Overview

Name: Benfotiamine
Synonyms: S-benzoylthiamine-O-monophosphate, Vitamin B1, Thiamine
Therapy Type: Supplement, Dietary (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)

Background

Benfotiamine is a synthetic, fat-soluble precursor of Vitamin B1 with high bioavailability. Taken orally, benfotiamine produces supra-physiological blood levels of the active coenzyme form of thiamine. This supplement is available by prescription in some countries, and over the counter in the U.S. and other places. It is used to treat diabetic neuropathy at doses of 150-300 mg per day.

Thiamine-dependent enzymes function in glucose metabolism. Thiamine deficiency, and reduced activity of thiamine-dependent enzymes in the brain, have been documented in Alzheimer's disease patients (e.g. Gibson et al., 1998). This deficiency has been related to changes in brain glucose metabolism and cognitive function (Sang et al., 2018). Earlier trials of high-dose conventional thiamine demonstrated little or no benefit on cognition (e.g. Meador et al., 1993). A pilot trial of benfotiamine in five people with Alzheimer’s reported an increase of 3.2 points on the MMSE after 18 months of 300 mg daily, but it lacked a placebo group for comparison (Pan et al., 2016).

Preclinical work from two different groups showed that increasing thiamine to very high levels using benfotiamine supplementation diminished pathology, was neuroprotective, and improved behavior deficits in mouse models of amyloidosis and tauopathy (Pan et al., 2010; Tapias et al., 2018). In toxin-induced parkinsonism models, benfotiamine was neuroprotective and improved behavior and movement (Wang et al., 2024; Bashir et al., 2024). Benfotiamine and related thiamine prodrugs have antiinflammatory and antioxidant actions, which have been suggested to be independent of their function as coenzymes (reviewed in Bettendorff 2023).

Amyotrophic lateral sclerosis patients have impaired thiamine metabolism, and one patient reported greater muscle strength and energy after benfotiamine and Vitamin B12 treatment (Mann, 2023).

Findings

From February 2015 to July 2020, a Phase 2 pilot study in New York tested the ability of benfotiamine to improve cognition in people with mild cognitive impairment or mild AD dementia. Seventy-one participants with PET-confirmed brain amyloid took 600 mg benfotiamine or placebo daily for one year, against a primary outcome of change from baseline in the ADAS-Cog. Secondary outcomes were change in brain glucose metabolism in the posterior cingulate by FDG-PET, as well ADCS-Activities of Daily Living, Neuropsychiatric Inventory, Clinical Dementia Rating, and Buschke Selective Reminding test. According to published results, the trial missed its primary endpoint. The benfotiamine group had a 43 percent slowing in decline on the ADAS-Cog, which fell short of statistical significance. Decline on the CDR was significantly delayed by 77 percent; no differences were noted in other secondary outcomes (Gibson et al., 2020, reviewed in Gibson et al., 2022). An exploratory analysis suggested improvement in brain glucose utilization on FDG-PET, with a better response in ApoE4 noncarriers than carriers. Benfotiamine increased blood thiamine levels 161-fold and significantly decreased the levels of abnormally glycated fats and proteins in blood, indicating normalization of glucose metabolism. No treatment-related adverse events were reported. A separate serum metabolomic and lipidomic profiling analysis was published (Bhawal et al., 2021).

A poster presentation at the 2022 CTAD conference in San Diego reported on a trial in China that compared one year of 300 or 600 mg benfotiamine to placebo, as an add-on to donepezil in 302 clinically diagnosed AD patients. The study found no significant change in the primary outcome of ADAS-Cog in the group as a whole (Pan et al., 2022, CTAD poster). The authors did report a dose-dependent slowing of decline on ADAS-Cog in the subgroup of people with moderate AD (MMSE between 11 and 19), but not in those with mild AD (MMSE 20-24). Adverse events were similar between treatment and placebo. This group had previously published Phase 1 results, where benfotiamine had similar safety findings at these doses (Sheng et al., 2021).

In March 2024, the New York investigators began a follow-on Phase 2 trial to test 18 months of benfotiamine in 406 people with mild AD (Feldman et al. 2024). The adaptive design will initially compare safety of 600 or 1,200 mg to placebo, then randomize participants to the highest safe dose or placebo. The primary outcome will be within-person change from baseline in ADAS-cog and CDR-SB. Secondary outcomes include other measures of cognition, pharmacokinetics, safety and tolerability. Exploratory endpoints span MRI, plasma biomarkers of amyloid, tau and neurodegeneration, and age-related glycation end products. This multicenter study, coordinated by the ADCS in San Diego, is supported by National Institute on Aging (press release), and is planned to run at 24 locations in the U.S. until December 2027.

For details on benfotiamine trials, see clinicaltrials.gov.

Last Updated: 28 Jan 2025

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References

Basic page Citations

Paper Citations

Gibson GE, Luchsinger JA, Cirio R, Chen H, Franchino-Elder J, Hirsch JA, Bettendorff L, Chen Z, Flowers SA, Gerber LM, Grandville T, Schupf N, Xu H, Stern Y, Habeck C, Jordan B, Fonzetti P. Benfotiamine and Cognitive Decline in Alzheimer's Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial. J Alzheimers Dis. 2020;78(3):989-1010. PubMed.
Gibson GE, Feldman HH, Zhang S, Flowers SA, Luchsinger JA. Pharmacological thiamine levels as a therapeutic approach in Alzheimer's disease. Front Med (Lausanne). 2022;9:1033272. Epub 2022 Oct 4 PubMed.
Bhawal R, Fu Q, Anderson ET, Gibson GE, Zhang S. Serum Metabolomic and Lipidomic Profiling Reveals Novel Biomarkers of Efficacy for Benfotiamine in Alzheimer's Disease. Int J Mol Sci. 2021 Dec 7;22(24) PubMed.
Sheng L, Cao W, Lin P, Chen W, Xu H, Zhong C, Yuan F, Chen H, Li H, Liu C, Yang M, Li X. Safety, Tolerability and Pharmacokinetics of Single and Multiple Ascending Doses of Benfotiamine in Healthy Subjects. Drug Des Devel Ther. 2021;15:1101-1110. Epub 2021 Mar 9 PubMed.
Feldman HH, Luchsinger JA, Léger GC, Taylor C, Jacobs DM, Salmon DP, Edland SD, Messer K, Revta C, Flowers SA, Jones KS, Koulman A, Yarasheski KE, Verghese PB, Venkatesh V, Zetterberg H, Durant J, Lupo JL, Gibson GE, ADCS BenfoTeam Study Group. Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimer's disease (BenfoTeam). PLoS One. 2024;19(5):e0302998. Epub 2024 May 29 PubMed.
Gibson GE, Sheu KF, Blass JP, Baker A, Carlson KC, Harding B, Perrino P. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer's disease. Arch Neurol. 1988 Aug;45(8):836-40. PubMed.
Sang S, Pan X, Chen Z, Zeng F, Pan S, Liu H, Jin L, Fei G, Wang C, Ren S, Jiao F, Bao W, Zhou W, Guan Y, Zhang Y, Shi H, Wang Y, Yu X, Wang Y, Zhong C. Thiamine diphosphate reduction strongly correlates with brain glucose hypometabolism in Alzheimer's disease, whereas amyloid deposition does not. Alzheimers Res Ther. 2018 Mar 1;10(1):26. PubMed.
Meador K, Loring D, Nichols M, Zamrini E, Rivner M, Posas H, Thompson E, Moore E. Preliminary findings of high-dose thiamine in dementia of Alzheimer's type. J Geriatr Psychiatry Neurol. 1993;6(4):222-9. PubMed.
Pan X, Chen Z, Fei G, Pan S, Bao W, Ren S, Guan Y, Zhong C. Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer's Disease. Neurosci Bull. 2016 Dec;32(6):591-596. Epub 2016 Oct 1 PubMed.
Pan X, Gong N, Zhao J, Yu Z, Gu F, Chen J, Sun X, Zhao L, Yu M, Xu Z, Dong W, Qin Y, Fei G, Zhong C, Xu TL. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain. 2010 May;133(Pt 5):1342-51. PubMed.
Tapias V, Jainuddin S, Ahuja M, Stack C, Elipenahli C, Vignisse J, Gerges M, Starkova N, Xu H, Starkov AA, Bettendorff L, Hushpulian DM, Smirnova NA, Gazaryan IG, Kaidery NA, Wakade S, Calingasan NY, Thomas B, Gibson GE, Dumont M, Beal MF. Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet. 2018 Aug 15;27(16):2874-2892. PubMed.
Wang K, Han C, Yang J, Xu W, Wang L, Li H, Wang Y. Benfotiamine protects MPTP-induced Parkinson's disease mouse model via activating Nrf2 signaling pathway. PLoS One. 2024;19(7):e0307012. Epub 2024 Jul 23 PubMed.
Bashir B, Mittal S, Muthukumar A, Vishwas S, Pandey NK, Gulati M, Gupta G, Dhanasekaran M, Kumar P, Dureja H, Veiga F, Paiva-Santos AC, Adams J, Dua K, Singh SK. Harnessing the neuroprotective effect of oral administration of benfotiamine in MPTP induced Parkinson's disease in rats. Eur J Pharmacol. 2024 Jan 5;962:176234. Epub 2023 Dec 2 PubMed.
Bettendorff L. Synthetic Thioesters of Thiamine: Promising Tools for Slowing Progression of Neurodegenerative Diseases. Int J Mol Sci. 2023 Jul 10;24(14) PubMed.
Mann RH. Impaired Thiamine Metabolism in Amyotrophic Lateral Sclerosis and Its Potential Treatment With Benfotiamine: A Case Report and a Review of the Literature. Cureus. 2023 Jun;15(6):e40511. Epub 2023 Jun 16 PubMed.

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