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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