Benefits
Nerve symptom and nerve function scores
In a 6-week placebo-controlled trial in 165 adults with diabetes and nerve symptoms, 300 or 600 mg a day improved the main nerve symptom score in the per-protocol analysis only, and a total symptom score did not differ from placebo. Trials of 12 months (600 mg a day) and 24 months (300 mg a day) found no significant effect on nerve structure, nerve function or symptom scores.
Endothelial function after a high-AGE meal or a cigarette
In 20 healthy smokers, 3 days of benfotiamine halved the drop in artery widening (flow-mediated dilation) after one cigarette, and in 13 adults with type 2 diabetes it blunted the drop after a high-AGE meal. A 6-week placebo-controlled trial in 31 adults with type 2 diabetes saw no meal-related drop to prevent, and a 12-week trial found no change in endothelial markers.
Blood thiamine levels compared with thiamine hydrochloride
In healthy volunteers, oral benfotiamine gave about 11 times the plasma thiamine exposure of thiamine hydrochloride and about twice the red blood cell thiamine diphosphate, the active coenzyme form. Long-term trials also showed large rises in blood thiamine, even where nerve outcomes did not change.
Advanced glycation end product (AGE) markers
Blood AGE markers rose less with benfotiamine than with placebo over 12 months in a memory trial, and serum AGEs rose less after a high-AGE meal in a 13-person study. A 12-week placebo-controlled trial in 82 adults with type 2 diabetes and early kidney involvement found no change in plasma or urinary AGEs at 900 mg a day.
Mechanism of action
Transketolase activation
In diabetic animals, benfotiamine activated transketolase, a thiamine-dependent enzyme. This shifted glucose breakdown products into the pentose phosphate pathway and reduced flux through three damaging pathways (hexosamine, AGE formation and protein kinase C), along with NF-kB activation in the retina.
Absorption after dephosphorylation in the gut
Benfotiamine is practically insoluble in water, organic solvents and oil. Lab researchers propose that it enters cells only after intestinal alkaline phosphatases remove its phosphate group, giving S-benzoylthiamine, which is absorbed and then turned into thiamine in red blood cells and the liver. This sets it apart from lipid-soluble disulfides such as allithiamine, sulbutiamine and fursultiamine.
Higher thiamine diphosphate in blood
Oral benfotiamine raises plasma thiamine and red blood cell thiamine diphosphate, the coenzyme form used by transketolase, more than thiamine hydrochloride in healthy volunteers. In a 24-month trial, whole blood thiamine and thiamine diphosphate rose markedly versus placebo.
Mainly peripheral rather than brain thiamine
In mice, a single oral dose or 14 days of benfotiamine raised thiamine in blood and liver but not in the brain, and it did not raise thiamine in cultured nerve cells. The authors concluded that it likely acts mainly in peripheral tissues.
Clinical trials
Randomized, double-blind, placebo-controlled multicenter phase 3 trial with three arms. (Stracke et al. 2008, Exp Clin Endocrinol Diabetes)
181 adults with symmetric distal nerve symptoms from diabetes were screened and 165 randomized to benfotiamine 600 mg/day, 300 mg/day or placebo for 6 weeks.
The primary Neuropathy Symptom Score differed between groups in the per-protocol analysis (p = 0.033) but only borderline in the intention-to-treat analysis (p = 0.055). The Total Symptom Score showed no significant difference after 6 weeks. Gains were larger at the higher dose; pain responded best. Treatment was well tolerated.
Randomized, double-blind, placebo-controlled phase 2 trial. Wörwag Pharma, a benfotiamine maker, sponsored the trial and supplied the product (Milgamma mono 300); three authors were its employees and two received honoraria from it. (Ziegler et al. 2026, BMJ Open Diabetes Res Care)
57 adults with type 2 diabetes and mild to moderate symptomatic nerve damage, randomized 1:1 to benfotiamine 300 mg twice daily or placebo for 12 months.
The primary outcome, change in corneal nerve fiber length, did not differ between groups. Other structural, nerve conduction and clinical measures were also similar; the Neuropathy Symptom Score showed a nonsignificant trend (p = 0.098). All six thiamine measures rose with benfotiamine. Adverse event rates were similar.
Randomized, double-blind, placebo-controlled trial. (Fraser et al. 2012, Diabetes Care)
67 adults with type 1 diabetes randomized to benfotiamine 300 mg/day or placebo for 24 months; 59 completed.
Whole blood thiamine and thiamine diphosphate rose markedly with benfotiamine (P < 0.001), but changes in peripheral nerve function and soluble inflammatory markers did not differ significantly from placebo.
Uncontrolled before and after study: each person ate the same test meal before and after a 3-day benfotiamine course. The abstract reports no placebo arm. (Stirban et al. 2006, Diabetes Care)
13 adults with type 2 diabetes.
Without benfotiamine, the high-AGE meal cut reactive hyperemia by up to 60.0% at 2 hours and flow-mediated dilation by up to 35.1% at 4 hours. After benfotiamine, neither drop occurred, and meal-related rises in endothelial markers (E-selectin, VCAM-1, ICAM-1), oxidative stress and serum AGEs were smaller.
Randomized, investigator-blinded crossover study, not placebo-controlled; 350 mg three times a day for 2 days, then 1,050 mg one hour before smoking. The product used was Milgamma, made by Wörwag, a benfotiamine maker; the authors declared no conflicts. (Stirban et al. 2012, Int J Vasc Med)
20 healthy adult smokers (mean age 38), each tested after smoking alone and after benfotiamine, 7 to 10 days apart.
Smoking one cigarette cut brachial artery flow-mediated dilation by about 50% (P < 0.001). After benfotiamine the drop was about 25% (P < 0.05 vs smoking alone), and the smoking-related rise in sVCAM-1 was prevented. Endothelium-independent dilation did not change.
Randomized, double-blind, placebo-controlled crossover trial with a 6-week washout. (Stirban et al. 2013, Diabet Med)
31 adults with type 2 diabetes and impaired fasting flow-mediated dilation (2.63 +/- 2.49%).
After placebo, a heated test meal did not lower flow-mediated dilation, microvascular function or autonomic nerve measures, and benfotiamine did not change this pattern fasting or after the meal. So the trial could not show that benfotiamine prevents a meal-related decline. Only in the subgroup with the highest baseline dilation did benfotiamine blunt a drop.
Randomized, double-blind, placebo-controlled trial (secondary outcomes); 300 mg three times a day of benfotiamine made by Wörwag Pharma. Funding came from an EU network grant and a medical research foundation in Zwolle; the authors declared no competing interests. (Alkhalaf et al. 2012, PLoS One)
82 adults with type 2 diabetes and urinary albumin of 15 to 300 mg per 24 hours (39 benfotiamine, 43 placebo).
Compared with placebo, benfotiamine did not significantly change plasma or urinary AGEs, plasma endothelial dysfunction markers (sVCAM-1, sICAM-1, soluble E-selectin) or low-grade inflammation markers (hs-CRP, SAA, MPO).
Randomized pharmacokinetic study with single and multiple benfotiamine doses. (Xie et al. 2014, J Clin Pharmacol)
Healthy Chinese volunteers; group size and doses are not given in the abstract.
Relative to thiamine hydrochloride, benfotiamine gave 1147.3 +/- 490.3% bioavailability for plasma thiamine and 195.8 +/- 33.8% for red blood cell thiamine diphosphate, with faster and greater absorption. Conversion produced large amounts of urinary hippuric acid, with no buildup after repeated doses.
Two randomized, double-blind, placebo-controlled phase 1 trials funded by Chinese government science grants. Benfotiamine was provided by Shanghai Rixin Biotechnology, a company developing Alzheimer's drugs in which two authors held shares. (Sheng et al. 2021, Drug Des Devel Ther)
108 healthy adults: 60 in single doses of 150 to 1,200 mg and 48 in repeated doses of 150, 300 or 600 mg over 10 days (placebo in each cohort).
Adverse events were similar in frequency and severity to placebo. The most common drug-related events were raised ALT and white blood cells in urine. Thiamine peaked in 1 to 2 hours and thiamine diphosphate in 8 to 24 hours, and both roughly doubled with repeated dosing.
Randomized, double-blind, placebo-controlled phase 2a trial (NCT02292238), funded by NIH grants and the Alzheimer Drug Discovery Foundation; capsules were supplied by Advanced Orthomolecular Research. The authors judged no adverse events to be drug related; the benfotiamine group had two strokes and the placebo group none. (Gibson et al. 2020, J Alzheimers Dis)
70 older adults with amnestic mild cognitive impairment or mild dementia due to Alzheimer's disease (34 benfotiamine 300 mg twice daily, 36 placebo).
On the primary outcome (ADAS-Cog), decline was smaller with benfotiamine but not statistically significant (p = 0.162 by intention to treat; the abstract's p = 0.125 is per protocol). Worsening on the Clinical Dementia Rating was 77% smaller (p = 0.034) and blood AGEs rose less (p = 0.044). An exploratory FDG PET pattern score favored benfotiamine (p = 0.002), but prespecified regional brain glucose uptake comparisons did not differ.