Compilation of scientific research on TTFD (Thiamine Tetrahydrofurfuryl Disulfide)

Below is a compilation of case reports and scientific studies published on thiamine tetrahydrofurfuryl disulfide (TTFD), the main ingredient in Thiamax. Many of these papers were originally published in Japan and China, and were never translated into English so are not widely available. For this reason, we decided to compile as many as we could gain access to:

Wernicke encephalopathy

Dopamine release 

Ears/ Deafness

  • 267 cases of sudden-onset deafness was treated with 150mg TTFD orally, with most therapeutic effect seen after 2-3 months of treatment (1964)
  • 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. (1963)
  • 65 cases of Meniere’s Diseases treated with TCM, vitamins including TTFD injections
  • 100 cases of senile deafness treated with cocktail including TTFD (2000)

Migraine

  • 60 cases of migraine treated with Chinese medicine, flunarizine, and TTFD (2004)
  • 24 cases of migraine treated with TTFD acupoint injection (1990)

Other brain conditions

Digestive motility

Neuropathic Beriberi

  • 194 cases of infantile beriberi cured with IM/IV thiamine and TTFD (1987)
  • 35 cases of infantile beriberi cured TTFD (2010)
  • Beriberi treated with 150mg IV one week, followed by 100mg oral long-term (2014)
  • 70 children with infantile beriberi cured with intravenous TTFD (1990)
  • Diuretics-induced beriberi polyneuropathy: a case report 100mg TTFD (2022)
  • 44 polyneuropathy patients treated with 50mg TTFD injection, no adverse effects reported (1990)

Other neuropathy

Cardiovascular Beriberi

Cardio-metabolic

Other conditions

Fatigue

 

Antioxidant and anti-inflammatory 

 

Heavy metal excretion 

  • The Effects of Thiamin Tetrahydrofurfuryl Disulfide on Detoxification of Organic Mercury in Rats (1992) 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) (1990) 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.
  • Methylmercury removal effect of TPD and TTFD: Summary of research presentation at the 278th meeting of the Vitamin B Research Committee (1984) 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 (1984) 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.
  • Elimination of Lead by TTFD and TPD from Central Nervous System of Postnatally Lead-exposed Rats (1992) 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 (1995) 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 (1995) 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 (1998) 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

 

Metabolism of TTFD 

Toxicity/teratogenicity studies 

  • Peer-reviewed study The Effects of Thiamine Tetrahydrofurfuryl Disulfide on Physiological Adaption and Exercise Performance Improvement” (2018) showed that the human dose equivalent of 2,800mg per day for 6 weeks produced no changes in liver function, histology, or any other biomarker associated with toxicity. The authors concluded that high-doses of TTFD are safe.
  • Research performed on the reproductive effects of TTFD (1972) in monkeys showed that massive doses of 500mg/kg for several months (a dose close to the estimated LD50), found no deaths. The human dose-equivalent would be 10,000-11,000mg per day. The same study also examined rabbits, and found no significant increase in incidence of fetal malformations or evidence of teratogenicity.
  • 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 (70Kg) 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 (1972). Intraperitoneal administration of 1000mg/kg also showed no sign of chromosome aberration, damage to sex organs or spermatogenesis (1971).
  • 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 (1976)

 

Toxicity of TTFD metabolites 

  • 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.
  • 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
  • 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
  • 4-Hydroxy-5-(methylsulfonyl) valeric acid
    Intravenous LD50 in mice: 1.5 grams/kg body weight
    LD50 estimate for a 70KG human: 3 grams intravenously
  • 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 (1971). 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 with pre-existing or induced hepatotoxicity, TTFD can may be metabolised slightly differently.

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).

 

*These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure or prevent any disease.

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