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 – Oral 50mg mild improvement, three days I.V 1000mg, then 100mg thereafter (2020) (link here)
- Wernicke encephalopathy in hemodialysis – 100mg/iv, later oral continued for 2 months until improvement (2009)
- A case of Wernicke's encephalopathy with severe cardiac sympathetic dysfunction – 100mg (2012)
- Postoperative W.E treated with 100mg IV TTFD (1998)
- Mitochondria rescue formula recommended for acute encephalopathy: including TTFD 100mg (2019)
- TTFD (100mg) used to treat encephalopathy w/ hyperammonemia (2003)
- Pediatric acute encephalopathy neuroprotection protocol – cocktail including 200mg TTFD in 15 children (2013)
- 10 cases of cerebral beriberi and basal ganglia damage treated with TTFD injections (2003)
- 200mg TTFD used in 31 children for childhood acute encephalopathy (part of protocol) (2014)
- 50 cases of cerebral hypoplasia improved with acupoint injection of acetyl glutamine and TTFD (1983)
- W.E/beriberi after intestinal resection - 150mg IV three days, 75mg long-term (2018)
- 48 cases of infantile cerebral beriberi (0-3 years old) treated with TTFD (1997)
- Two cases of Beriberi mimicking Guillain-Barré syndrome – IV TTFD 100mg resolved this (2008)
- 10 cases of infantile cerebral beriberi cured with B1 HCL and TTFD (1980)
- W.E/Shoshin beriberi - 150mg/IV, 75mg oral long-term (2013)
- Chemotherapy induced W.E – IV thiamine HCL followed by TTFD 75mg long-term (2008)
- TTFD used in a case of alcoholic Wernicke encephalopathy with lesions in cranial nerve nuclei (2022)
- TTFD increased dopamine release in the cortex, hypothalamus and brainstrem. (2018)
- TTFD increased D1-receptor-mediated dopaminergic activity in the medial-prefrontal cortex (2018).
- TTFD increased dopaminergic activity in the ventral lateral side of the ventral tegmental area in the brain and was also accompanied increased voluntary activity (2019) .
- TTFD activation of noradrenergic and serotonergic neurons in conjunction with dopaminergic activity.
- 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)
- 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
- 75mg TTFD improved cerebral blood flow in deficiency (2012)
- Subacute spinal degeneration caused by B12 deficiency treated with B12 and 75mg TTFD long-term (2020)
- 47 cases of lumbar disc protrusion treated with acupoint injection, B12 and TTFD (1994)
- 1 case of drug-induced diplopia (vision) treated with methyl B12 and TTFD (2021)
- 40 patients with cerebrovascular disease addressed using acetyl glutamine and TTFD scalp acupoint injections (2001)
- TTFD used to address brainstem dysfunction (1982)
- TTFD studied in brainstem potentials (1979)
- 21 patients subacute necrotizing encephalomyelopathy treated with thiamine derivatives TPD/TTFD (1973)
- 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, one experienced worsening of behavior/symptoms, two experienced rash (2002)
- Guillain Barre Syndrome treated with TTFD and vitamin B12 (2022) (link here)
- Severe gastroparesis and constipation due to post-gastrectomy thiamine deficiency was resolved after three days of intravenous TTFD (100mg) followed by a daily oral dose of 75mg.
- TTFD stimulated gastric secretions and intestinal motility (1964)
- Intravenous administration of TTFD induced a slight increase in tone and a “remarkable increase” in the amplitude of rhythmic contractions of the small intestine for twenty minutes. Furthermore, TTFD applied topically inside lumen of the intestine also elicited excitation.
- TTFD stimulated enteric neurones and enhanced intestinal motility in isolate intestines
- Motility was increased in two other studies here and here
- TTFD was the only form of thiamine which could counteract anti-cholinergic intestinal relaxants (atropine and paparavine) to restore gut motility
- 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)
- Malabsorption of thiamine and subsequent deficiency in chemotherapy patients, which did not respond to thiamine HCL, was treated with TTFD (50mg) (1969)
- 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)
- 13 children with ocular nerve palsy cured with TTFD (2010)
- 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)
- 36 cases of cervical spondylotic radiculopathy treated with control of TTFD and naproxen – 75% effective (2009)
- 1 case of polerarteritis nodosa w/peripheral neuritis treated with cocktail including TTFD (2017)
- 1 case of central paralytic dysphagia (tuberculosis meningitis) unresponsive to conventional treatment cured by injection of TTFD at meridian acupoint (1974)
- 60 cases of postherpetic neuralgia treated with cocktail including TTFD (2012)
- 30 cases diabetic neuropathy, 75mg TTFD used as a control in– 60% effective (2002)
- 26 cases of delayed peripheral neuropathy due to organophosphate poisoning treated with acupuncture and TTFD injection (2001)
- 38 cases of facial neuritis treated with acupuncture and vitamins including TTFD injection (1999)
- Beriberi neuropathy and shoshin beriberi that developed 6 years after gastrectomy on the cardia side – 100mg TTFD longterm (2013)
- 18 patients with non-diabetic peripheral neuropathy 1-3 months, no serious side effects (1964)
- TTFD effective for “so-called neuralgia” in multi-centre, double-blind placebo-controlled trial (1983)
- 50 infants treated with TTFD for cardiac beriberi (1997)
- Beriberi w/ pulmonary hypotension - 50mg long-term (2019)
- 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)
- Cardiac failure 100mg IV (1987)
- Heart and circulatory failure (2008)
- TTFD administered to 15 year old boy to treat beriberi, remained on the therapy long-term (2012)
- Shoshin beriberi – IV TTFD 150mg for 11 days, indefinite oral dose 150mg TTFD long-term (2005)
- 50mg TTFD used to treat edema and weight gain and marginal thiamine deficiency – authors recommend TTFD instead of thiamine HCL (2021)
- Cardiac Beriberi with pulmonary hypertension & shock – 50mg TTFD long-term (2022)
- A case of Shoshin beriberi with acute right heart failure and acute renal failure – 200mg TTFD (2021)
- Successful Resuscitation of Cardiac Arrest After Refeeding Syndrome Associated with Hiatal Hernia, 1500mg for two days, followed by 1000mg (IV) for 3 days. 100mg orally was then continued (2022)
- Alcoholic rhabdymylosis – treated with 200mg TTFD (2021)
- 75mg TTFD used in mitochondrial myopathy long-term (2000)
- Biguanide-induced lactic acidosis treated with 100mg, then 300mg TTFD (2017)
- Diabetic lactic acidosis – 100mg/day IV for 7 days resolution in symptoms, followed by 75mg indefinitely (2008)
- Lactic acidosis caused by low-dose metformin: Thiamine HCL 100mg followed by 75mg TTFD long-term, normalization of all liver values (2014)
- 6 infants (0-1 yrs old) treated with TTFD for childhood congenital lactic acidosis (2005). Children responsive were kept on high doses permanently with no adverse effects.
- Cardiomyopathy associated with mitochondrial disease that developed heart failure, treated with 100mg long (2017)
- 35 patients treated for hyperthyroidism with TTFD as adjunctive treatment (1999)
- 50 cases of costochondritis cured with Analgin + TTFD injection (1993)
- 50 cases of urinary incontinence treated with acupoint injection of combination of acetyl glutamine, TTFD and/or r-aminobutyric acid (1990)
- 118 cases of herpes zoster treated with TTFD in conjunction with acyclovir and traditional Chinese medicine (2013).
- 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) (2001)
- Thiamine deficiency in hemodialysis patient treated with 100mg TTFD injections (2022)
- Anti-stress properties: 100mg reduced plasma levels of neuropeptide-Y, thought to be involved in the stress response (2012)
- TTFD promoted recovery from post-viral fatigue in animal model (2009)
- Abnormal levels of thiamine metabolites were found in an animal model of chronic fatigue. TTFD administration normalized fatigue by increasing energy expenditure (2004)
- The Effects of Thiamine Tetrahydrofurfuryl Disulfide on Physiological Adaption and Exercise Performance Improvement - TTFD supplementation signiﬁcantly increased the endurance and grip strength and demonstratedbeneﬁcial effects on lactate production and clearance rate after an acute exercise challenge. (2018)
- Improved fatigue in high-temperature workers (at doses 25mg and 50mg) (1971)
- Thiamine tetrahydrofurfuryl disulfide improves energy metabolism and physical performance during physical-fatigue loading in rats (2009)
Antioxidant and anti-inflammatory
- TTFD prevented drug-induced otoxocity by reducing accumulation of reactive oxygen species and preventing cell death (2021)
- In the eye, TTFD was demonstrated to modulate metabolism under inflammatory and hypoxic condition to reduce the inflammation and maintain mitochondrial function (2020)
- Fursultiamine, a vitamin B1 derivative, enhances chondroprotective effects of glucosamine hydrochloride and chondroitin sulfate in rabbit experimental osteoarthritis (2005)
- Protection against cardiac arrhythmia by maintaining intracellular potassium concentrations been shown (1971)
- When checked against 11 other forms, TTFD was the only derivative to protect against cardiac arrhythmia (1971)
- TTFD also protected heart muscle against strophanthin G toxicity, whilst ordinary thiamine did not. (1973)
- Atrial toxicity by N-ethylmaleimide was also prevented by TTFD. (1979)
- TTFD studied in China for its protective effects against radiation poisoning (2020)
- Oral TTFD capable of suppressing dermal connective tissue permeability (1969)
- TTFD and other disulfide derivatives were also found reduce inflammation and tissue permeability caused by various chemicals including chymotrypsin and acetic acid (1967)
- TTFD blocked activation of the arachidonic acid cascade, reduce numerous proinflammatory mediators and reduce abnormal coronary blood flow (1985)
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
- The metabolic fate of methyl tetrahydrofurfuryl sulfide and its related compounds in rats (1970)
- Enzymatic Studies on the Metabolism of the Tetrahydrofurfuryl Mercaptan Moiety of Thiamine Tetrahydrofurfuryl Disulfide Microsomal S-Transmethylase (1973)
- Enzymatic Studies on the Metabolism of the Tetrahydrofurfuryl Mercaptan Moiety of Thiamine Tetrahydrofurfuryl Disulfide: II. Sulfide and Sulfoxide Oxygenases in Microsomes (1973)
- Enzymatic Studies on the Metabolism of the Tetrahydrofurfuryl Mercaptan Moiety of Thiamine Tetrahydrofurfuryl Disulfide: III. Oxidative Cleavage of the Tetrahydrofuran Moiety (1973)
- Enzymatic Studies on the Metabolism of the Tetrahydrofurfuryl Mercaptan Moiety of Thiamine Tetrahydrofurfuryl Disulfide: IV. Induction of Microsomal S-Transmethylase, and Sulfide and Sulfoxide Oxygenases in the Drug-treated Rat (1973)
- TTFD is “broken apart” via disulphide exchange inside the cell (1975)
- Disulfide exchange may occur with glutathione, cysteine or haemoglobin (1968)
- PET imaging of 11C-labeled thiamine tetrahydrofurfuryl disulfide, vitamin B1 derivative: First-in-human study (2021) After administration, TTFD was high in the liver, kidney, urinary bladder, heart, spine, brain, spleen, pancreas, stomach, salivary and pituitary glands. Accumulation in tissue and activation into thiamine pyrophosphate was greater than ordinary thiamine salts.
- VB1 Derivative Fursultiamine Hydrochloride, Assessment of Brain Penetration after Intravenous Administration (2011)
- Rapid penetration into red blood cells (1992)
- High red blood cell penetration and conversion into active thiamine pyrophosphate (2016)
- Comparative metabolic studies have found that the metabolism of TTFD is almost identical in both mammals and humans, demonstrating that animal studies hold value (1970)
- 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
- 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.
- Inorganic sulfate: non-toxic
Intravenous LD50 in mice: In excess of 5 grams/kg body weight
LD50 estimate for a 70KG human: 28.5 grams intravenously
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).