Is Thiamine Tetrahydrofurfuryl Disulfide (TTFD) Toxic? Refuting Andrew Cutler’s Claims

I regularly receive correspondence from people asking whether thiamine tetrahydrofurfuryl disulfide (abbreviated TTFD), a thiamine (vitamin B1) derivative, is toxic or not. Most people following this line of inquiry base the assumptions of “toxicity” on statements previously made by the famous (and now deceased) Andrew Cutler, PhD. Cutler is most well known for his work on mercury chelation and detoxification protocols and has amassed thousands of followers over the years.

He was strongly opposed to the application of TTFD therapeutically and explicitly advised people against using this molecule as a nutritional supplement for thiamine repletion and/or heavy metal detoxification.

Much of what he said on this topic was documented in the archives of the Onibasu website which can be found here. Cutler’s statements on TTFD were speculative in nature, based on anecdotes and were never backed by any scientific evidence (to my knowledge).

The main claims made by Cutler are listed below:

1. TTFD is hepatotoxic, and adverse effect to TTFD are consistent with liver damage

2. No clear benefit to using TTFD and benfotiamine is much better choice

3. TTFD does not influence heavy metal excretion

In this article, I will refute each of the above claims with evidence.

Claim 1: Is TTFD toxic?

Cutler speculated that the mercaptan part of TTFD was responsible for toxicity, and that this primarily affected the liver. The word “mercaptan” refers to the thiol group which breaks away from thiamine after its absorption into the cell. This mercaptan group essentially accounts for the “TFD” of the abbreviation TTFD.

After TTFD is absorbed, it gets “broken apart” (the disulfide bond is chemically reduced) by glutathione, cysteine, or haemoglobin to release the free thiamine molecule which become trapped inside the cell.

The prosthetic mercaptan is released and then rapidly metabolised by the liver through methylation and later sulfoxidation by liver mono-oxygenase enzymes into breakdown products which are then excreted in urine.

The original series of studies on the enzymatic breakdown of TTFD can be found here:

The breakdown products are shown below:

In humans, approximately 82-90% of these metabolites are excreted within 24hrs and 100% are excreted within 48hrs.

Are any of these breakdown products toxic?

A study titled “Pharmacological study of S-alkyl side chain metabolites of thiamine alkyl disulfides” sought to determine the acute and sub-acute toxicity levels of each metabolite. They concluded that toxicity of these breakdown products was low.

The acute toxicity of a substance is estimated by the “LD50”, which means the dosage that is required kill 50% of the animals in the study group. The higher the LD50, the lower the toxicity. The lethal dose intravenously is generally much lower than oral dosing (by roughly 4-6 times)

I have listed the established toxicity for the primary breakdown products below:

  • Inorganic sulfate: Non-toxic

  • Delta-methylsulfonyl-gamma-valerolactone

Intravenous LD50 in mice: In excess of 5 grams/kg body weight

LD50 estimate for a 70KG human: 28.5 grams intravenously

Orally, this is likely much higher.

  • Delta-methylsulfinyl-gamma-valerolactone

Oral LD50 in mice: 6 grams/kg body weight

LD50 estimate for a 70KG human: 34 grams orally

  • 4-Hydroxy-5-(methylsulfonyl)valeric acid

Intravenous LD50 in mice: 1.5 grams/kg body weight

LD50 estimate for a 70KG human: 8.3 grams intravenously

Orally, this is likely much higher.

By themselves, these metabolites are only toxic when dosed in unrealistic and massive amounts. These numbers are not relevant from a clinical perspective.

Now lets look at the established toxicity of TTFD:

  • Intravenous LD50 in mice is 450mg/kg (equivalent of 2.5 grams intravenous in humans)

  • Oral LD50 in mice is 2200mg/kg (equivalent to approximately 180mg/kg in humans: 12.5 grams for a 70KG adult)

The potential toxicity of TTFD is therefore similar to that of niacinamide, a vitamin B3 supplement (with an oral LD50 of 2,500mg/kg in mice).

No one would realistically be able to orally consume 12 grams per day for therapeutic reasons. Like niacinamide, it is dosed in vastly lower quantities. Going above one gram is rare, and the average dose probably sits between 200-400mg per day.

That said, research performed on the reproductive effects of TTFD in monkeys showed that massive doses of 500mg/kg (which is close LD50 of 550mg/kg for that species) found no deaths. To put this in context, it would be the human equivalent of 10-11 grams every day for several months.

That same study also looked at massive doses in rabbits. No significant increase in incidence of foetal malformations was observed. No significant teratogenic effects or developmental abnormalities in pregnancy occurred.

As referenced in this document, Takeda’s research by Mizutani demonstrated that administration of 100, 300 and 500mg/kg in rats for two generations from the time of maturation to the time of reproduction showed no abnormalities. The average human equivalent of these doses would be 570mg, 1.7 grams and 2.8 grams per day.

The results of another study showed that long-term oral administration of 30-300mg/kg to pregnant animals failed to produce any significant developmental abnormality. Intraperitoneal administration of 1000mg/kg also showed no sign of chromosome aberration, damage to sex organs or spermatogenesis.

In animals with artificially induced liver damage by carbon tetrachloride and/or hepatic dysfunction due to choline deficiency, the breakdown products of TTFD were assessed. They showed that the quantity of excreted metabolites in the hepatotoxic group were equal to the control, and in choline deficiency the quantity of excreted metabolites was only slightly reduced. In the hepatotoxic group, a qualitative difference was found with a lower proportion of methyl metabolites (MTHFSO, MTHFS02). This suggests, even in hepatotoxicity, TTFD metabolites can still be excreted albeit at slightly different ratios.

And for those that are curious about the efficacy of animal research on TTFD, the comparative metabolic studies have found that the metabolism of TTFD is essentially the same in animals and humans. It is also worth taking into consideration the fact that TTFD is a rich source of organosulfur compounds. In supraphysiologic doses (12 grams) these compounds can cause damage, but can also be extremely therapeutic at lower doses. Consider allicin, or indole-3-carbinol, both of which are used widely as therapeutic agents, but both have vastly lower LD50s (significantly higher toxicity compared with TTFD).

2018 study – No liver toxicity with massive doses

To quote Cutler:

My guess is the tetrahydrofurfuryl mercaptan part kills your liver.

There is no evidence to support this statement. A peer-reviewed study published in 2018 titled “The Effects of Thiamine Tetrahydrofurfuryl Disulfide on Physiological Adaption and Exercise Performance Improvement” monitored the effects of different doses TTFD in 30 animals for a period of 6 weeks.

The highest oral dose used was 500mg/kg in 10 test subjects, which is the human equivalent to 40mg/kg which, in a 70KG human, is 2.8 GRAMS per day for 6 weeks. Remarkably, they showed that this highest dose produced significant improvement in endurance capacity and lactate homeostasis.

More importantly, this study also performed comprehensive measures of sub-acute toxicity with the aim of evaluating the safety of high doses in humans.

Evan at the highest dose taken for 6 whole weeks, no changes in behaviour, diet, growth curve, or organ weight (liver, kidney, muscle, heart, lung etc) was observed.

Furthermore, to assess liver function they performed comprehensive metabolic analysis including liver enzymes (ALT, AST), creatine, uric acid, total cholesterol, triglycerides, albumin, total protein, ammonia, creatine kinase, and total protein. The only significant changes were a slight reduction in total cholesterol and significant reduction in lactate, creatine kinase and blood urea nitrogen (all of which are considered positive changes). Every other liver marker was perfectly in range.

To gain further insight into the liver function and the health of other tissues, they performed histopathological analysis of the tissue under microscope:

These findings showed that massive doses of TTFD caused no pathological changes in any tissue whatsoever.

"We found that TTFD supplementation did not affect the growth, dietary, behaviors, body compositions, and biochemistries for the whole duration of the study. Actually, TTFD has higher bioavailability and distribution than thiamine in a variety of organs, especially in the muscle, liver, kidney, and heart. Histological observation which can reveal pathological changes with the long-term and high-dose supplementation demonstrated that the TTFD did not cause or induce organ abnormalities.”

The authors went on to conclude:

“In the current study, we proposed that the higher thiamine derivative, TTFD, could significantly improve physical activities and physiological adaption with evidence-based safety validation. For practical application, we recommend that athletes should consume a daily intake of 40 mg/kg TTFD (equivalently converted from mouse 500 mg/kg dose based on body surface area between mice and humans by formula from the US Food and Drug Administration) to improve energy regulation for higher performance in a combined nutritional strategy, including carbohydrate loading for efficient energy demand during extended exercise.”

This group of researchers were so convinced of TTFD’s safety that they recommended athletes take the equivalent of 2.8 GRAMS per day to improve athletic performance. Whilst I do not personally advise that someone take that quantity, I do believe it is safe.

Human evidence

As one of the first medical doctors granted approval to use TTFD as a clinical intervention in the Western world, Dr Derrick Lonsdale obtained a special licence from the FDA to import this molecule and studied its effects in his child patients. In his own words:

“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.”

Some reports published by Lonsdale and other authors include:

  • 22 children with Down’s Syndrome, 12 of which were administered TTFD for 12 months and 12 of which were administered TTFD for 6 months. No serious adverse events noted.

  • TTFD used to address brainstem dysfunction

  • TTFD studied in brainstem potentials

  • 21 patients subacute necrotizing encephalomyelopathy treated with thiamine derivatives TPD/TTFD

  • 10 children treated with TTFD, no serious adverse events reported, one experienced worsening of behavior/symptoms, two experienced rash

  • 44 polyneuropathy patients treated with 50mg TTFD injection, no adverse effects reported.

  • Prosultiamine (TPD) at 300mg per day for 12 weeks (TPD, a very similar molecule to TTFD) used to treat spinal cord injury in human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis (2013). Significant improvement in motor functions and bladder control, as well as reducing viral numbers in blood. Only adverse symptom was mild epigastric discomfort. No safety concerns.

However, it is worth noting that TTFD is not well known in Western medicine. The regions of the world which use TTFD extensively include Japan, China, and other countries in the Far East.

Japanese cases

Unfortunately much of the Japanese literature is not published in English, so it can be difficult to obtain. Furthermore, TTFD is prescribed so frequently for treating thiamine deficiency that much of the literature refers to to it simply as “thiamine” or “vitamin B1”, using the terms interchangeably. This can make it harder to identify studies using this type of therapy.

Below are at least 33 reports, including some in children, which document the benefits of TTFD clinically. In all of the papers I have read, I have not once seen mention of safety concerns using this. In several reports, hundreds of milligrams are maintained indefinitely with no apparent issues.