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.
267 cases of sudden-onset deafness was treated with 150mg TTFD orally, with most therapeutic effect seen after 2-3 months of treatment
20 cases of perceptive deafness, 20 cases of laryngeal disease, 7 cases of facial nerve palsy and 3 cases of anosmia injected with TTFD 50mg once per day for 5-20 days. 60% effective and no side effects.
24 subjects without nutritional deficiency, 20 cases of alcoholism, and 48 cases of alcoholism with signs of deficiency and/or liver disease were given either TTFD, Thiamine propyldisulfide (a similar disulfide derivative), or thiamine HCL. They showed no toxic effects at 3-6 months in any group, and demonstrated that oral TTFD/TPD increased whole blood, erythrocyte, and cerebrospinal fluid thiamine levels at an equivalent level to intravenous thiamine HCL.
Beriberi treated with 150mg IV one week, followed by 100mg oral long-term (2014)
Cardiac failure 100mg IV (1987)
TTFD administered to 15 year old boy to treat beriberi, remained on the therapy long-term
18 patients with non-diabetic peripheral neuropathy 1-3 months, no serious side effects
Wernicke encephalopathy in hemodialysis – 100mg/iv, later oral continued for 2 months until improvement (2009)
Diabetic lactic acidosis – 100mg/day IV for 7 days resolution in symptoms, followed by 75mg indefinitely (2008)
Beriberi w/ pulmonary hypotension - 50mg long-term (2019)
W.E/beriberi after intestinal resection - 150mg IV three days, 75mg long-term (2018)
W.E/Shoshin beriberi - 150mg/IV, 75mg oral long-term (2013)
A case of Wernicke's encephalopathy with severe cardiac sympathetic dysfunction – 100mg (2012)
Marked anasarca with impaired consciousness, which was thought to be caused by shoshin beriberi due to impaired vitamin B1 utilization. – TTFD 40mg +400mg HCL, followed by 2 months+ TTFD 100mg (2015)
Beriberi neuropathy and shoshin beriberi that developed 6 years after gastrectomy on the cardia side – 100mg TTFD longterm (2013)
Chemotherapy induced W.E – IV thiamine HCL followed by TTFD 75mg long-term (2008)
Postoperative W.E treated with 100mg IV TTFD (1998)
Cardiomyopathy associated with mitochondrial disease that developed heart failure, treated with 100mg long-term (2017)
Mitochondria rescue formula recommended for acute encephalopathy: including TTFD 100mg (2019)
Pediatric acute encephalopathy neuroprotection protocol – cocktail including 200mg TTFD in 15 children (2013)
200mg TTFD x 31 children childhood acute encephalopathy (part of protocol) (2014)
Lactic acidosis caused by low-dose metformin: Thiamine HCL 100mg followed by 75mg TTFD long-term, normalization of all liver values (2014)
Beriberi mimicking Guillain-Barré syndrome – IV TTFD 100mg resolved this
Shoshin beriberi – IV TTFD 150mg for 11 days, indefinite oral dose 150mg TTFD long-term
6 infants (0-1 yrs old) treated with TTFD for childhood congenital lactic acidosis. Doses included 35mg/KG – 50mg/KG. Some cases were unresponsive to thiamine HCL, where ONLY TTFD was able reduce lactate significantly. The authors said “fursulthiamine hydrochloride was significantly superior to thiamine hydrochloride in reducing lactate.” Only the cases which used TTFD survived. Children were kept on high doses permanently with no adverse effects.
75mg TTFD improved cerebral blood flow in deficiency
75mg TTFD used in mitochondrial myopathy long-term
50mg TTFD used to treat edema and weight gain and marginal thiamine deficiency – authors recommend TTFD instead of thiamine HCL (2021)
Biguanide-induced lactic acidosis treated with 100mg, then 300mg TTFD (2017)
100mg used to treat encephalopathy w/ hyperammonemia (2003)
Subacute spinal degeneration caused by B12 deficiency treated with B12 and 75mg TTFD long-term (2020)
Statement by a Japanese physician: recommendation to use TTFD instead of thiamine HCL due to superior qualities.
Chinese cases
Like Japanese research, most (if not all) of the Chinese studies using TTFD are not published in English. However, it is clear that the Chinese medical system uses TTFD frequently and has done for several decades. Most of the studies below were reported within the last 20-30 years.
Once again, I could not find any concern over the safety of using this molecule from a safety standpoint, and it was demonstrated as remarkably effective for a variety of conditions. The Chinese not only use it for addressing deficiency, but also for non-deficient conditions where it is often injected directly into acupoints either alone, or in combination with other nutrients/medications. Below are 31 case reports documenting TTFD treatment in over 1,900 patients:
194 cases of infantile beriberi cured with IM/IV thiamine and TTFD (1987)
50 infants treated with TTFD for cardiac beriberi (1997)
70 children with infantile beriberi cured with intravenous TTFD (1990)
48 cases of infantile cerebral beriberi (0-3 years old) treated with TTFD (1997)
35 cases of infantile beriberi cured TTFD (2010)
10 cases of infantile cerebral beriberi cured with B1 HCL and TTFD
10 cases of cerebral beriberi and basal ganglia damage treated with TTFD injections (2003)
125 children with pneumonia treated using TTFD as primary treatment (10mg IM <3 months old, 20mg IM <6 months, 20mg twice per day >6 months old)
283 out of 285 children with rectal prolapse cured by TTFD injection into “changqiang” acupoint (1988)
89 cases of rectal prolapse also treated with TTFD acupoint injection (1998)
50 cases of cerebral hypoplasia improved with acupoint injection of acetyl glutamine and TTFD (1983)
35 patients treated for hyperthyroidism with TTFD as adjunctive treatment (1999)
50 cases of costochondritis cured with Analgin + TTFD injection (1993)
13 children with ocular nerve palsy cured with TTFD (2010)
50 cases of urinary incontinence treated with acupoint injection of combination of acetyl glutamine, TTFD and/or r-aminobutyric acid (1990)
26 cases of delayed peripheral neuropathy due to organophosphate poisoning treated with acupuncture and TTFD injection (2001)
47 cases of lumbar disc protrusion treated with acupoint injection, B12 and TTFD (1994)
38 cases of facial neuritis treated with acupuncture and vitamins including TTFD injection (1999)
60 cases of migraine treated with Chinese medicine, flunarizine, and TTFD (2004)
24 cases of migraine treated with TTFD acupoint injection (1990)
40 patients with cerebrovascular disease addressed using acetyl glutamine and TTFD scalp acupoint injections (2001)
30 cases diabetic neuropathy, 75mg TTFD used as a control in– 60% effective (2002)
69 cases of Bell’s Palsy, TTFD used with acyclovir (1999)
120 cases of Bell’s Palsy treated with oral TTFD, methylb12, and/or electroacupuncture and facial muscle exercise (2019)
65 cases of Meniere’s Diseases treated with TCM, vitamins including TTFD injections
118 cases of herpes zoster treated with TTFD in conjunction with acyclovir and traditional Chinese medicine (2013).
100 cases of senile deafness treated with cocktail including TTFD (2000)
36 cases of cervical spondylotic radiculopathy treated with control of TTFD and naproxen – 75% effective (2009)
60 cases of postherpetic neuralgia treated with cocktail including TTFD
1 case of polerarteritis nodosa w/peripheral neuritis treated with cocktail including TTFD
1 case of central paralytic dysphagia (tuberculosis meningitis) unresponsive to conventional treatment cured by injection of TTFD at meridian acupoint (1974)
1 case of drug-induced diplopia treated with methyl B12 and TTFD
Baker and colleagues found that orally administered TTFD was equivalent to intravenous administration of thiamine HCL at increase RBC, WBS and cerebrospinal fluid levels of thiamine activity.
They concluded:
“Orally administered allithiamine vitamers are recommended for prophylaxis and treatment of thiamine deficits because they have the same biological properties as parenterally administered water-soluble thiamines.”
Another study compared IV TTFD vs thiamine HCL. They also showed that when 100mg+ was administered, it was superior to ordinary thiamine at increasing thiamine phosphate esters in the brain.
Many studies have demonstrated of superiority of oral TTFD over thiamine salts (HCL and mononitrate) for addressing deficiency and increasing thiamine content in tissues. Since this is well established, I will not review the evidence here. Instead, we will focus on the claim that there is “no benefit” from taking TTFD over benfotiamine.
CLAIM #2 No benefit to using TTFD over Benfotiamine?
Both TTFD and Benfotiamine are derivatives with much greater bioavailability than other forms of thiamine. I personally favour and am biased towards TTFD, mainly because I have found it to be more effective clinically at addressing thiamine-responsive conditions. However, there are many people who either do not tolerate TTFD, are non-responsive, or who prefer benfotiamine and respond better to this derivative.
At this point, it is uncertain which form is superior. What we do know is that each form has different pharmacokinetics (breakdown), and likely have different mechanisms of action aside from delivering thiamine in high quantities to the cell.
Both forms have very high bioavailability, although some research suggests that benfotiamine may be absorbed at a faster rate (with some studies showing greater bioavailability across the board). One older study showed greater absorption of benfotiamine and increased free thiamine content in red blood cells compared with TTFD in the short-term, although the levels equalized at 10 hours. Alternatively, a different study showed that TTFD had greater bioavailability than benfotiamine in red blood cells.
A more recent analysis in 2013 showed that both forms were absorbed at a similar rate. Benfotiamine produced a much greater increase in plasma TPP (which is to be expected, considering its pharmacokinetics). On the other hand, TTFD produced greater increases of thiamine and TPP in red blood cells. The pharmacokinetic studies on urinary excretion of TTFD metabolites indicate almost 100% absorption. Overall, its clear that both form are readily capable of increasing thiamine levels in comparison with ordinary thiamine salts.
Another point of discussion is whether or not benfotiamine can increase levels in the brain. The data on this has produced mixed results. One study showed that benfotiamine did not influence brain levels, along with a different report which showed no change in TPP levels. On the other hand, another study showed that high doses of benfotiamine did increase TPP levels in the brain after 30 days. Benfotiamine also outperformed TTFD at increasing thiamine levels in the brain in another trial and demonstrated higher bioavailability. It was also effective at reducing amyloid deposition in the brain, whereas TTFD was not. I am convinced that benfotiamine does indeed reach the brain.
Likewise, TTFD also penetrates the brain. Real-time PET imaging in both animals and humans demonstrated that TTFD rapidly enters the brain and spinal cord, along with many other organs. The thiamine transferred to the brain also increases active TPP. It therefore appears that BOTH make their way to the brain.
Why the difference in clinical response?
The major differences may not actually relate to replenishment of thiamine (which both appear to do very well), but rather be due to non-coenzyme roles and secondary effects. Independent of its ability to generate the TPP coenzyme, benfotiamine has been shown to possess numerous antioxidant, anti-inflammatory, and cell-signalling roles. Benfotiamine has been more extensively studied in the West and many of the mechanisms have been laid out quite well.
In contrast, TTFD has not been studied as much outside of Japan and China, and its non-coenzyme or pharmacological effects have been less well characterised. Based on the available evidence, it does indeed seem to have some unique qualities which differentiate it from benfotiamine.
For example, novel effects of TTFD in high doses on the brain have been studied by a group out of Japan led by Toshiaki Hata over the past four years. They originally showed increased voluntary activity (in endurance tests) and increased release of dopamine in the cortex, hypothalamus and brainstem.
In 2018, identified increased D1-receptor-mediated dopaminergic activity in the medial-prefrontal cortex. The same group later showed increased dopaminergic acivity in the ventral lateral side of the ventral tegmental area in the brain which also accompanied increased voluntary activity in 2019. In the most recent analysis, they found increased activation of noradrenergic and serotonergic neurons in conjunction with dopaminergic activity.
TTFD stimulates gastric secretions and intestinal motility in humans via activating neurons in the enteric nervous system. There have been several studies showing improved peristalsis from administration of this compound either orally or injected. In contrast, benfotiamine has no such effect.
TTFD has a particular affinity for the heart, and has been shown to maintain intracellular concentrations of potassium in the atria in the event of cardiotoxicity. When checked against 11 other forms, TTFD was the only derivative to protect against cardiac arrhythmia.
TTFD also protected heart muscle against strophanthin G toxicity, whilst ordinary thiamine did not. Atrial toxicity by N-ethylmaleimide was also prevented by TTFD.
The authors explained
“it was revealed that the protective effect of TTFD on the atrial toxicity of NEM is not due to the thiamine derived from TTFD transferred to the tissue, but to the alkyl mercaptan body”
Another study showed cardiac protection against metabolic inhibitors and toxins including meralluride, pentobarbital, dinitrophenol and cyanide, whereas other derivatives included benfotiamine were not protective. Like the previous report, the authors concluded that "the S-S bond of thiamine alkyldisulfides is indispensable for the production of the positive inotropic action”.
In other words, the protective effect is thought to be precisely BECAUSE of the mercaptan group which is not present in other thiamine derivatives/forms. This suggests, rather than being a “toxin”, the mercaptan may have useful antioxidant and/or anti-inflammatory properties.
Interestingly, TTFD in a high dose (40mg/kg) is said to have provided mice with significant protection against radiation. Likewise, TTFD has also been studied in China for its protective effects against radiation.
Thiamine propyldisulfide (very similar molecule to TTFD) was shown to protect against cyanide poisoning, whereas benfotiamine was not. This was due to activation of the rhodnase enzyme in the liver.
Oral TTFD was the only derivative capable of suppressing dermal connective tissue permeability. TTFD and other disulfide derivatives were also found reduce inflammation and tissue permeability caused by various chemicals including chymotrypsin and acetic acid. TTFD was the only derivative capable of reducing rat paw edema when injected intraperitoneally, whereas other forms including benfotiamine were ineffective.
Another anti-inflammatory action of TTFD is the ability to block activation of the arachidonic acid cascade, reduce numerous proinflammatory mediators and reduce abnormal coronary blood flow.
More recent evidence also shows interesting antioxidant effects, such as preventing drug-induced otoxocity by reducing accumulation of reactive oxygen species and preventing cell death. In the eye, TTFD was demonstrated to modulate metabolism under inflammatory and hypoxic condition to reduce the inflammation and maintain mitochondrial function.
To round thing up, it is quite clear that TTFD is not toxic. Although this does nothing to explain the fact that some people are “intolerant” to TTFD. In my experience, perhaps 10-20% of people do not feel well when taking TTFD and respond to other forms of thiamine much better.
Metabolism of TTFD & possible reasons for poor tolerance
The initial studies performed in the late 1960s identified liver mono-oxygenase enzymes (unknown at the time) responsible for catalysing the breakdown of the MTHFS/MTHFSO through a set of reactions involving sulfoxidation.
The metabolism of TTFD proceeds like this:
Disulfide exchange to break apart the molecule, releasing thiamine, with the use of either glutathione, cysteine, or hemoglobin.
The product is methylated (using S-adenosyl methionine) to form Methyltetrahydrofurfurylsulfide (MTHFS)
MTHFS undergoes sulfoxidation by *unknown* enzymes in the liver and is converted into MTHF-sulfoxide and MTHF-sulfone
Although the exact identity of those enzymes have not been investigated since (to my knowledge), some key characteristics which might provide some insight into the enzyme’s identity:
The enzyme was activated/induced by phenobarbital 2-fold
The enzyme was responsible for catalyzing the conversion of a sulfide to a sulfoxide, and further to a sulfone
The enzyme uses NADPH and oxygen
The enzyme is presumably also capable of metabolizing the tetrahydrofuran ring of TFD
In searching through the literature in my attempt to identify the enzyme (or group of enzymes) responsible, I have come to the conclusion that it is not a flavin mono-oxygenase enzyme (because phenobarbital has no inducing effect on FMO), and therefore it likely belongs the CYP450 family of enzymes.
CYP450
Similar organosulfur compounds to TTFD are also found in garlic (sulfides and disulfides). These compounds are metabolized mostly in the liver CYP450 enzymes. Interestingly, the step-by-step breakdown of garlic compounds is very similar to that which was described for the breakdown of TTFD:
Reduction (via disulfide exchange)
Methylation (via SAM-e)
Sulfoxidation (Sulfide converted to Sulfoxide converted to Sulfone)
Conjugation with glutathione
As you can see above, the CYP enzyme primarily responsible for sulfoxidation of these kinds of organosulfur compounds is called CYP2E1.
Could this be the same enzyme responsible for metabolising TTFD?
CYP2E1 is induced 1.7 fold with phenobarbital, which is very similar to the 2-fold induction found in the original study on TTFD. Tetrahydrofuran, the chemical ring of the TFD molecule, is ALSO metabolized by CYP2E1.
With the above considered, I think it is highly possible that the unidentified enzyme responsible for breaking down the TFD mercaptan to its respective sulfoxide and sulfone metabolites is actually CYP2E1.
With that in mind, we can speculate that genetic polymorphisms on genes encoding this enzyme could theoretically alter processing ability. Either increased or decreased enzyme activity might result in a “backlog” of unmetabolized compounds or intermediates, which may help to explain why some people experience “sulfur” type symptoms and others do not, even at high doses. This also potentially applies to garlic and other sulfur-containing vegetables.
Even outside of the context of genetic polymorphisms, other inhibitors of the CYP enzymes could slow down clearance of substrate and potentially produce a “backlog”. This may be why some individuals do well with liver/detoxification supporting nutrients and supplements.
Glutathione status
In an article I wrote in 2020 on paradoxical reactions with TTFD, I hypothesized that some people’s intolerance to this molecule may relate to poor glutathione recycling capacity.
The disulfide bond of TTFD (and sulbutiamine) must be chemically reduced using a reducing agent. In vivo, this is achieved either by glutathione, free cysteine, or hemoglobin. This was demonstrated in numerous studies, with one showing a rapid decrease in red blood cell GSH (reduced glutathione). That same study showed that the GSH was regenerated 5-10 MINUTES. Naturally, some people have interpreted this to mean that TTFD “depletes” glutathione in everyone.
However, based on the above logic, sulbutiamine (another disulfide thiamine derivative) should also theoretically deplete glutathione because of its disulfide bond. Except it doesn’t:
Sulbutiamine was shown INCREASE reduced glutathione concentrations and glutathione-S-transferase activity, protect against oxidative stress and cell death. This finding was replicated in a different study, also showing increased antioxidant protection via activation of Nrf-2, resulting in upregulation of total catalase and GSH.
Some authors predict that sulbutaimine’s neuroprotective and antoxidant roles may stem specifically from its bound sulfur content, including the disulfide bond, which is also present on the TTFD molecule.
We know that TTFD has antioxidant and anti-inflammatory roles similar to sulbutiamine. It is therefore highly unlikely that TTFD has a “depleting” effect on the total pool of glutathione, or even reduced glutathione in most people. Rather, the effect probably only applies to a sub-population.
With that said, glutathione conjugation and clearance of organosulfur compounds is likely involved in the clearance of TTFD metabolites. Furthermore, it is still possible that if someone has an extremely poor capacity for glutathione recycling, it could theoretically influence their ability to clear TTFD.
Secondly, like with other organosulfur compounds, conjugation with glutathione may also be necessary to actually carry them out of the body. This means that for some people could benefit from enhancing the glutathione system if they find that they are intolerant of TTFD. From a clinical perspective, I have seen this work in some cases.
Sulfoxidation & sulfite
The initial breakdown product of TTFD (MTHFS) is quite similar to other sulfide organosulfur compounds found in allium vegetables (dipropenyl sulfide and diallyl disulfide). Some of these compounds are hydrogen sulfide donors (a vasoactive gas with both anti-inflammatory and pro-inflammatory roles), and can also induce a mitochondrial enzyme called sulfide:quinone reductase (SQR).
Hydrogen sulfide is broken down by the SQR enzyme and following several steps, can eventually yield inorganic sulfate. An intermediary in the pathway is sulfite, which is considered quite toxic. Sulfite can be detoxified through a molybdenum-dependent enzyme called sulfite oxidase to produce non-toxic inorganic sulfate. Additionally, another breakdown product of TTFD is a sulfone. Sulfones can be transformed into sulfur dioxide, which may also readily convert to sulfite.
People who ordinarily have sensitivities to organosulfur compounds tend to respond well to molybdenum supplementation, likely through enhancing sulfite-oxidase activity to clear excess sulfite. Part of the reason for unwanted symptoms with TTFD may therefore relate to a build-up of sulfite and difficulty breaking it down. Clinically, I have seen numerous individuals gain tolerance of TTFD only after adding in 500-1000mcg of molybdenum supplementation, which I believe is due to enhancing the clearance of sulfite.
There will also always be a very minute percentage of people who also display a genuine allergy/anaphylactic reaction to TTFD, which is also the case with thiamine HCL. Of course, anyone who takes thiamine should be aware of that possibility.
It is also possible that the extra molecule excreted via the urine are conjugated with either glutathione or through glucuronidation.
It is worth noting that some of the breakdown metabolites of organosulfur compounds are considered therapeutically relevant. Their ability to enhance the endogenous antioxidant system and donate sulfur in the liver are considered to be mechanisms of protection. However, context is always important and some people do not do well with these dietary compounds for whatever reason.
As Lonsdale, Marrs, and myself have explained elsewhere: intolerance can sometimes simply be the initial “paradoxical” reaction which subsides after a short while of using a low dose. Symptoms can also be related to increased demand for other B vitamins, electrolytes, and perhaps even other minerals.
As a final note, I believe it is possible that someone with a high burden of heavy metals may also react negatively to taking TTFD. In my experience this is a small percentage of people, but they exist nonetheless. And that brings us to the final claim…
Claim 3: TTFD does not increase heavy metal excretion
The last of Cutler’s claims I would like to address is that TTFD does not increase heavy metal excretion.
Because the TFD mercaptan group is a single thiol, and not a dithiol, Cutler believed it would not promote the excretion of heavy metals. He criticized the design/validity of the results of Dr Derrick Lonsdale’s studies which demonstrated increased excretion, so for the purpose of this article I will not include those studies.
To counter Cutlers position, here are at least 10 other studies showing increased heavy metal excretion with TTFD and disulfide derivatives:
The Effects of Thiamin Tetrahydrofurfuryl Disulfide on Detoxification of Organic Mercury in Rats Rats were injected with methylmercury for 7 days. Some of that group were later injected with TTFD for 7-21 days. The effect of TTFD was compared with D-penicillamine and the dithiol Dimercaprol (both of which can mobilize, albeit much less effective than DMSA/DMPS). They found that TTFD reduced total content of mercury in the brain, kidney, lung, heart and liver. In the liver TTFD was more effective than the other medications, but in the other organs it was less effective.
Acceleration of Mercury Excretion in Human by Administration of Thiamin Tetrahydrofurfuryl Disulfide (TTFD) Oral administration of TTFD was compared with Benfotiamine. The TTFD group showed significant increases in mercury in the hair, whereas no such increase was shown in the benfotiamine group. They concluded that enhanced hair excretion of mercury was due to the TFD mercaptan side chain of the TTFD molecule.
About the action of 1-I-11 Thiamine propyldisulfide (TPD) to promote the excretion of methylmercury in the body: Abstract of the 35th Annual Meeting of the General Research Meeting: Japanese Society of Vitamin Society Thiamine propyl disulfide (structurally very similar to TTFD) was investigated for mercury removal effects. A control group of mice were injected with mercury chloride, some were given TPD and others were given penicillamine. The survival rate was much higher in the TPD-treated group, showing higher excretion of mercury and less accumulation in the organs.
Methylmercury removal effect of TPD and TTFD: Summary of research presentation at the 278th meeting of the Vitamin B Research Committee Two experiments were performed. The first compared thiamine propyldisulfide (TPD) with penicillamine against a control group, and all groups were injected with methylmercury. Survival rate was 44% in the controls, 75% in the penicillamine group and 88% in the TPD group. A second experiment used also used TTFD, and similar effects were found. Adverse events were significantly lower in the TPD/TTFD groups with less mercury deposition in the brain, pancreas, liver, and kidney.
The effect of thiamine tetrahydrofurfuryl disulfide on promoting mercury excretion: Vitamin B Research Committee 280th Conference Abstract of the research presentation 10 participants were administered 50mg TTFD before bed each day. Urinary mercury concentration was measured and compared with prior urine results for these same individuals. In 9 out of 10 subjects, there was a statistically significant increase in urinary excretion of mercury. Furthermore, they found no change in the excretion of other minerals such as sodium, potassium, calcium, magnesium, or iron.
Effect of Thiamine propyl disulfide on lead poisoning (Summary of research presentation at the 95th Council) Two groups of mice were studied after 6 days of intravenous administration with lead. One group was given TPD daily, and urine/faeces was measured for the next 36 days. Total urinary excretion of lead in the TPD-treated group was significantly higher than the control. Lead-content in all organs was also reduced. A similar study was performed in rabbits, but instead they administered TPD BEFORE loading animals with lead. They found no change in excretion between the TPD treated group and controls.
A research group at the College of Pharmacy in Seoul, Korea performed multiple studies on TTFD and lead intoxication throughout the 1990s and found very interesting results:
Elimination of Lead by TTFD and TPD from Central Nervous System of Postnatally Lead-exposed Rats Within 1 day of parturition, experimental rat mothers nursing their pups as well as the pups were given drinking water containing 0.2% lead acetate. Groups were further divided and administered either TTFD, TPD, or penicillamine. Animals were sacrificed at 2 or 8 weeks and five regions of the brain were analysed. The rats administered TTFD and TPD had significantly lower levels of lead in every region of brain compared with the lead-treated group, and the effect was equivalent to penicillamine (an effective chelator of lead).
Thiamine deficiency as one of the mechanisms for neurotoxicity induced by lead intoxication in rats. One group of rats was administered with lead, whilst another was administered TTFD + lead. The lead group had much higher levels of lead in the brain compared with controls, and also had lower thiamine content in the brain and significant reduction in transketolase enzyme activity. Furthermore, this group showed changes in brain phospholipid content and myelin protein, and had reduced electro-shock seizure threshold. All of these effects were reversed in the TTFD + lead group. TTFD reduced brain lead concentration below the control group, normalized thiamine content and transketolase activity, normalized protein/phospholipid content and normalized seizure potential. The authors concluded: “The results from the present study may indicate that neurotoxicity of lead in rats may be mediated at least in part through the changes of thiamine status.”
Effect of Lead Intoxication on Thiamine Content and Transketolase Activity in the Brain of Rats Another study looked at the effect of lead intoxication on thiamine content and thiamine activity in several regions of the brain. Once again, they showed that lead impaired thiamine activity (tranketolase) and reduced thiamine content. They also showed that TTFD reverse brain lead accumulation, restored thiamine content and transketolase activity back to normal.
Thiamine Effects on Electroshock Seizure Threshold of Lead-exposed Rats This study reproduced all previous findings published by this group. Co-administration with TTFD reduced organ lead content, restore thiamine activity, and increased seizure threshold.
To summarise, TTFD does indeed appear to influence heavy metal (mercury and lead) accumulation and excretion despite it not being a dithiol. But just so that I am clear, I DO NOT recommend relying on TTFD as a heavy metal mobilizer or chelator. If someone has serious heavy metal toxicity, there are numerous other well-established ways to support and enhance clearance in a safe way. Rather, I have presented the evidence to demonstrate that Cutler’s statements on this topic were factually inaccurate.
Conclusion
This article presents evidence to support the following conclusions:
TTFD is not toxic at therapeutic doses. This is support by in vitro, animal, and human studies. The molecule has been in use for over half a century and is used extensively in medical practice in Eastern countries. No safety concerns or claims of toxicity have been raised, apart from those made by Cutler.
TTFD does have unique benefits which are not shared by other forms including benfotiamine. Just like benfotiamine also has benefits which are not found with TTFD. For this reason, some people will benefit from one form and other will benefit from a different form. I regularly see people who were only responsive to TTFD, only responsive to benfotiamine, or even only responsive to thiamine HCL! Response to therapy is highly individual.
TTFD was shown to influence heavy metal retention and excretion. This does not mean it that it is anywhere near as effective as DMSA, DMPS or EDTA. It also doesn’t mean that one should use TTFD solely for its effect on heavy metals, since there are more efficient ways of dealing with heavy metal toxicity.
TTFD is a safe and non-toxic means of increasing thiamine status. However, some people do not tolerate it very well for various reasons. Sometimes this can be improved, whereas in some cases it can’t. In my experience, this form is excellent for most people, but there will always be some who are sensitive to certain supplements. Sensitivity or intolerance does not equate to a supplement being a genuine toxin, like Cutler has claimed.
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