Thiamine (Vitamin B1) - A common deficiency in disorders of energy metabolism, cardiovascular and nervous system dysfunction

Keit

Ambassador
Ambassador
FOTCM Member
Just stumbled upon the following recent research. The original article in Russian, and here's a quote from the article:

Researchers from the A. N. Belozersky Institute of Physical and Chemical Biology, together with colleagues from the Karolinska Institute and the Medical and Genetic Research Center, suggest using high doses of cocarboxylase to fight lung cancer.

The cocarboxylase molecule is formed from vitamin I1 (or thiamine) and serves as a cofactor for different enzymes. The cofactor is the non-protein part of the enzyme, which is necessary for it to perform certain reactions. Cocarboxylase, in particular, is needed to separate the "acid" group (i.e. chemical group -COOH) from α-ketoacids and in the reactions of α-ketosaccharides exchange.

Cocarboxylase directly affects the carbohydrate metabolism and indirectly the synthesis of nucleic acids, proteins and lipids. It is used in medicine as part of the complex treatment of various diseases: diabetes, renal and hepatic failure, heart rhythm disorders and many others, in fact, that is why it is called the medicinal form of vitamin B1.

And here's the paper:

 

RedFox

The Living Force
FOTCM Member
I've been taking thiamine TTFD regularly for over a year now, so wanted to report back the results.
Started slowly at 50mg for a while, and worked up to 200mg daily.

My health is vastly improved from where it was, with physical and mental stamina being the main results. Exercise can be done without my energy/health crashing for the rest of the week, and I also now get the endorphins from it which I didn't use to seem to do.
I can be exhausted/stressed out, but can easily push through it. Strong emotions/stress are no longer overwhelming, and (with practice) I have been able to get a handle on them. Most of my neurotic thinking vanished one day about 3 months ago. Brain fog has reduced considerably.
I've also been able to gain and retain weight in the form of muscle or fat, and I no longer loose weight/muscle if I fast (although there is more to this than just the thiamine, the thiamine cemented this ability). I've gained 5-6 kg (now stable at 80kg) over the last few months.
Both fasting and cold showers are easy, and along with exercise generate a huge amount of heat.
Now I'm mostly left with the remnants of the behaviors associated with having low energy, poor nervous system control and brain fog for most of my life - and with some will power I'm slowly rewriting them.

A few observations along the way. About 6 months in I started getting some interesting detox symptoms from taking the thiamine, which lasted a month or two. Magnesium as well as selenium is important here. Whatever was going made my urine smell strongly of sulphur and metal for a month.

For anyone who is skinny and has trouble retaining weight it's worth considering.
The additional steps I took before the thiamine that helped stabilize my weight are as follows (based on research/observations/testing, so consider it speculative):
About 5 years ago I was around 65kg, unable to gain weight (despite over eating and/or exercising) and could easily loose weight from stress/lack of sleep/exposure to chemicals/missing meals etc
My body seemed to run off sugar (in spite of keto), and as such would break down muscle quickly in order to provide sugar. I couldn't fast without massive weight loss and cold showers/exercise over stressed me.
Time restricted eating over the course of a year or two helped a lot. Basically eat a large amount of food, but limit the window to less than 8 hours (12 hours max). Don't activate your liver/digestive system outside of those 8-12 hours. To do it properly means nothing but water outside of that 8-12 hour window (including no exposure to chemicals/no smoking). Doing this stabilized my weight, and I was able to creep up to 70kg.
Revisiting this led me to the next step - the liver dumping toxins into the gut at night was triggering the digestive system/liver to restart. So I did a month of taking zeolites and clay to mop up whatever it was/stop it getting absorbed again. The result was improved health, better sleep and gaining 3-4kg of weight.
 

RedFox

The Living Force
FOTCM Member
Just adding something I found, which may link depleted thiamine to several other issues:

Are High Folate and Vitamin B12 Linked to Low Thiamine in Autism and Other Disorders?

by Derrick Lonsdale MD, FACN, CNS

May 15, 2017

Autism is now classified as an epidemic in the United States. It can only be understood by first recognizing that it is caused by biochemical changes in the brain. There are only two ways in which these changes are brought about. One is genetics. The other is nutrition. The focus of research has been almost exclusively in terms of genetics. Very little has been said about nutrition. A recent epidemiological study found elevated concentrations of folate and vitamin B12 during pregnancy associated with autism. In this post I want to discuss the potential relationship of autism with B vitamins. In order to introduce the subject, I must digress.

High Folate and Vitamin B12 in the Face of Other Vitamin Deficiencies
Many years ago I was confronted by the case of a six-year-old child who had been suffering from an extraordinarily common problem for approximately two years. He would develop a sore throat, fever and swollen glands in the neck. Of course, these episodes had always been treated with antibiotics as infections but there was no valid explanation of why they were repeated. His case had been reviewed at prestigious medical institutions and he had been admitted to a hospital when, during a febrile episode, a gland in the neck was removed for biopsy. The report arrested my attention, because it was described as “a swollen gland whose architecture was otherwise normal”. Another part that arrested my attention was that his diet was appalling, full of sugar, so I had a blood test performed that showed that he was vitamin B1 deficient. But there was another strange association. Folate, a B vitamin and vitamin B12, also a B vitamin, both had very high concentrations in the blood. This had been discovered at the same hospital where the gland had been removed.

The doctor had told the child’s mother about this and accused her of giving the child too many vitamins. She was very perplexed because she denied that she had been giving any vitamins, but they would not believe her. Because of this history, I performed the same tests and both these vitamins were indeed elevated in the blood. Because of the sugar association and the finding of vitamin B1 deficiency, I treated the child with megadoses of thiamine (vitamin B1) and sent him home. To my great surprise, not only did his health improve drastically, his feverish episodes ceased and the repeat of the blood tests showed that the levels of folate and vitamin B12 had fallen into the normal range.

I asked the mother to stop the vitamin B1 which she did reluctantly. Three or four weeks later the child had another episode of swollen glands in the neck with fever. The mother also reported that he had sleep walked and, going downstairs, he had urinated spontaneously. Of course, this implicated a mechanism in the brain. I readmitted him to the hospital and I found that the folate and B12 levels had again shot up. I treated him with thiamine again. The fever and swollen glands remitted and the levels of folate and B 12 dropped again into the normal range. Well, of course, this was a natural experiment that sent me to the library to try to come up with an explanation of the relationship between these three B vitamins. It appears to be an important phenomenon because recently, a paper has been produced in which folate and B 12 have both been found to be increased over the normal range in autism.


The Engines in the Body
First of all, I had to try to explain why there was a very obvious response to the megadose thiamine. One thing that I had learned is that the part of the brain that deals with a defense against stress becomes very irritable when cellular metabolism becomes inefficient. Thiamine deficiency in that part of the brain produces the same action as a mild to moderate lack of oxygen, because both spell “danger”. When a bacterial or viral infection attacks us, we go into a defensive mode. This is, of course, the illness. The fever makes the action of the microorganism less efficient. Swollen glands are created to catch the dead microorganisms as they are washed into the lymphatic system. My hypothetical explanation is that the thiamine deficiency created brain irritability that repeatedly went into a defensive mode under the false impression that the child was being attacked by a microorganism.

The Transmission in the Body
This again is a hypothesis and I must digress again. Let us take a car as an example of a machine. The engine produces energy and that energy is passed through a transmission that enables the car to go into action. Bewildering as it may seem, the human body is a chemical machine and we can only understand how it functions by understanding the chemistry. As I have said many times in this forum, thiamine has the responsibility of producing energy. It is exactly like a spark plug in a car engine. But because the human body is also a machine, it has to have the equivalent of a transmission. To put it simply, energy is produced by thiamine and stored in the form of a chemical substance known as ATP. Without going into the technological details, ATP is consumed by releasing energy used to drive the transmission that enables bodily functions. The transmission is an energy consuming series of chemical changes known as transmethylation. These chemical changes require folic acid and vitamin B12. Because of thiamine deficiency the ability to produce ATP was compromised. This resulted in lack of energy that affected the transmission. Folic acid and vitamin B12 simply collected in the blood because because they were not being used. As soon as thiamine restoration took place, the transmission became more efficient and the folate and B12 were consumed in the action.

What Has This to Do with Autism ?
The present disease model states that each disease has a unique cause that demands a unique treatment. Genetic research has revealed thousands of possible gene mutations involved in the underlying cause of autism and I have no doubt that this produces variations on a common theme, perhaps explaining why each child with autism is unique in his own right. Thiamine deficiency can express itself in many different ways, depending on which part of the brain is affected. If it can express itself in repeated episodes that exactly imitate a throat infection in one individual and autism in another, we surely have to change how we see health and disease. Both thiamine and vitamin D deficiency have been described in the medical literature as a cause of autism. I have concluded that anything that interferes with an efficient use of oxygen in the brain creates symptoms that may well be interpreted as “psychological”. Most gene mutations don’t have an effect on their own. Serious prolonged stress and/or vitamin deficient malnutrition may have to be present for the disease to be expressed.

With B12/folate being at high levels in the blood, would the body register it as B12/folate deficiency - because they weren't being used?

So I'd like to propose a hypothesis, that thiamine deficiency induces symptoms of B12/folate deficiency, in-spite of high blood levels (perhaps someone already covered this, but I couldn't find it?).

It seems B12/folate deficiency can cause a host of health problems, including megaloblastic anemia:
Vitamin B12 or folate deficiency anaemia occurs when a lack of either of these vitamins affects the body's ability to produce fully functioning red blood cells.

Red blood cells carry oxygen around the body. Most people with vitamin B12 or folate deficiency anaemia have underdeveloped red blood cells that are larger than normal. The medical term for this is megaloblastic anaemia.

A vitamin B12 or folate deficiency can be the result of a variety of problems.

So in this situation, if the hypothesis is correct, thiamine deficiency can induce hypoxia if malformed blood cells are being produced as a result.

A possible correlation to that hypothesis is that some forms of megaloblastic anemia respond to thiamine, specifically if the thiamine transporter is mutated (inducing thiamine deficiency):
Thiamine responsive megaloblastic anemia syndrome (also known as Rogers Syndrome) is a very rare genetic disorder affecting a thiamine transporter, which is characterized by megaloblastic anemia, diabetes mellitus, and hearing loss. The condition is treated with high doses of thiamine (vitamin B1).

In most cases (80-99%), people with this condition experience poor appetite (anorexia), diarrhea, headache, and lethargy.[1] Thiamine responsive megaloblastic anemia syndrome is associated with progressive sensorineural hearing loss. Additional manifestations include optic atrophy, short stature, enlarged liver, and an enlarged spleen.[2] Some cases may affect the heart, leading to abnormal heart rhythms.[3]

A second hypothesis on top of the first - the hypoxia from the malformed blood cells would potentially produce iron overload (as the body attempts to compensate for the lack of oxygen). Additionally, the first hypothesis being that thiamine deficiency means B12/folic acid is not used - thus equalling a state of deficiency.

Possible correlations:
Folic Acid Deficiency and Iron Overload

Mortimer S. Greenberg, MD; Norman D. Grace, MD

Author Affiliations

Arch Intern Med. 1970;125(1):140-144. doi:10.1001/archinte.1970.00310010142017

Abstract

Two patients with iron overload and liver disease had folic acid deficiency. In one patient it was associated with elevation of serum iron level and reappearance of iron in hepatic cells. Treatment with folic acid was followed by decrease in both serum and hepatic cell iron levels. In the other patient folic acid deficiency was associated temporally with the onset of diabetes mellitus and with a severe and fatal bout of right-sided cardiac failure. The clinical courses of these patients suggest that folic acid deficiency may influence the tissue distribution of iron in man in a manner analogous to that demonstrated in experimental animals.

My first hypothesis is probably way to simplified, and likely the proposed correlations rely on other mechanisms and genetic predispositions. But thought it was worth mentioning as an idea.
 

RedFox

The Living Force
FOTCM Member
Sharing some posts from facebook by Elliot that may be useful for people.

Why are some people unable to tolerate the TTFD form of thiamine? Did you know that TTFD temporarily depletes glutathione?
In this short series, we will be examining some of the potential reasons why certain individuals experience negative reactions and side effects from TTFD supplementation.
First of all, it is essential to understand the basics behind TTFDs molecular configuration and how it is processed by cells.
TTFD contains thiamine, but is NOT the SAME as thiamine. Simply put, the primary difference is an extra chemical group called a mercaptan group. This group is like what is also found in allicin, which is a compound found in garlic.
The mercaptan group is connected to the thiamine molecule via a special sulfur-sulfur bond called a disulphide bond. The unique chemical group is responsible for TTFD’s ability to traverse membranes in the body without the need for a transport system.
TTFD, with its special mercaptan group, is mostly absorbed whole as TTFD in the gastrointestinal tract. As it travels through the blood, it can enter the brain and many other organs. One of the main sites of absorption is actually in the red blood cells.
Upon penetration of the red blood cell membrane, TTFD must first be PROCESSED or “broken apart” before it can release the thiamine contained within its chemical structure. The ancillary mercaptan sulfur group must then be utilized and/or detoxified through alternative pathways.
I believe that main issues with tolerability are: 1. Errors in this processing or 2. Compromised detoxification of the sulfur groups.
HOW TTFD IS PROCESSED IN CELLS
For TTFD to “release” its thiamine, its disulfide bond must gain electrons from another donor molecule. In chemical terms, this process is referred to as chemical reduction. Once this reduction occurs, free thiamine is “released”.
The molecule which has been shown to do this most effectively is GLUTATHIONE. Glutathione is the cell’s primary antioxidant. As an antioxidant, it can be found in its “reduced” form with an extra electron that can be donated, or its “oxidized” form after it has donated its electron. The process is as follows: Reduced glutathione (GSH) donates an electron, and so goes on to form oxidized glutathione (GSSG). GSSG is then recycled back to GSH through gaining electrons via the enzyme glutathione reductase (vitamin B2 dependent and NADPH).
In the context of TTFD – GSH in red blood cells chemically reduces TTFD via a process called “disulfide exchange” (using glutaredoxin) (1). Reduced glutathione becomes oxidized glutathione, TTFD “releases” thiamine, producing free thiamine inside the cell and an extra TFD group left over.
So in simple terms, to obtain thiamine from TTFD, you inevitably use up glutathione in the form of GSH. That’s right. The initial phase of processing TTFD requires that cells have enough reduced glutathione. Furthermore, the more GSH you have – the faster the rate of this reaction.
I recently corresponded with one individual who only gained tolerance of TTFD after supplementing with 200mcg of selenium in the form of sodium selenite. Selenium supplementation in different forms has been shown to increase red blood cell GSH levels by up to 35% (2). This is thought to occur due to selenium’s ability increase glutathione synthesis through upregulating the enzyme gamma-glutamylcysteine synthetase (3). I suspect that poor glutathione status might be one of the reasons for benefit from selenium.
Having enough glutathione is clearly very important, but recycling it is also essential to maintain a pool of glutathione in its reduced form. Unfortunately, TTFD places a burden on this system. This was demonstrated in one old study from Japan which showed that TTFD administration rapidly lowered GSH (4). However, in that same experiment GSH levels were restored within 5-10 minutes. This was accomplished by the vitamin B2 (as FAD)-dependent enzyme glutathione reductase, which donates electrons to GSSG with the reducing power of NADPH to recycle it back to GSH.
These are key points which might help us to understand why some people do not benefit from TTFD. First, cells need enough GSH to cleave thiamine. Second, cells also need to be able to recycle the glutathione which has become oxidized.
Immediately, we see two potential issues that could arise when someone supplements with TTFD.
First: In someone who has poor glutathione (GSH) status, they might theoretically be less able to generate thiamine from TTFD. There are many reasons why someone may have poor glutathione status.
- Low precursors (cysteine, glutamate, glycine)
- Chronic oxidative burden and/or inflammation
- Other nutrient deficiencies necessary to produce glutathione (such as B6 or selenium)
Some basic ways to measure glutathione status include: Whole blood glutathione, gamma-glutamyl-transpeptidase, pyroglutamic acid on an OAT
Second: Someone may have enough resources to make glutathione, but if they cannot RECYCLE it through glutathione reductase, then taking a substance which depletes their GSH further (like TTFD) might not be a good idea.
A total/functional riboflavin deficiency is the probably the main culprit when looking at poor glutathione reductase activity. The glutathione reductase enzyme also requires adequate NADPH to drive the enzymatic reaction. NADPH is derived from niacin (vitamin B3) but is also generated in the pentose phosphate pathway which, ironically, also requires thiamine. Restoring NADPH levels through supplementing with ordinary thiamine and supporting the pentose phosphate pathway via other means might be advised BEFORE starting with TTFD.
In the context of poor enzyme activity, without the reducing powder to drive GSSG back to GSH, the oxidized form of glutathione can theoretically drift towards the path of generating a free radical called the glutathione radical (5). This alone could further contributes to oxidative stress and cell damage.
How to know if RBC glutathione reductase activity is sufficient? This can be tested and is one of the markers for riboflavin status. Some other ways to assess riboflavin status include glutaric acid, whole blood B2, adipic, suberic, ethylmalonic acids, and urinary succinic acid can also be indicative.
Interestingly, here is one of the links between B1 and B2. Older research in Japan showed that TTFD supplementation could lead to a secondary B2 deficiency through increased urinary excretion (6). The increase need for glutathione reductase could at least also contribute to this effect. When taking TTFD, it has downstream effects on other nutrients. Hence, these supporting nutrients should probably also be taken in conjunction with high-dose supplementation.
To summarise, the initial cellular processing of TTFD requires adequate levels of reduced glutathione. Glutathione becomes oxidized, and so TTFD has can have a depleting effect on GSH and increase the requirement for recycling. If there is insufficient active B2 (as FAD) or NADPH levels, glutathione is not likely to be recycled sufficiently and may lead to GSSG radical formation.
It is therefore possible that the glutathione-depleting effect of TTFD could be responsible for some of the side effects associated with supplementation. This is probably most applicable in individuals with poor glutathione recycling and underlying oxidative stress.
Therefore, nutrient therapy which may support this initial phase of TTFD metabolism include:
- Selenium (improve GSH levels)
- Riboflavin (improve GSSG-GSH recycling)
- Niacin (increase NADPH)
- Ordinary thiamine (increase NAPH via PPP)
- NAC, glycine and/or glutathione TAKEN AWAY FROM TTFD (improve GSH status)
In the next piece, we will examine some of the following steps in the breakdown of TTFD with a focus on the nutrient cofactors and biochemical processes necessary for adequate clearance and detoxification of the mercaptan group. These include methylation, Phase I biotransformation, and sulfoxidation.
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Get extreme anxiety or depression from TTFD supplementation? You should read on:
Did you know that TTFD uses up SAM-e, and therefore can be taxing on methylation?
I recently had a male client who explained that TTFD therapy initially produced great increases in mental clarity, energy, and almost euphoria. However, within a few days this shifted towards feelings of depletion, depression, and cognitive impairment. Funnily enough, these symptoms were the same flavour as those caused by niacin (a methyl buffer). For him, the antidote to this in the past has been methyl folate and methyl B12. I have seen this occur in multiple people now.
Furthermore, I have had countless individuals report extreme anxiety and agitation from taking TTFD. Oftentimes, it is assumed that these symptoms are caused by the sulfur content of the molecule, or alternatively are a paradoxical reaction. Sometimes it subsides, other times it doesn’t. The reason for this, in my opinion, is related to changes in methylation.
In the previous piece, I discussed some of the problems that could occur with TTFD supplementation. Specifically, we examined how TTFD temporarily depletes glutathione (GSH) and increases the requirement for activated riboflavin and NADPH. I also provided some recommendations for how one might improve this initial processing of TTFD in cells.
Following on from that, we will now look at the next phase of TTFD processing to help pinpoint some of the reasons why some people suffer negative reactions to TTFD. In short, breaking down the intermediates involved in TTFD metabolism requires adequate methylation capacity.
Once TTFD has been reduced (or “broken apart”) by glutathione (GSH), it is further bound or conjugated with more GSH, presumably using the enzyme glutathione-s-transferase. This reaction produces a conjugate called glutathione tetrahydrofurfuryl disulphide (GTFD).
As you can see from the diagram, this GTFD conjugate needs to be METHYLATED. Methylation is the process by which a methyl group is attached to its structure from a donor molecule (a “methyl donor”).
The major methyl donor in cells is called S-adenosyl Methionine, commonly known as SAM-e. Many of you are probably familiar with SAM-e, but for those who are new to this topic, I will briefly touch on the basics.
SAM-e is generated through a biochemical cycle called the methylation cycle. Dietary protein provides amino acids, one of which is methionine. Through combining with ATP, methionine can be “activated” to generate SAM-e. SAM-e possesses a methyl group, which can go on to be donated to a variety of different molecules via methyltransferase enzymes. In simple terms, attaching a methyl group to a molecule serves to change its function in some way.
This process of methylation is involved in DNA base synthesis, gene expression, detoxification, neurotransmitter production/clearance, and many, MANY other processes. As SAM-e is the major cellular methyl donor, it is important that cells maintain a consistent level of SAM-e to fulfil all those functions.
For example, changes in methylation have been implicated in numerous mental health conditions, including depression and anxiety disorders. Since methylation is required for the synthesis of neurotransmitters and maintaining neurochemical balance in the brain, it is thought that undermethylation can be responsible for producing underlying neurochemical abnormalities which lead to neuropsychiatric symptoms.
IMPORTANT POINT: For the above reasons, SAM-e has been used effectively as a fast-acting anti-depressant medication (1), and is also useful as an anti-anxiety agent in specific cases (2).
Once SAM-e has donated its methyl group, it becomes SAH (S-adenosyl Homocysteine) and later homocysteine. Fortunately, homocysteine can be recycled to methionine. This can occur through two main pathways, one of which involves the utilization of folate and vitamin B12, whilst the other utilizes betaine. The newly recycled methionine can then be activated once more to SAM-e, and so the cycle is goes on to maintain sufficient levels of methylation. This is how the process SHOULD work in healthy cells.
In unhealthy cells with underlying nutrient deficiencies, the capacity to run through the methylation cycle can become compromised. Elevated homocysteine with a relative inability to recycle homocysteine back to methionine may result in reduced levels of SAM-e. And because SAM-e is the primary methyl donor in the cell, methylation (and by default all the MANY processes which require methylation) can become compromised.
The important point to understand in this context is that that methylation is involved in the clearance of the intermediate molecule GTFD. Through the enzyme thiol-s-methyltransferase, SAM-e donates a methyl group to GTFD to generate METHYL tetrahydrofurfuryl disulphide (MTHFD). MTHFD is then funnelled through the sulfoxidation pathway in the liver, which we will examine in the next article.
The nuts and bolts of this is: TTFD breakdown uses up SAM-e!
Recall that SAM-e will then go on to become homocysteine, which then further requires recycling via B12/Folate/Betaine dependent pathways.
In other words, by using up SAM-e, TTFD theoretically also increases requirement for those nutrients involved in the methylation cycle. Might this be one of the mechanisms by which TTFD therapy can go on to “unmask” an underlying folate/B12 deficiency in some people?
Dr Lonsdale spoke about cases of folate deficiency occurring after undertaking thiamine therapy. I have also seen this on several occasions, and I suspect that it relates the above mechanisms.
Secondly, the lack of SAM-e likely then produces neurochemical changes which are potentially responsible for the sudden feelings of anxiety or depression that some people experience. This would especially apply to those people who already have compromised methylation, or tend towards lower levels of SAM-e, folate, B12, or a combination of all three.
To conclude, this highlights the importance of B complex therapy in conjunction with TTFD. As we saw previously, not only does TTFD increase the requirement for riboflavin, but it would also seem that is increases the need for folate and vitamin B12.
If you are one of the people who experiences depletion, depression, or anxiety from taking the TTFD form of thiamine, then you might want to try adding in methylfolate, methyl B12, betaine, or alternatively SAM-e.
In the next piece, we will delve into the final stages of TTFD clearance – looking at the process of phase I biotransformation and sulfoxidation.

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RedFox

The Living Force
FOTCM Member
Sharing Elliots latest article for reference:

Paradoxical Reactions With TTFD: The Glutathione Connection​

Poor glutathione status may underlie negative reactions to high dose TTFD therapies.


Some individuals experience negative reactions and the worsening of symptoms when they begin thiamine repletion therapies using the more biologically available formulations like thiamine tetrahydrofurfuryl disulfide (TTFD). Dr. Lonsdale calls these paradoxical reactions. In this article, I examine the chemistry beyond these reactions and provide some hypotheses regarding why they happen and how to mitigate them.

TTFD Basics​


In order to understand why some individuals react negatively to TTFD supplementation, it is essential to understand the basics behind TTFDs molecular configuration and how it is processed by cells. The primary difference between ordinary thiamine and TTFD is an extra chemical group called a mercaptan group. The mercaptan is derived from allicin, a compound found in garlic, and is connected to the thiamine molecule via a special sulfur-sulfur bond called a disulfide bond. Importantly, it is this unique chemical group that accounts for TTFD’s ability to traverse membranes in the body without the need for a transport system.

Upon ingestion, TTFD is mostly absorbed into the blood from the gastrointestinal tract in whole form as TTFD. As it travels through the blood, it can penetrate the brain and other organs without cellular transporters. One of the main sites of absorption is the red blood cells. Upon penetration of the red blood cell membrane, TTFD must first be processed or “broken apart” before it can release the thiamine contained within its chemical structure. After thiamine is released into the cell, the ancillary mercaptan group must also be processed and/or detoxified through alternative pathways. It is therefore theoretically plausible that errors involved in the processing of TTFD could contribute toward negative side effects or reactions to this nutrient.

How TTFD Is Processed Inside the Cell: The Glutathione Connection​


For TTFD to “release” its thiamine, its disulfide bond must gain electrons from another donor molecule. In chemical terms, this process is referred to as reduction. Once this reduction occurs, thiamine is freed and can then go on to participate in cellular biochemical reactions.

Of the few molecules which have been shown to reduce TTFD, glutathione performs this function most effectively. As the cell’s primary antioxidant, glutathione is responsible for donating electrons to neutralize reactive oxygen species, and can either be found in its reduced form or its oxidized form. Once a reduced glutathione molecule (GSH) has donated its electron, it bridges with another to molecule to form oxidized glutathione (GSSG). GSSG is then recycled back to two GSH molecules through accepting electrons from NADPH via the enzyme glutathione reductase (vitamin B2 as FAD dependent).
TTFD and Glutathione


When TTFD enters cells, GSH in red blood cells chemically reduces TTFD via a process called “disulfide exchange” (presumably using a protein called glutaredoxin). Reduced glutathione becomes oxidized glutathione and TTFD “releases” thiamine to producing free thiamine inside the cell with an extra TFD mercaptan group left over.

The initial phase of processing TTFD requires that cells have enough reduced glutathione. Furthermore, the more GSH you have – the faster the rate of this reaction. So in simple terms, to obtain thiamine from TTFD the cells “use up” their reduced glutathione.

I recently had correspondence with one individual who only gained tolerance of TTFD after supplementing with 200mcg of selenium in the form of sodium selenite. Selenium supplementation in different forms has been shown to increase red blood cell GSH levels by up to 35%. This is thought to occur due to selenium’s ability increase glutathione synthesis through upregulating the enzyme gamma-glutamylcysteine synthetase. I suspect that poor glutathione status might be one of the reasons for benefit from selenium.

Having enough glutathione is clearly very important, but recycling it is also essential to maintain a pool of glutathione in its reduced form. Unfortunately TTFD can place a burden on this system, and this was demonstrated in one old study from Japan which showed that TTFD administration rapidly lowered red blood cell GSH. Interestingly enough, that same experiment showed that GSH levels were restored within 5-10 minutes. This restoration was accomplished by the vitamin B2 (as FAD)-dependent enzyme glutathione reductase, which donates electrons to GSSG with the reducing power of NADPH to recycle it back to two GSH.
What this basically means is that cells require a robust antioxidant system to properly process TTFD and return back to their original state. First, cells need enough of the antioxidant GSH to cleave thiamine. Second, cells also need to be able to recycle the oxidized glutathione back to its reduced state.

Poor Glutathione Status and Difficulty With TTFD​


Immediately, we see two potential issues that could arise from TTFD supplementation which might provide a better understanding of why some people may not tolerate this molecule.

In someone who has poor glutathione (GSH) status, they might theoretically be less able to cleave thiamine from TTFD. There are many reasons why someone may have poor glutathione status:

  • Low precursors (cysteine, glutamate, glycine)
  • Chronic oxidative burden and/or inflammation
  • Deficiencies in the nutrients required to generate, process, or utilize glutathione (B6 or selenium)

Alternatively, an individual may have enough resources to make glutathione, but if they cannot recycle it through the necessary machinery (i.e glutathione reductase), then taking a substance which depletes their GSH (like TTFD) might further contribute towards their oxidative burden.

A total and/or functional riboflavin deficiency is the probably the most common culprit responsible for poor glutathione reductase activity. The glutathione reductase enzyme also requires adequate reducing power from NADPH to drive the enzymatic reaction. NADPH is derived from niacin (vitamin B3) and is generated in the pentose phosphate pathway which, ironically, requires the thiamine-dependent enzyme transketolase.
In the context of poor enzyme activity, without the reducing powder to drive GSSG back to GSH, the oxidized form of glutathione can theoretically drift towards the path of generating a free radical called the glutathione radical. This alone could further contributes to oxidative stress and cell damage.
Below is a hypothetical scenario to demonstrate my point:
  1. An individual suffers from long-term thiamine deficiency and has suboptimal riboflavin status
  2. Thiamine deficiency leads to lower activity of transketolase
  3. Low transketolase activity produces a lack of NADPH
  4. A lack of NADPH and a lack of FAD means that glutathione reductase is unable to efficiently recycle glutathione, which produces an imbalance between reduced/oxidized glutathione.
  5. Intracellular GSH is further lowered by taking high dose TTFD, and there is not enough enzyme activity to recycle it back
  6. Oxidative stress is made worse
In the above scenario, taking a high dose of TTFD may not be appropriate. Rather, restoring NADPH levels through supplementing with ordinary thiamine and supporting the glutathione system via other measures might be advised before starting with TTFD. Optimal riboflavin status is also necessary for the above processes to run smoothly.
Older research in Japan showed that TTFD supplementation could lead to a secondary B2 deficiency through increased urinary excretion. The increased need for glutathione reductase could at least also contribute to this effect. When taking TTFD, it has downstream effects on other nutrients. Hence, these supporting nutrients should also be taken in conjunction when someone is supplementing TTFD in high doses.
Some basic laboratory measurements of glutathione status include:

  • Whole blood glutathione (low)
  • Gamma-glutamyl-transpeptidase (high)
  • Urinary pyroglutamic acid (high)
Furthermore, there are several functional markers which can be measured to assess riboflavin status, including direct measurement of red blood cell glutathione reductase activity:
  • Urinary glutaric acid (high)
  • Whole blood B2
  • Urinary adipic, suberic, ethylmalonic acids (high)
  • Urinary succinic acid (high) can also be suggestive along with a few other organic acids
  • Erythrocyte glutathione reductase activity (low)

To summarize, the initial cellular processing of TTFD requires adequate levels of reduced glutathione. Glutathione becomes oxidized, and so TTFD has can have a depleting effect on GSH and increase the requirement for recycling. If there is insufficient active B2 (as FAD) or NADPH levels, glutathione is not likely to be recycled sufficiently and may lead to GSSG radical formation.

It is therefore possible that the glutathione-depleting effect of TTFD could be responsible for some of the side effects associated with supplementation. This is probably most applicable in individuals with poor glutathione recycling and underlying oxidative stress. Therefore, nutrient therapies that may support this initial phase of TTFD metabolism include:

  • Selenium (improve GSH levels)
  • Riboflavin (improve GSSG-GSH recycling)
  • Niacin (increase NADPH)
  • Ordinary thiamine (increase NAPH via PPP)
  • NAC, glycine and/or glutathione TAKEN HOURS AWAY from TTFD (GSH precursors)
 

Keyhole

Ambassador
Ambassador
FOTCM Member
Over the past few years I have been pretty much hyper-focused on learning about this nutrient. In that time, I have spent hundreds if not thousands of hours trawling through the literature on this subject, digesting and assimilating it, and trying to apply it clinically to a bunch of different people with different health conditions.

One problem I have come across is trying to explain the benefits that some people witness only when they reach a "megadose" of this vitamin. By megadose, I am referring to consuming 100 to 4,000 times the daily recommended nutritional intake. For some people with neurological illness, the difference is literally night and day. It would seem that these changes simply cannot be explained by nutritional repletion or addressing a deficiency.

  • I since have come to the conclusion that mega-doses of thiamine are not simply working to address a deficiency, and that one does not need to be "deficient" to benefit from pharmacologic doses of this nutrient.

  • Rather, thiamine is functioning as a metabolic stimulant to restore oxidative energy metabolism in cells that has been inhibited by factors unrelated to nutritional status (toxicity, inflammation, oxidative stress, infection)

I recently published a piece explaining the rationale behind using this nutrient as a medicine, rather than simply boosting nutritional status. Apologies in advance if it is slightly heavy on the biochemistry (one can skip over those details if they want), although I needed to include it to establish my point as it is evidenced in the literature.

Mega-Dose Thiamine: Beyond Addressing “Deficiency”


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 beyond the RDA. The question I then began asking myself was this:

“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, because 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 has 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, extremely 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.


The basics of enzymes

To appreciate how 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.

1605696082812.png


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.

1605696094038.png

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.

1605696106852.png


A variety of inherited genetic conditions feature the production of defective enzymes with poor cofactor affinity. For these unfortunate individuals, the levels of nutrients found in food are simply not sufficient to overcome the genetically determined lack of affinity. However, a successful strategy used for these conditions is the administration of pharmacologic/mega-doses of the nutrient cofactor.


1605696122019.png


By saturating the cell, you 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.

Examples of nutrient-responsive genetic conditions include:


  • 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 at this point that these genuine genetic defects are extremely rare and are not applicable to the large majority of people. However, similar principles can also be applied when an enzyme has been inactivated by other factors.

Not just genetics

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 (etc), 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.

However, 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 LPS coming from a leaky BBB). Microglia produce myeloperoxidase and downstream products including hypochlorous acid and mono‐N‐chloramine – all of which are powerful inhibitors of KGDH. Heavy metals including aluminium 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 MPP+ 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).

Oxidative stress and chronic inflammation are the hallmarks of chronic disease – whether it be due to chronic infection, toxicity, biotoxin exposure, or whatever else - and both factors appear to inhibit/inactivate KGDH.

1605696136728.png


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 through saturating the enzymes with ultra high doses. 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”.

In this study on several groups of rats who were not deficient in thiamine, researchers investigated the effects of traumatic brain injury (TBI) on brain energy metabolism. 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.

However, administering massive doses of thiamine to the rats before TBI was able to completely protect the KGDH enzyme. The thiamine-treated group maintaining 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 3 days post-TBI.

1605696148080.png



This 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 neuroexcitotoxicity. 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 readers reference, here are a quick list of conditions which are thought to involve neuroexcitotoxicity 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). 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 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 transketolase activity and thiamine.
High doses 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.


Human evidence

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.

Him and his colleagues completed a larger study on 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 one hundred to one thousand 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.
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 hyperfocused on correcting a deficit, we can 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.

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.

Here are a list of some of the non-coenzyme targets of high dose Benfotiamine:


1605696166342.png

Some other non-cofactor roles of thiamine include:



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 any and all disorders involving mitochondrial dysfunction and chronic oxidative stress. This especially applies to neurological diseases, but also is probably applicable in most other conditions. And 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.
 
Last edited:

mrtn

Dagobah Resident
From the article posted by @RedFox
..or glutathione TAKEN HOURS AWAY from TTFD
I took reduced glutathione and [alli]thiamine together in the morning for some month now. I guess I have to change that.

I also found some typos in that article
it bridges with another to molecule to form oxidized glutathione (double 'to')

is the probably the most common culprit (double 'the')
And some typos in the last article posted by you @Keyhole above
called alpha ketoglutarate.. ('is called')

This demonstrated was that

dystonia was reverse ('reversed'?)
 

Mike Rocket

A Disturbance in the Force
Thiamine HCL has poor bioavailability, especially if the gut is not working efficiently. Ecological formulas or Cardiovascular research are the only companies I know of, and ebay is the only source in the UK. I am thinking about becoming a supplier in the UK though, but I don't have enough money behind me at the moment to do that.

Furthermore, thiamine is not always going to be low in everyone, so it may be that you don't need it (hence why you are not seeing benefit). It is difficult to say without a full picture, or some testing
Thank you for the clarification.


That one is for 25 pounds, YHB has it for 20. Looks like the same product.
This is on Amazon as well...
 

Mike Rocket

A Disturbance in the Force
Over the past few years I have been pretty much hyper-focused on learning about this nutrient. In that time, I have spent hundreds if not thousands of hours trawling through the literature on this subject, digesting and assimilating it, and trying to apply it clinically to a bunch of different people with different health conditions.

One problem I have come across is trying to explain the benefits that some people witness only when they reach a "megadose" of this vitamin. By megadose, I am referring to consuming 100 to 4,000 times the daily recommended nutritional intake. For some people with neurological illness, the difference is literally night and day. It would seem that these changes simply cannot be explained by nutritional repletion or addressing a deficiency.

  • I since have come to the conclusion that mega-doses of thiamine are not simply working to address a deficiency, and that one does not need to be "deficient" to benefit from pharmacologic doses of this nutrient.

  • Rather, thiamine is functioning as a metabolic stimulant to restore oxidative energy metabolism in cells that has been inhibited by factors unrelated to nutritional status (toxicity, inflammation, oxidative stress, infection)

I recently published a piece explaining the rationale behind using this nutrient as a medicine, rather than simply boosting nutritional status. Apologies in advance if it is slightly heavy on the biochemistry (one can skip over those details if they want), although I needed to include it to establish my point as it is evidenced in the literature.
Hi, Keyhole. Others have posted comments about obtaining TTFD Thiamine, and currently, it appears that Ecological Formulas is the only real supplier for this for most of us. I'm not asking for a product endorsement, but does this look like a decent source of TTFD you have been referencing? Thanks!
Over the past few years I have been pretty much hyper-focused on learning about this nutrient. In that time, I have spent hundreds if not thousands of hours trawling through the literature on this subject, digesting and assimilating it, and trying to apply it clinically to a bunch of different people with different health conditions.

One problem I have come across is trying to explain the benefits that some people witness only when they reach a "megadose" of this vitamin. By megadose, I am referring to consuming 100 to 4,000 times the daily recommended nutritional intake. For some people with neurological illness, the difference is literally night and day. It would seem that these changes simply cannot be explained by nutritional repletion or addressing a deficiency.

  • I since have come to the conclusion that mega-doses of thiamine are not simply working to address a deficiency, and that one does not need to be "deficient" to benefit from pharmacologic doses of this nutrient.

  • Rather, thiamine is functioning as a metabolic stimulant to restore oxidative energy metabolism in cells that has been inhibited by factors unrelated to nutritional status (toxicity, inflammation, oxidative stress, infection)

I recently published a piece explaining the rationale behind using this nutrient as a medicine, rather than simply boosting nutritional status. Apologies in advance if it is slightly heavy on the biochemistry (one can skip over those details if they want), although I needed to include it to establish my point as it is evidenced in the literature.
 

Keyhole

Ambassador
Ambassador
FOTCM Member
Hi! @Mike Rocket

There are two companies who sell this -

  • Ecological Formula's - Allithiamine

  • Objective Nutrients - Thiamax (my company)
Obviously, I am biased in my endorsement - so I will not endorse either ;-). Whichever brand one chooses, it provides the same raw ingredient. The one is a lower dose but is cheaper to buy, whereas the other is higher dose and more expensive per bottle.
 

anka

The Living Force
FOTCM Member
There are two companies who sell this -

  • Ecological Formula's - Allithiamine

  • Objective Nutrients - Thiamax (my company)
Keyhole , I want to ask on behalf of our CzechoSlovakian team. Would there be a chance to order some thiamin to Czech? First we would like to get some for ourselves. However, if we wanted to be the middle man and authorized distributor of your product here, would you be able to supply on regular basis? It happens very often that e-shops in Czech have a shortage of any B1 supplement and I think if there was a chance for them to have another supplier they would go for it. What are your thoughts on this?
 
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