Jun 8, 2020
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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Apr 11, 2019
I just came across methylation After doing research in Iodine.
Sounds like a critical pathway. On doctor has written a book about it. I have not read it.

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