case report detailed high-dose thiamine injection in patients with Parkinson’s disease, all of which had “normal” plasma thiamine levels, meaning that they were not classically diagnosed as having deficiency. The patients experienced between 30 and 77% improvement in motor coordination. We have seen from the research above that the neurotoxic metabolites which are thought to drive Parkinson’s also have the strong capacity to inhibit thiamine-dependent enzymes. It is therefore no wonder why thiamine can have such as tremendous impact on this condition.

Constantini and colleagues completed a larger study with 50 patients two years later, and found that 100mg thiamine injection twice per week produced massive improvement in both motor and non-motor symptoms, with some patients experiencing complete clinical remission.

Are these results simply addressing a deficiency or is something else going on here?

The daily recommended dietary intake of thiamine is merely 1 – 1.5 mg per day. Surely, if the benefits were simply due to nutritional repletion then we would see benefits at similar levels, or even 10x that amount? Except we do not. Rather, most people are required to consume 100 to 1000 times the daily recommended intake to see restoration of metabolism and symptomatic improvement. This is what I see in clinical practice on a frequent basis, and this is also what has been demonstrated in the case literature.

Beyond Treating A Deficit

The sheer amount of the nutrient necessary for clinical improvement is not consistent with simply addressing a deficit. Nutritional repletion is by no means an adequate explanation for this magnitude of effect. It IS consistent with stimulating enzyme activity to overcome inactivation, however.
Constantini hit the nail on the head with one quote from another paper:

We may suppose that symptoms decrease when the energetic metabolism and other thiamine-dependent processes return to physiologic levels. Our aim was not to correct a systemic deficit of thiamine, but rather to increase the activity of enzymes involved in cell production energy in selective brain regions.

Indeed, Constantini understood that thiamine could be used as metabolic enhancement to stimulate the enzymes involved in energy metabolism which had otherwise been inhibited by other factors. This is where we are dealing with a “functional deficiency” which can only be addressed by supraphysiologic concentrations to saturate the cell for improved bioenergetics. As I said mentioned previously, Dr. Derrick Lonsdale has highlighted on many occasions how thiamine’s effective is due to its pharmacological action, rather than nutritional repletion.

Rather than remaining hyper-focused on correcting a deficit, we should be using this molecule to improve bioenergetics regardless of nutrient status. This means that someone does not necessarily need to be nutritionally deficient to benefit from thiamine supplementation at high doses.

The Non-Enzyme Functions of Thiamine

It is worth noting here that there are a few other variables which I have not discussed thus far. Outside of the context of genuine inherited genetic defects, there are numerous polymorphisms in genes related to thiamine transport and metabolism. These polymorphisms can influence enzyme activity, albeit to a lesser extent, and can predispose one to developing a deficiency. Nonetheless, this does not alter the fundamental principles laid out in this article. It is also important to understand that the clinical improvements demonstrated are not just due to thiamine’s role as a cofactor to drive biochemical reactions to their completion. Rather, this nutrient exerts numerous non-coenzyme functions including allosteric regulation of other enzymes in energy metabolism, direct anti-oxidant and anti-inflammatory actions. It has been shown to influence the transcription of genes involved in modulating and dampening inflammation and oxidative stress upstream. Thiamine and benfotiamine supplements exhibit “anti-stress” properties in the brain, protecting against stress induced suppression of hippocampal neurogenesis. These effects stem from anti-oxidant, rather than coenzyme roles. A review of thiamine’s non-enzyme actions can be found here.

Thiamine as a Front Line Therapy

At this point, I hope that the reader can appreciate some of the potentially beneficial applications of thiamine therapy in high doses. Since this nutrient exhibits extremely low toxicity, is relatively cheap and easy to access, I believe that it should be considered as a front-line therapy, in conjunction with other interventions, for disorders involving mitochondrial dysfunction and chronic oxidative stress. This especially applies to neurological diseases. Whilst many people do not require pharmacological doses, there are many who DO benefit from this. I have seen it on many occasions, and I am sure that I will continue to do so in the future. As it currently stands, the therapeutic potential of this nutrient is untapped.

Disclaimer

I should note, before beginning any type of treatment, consult your physician. The work above represents the current state of research and observations from my own clinical practice. It should not constitute medical advice. Please be aware that although this vitamin is non-toxic and one cannot overdose, some individuals with longstanding health issues exhibit negative reactions upon taking even small doses of thiamine. These reactions are often associated changes in electrolyte homeostasis, other nutrient deficiencies and/or can be associated with the formulation of thiamine administered. There are a number of articles on these reactions on this site under the search terms, paradoxical reaction, refeeding syndrome, and more recently, calcium management and heart function.

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.

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Photo by Jack Carter on Unsplash.

This article was published originally on EONutrition on November 17, 2020 and edited and republished here with permission.

Protein, Protein Folding, and Enzyme Activity

by Derrick Lonsdale MD, FACN, CNS

Published on March 15, 2023

7056 views

As everybody knows, organic food consists of proteins, fats and carbohydrates. In this post I am going to indicate how protein is used to create enzymes. There are animal and vegetable proteins in food. The first thing that happens when one of these proteins is ingested is that digestion breaks it down into a range of chemical substances known as amino acids. They are absorbed and circulate in the blood stream. If they are not used, they are excreted in the urine. The ones chosen to construct enzymes are then reconstituted into these biologically active proteins. As most people know, the body uses enzymes in much the same way as a complex man made machine uses cogwheels. They connect the power to the action and are essentially the “workhorses” of the body.

How Enzymes Work

In order to understand some of the principles, I am going to take an enzyme known as pyruvic dehydrogenase as an example. This enzyme initiates energy production by stimulating the metabolism of glucose, the sugar that is used in the body as fuel for its cells, particularly those in the brain. The combustion of glucose is achieved by its combination with oxygen, the principle of all forms of combustion. We have many different names for this process, depending on the speed of the reaction. Singeing, fire and explosion represent the different speeds of combustion and it must be emphasized that it is never complete. There is always ash.

However, in the body this is a very unique process. The combination of glucose with oxygen begins the complex process of energy production. The “ash” is carbon dioxide and water. The enzyme functions by bringing the oxygen and glucose together but the combustion, known as “oxidation” can only be achieved in the presence of vitamin B1 (thiamine) and magnesium. These are known as cofactors to the enzyme and are supplied in the organic food which we are designed to consume. It is important to understand that this is the gateway to the production of energy which enables us to function and explains why thiamine and magnesium are essential ingredients of health through diet. Without their sufficiency, energy production suffers and an incomplete supply of energy interferes with normal activity of the entire body and brain. This oxidation initiates action in the citric acid cycle, essentially the “engine” in each of our cells. It is a complicated process that I do not need to discuss here, but it leads to the production of a chemical substance known as adenosine triphosphate (ATP). This substance stores energy and the nearest comparison is a battery. For this reason, it is sometimes referred to as “energy currency”.

An Enzyme Is a Protein

I pointed out above that the protein in food is broken down to amino acids that are absorbed into the body and reconstituted to form the biologically useful proteins known as enzymes. An enzyme is created by collecting a group of amino acids together in a bunch to form a chain. The electrical properties of the atoms and molecules in these amino acids enable the chain to be created by what is essentially a magnetic action between its ingredients.

The next thing that happens is absolutely vital to the biochemical action of the protein/enzyme. The protein has to be folded for storage and unfolded for action. The action of folding is repetitively unique to the enzyme. Research that is going on concerning this process is essential to a better understanding of an associated disease process. Mother Nature dictates the folding process which is exquisitely complex. In order to understand how this automatic process takes place, we need to know the exact design and electrical properties of the chain, facts that are still hidden in mystery. What we do know is that there is a whole series of diseases where the enzymes are misfolded or even completely unfolded. Unlocking the exact method by which folding and unfolding takes place leads to an understanding of the basic cause of the respective disease in which this mechanism has failed. There are about 50 different diseases in which this mechanism is responsible. As a group, the respective diseases are known as proteopathies. Alzheimer’s and Parkinson’s diseases are both known as examples of proteopathies and their solution depends on our understanding of this folding and unfolding process. A review of this field of science refers to the advances that have been made over the last decade in our understanding of the fundamental nature and consequences involved.

The Role of Thiamine in Protein Folding

It has long been known that thiamine is involved in the metabolism of Alzheimer’s disease and some attempts have been made to use megadoses of thiamine in its treatment. In fact, the earliest and perhaps best example of an interaction between nutrition and dementia is related to thiamine. Throughout the last century, research showed that thiamine deficiency is associated with neurological problems including cognitive deficits and encephalopathy. Multiple similarities exist between classical thiamine deficiency and Alzheimer’s disease. Benfotiamine, a derivative of thiamine ameliorated the clinical and biological pathologies that define Alzheimer’s disease. A 12-month treatment with this agent tested whether clinical decline would be delayed in the treated group compared to a placebo group. There was a “nearly statistically significant improvement” in the treated group, a fact that the authors have concluded that they need to repeat the study. A huge number of proteins that occur in the body have to be folded into a specific shape in order to become functional. Because of the known involvement of thiamine, it has been hypothesized that it plays an important part in the folding and unfolding mechanism of the respective proteins.

Prevention Is Better Than Cure

We have hypothesized that thiamine deficiency disease is common in America because of what we have called high calorie malnutrition. It has suggested that this common form of diet acts as a forerunner to one of these proteopathies because of the prolongation of the deficiency. We have suggested that the symptoms caused by high calorie malnutrition are those that collectively give rise to “the walking sick”, the individuals that are haunting the offices of physicians and who are being so frequently diagnosed as psychosomatic disease. Many of these patients have done their own research work and have concluded that the symptoms are arising from vitamin deficiency disease. Many have learned this from the posts on this website. When they go back to their physicians, claiming the true cause of their symptoms, they are almost invariably ignored and often considered to be psychiatric cases. Without a proper discussion concerning diet, many of these individuals continue with the symptoms indefinitely, concluding that they have untreatable disease. Perhaps they are not particularly surprised and may even be a little relieved when new symptoms have appeared and are diagnosed as a recognizable neuropathy such as Parkinson’s or Alzheimer’s disease. That is why it has been hypothesized that thiamine and magnesium are “keys to disease“.

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This article was published originally on February 17, 2021.