Benfotiamine
1. Identity
Chemical Names and Classification
Benfotiamine (rINN, or S-benzoylthiamine O-monophosphate) is a synthetic, fat-soluble, S-acyl derivative of thiamine (vitamin B1). It is a synthetic S-acyl derivative of thiamine. Its systematic chemical name is S-benzoylthiamine O-monophosphate, and it is also identified by the CAS registry number 22457-89-2. Benfotiamine is a lipid derivative of thiamine, specifically a synthetic S-acyl Vitamin B1 analogue, and it has very low solubility in water or other aqueous solvents.
Among thiamine derivative types, allithiamine, TTFD, and SuBT are disulfides, while benfotiamine, dibenzoylthiamine (DBT), and S-benzoylthiamine (S-BT) are thioesters. This thioester classification is chemically significant, as it distinguishes benfotiamine's absorption and metabolism from those of the disulfide class of lipophilic thiamine analogues.
Natural Source and Relationship to Allithiamines
The first lipophilic thiamine derivative was isolated from garlic (Allium sativum) extracts in the early 1950s. It is an allyl disulfide derivative called allithiamine. Since then, several analogs of this molecule were synthesized with the hope that they would be better absorbed and have a higher bioavailability. Benfotiamine itself is not found naturally in foods; it is a fully synthetic compound. Benfotiamine is a synthetic thiamine analogue in a class of natural products referred to as allithiamines. Allithiamines are lipid-soluble molecules that are produced by plants from the Allium genus, in the garlic family.
Common Preparations and Dosage Forms
As of 2017, benfotiamine was marketed as a pharmaceutical drug in many countries under the following brand names: Benalgis, Benfogamma, Benforce, Benfotiamina, Biotamin, Biotowa, Milgamma, and Vilotram. It was also marketed in some jurisdictions as a combination drug with cyanocobalamin as Milgamma, in combination with pyridoxine as Milgamma, in combination with metformin as Benforce-M, and with thiamine as Vitafos.
It is approved in some countries as a medication or dietary supplement to treat diabetic sensorimotor polyneuropathy. It is marketed as a dietary supplement in the US and in China, and as a pharmaceutical drug in Ukraine, Russia, India, Korea, and Japan. In supplement form, benfotiamine is available primarily as oral capsules and tablets.
2. Historical and Traditional Use
Development in Japan
Although thiamine has been used to treat thiamine deficiency disorders due to its low bioavailability, several lipophilic thiamine derivatives were developed. The first lipophilic thiamine derivative was found in garlic and was named allithiamine for the Allium genus to which garlic belongs. Afterwards, several lipophilic analogs were synthesized, including fursultiamine, sulbutiamine, and benfotiamine. This work was mostly done in Japan in the 1950s and 1960s, because beriberi was a widespread health problem in Japan.
Benfotiamine was developed in the late 1950s in Japan. Starting with a compound developed in Japan in the 1960s to address vitamin deficiencies in the general population, researchers focused on benfotiamine — a precursor or "prodrug" of thiamine. First discovered in Japan in the 1950s, benfotiamine was patented for use in the United States in 1962 but was never marketed there at that time.
Use in Germany and Europe
The supplement has been widely used in Japan and Europe for decades, where it is well-tolerated with no reports of serious adverse events. Benfotiamine is primarily marketed as an over-the-counter drug to treat diabetic polyneuropathy. In Germany and other European countries, the compound was used clinically for alcoholic and diabetic neuropathy for several decades prior to its introduction as a dietary supplement in the United States. It was sold under the trade name Milgamma in Germany, often in combination with other B vitamins.
3. Key Constituents, Active Compounds, and Mechanisms of Action
Metabolic Conversion to Active Thiamine
Benfotiamine (S-benzoylthiamine O-monophosphate) is a synthetic S-acyl derivative of thiamine. Once absorbed, benfotiamine is dephosphorylated by ecto-alkaline phosphatase to lipid-soluble S-benzoylthiamine. Benfotiamine is dephosphorylated to S-benzoylthiamine by phosphatases present on the cell membrane. S-benzoylthiamine then enters the cell and is converted to thiamine by thioesterases. A portion of thiamine is further phosphorylated by thiamine pyrophosphokinase to TPP, which serves as coenzyme in glycolysis, the Krebs cycle, and the pentose phosphate cycle.
Superior Bioavailability
Benfotiamine is more bioavailable and has higher tissue penetration than thiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and thiamine diphosphate (TDP) in erythrocytes after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. Animal autoradiographic studies found that in muscle and brain tissue, a 5 to 25 fold higher amount of tracer incorporation was registered following benfotiamine as compared with thiamine application, whereas in all other organs the difference in the label was mostly between 10 and 25 fold.
The bioequivalence of thiamine in two therapeutically used preparations was tested in 10 healthy young men. Thiamine was orally administered either as lipophilic benfotiamine or as water-soluble thiamine mononitrate. Biokinetic data, measured as area under the curve and maximal concentration in plasma and hemolysate after ingestion, demonstrated a significantly improved bioavailability from the lipophilic derivative despite an ingested dose of only 40% as compared with the water-soluble salt. A superior cellular efficacy of benfotiamine was also concluded from the short-term stimulation of the thiamine-dependent transketolase activity in erythrocytes.
An important caveat on central nervous system penetration was established in animal research: though thiamine levels rapidly increased in blood and liver to reach a maximum after one or two hours following oral benfotiamine administration in mice, no significant increase was observed in the brain. This observation has shaped the debate over benfotiamine's utility in neurological conditions such as Alzheimer's disease, as discussed below.
Transketolase Activation and the AGE-Inhibition Mechanism
Transketolase is an enzyme that directs the precursors of advanced glycation end products (AGEs) to the pentose phosphate pathway. Benfotiamine administration increases the levels of intracellular thiamine diphosphate, a cofactor necessary for the activation of transketolase, resulting in the reduction of tissue levels of AGEs. The elevated level of AGEs has been implicated in the induction and progression of diabetes-associated complications.
The landmark mechanistic study by Hammes et al. (2003), published in Nature Medicine, clarified the multi-pathway scope of this action: three of the major biochemical pathways implicated in the pathogenesis of hyperglycemia-induced vascular damage — the hexosamine pathway, the advanced glycation end product (AGE) formation pathway, and the diacylglycerol (DAG)–protein kinase C (PKC) pathway — are activated by increased availability of the glycolytic metabolites glyceraldehyde-3-phosphate and fructose-6-phosphate. Benfotiamine can inhibit these three pathways, as well as hyperglycemia-associated NF-κB activation, by activating the pentose phosphate pathway enzyme transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars. In retinas of diabetic animals, benfotiamine treatment inhibited these three pathways and NF-κB activation by activating transketolase, and also prevented experimental diabetic retinopathy.
Antioxidant and Anti-inflammatory Properties
The thioester benfotiamine has been extensively studied and has beneficial effects both in rodent models of neurodegeneration and in human clinical studies. Benfotiamine has antioxidant and anti-inflammatory properties that seem to be mediated by a mechanism independent of the coenzyme function of thiamine diphosphate (ThDP). Studies have shown its antioxidant and anti-inflammatory potential in activated immune and glial cells.
Role of Thiamine Diphosphate (TPP) as Coenzyme
TPP is an essential cofactor for steps regulating glycolysis, the pentose phosphate cycle, and the Krebs cycle. These pathways are critical to cellular energy production. By substantially increasing intracellular TPP levels beyond what standard thiamine supplementation can achieve, benfotiamine amplifies the coenzyme availability for these metabolic processes.
4. Scientific Evidence by Area of Use
4.1 Diabetic Peripheral Neuropathy (DPN)
In patients with diabetes and diabetic sensorimotor polyneuropathy (DSPN), the efficacy and safety of benfotiamine have been investigated in four randomized, double-blind clinical trials. Their duration ranged from 3 to 12 weeks, and various daily dosages and endpoints were studied.
BEDIP Study (2005): The Benfotiamine in Diabetic Polyneuropathy (BEDIP) trial reported an improvement in neuropathic symptoms and signs at 3 weeks with the dose of 100 mg four times per day. The primary findings from this three-week, randomized, controlled pilot study were: a statistically significant (p = 0.0287) improvement in the neuropathy score was observed in the group given active drug when compared to the placebo-treated controls. There was no statistically significant change observed in the tuning fork test. The most pronounced effect on complaints was a decrease in pain (p = 0.0414). No side effects attributable to benfotiamine were observed. The differences between the groups cannot be attributed to a change in metabolic parameters since there were no significant alterations in HbA1 levels and blood sugar profiles.
BENDIP Study (2008): The Benfotiamine in Diabetic Polyneuropathy (BENDIP) trial showed a significant improvement of neuropathic symptoms at 6 weeks with a dosing scheme of 300 mg twice daily, but not 300 mg/day. This dose-dependency observation is noteworthy for establishing a minimum effective dose.
24-Month Type 1 Diabetes Trial (2012): Inclusion criteria were age 18 to 60 years, type 1 diabetes (>15-year duration), and normo- or microalbuminuria. The study was conducted as a parallel, randomized, double-blind, placebo-controlled prospective trial of 24-month duration. Patients in the active group were given 300 mg benfotiamine per day. Despite a marked improvement in thiamine status, long-term high-dose benfotiamine had no significant effect on peripheral nerve function or inflammatory markers in patients with type 1 diabetes. This negative result over a longer duration underlines the mixed nature of the clinical evidence.
BOND Study (2026): The most recent and comprehensive RCT — the Benfotiamine On morphometric, Neurophysiological and clinical measures in type 2 Diabetes patients (BOND) study — was a 1:1 randomized double-blind, placebo-controlled parallel group monocentric phase II trial that compared the efficacy and safety of 1-year treatment with benfotiamine 300 mg two times per day versus placebo over 12 months in participants with type 2 diabetes and mild-to-moderate symptomatic DSPN. The primary endpoint was the change in corneal nerve fiber length (CNFL) assessed by corneal confocal microscopy (CCM) from baseline to 12 months. In type 2 diabetes patients with symptomatic DSPN, treatment with benfotiamine for 12 months was well tolerated, but had no significant effects on multiple morphometric, neurophysiological and clinical measures of neuropathy.
Overall assessment for DPN: Several studies conducted over periods up to 12 weeks indicated that benfotiamine alone or in combination with vitamin B6 and B12 may alleviate neuropathic symptoms in patients with DSPN. Except for one short-term trial over 12 weeks demonstrating that benfotiamine in combination with vitamin B6 and B12 improved nerve conduction velocity (NCV), no study in people with diabetes has shown that benfotiamine may favorably modify the natural history of DSPN. There is an unmet need for longer-term studies to demonstrate that benfotiamine offers a pathogenesis-derived approach that may delay or halt the clinical, functional or morphological progression of DSPN. In summary, the short-term symptomatic evidence is positive but limited by small sample sizes, short durations, and heterogeneous outcomes; longer-term structural evidence remains largely negative.
4.2 Diabetic Retinopathy
Preclinical evidence is substantial. In retinas of diabetic animals, benfotiamine treatment inhibited three hyperglycemic damage pathways and NF-κB activation by activating transketolase, and also prevented experimental diabetic retinopathy. Administering high-dose benfotiamine prevented the development of retinopathy by halting AGE formation. Benfotiamine helps decrease retinal capillary changes, and high-dose benfotiamine therapy increases the activity of transketolase in the retina, helping to prevent the development of retinopathy. Benfotiamine has been studied in laboratory models of diabetic retinopathy, neuropathy, and nephropathy.
As of the current evidence base, the retinopathy data in humans are lacking. The pivotal mechanistic findings by Hammes et al. (2003) were conducted in diabetic animals, and no large RCTs specifically targeting diabetic retinopathy as a primary endpoint in humans have been published.
4.3 Diabetic Nephropathy and Endothelial Function
Benfotiamine administration to type 2 diabetes patients consuming a high-AGE diet decreased the level of circulating AGEs and oxidative stress markers. However, a larger randomized controlled trial of 82 patients with diabetic nephropathy showed that benfotiamine treatment (300 mg, 3 times per day) for 12 weeks did not significantly change markers of endothelial function, including sVCAM-1. While the evidence is mixed, potential mechanisms of action of benfotiamine include reduction of endogenous AGEs and dicarbonyl production as well as reduction of oxidative stress.
In another study on type 2 diabetes patients with nephropathy, combined treatment with benfotiamine and inhibitors of the angiotensin-converting enzyme or angiotensin receptor blockers improved the thiamine status but did not decrease albuminuria. Thus, the nephropathy evidence in humans is currently negative or inconclusive despite promising animal data.
4.4 Alcoholic Polyneuropathy
A three-armed, randomized, multicentre, placebo-controlled double-blind study examined the efficacy of benfotiamine versus a combination containing benfotiamine and vitamins B6 and B12 in outpatients with severe symptoms of alcoholic polyneuropathy (the Benfotiamine in treatment of Alcoholic Polyneuropathy, BAP I study). The study period was 8 weeks and 84 patients fulfilled all prerequisite criteria and completed the study as planned. Benfotiamine led to significant improvement of alcoholic polyneuropathy. Vibration perception (measured at the tip of the great toe) significantly improved in the course of the study, as did motor function and the overall score reflecting the entire range of symptoms of alcoholic polyneuropathy. A tendency toward improvement was evident for pain and coordination; no therapy-specific adverse effects were seen.
The evidence for benfotiamine in alcoholic polyneuropathy has historically been used as the basis for its pharmaceutical licensure in Germany. This represents one of the more consistently positive clinical areas in the literature, though the number of large RCTs remains small.
4.5 Alcohol Dependence
A randomized, double-blind, placebo-controlled trial was conducted on 120 non-treatment seeking, actively drinking, alcohol dependent men and women volunteers (mean age = 47 years) who met DSM-IV-TR criteria for current alcohol dependence. Subjects were randomized to receive 600 mg benfotiamine or placebo once daily by mouth for 24 weeks, with 6 follow-up assessments scheduled at 4-week intervals. No significant adverse events were noted and alcohol consumption decreased significantly for both treatment groups. Alcohol consumption decreased from baseline levels for 9 of 10 benfotiamine-treated women after 1 month of treatment compared with 2 of 11 on placebo. This trial was primarily a safety/tolerability study, and the reduction in alcohol consumption was observed in both groups, limiting firm conclusions about benfotiamine-specific efficacy.
4.6 Cognitive Decline and Alzheimer's Disease
In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer's disease (AD), including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation.
In 2020, Gibson et al. performed a double-blind, early phase IIa randomized placebo-controlled clinical trial to assess whether benfotiamine is safe, efficacious, and feasible for patients with mild cognitive impairment or mild dementia. Patients were treated with 300 mg of benfotiamine or placebo, twice a day for 12 months. Benfotiamine treatment was safe and effective in raising thiamine concentrations in the periphery. Importantly, benfotiamine was effective in suppressing cognitive decline, as measured by Alzheimer's Disease Assessment Scale (ADAS-Cog) and clinical dementia rating (CDR). It also reduced increases in advanced glycation end products.
Specifically, the decline in ADAS-Cog was diminished by 43% (p<0.125). Worsening of the CDR was 77% lower (p<0.034). Considerable data suggests that the thiamine-dependent transketolase regulates AGE, which are elevated in AD. In the pilot trial, benfotiamine reduced AGE (p<0.044).
These encouraging results warrant a larger clinical trial to confirm these findings. Benfotiamine has no adverse effects and improves cognitive outcome in patients with mild Alzheimer's disease (AD). A follow-up phase IIa/IIb seamless trial (BenfoTeam) has been registered to extend this research with larger sample sizes and longer follow-up. The Alzheimer's disease evidence is currently classified as preliminary and hypothesis-generating; it should not be interpreted as established efficacy.
5. Body Systems and Health Areas
Peripheral Nervous System
The most extensively studied area for benfotiamine is peripheral nerve function. Benfotiamine mainly acts on peripheral tissues through an increase in transketolase activity. Its documented utility in diabetic sensorimotor polyneuropathy and alcoholic polyneuropathy reflects this primary site of action.
Central Nervous System
Overall, benfotiamine is a promising therapeutic agent for improving neuronal function and protecting against inflammation and oxidative stress-induced cell death in the CNS. Benfotiamine, a lipophilic thiamine derivative, has been shown to improve spatial memory, reduce Aβ deposition and tau phosphorylation, and increase thiamine levels in cortical areas of transgenic AD mice. Brain penetration in humans remains uncertain, as noted in the pharmacokinetics section.
Cardiovascular and Vascular System
In diabetic mice, benfotiamine improved diastolic and systolic function and cardiac perfusion, while reducing cardiomyocyte apoptosis and interstitial fibrosis. In diabetic mice with ischemic limbs, benfotiamine improved healing through stimulation of reparative angiogenesis and inhibition of endothelial cell apoptosis, and these therapeutic effects were mediated by activation of protein kinase B and Akt. In human studies, endothelial function improvement has been documented in specific contexts but has not been consistently replicated across larger trials.
Metabolic / Glucose Metabolism Pathways
As a lipid-soluble analogue of thiamine, benfotiamine has been extensively studied in the context of diabetic complications. In 2003, Hammes et al. found that benfotiamine inhibits three major pathways implicated in hyperglycemic vascular damage — the hexosamine pathway, the AGE formation pathway, and the DAG–PKC pathway. Benfotiamine managed this by activating transketolase, which converts glyceraldehyde-3-phosphate and fructose-6-phosphate into pentose-5-phosphates and other sugars, thus decreasing the levels of substrates that activate the three detrimental pathways in hyperglycemia.
Retinal and Renal Microvasculature
Benfotiamine improves complications observed in type 2 diabetes, with animal data supporting protection of both retinal and renal microvasculature. In humans, the evidence remains preclinical or mixed, as described in the evidence sections above.
6. Dosage Forms and Dosages Reported in Studies
- BEDIP Study (2005): 100 mg four times per day (400 mg/day total) for 3 weeks.
- BENDIP Study (2008): 300 mg twice daily (600 mg/day) or 300 mg/day for 6 weeks; the 600 mg/day arm showed significant benefit.
- 24-Month Type 1 Diabetes Trial (2012): 300 mg benfotiamine per day for 24 months.
- BOND Study (2026): 300 mg two times per day (600 mg/day) for 12 months.
- Alzheimer's Disease Phase IIa Trial (2020): 300 mg of benfotiamine twice daily (600 mg/day) for 12 months.
- Alcohol Dependence RCT (2013): 600 mg benfotiamine once daily by mouth for 24 weeks.
- Diabetic Nephropathy RCT: 300 mg, 3 times per day (900 mg/day), for 12 weeks.
- Safety / pharmacokinetic ascending-dose studies: Multiple doses studied: 150 mg, 300 mg, and 600 mg.
7. Safety Considerations and Interactions
General Tolerability
The overall incidence of adverse events with benfotiamine was similar to that reported with placebo (20%). The incidence and severity of adverse events were similar between benfotiamine and placebo groups. No side effects attributable to benfotiamine were observed in the BEDIP study. The supplement has been widely used in Japan and Europe for decades where it is well-tolerated with no reports of serious adverse events.
Adverse Events in Formal Dose-Escalation Studies
A total of 12 (20%) subjects reported at least one adverse event during a single ascending dose study. Twelve subjects reported adverse events that were considered to be drug-related, including 9 (18%) of 50 subjects treated with benfotiamine and 3 (30%) of 10 subjects treated with placebo. The most frequently reported drug-related adverse event was increased ALT, which was reported by 2 (4%) benfotiamine subjects and 1 (10%) placebo subject. Urinary WBC was reported by 2 (4%) of 32 subjects who received the active treatment. The rates of ALT elevation and other events were not significantly different from placebo.
Metabolic Byproduct: Hippuric Acid
The transformation process of benfotiamine to thiamine produces a large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple doses of benfotiamine. This is a pharmacokinetically relevant finding indicating the body efficiently clears this metabolite.
Pharmacokinetic Accumulation
In single ascending dose studies, the median time to reach maximum concentration (Tmax) for thiamine was 1.0 to 2.0 hours, 3.5 to 8.0 hours for thiamine monophosphate (TMP), and 8.0 to 24.0 hours for thiamine diphosphate (TDP) after administration of benfotiamine. Thiamine exhibited a relatively long elimination half-life in all doses studied, resulting in an accumulation ratio of 1.96 to 2.11 and an accumulation ratio based on Cmax of 1.60 to 1.88 following 7 days of multiple dosing.
Alcoholic Polyneuropathy and Vitamin B Combination Preparations
Combination preparations containing benfotiamine together with vitamins B6 and B12 have been studied in randomized trials for alcoholic polyneuropathy. The clinical evidence has consistently shown no therapy-specific adverse effects in these populations.
BOND Study Adverse Events (2026)
In the BOND study, the placebo group had 140 treatment-emergent adverse events (TEAEs). Five participants in the benfotiamine group had considerably more TEAEs, including serious adverse events (SAEs), which were rated as not related or unlikely to the study drug. The overall profile was considered consistent with an acceptable safety record at the 600 mg/day dose over 12 months.
Brain Penetration Limitations
A pharmacokinetically relevant limitation has been documented: benfotiamine prevents the progression of diabetic complications, probably by increasing tissue levels of thiamine diphosphate and enhancing transketolase activity. However, as the brain is particularly sensitive to thiamine deficiency, whether intracellular thiamine and thiamine phosphate levels are reliably increased in the brain after oral benfotiamine administration remains an area of active study. Animal data suggest limited brain penetration at standard oral doses, though the clinical Alzheimer's trial observed peripheral thiamine increases of over 100-fold, and the trial authors indicated that some centrally-mediated benefit may occur.
Regulatory Status and Combined Preparations
Many vitamin B1 analogues, such as benfotiamine, fursultiamine, and sulbutiamine, are synthetic derivatives of thiamine. Most were developed in Japan in the 1950s and 1960s as forms intended to improve absorption compared to thiamine. Some are approved for use in some countries as a drug or non-prescription dietary supplement for treatment of diabetic neuropathy or other health conditions.
References
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