TTFD - Page 2

Paradoxical Reactions With TTFD: The Methylation Connection

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In a previous piece, I discussed some of the problems that could occur when supplementing with a particularly potent form of thiamine called tetrahydrofurfuryl disulfide or TTFD. Specifically, we examined how TTFD can temporarily deplete glutathione (GSH) and increase the recycling requirements (using 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 when beginning supplementation. In short, the clearance of TTFD breakdown products requires adequate methylation capacity and many individuals who are thiamine deficient have insufficient methylation.

From Glutathione to Methylation

Once TTFD has been reduced (or “broken apart”) by glutathione (GSH), it is further bound or conjugated with more GSH, likely using the enzyme glutathione-s-transferase. This reaction produces a conjugate called glutathione tetrahydrofurfuryl disulfide (GTFD).

TTFD and methylation

The above diagram shows that this GTFD conjugate then 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.

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 it then donates 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.

After having donated its methyl group, SAM-e becomes SAH (S-adenosyl homocysteine) and later homocysteine. Homocysteine can either be recycled back to methionine with the use of multiple nutrients (including folate and vitamin B12), or alternative can be drawn down through the transsulfuration pathway to generate cysteine.

The newly recycled methionine can further serve as the source of more SAM-e, which continues to be utilized in methylation reactions. This is ideally how the process should work.

Methylation is involved in DNA base synthesis, gene expression, detoxification, neurotransmitter production/clearance, and many other processes. As SAM-e is the major cellular methyl donor, cells must maintain a consistent level of SAM-e to fulfill those functions.

Since methylation is required for the synthesis and clearances of neurotransmitters and maintaining neurochemical balance in the brain, it is thought that changes in methylation status can be responsible for the underlying neurochemical abnormalities present in various psychiatric disorders. For the above reasons, SAM-e has been used effectively as a fast-acting anti-depressant medication and is also useful as an anxiolytic agent in specific cases.

In the context of longstanding deficiencies in the nutrients required to maintain a healthy methylation cycle, a relative inability to recycle homocysteine can yield elevated levels of homocysteine and consequentially less SAM-e. And because SAM-e is the primary methyl donor in the cell, methylation (and by definition, all of the many processes which require methylation) can become compromised.

TTFD and SAM-e

The above information is relevant to this topic because the breakdown of TTFD requires adequate levels of SAM-e. Through the enzyme thiol-s-methyltransferase, SAM-e donates a methyl group to GTFD to generate methyl tetrahydrofurfuryl disulfide (MTHFD). MTHFD is then later funneled through the sulfoxidation pathway in the liver to be cleared primarily through the urine.

The nuts and bolts of this: TTFD metabolism can deplete SAM-e. A lack of SAM-e could potentially help to explain some of the following side effects which are common with this therapy – including insomnia, anxiety, agitation, restlessness, flat mood, fatigue, and/or mild depression.

Oftentimes, it is assumed that these symptoms are caused by an inability to process the sulfur content of the molecule, or are simply a manifestation of the “paradoxical reaction”. Sometimes it subsides within a few days or weeks, whereas other times it doesn’t. The reason for this, in some people at least, might relate to changes in methylation status.

Furthermore, by using up SAM-e, TTFD could also theoretically increase the requirement for some of the other nutrients involved in the methylation cycle. These might include the B complex vitamins, particularly folate, riboflavin, and vitamin B12.

Clinical Experience Suggests A Relationship Between Methylation and TTFD Response

I recently had a client who explained that supplementing TTFD initially produced great increases in mental clarity, energy, and almost euphoria. However, within a few days, this shifted towards feelings of “depletion”, flatness, depression, and cognitive impairment. The individual described the symptoms as remarkably similar to those produced by other supplements which are referred to as “methyl buffers” – capable of affecting methylation capacity. For this same individual, the remedy was to supplement with extra methylfolate and methylcobalamin (vitamin B12) to increase methylation.

And so, 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 has documented cases of folate deficiency being “unmasked” in some people after undertaking thiamine therapy. I have also seen this on several occasions, and I suspect in some cases, it might be somewhat related.

Secondly, a lack of SAM-e can then theoretically produce neurochemical changes which are potentially responsible for sudden feelings of anxiety or depression that some people tend to 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 well as monitoring nutritional status at regular intervals if experiencing negative symptoms or side effects from this nutrient. If you are one of the people who experience depression or anxiety from taking the TTFD form of thiamine, then you might want to try investigating methylation status, or experiment with methylfolate, methyl B12, betaine, or SAM-e.

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This article was published originally on January 7, 2021. 

About TTFD: A Thiamine Derivative

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I recently received notification concerning a “review” posted on HerbCustomer, a commercial website that has been active since February 26, 2010. This so-called “review” was posted on January 16, 2018 by iHerbCustomer entitled “Dangerous allithiamine derivative with no thiamine activity”. The email was posted as well. This person made a potentially libelous statement by referring to me as lying about this thiamine derivative. Its commercial name is Lipothiamine. Its chemical name is thiamine tetrahydrofurfuryl disulfide (TTFD) and this post is to refute the accusations that are made public by this individual.

History of Thiamine Research

Thiamine is the chemical name for vitamin B1 and its deficiency in the diet has long been known as the cause of beriberi. This disease has been known for thousands of years but its underlying cause was only discovered in the closing years of the 19th century. Since beriberi was commonest in the rice consuming cultures, it is not surprising that the major research came from Japan. In the middle of the last century a group of university-based scientists was convened and they wrote a book (Review of the Japanese Literature on Beriberi and Thiamine). This was translated into English, ostensibly because these scientists wished to let people in the West know and understand the pernicious nature of disease resulting from thiamine deficiency. I was fortunate enough to receive a copy of this book from one of the scientists involved. The information in this post is derived from it. Because they were scientists and were well aware of the clinical effects of beriberi, their studies were very extensive. They knew that thiamine existed in garlic and much of their experimentation focused on studies of the garlic bulb. They discovered that there was a natural mechanism in garlic that created a derivative of thiamine and called it allithiamine. Note that this is a naturally occurring substance and the term should be entirely restricted to it.

On a number of occasions I have seen thiamine derivatives being called “The alithiamines” and one commercial product is called Allithiamine with a capital a. The name was given to this naturally occurring product because garlic is a member of the allium species of plants. It can be found in other members of the allium species. Because the Japanese scientists already knew a great deal about the clinical expressions caused by thiamine deficiency, they originally thought that this new derivative might have lost its vitamin dependent activity. They went on to test it in animal studies and found that it had a much greater biologic effect than the original thiamine from which it was derived. They found that it was extremely important that allithiamine was a thiamine disulfide derivative (disulfides are important in human physiology) and they synthesized many different types of thiamine disulfide as well as many non-disulfide derivatives, carefully testing each one for their biologic activity.

What is TTFD?

Without going into the biochemical details, what we now know is that thiamine tetrahydrofurfuryl disulfide (TTFD, Lipothiamine) is, for a number of reasons, the best of the bunch of synthetically produced derivatives and has exciting possibilities in therapy. For example, it has been shown from animal studies that Benfotiamine, a non-disulfide derivative, does not get into the brain whereas TTFD enables absorption of thiamine into the brain where it stimulates energy synthesis. When we take in thiamine, occurring only in our naturally formed food, it is biologically inert. It has to be “activated” within the body that possesses genetically determined mechanisms for its absorption and activation. To cut a technically difficult explanation, let me state that TTFD bypasses this process. It enables thiamine to split away from its disulfide attachment and enter the cells where its activity is required. The concentration achieved in the target cells is much greater than that achieved by the administration of the thiamine from which it was derived.

The Japanese scientists studied the effect of cyanide in mice and found that thiamine propyl disulfide (TPD), a forerunner of TTFD, gave significant protection from the lethal effect of this poison, an incredible discovery that alone should raise eyebrows. They studied this effect and were able to show its mechanism. They also found that it would protect animals from the effect of carbon tetrachloride, a poison that affects the liver. It is using its vitamin actions in a therapeutic manner.

Being myself a consultant pediatrician in a prestigious medical institution, I was able to obtain an independent investigator license (IND) from the Federal Drug Administration, and obtained TTFD from Takeda Chemical Industries in Osaka, Japan, the makers of this product. TTFD is a prescription item in Japan, sold under the commercial name of Alinamin. I have read several publications, showing that it reverses fatigue in both animal and human studies. I was able to study the value of this incredible substance in literally hundreds, if not thousands of patients. Far from being toxic, as this person claims, I never saw a single item that suggested toxicity. Its therapeutic potential is largely untapped in America. This is because the current medical model does not recognize that defective energy metabolism, genetic errors and the nature of stress are the interrelated components whose variable effects in combination are the cause of disease. Do not mistake the use of the word stress, a word that is so commonly used inappropriately. An infection and any form of physical or mental trauma represent a form of stress. It is the ability or the inability to meet the required energy demand to resist that stress that matters in the preservation of health.

Clinical Benefits of TTFD

It is important to understand that the beneficial activity of TTFD is exactly the same as the thiamine from which it is derived. It is the mechanism of its introduction to cells, particularly those in the brain, that enable it to have such an effect on energy metabolism. Because of its strategic position in the cell, thiamine is of vast importance in oxidative metabolism in the complex mechanisms of energy production. There are at least two methods by which thiamine deficiency can be induced. The commonest one is an excess of sugar and fat that overwhelms the capacity of thiamine to conduct the mechanisms involved in energy synthesis. The discovery that thiamine has a part to play in fat metabolism is quite recent. The other one is because of genetic errors involving its biochemical action. However, we now know from a relatively new science called epigenetics that some mistakes in DNA can be overcome by the use of an appropriate nutritional substance like thiamine. The completely non-toxic use of TTFD depends merely on its ability to introduce thiamine into the cells of the body that require its magic. Under these circumstances, the big doses of thiamine are acting like a pharmaceutical by stimulating the missing action. We are not dealing with simple vitamin replacement. This should represent a new era in medicine when nutrient biochemistry takes its place in patient care.

Conclusion

The person that wrote this criticism fails to understand that TTFD and other thiamine derivatives represent a new basic principle of therapy. It recognizes that healing is a function of the body, not the activity of a so-called “healer”. All it requires is the foundation substances needed for repair and sufficient energy to use them. It demands a dramatic change in thinking about health and disease. If you understand the principles involved, it forces the conclusion that the word “cure” is a pipe dream. The only form of pharmaceutical drug that matters is one that safely kills an attacking microbe. Almost all the rest of them merely relieve symptoms and have no effect on the ultimate outcome.

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Back Pain and B Vitamins: Notes from Personal Experience

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Throughout the history of medicine, performing research on oneself has been time-honored. Before I describe the experiment on myself, I must digress. As many readers on this website know, I have written a great deal about thiamine and its use in therapy. In particular, I have long been interested in a derivative of this vitamin that is to be found naturally occurring in garlic. It has been synthesized and sold under various trade names. Its chemical name is complex, so I use the initials TTFD. Without going into details, its action is superior to that of the thiamine from which it is derived. I have used TTFD for the treatment of hundreds, if not thousands, of patients. Over the years, I became certain that there was no bad side to its use, whatever the dose. My experiment proved me wrong but in a way that I should have anticipated.

Vitamins Work Together

Vitamins work as a team and thiamine is a member of a group of vitamins known as the B complex that is vital to energy metabolism. We are however beginning to learn that vitamins, either singly or given in a group, can be used as drugs and it requires a great deal of research in order to understand completely these relationships if they are used therapeutically. As I have a particular condition that is precancerous, I have been attempting to find ways and means of preventing the possible onset of cancer by the daily use of a variety of nutrient supplements. We now know that thiamine is implicated in many conditions, including cancer.

For some time I had been taking 100 mg of TTFD a day and one tablet of B complex. I raised the dose of TTFD to 200 mg a day without raising the dose of B complex to see if I could perceive any difference in what I experienced. After about a month with this dose, I was getting into bed one evening and was suddenly afflicted with the worst pain in my left leg that I had ever experienced. It appeared to be muscular pain because any movement would sharply increase the pain and often cause me to cry out involuntarily. Sleep was of course impossible and at about 3 AM, one night last week, I remembered a manuscript that I had come across that purported to relieve pain by an injection of vitamins B1, B6, and B12, administered separately or in combination. I took three tablets of B complex (three times the previous daily dose) and about 15 minutes later I noticed some diminution in the pain. I waited a while before repeating the dose of B complex twice more and within about 45 minutes I was pretty well pain free. It was a shattering experience that demanded some form of explanation, if possible.

The Mechanics and Biochemistry of B Vitamins

My personal explanation is as follows. Each member of the B group of vitamins has a vital part to play in energy metabolism and I had produced an artificial balance between them that severely decreased the efficiency of their combined action. An analogy may help to explain what I am talking about. Imagine a machine that relies on cogwheels, such as a clock. The motor, whether it be clock-work or electric, passes the energy via the cog-wheels to the hands of the clock. The very first cogwheel in the series is the master, because without it nothing happens. The rest of the cogwheels are just as important but only function because of the first one.

The energy that our cells require is passed through a series of enzymes that are the equivalent of the cogwheels. Each enzyme requires one or more cofactors that can be thought of as a special lubricant that differs for each cogwheel. Imagine now that the first cogwheel is an enzyme that requires thiamine and you have added so much lubricant that it causes the meshing with the next cogwheel to slip. The motor keeps running but the transmission breaks down. Like all analogies, this is imperfect. Thiamine is known as the rate limiting factor in the enzyme complex that demands the presence of all the B vitamins. You can think of thiamine as being the dominant member but no less essential than the others.

Vitamins as Drugs

A drug is  “a substance that, when ingested, alters physiological actions in the body”. That definition automatically excludes each vitamin and essential mineral, such as magnesium, as a drug under normal healthy circumstances because each is essential to normal human and animal physiology. However, we are completely dependent on appropriate nutrition in order to acquire the vitamins and essential minerals. Because we no longer obey the life rules of Mother Nature, it has become exceedingly easy to develop (non-caloric) nutrient deficiency. It particularly applies to the B complex because of its essential role in liberating energy from glucose. We know from studies of thiamine deficient diets in human subjects that the earliest symptoms are “emotional” in character and may be classified as “psychosomatic”. If the symptoms are not recognized and go on for years, we can assume that the structure of the enzymes deteriorates. If and when clinical and biochemical recognition occurs, it would seem logical to assume that the vitamin cofactor would have to be increased drastically in order to reconstitute the enzyme. The vitamin is therefore used under those circumstances as a drug until reconstitution is complete. When the normal activity of the enzyme is restored, the vitamin returns to its state as a nutrient and its therapeutic dose needs to be reduced.

Prevention Versus Recovery

In my case, the explanation may be different. I was taking a colossal dose of TTFD with insufficient concentrations of the B complex, perhaps causing an imbalance in the selective activities of each. If that is the mechanism, I can only guess that it interfered with oxidative metabolism. Also, I can no longer state that there is no “toxicity” from taking large doses of TTFD. It does seem to imply that the remainder of the B complex should always be used with TTFD. We know that beriberi patients required 100 mg of thiamine three times a day for months. If blood sugar was normal they always responded. If there was hyperglycemia the response was slower. If there was hypoglycemia, some did not respond at all. We can be sure that the thiamine dependent enzymes were sick and that they were being reconstituted by thiamine being used as a drug. Thus, my situation is quite different than treating a thiamine deficient patient. High doses are required only for sick thiamine dependent enzymes that have long been lacking sufficient concentrations of their cofactor(s). Preventive therapy is different than long-term deficiency.

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

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