The Beneficial Effects of a Combination Therapy of Oral Benfotiamine and Methylcobalamin in the Treatment of Parkinson’s Disease: Case Reports and Review of the Literature
Main Article Content
Abstract
Evidence suggests that there may be an association between Parkinson’s disease (PD) and aberrations in thiamine (vitamin B1) utilization and processing. Low free thiamine levels have been found in the cerebrospinal fluid of patients with PD. Two independent research groups have reported improved symptomatology in patients with PD following high-dose parenteral thiamine therapy. Experimental models further support this connection. Benfotiamine, a lipid-soluble thiamine derivative with enhanced oral bioavailability, along with methylcobalamin, an active form of vitamin B12, have demonstrated neuroprotective properties. Here we describe two cases of patients with PD who experienced marked improvements in tremor, fatigue, cognition, and overall quality of life following oral treatment with benfotiamine and methylcobalamin.
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How to Cite
MANN, Richard H.; BARATTA, Larry G..
The Beneficial Effects of a Combination Therapy of Oral Benfotiamine and Methylcobalamin in the Treatment of Parkinson’s Disease: Case Reports and Review of the Literature.
Medical Research Archives, [S.l.], v. 13, n. 5, may 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6580>. Date accessed: 23 june 2025.
doi: https://doi.org/10.18103/mra.v13i5.6580.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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22. Tapias V, Jainuddin S, Ahuja M, et al. Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet. 2018;15:2874-2882. doi:10.1093/hmg/ddy201
23. Vignisse J, Sambon M, Gorlova A, et al. Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels. Mol Cell Neurosci. 2017;82:126-136. doi:10.1016/j.mcn.2017.05.005
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26. Pan X, Chen Z, Fei G, et al. Long-term cognitive improvement after benfotiamine administration in patients with Alzheimer’s disease. Neurosci Bull. 2016;32:591-596. doi:10.1007/s12264-016-0067-0
27. Gibson GE, Luchsinger JA. Benfotiamine and cognitive decline in Alzheimer’s disease: results of a randomized placebo-controlled phase IIa clinical trial. J Alzheimers Dis. 2020;77:989-1010. doi:10.3233/JAD-200896
28. Pavlović DM. Thiamine deficiency and benfotiamine therapy in brain diseases. Am J Biomed Sci Res. 2019;8:1-5. doi:10.34297/AJBSR.2019.03.000621
29. Costantini A, Pala MI, Compagnoni L, Colangeli M. High-dose thiamine as initial treatment for Parkinson’s disease. BMJ Case Rep. 2013;2013:bcr2013009289. doi:10.1136/bcr-2013-009289
30. Costantini A, Pala MI, Grossi E, et al. Long-term treatment with high-dose thiamine in Parkinson disease: an open-label pilot study. J Altern Complement Med. 2015;21:740-747. doi:10.1089/acm.2014.0353
31. Costantini A, Fancellu R. An open-label pilot study with high-dose thiamine in Parkinson’s disease. Neural Regen Res. 2016;11:406-407. doi:10.4103/1673-5374.179047
32. Costantini A, Pala MI, Catalano ML, Notarangelo C, Careddu P. High-dose thiamine improves fatigue after stroke: a report of three cases. J Altern Complement Med. 2014;20:683-685. doi:10.1089/acm.2013.0461
33. Costantini A, Immacolata PM, Erika T, Serena M, Stefania V, Roberto F. Thiamine therapy for dystonia type 1. ARC J Neurosci. 2018;3:1-4. doi:10.20431/2456-057X.0301001
34. Costantini A, Giorgi R, D’Agostino S, Pala MI. High-dose thiamine improves the symptoms of Friedreich’s ataxia. BMJ Case Rep. 2013;2013:bcr2013009424. doi:10.1136/bcr-2013-009424
35. Costantini A, Nappo A, Pala MI, Zappone A. High dose thiamine improves fatigue in multiple sclerosis. BMJ Case Rep. 2013;2013:bcr2013009144. doi:10.1136/bcr-2013-009144
36. Costantini A, Pala MI, Colangeli M, Savelli S. Thiamine and spinocerebellar ataxia type 2. BMJ Case Rep. 2013;2013:bcr2012007302. doi:10.1136/bcr-2012-007302
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38. McCarter SJ, Stang C, Turcano P, et al. Higher vitamin B12 level at Parkinson’s disease diagnosis is associated with lower risk of future dementia. Parkinsonism Relat Disord. 2020;73:19-22.
39. Wu Y, Zhao Z, Yang N, et al. Vitamin B12 ameliorates the pathological phenotypes of multiple Parkinson’s disease models by alleviating oxidative stress. Antioxid. 2023;12:153. doi:10.3390/antiox12010153
40. Christine CW, Auinger P, Joslin A, Yelpaala Y, Green R; Parkinson Study Group-DATATOP Investigators. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018;33:762-770. doi:10.1002/mds.27301
41. Mizuno Y, Matuda S, Yoshino H, Mori H, Hattori N, Ikebe S. An immunohistochemical study on alpha-ketoglutarate dehydrogenase complex in Parkinson’s disease. Ann Neurol. 1994;35:204-210. doi:10.1002/ana.410350212
42. Munujos P, Coll-Cantí J, Beleta J, González-Sastre F, Gella FJ. Brain pyruvate oxidation in experimental thiamin-deficiency encephalopathy. Clin Chim Acta. 1996;253:13-25. doi:10.1016/0009-8981(96)06385-1
43. Lange K, Nakamura Y, Chen N, et al. Diet and medical foods in Parkinson’s disease. Food Sci Hum Wellness. 2019;8:10-16. doi:10.1016/j.fshw.2019.03.006
44. Sjöquist B, Johnson HA, Neri A, Lindén S. The influence of thiamine deficiency and ethanol on rat brain catecholamines. Drug Alcohol Depend. 1988;22:187-193. doi:10.1016/0376-8716(88)90017-8
45. Mousseau DD, Rao VL, Butterworth RF. Vesicular dysfunction during experimental thiamine deficiency is indicated by alterations in dopamine metabolism. Eur J Pharmacol. 1996;317:263-267. doi:10.1016/s0014-2999(96)00842-4
46. Jiménez-Jiménez FJ, Molina JA, Hernánz A, et al. Cerebrospinal fluid levels of thiamine in patients with Parkinson’s disease. Neurosci Lett. 1999;266:33-36. doi:10.1016/s0304-3940(99)00515-7
47. Yamashita H, Zhang YX, Nakamura S. The effects of thiamin and its phosphate esters on dopamine release in the rat striatum. Neurosci Lett. 1993;158:229-231. doi:10.1016/0304-3940(93)90271-l
48. Håglin L, Domellöf M, Bäckman L, Forsgren L. Low plasma thiamine and phosphate in male patients with Parkinson’s disease is associated with mild cognitive impairment. Clin Nutr ESPEN. 2020;37:93-99. doi:10.1016/j.clnesp.2020.03.012
49. Håglin L, Johansson I, Forsgren L, Bäckman L. Intake of vitamin B before onset of Parkinson’s disease and atypical parkinsonism and olfactory function at the time of diagnosis. Eur J Clin Nutr. 2017;71:97-102. doi:10.1038/ejcn.2016.181
50. Alizadeh M, Kheirouri S, Keramati M. What dietary vitamins and minerals might be protective against Parkinson’s disease? Brain Sci. 2023;13:1119. doi:10.3390/brainsci13071119
51. Brandis K, Holmes I, England S, Sharma N, Kukreja L, DebBurman S. α-Synuclein fission yeast model: concentration-dependent aggregation without plasma membrane localization or toxicity. J Mol Neurosci. 2006;28:179-191. doi:10.1385/jmn:28:2:179
52. Pan X, Sang S, Zhong C. Brain energy improvement as an emerging approach for Alzheimer’s disease treatment. Neurosci Bull. 2021;37:892-893. doi:10.1007/s12264-021-00679
2. Luong KVQ, Nguyen LTH. The beneficial role of thiamine in Parkinson’s disease: preliminary report. J Neurol Res. 2012;2:211-214. doi:10.1016/j.jns.2012.02.008
3. Meade RM, Fairlie DP, Mason JM. Alpha-synuclein structure and Parkinson’s disease: lessons and emerging principles. Mol Neurodegener. 2019;22:29. doi:10.1186/s13024-019-0329-1
4. Liu D, Ke Z, Luo J. Thiamine deficiency and neurodegeneration: the interplay among oxidative stress, endoplasmic reticulum stress and autophagy. Mol Neurobiol. 2017;54:5440-5448. doi:10.1007/s12035-016-0079-9
5. Bubber P, Ke ZJ, Gibson GE. Tricarboxylic acid cycle enzymes following thiamine deficiency. Neurochem Int. 2004;45:1021-1028. doi:10.1016/j.neuint.2004.05.007
6. Jadiya P, Garbincius JF, Elrod JW. Reappraisal of metabolic dysfunction in neurodegeneration: focus on mitochondrial function and calcium signaling. Acta Neuropathol Commun. 2021;7:124. doi:10.1186/s40478-021-01224-4
7. Thornalley PJ, Babaei-Jadidi R, Al Ali H, et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia. 2007;50:2164-2170. doi:10.1007/s00125-007-0771-4
8. Langlais PJ. Alcohol-related thiamine deficiency: impact on cognitive and memory functioning. Alcohol Health Res World. 1995;19:113-121.
9. Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes. 2008;116:600-605. doi:10.1055/s-2008-1065351
10. Woelk H, Lehrl S, Bitsch R, Köpcke W. Benfotiamine in treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP I Study). Alcohol Alcohol. 1998;33:631-638. doi:10.1093/alcalc/33.6.631
11. Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern Med J. 2014;44:911-915. doi:10.1111/imj.12522
12. Gibson GE, Sheu KFR, Blass JP, et al. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol. 1988;1:836-840. doi:10.1001/archneur.1988.00520320022009
13. Laforenza U, Patrini C, Poloni M, et al. Thiamin mono- and pyrophosphatase activities from brain homogenate of Guamanian amyotrophic lateral sclerosis and parkinsonism-dementia patients. J Neurol Sci. 1992;1:156-161. doi:10.1016/0022-510x(92)90162-e
14. Bettendorff L, Mastrogiacomo F, Wins P, Kish SJ, Grisar T, Ball MJ. Low thiamine diphosphate levels in brains of patients with frontal lobe degeneration of the non-Alzheimer’s type. J Neurochem. 1997;69:2005-2010. doi:10.1046/j.1471-4159.1997.69052005.x
15. Gruber-Bzura BM, Krzysztoń-Russjan J, Bubko I, et al. Role of thiamine in Huntington’s disease pathogenesis: in vitro studies. Adv Clin Exp Med. 2017;26:751-760. doi:10.17219/acem/63091
16. Pan X, Gong N, Zhao J, et al. Powerful beneficial effects of benfotiamine on cognitive impairment and beta-amyloid deposition in amyloid precursor protein/presenilin-1 transgenic mice. Brain. 2010;133:1342-1351. doi:10.1093/brain/awq069
17. Loew D. Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J Clin Pharmacol Ther. 1996;34:47-50.
18. El Hefnawy MH, Ramadan H, Rabie D, Effat A. Oral benfotiamine 300 mg versus intramuscular thiamine in diabetic patients with peripheral neuropathy. J Endocrinol Diabetes. 2022;22:1-9. doi:10.15226/2374-6890/9/1/001156
19. Bozic I, Lavrnja I. Thiamine and benfotiamine: focus on their therapeutic potential. Heliyon. 2023;9:e21839. doi:10.1016/j.heliyon.2023.e21839
20. Moraes RCM, Singulani MP, Gonçalves AC, Portari GV, Torrão AS. Oral benfotiamine reverts cognitive deficit and increases thiamine diphosphate levels in the brain of a rat model of neurodegeneration. Exp Gerontol. 2020;141:111097. doi:10.1016/j.exger.2020.111097
21. Moraes RCM, Lima GCA, Cardinali CAEF, et al. Benfotiamine protects against hypothalamic dysfunction in a STZ-induced model of neurodegeneration in rats. Life Sci. 2022;306:120841. doi:10.1016/j.lfs.2022.120841
22. Tapias V, Jainuddin S, Ahuja M, et al. Benfotiamine treatment activates the Nrf2/ARE pathway and is neuroprotective in a transgenic mouse model of tauopathy. Hum Mol Genet. 2018;15:2874-2882. doi:10.1093/hmg/ddy201
23. Vignisse J, Sambon M, Gorlova A, et al. Thiamine and benfotiamine prevent stress-induced suppression of hippocampal neurogenesis in mice exposed to predation without affecting brain thiamine diphosphate levels. Mol Cell Neurosci. 2017;82:126-136. doi:10.1016/j.mcn.2017.05.005
24. Bashir B, Mittal S, Muthukumar A, et al. Harnessing the neuroprotective effect of oral administration of benfotiamine in MPTP induced Parkinson’s disease in rats. Eur J Pharmacol. 2024;5:176234. doi:10.1016/j.ejphar.2023.176234
25. 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;15:e40511. doi:10.7759/cureus.40511
26. Pan X, Chen Z, Fei G, et al. Long-term cognitive improvement after benfotiamine administration in patients with Alzheimer’s disease. Neurosci Bull. 2016;32:591-596. doi:10.1007/s12264-016-0067-0
27. Gibson GE, Luchsinger JA. Benfotiamine and cognitive decline in Alzheimer’s disease: results of a randomized placebo-controlled phase IIa clinical trial. J Alzheimers Dis. 2020;77:989-1010. doi:10.3233/JAD-200896
28. Pavlović DM. Thiamine deficiency and benfotiamine therapy in brain diseases. Am J Biomed Sci Res. 2019;8:1-5. doi:10.34297/AJBSR.2019.03.000621
29. Costantini A, Pala MI, Compagnoni L, Colangeli M. High-dose thiamine as initial treatment for Parkinson’s disease. BMJ Case Rep. 2013;2013:bcr2013009289. doi:10.1136/bcr-2013-009289
30. Costantini A, Pala MI, Grossi E, et al. Long-term treatment with high-dose thiamine in Parkinson disease: an open-label pilot study. J Altern Complement Med. 2015;21:740-747. doi:10.1089/acm.2014.0353
31. Costantini A, Fancellu R. An open-label pilot study with high-dose thiamine in Parkinson’s disease. Neural Regen Res. 2016;11:406-407. doi:10.4103/1673-5374.179047
32. Costantini A, Pala MI, Catalano ML, Notarangelo C, Careddu P. High-dose thiamine improves fatigue after stroke: a report of three cases. J Altern Complement Med. 2014;20:683-685. doi:10.1089/acm.2013.0461
33. Costantini A, Immacolata PM, Erika T, Serena M, Stefania V, Roberto F. Thiamine therapy for dystonia type 1. ARC J Neurosci. 2018;3:1-4. doi:10.20431/2456-057X.0301001
34. Costantini A, Giorgi R, D’Agostino S, Pala MI. High-dose thiamine improves the symptoms of Friedreich’s ataxia. BMJ Case Rep. 2013;2013:bcr2013009424. doi:10.1136/bcr-2013-009424
35. Costantini A, Nappo A, Pala MI, Zappone A. High dose thiamine improves fatigue in multiple sclerosis. BMJ Case Rep. 2013;2013:bcr2013009144. doi:10.1136/bcr-2013-009144
36. Costantini A, Pala MI, Colangeli M, Savelli S. Thiamine and spinocerebellar ataxia type 2. BMJ Case Rep. 2013;2013:bcr2012007302. doi:10.1136/bcr-2012-007302
37. Shen L. Associations between B vitamins and Parkinson’s disease. Nutrients. 2015;27:7197-7208.
38. McCarter SJ, Stang C, Turcano P, et al. Higher vitamin B12 level at Parkinson’s disease diagnosis is associated with lower risk of future dementia. Parkinsonism Relat Disord. 2020;73:19-22.
39. Wu Y, Zhao Z, Yang N, et al. Vitamin B12 ameliorates the pathological phenotypes of multiple Parkinson’s disease models by alleviating oxidative stress. Antioxid. 2023;12:153. doi:10.3390/antiox12010153
40. Christine CW, Auinger P, Joslin A, Yelpaala Y, Green R; Parkinson Study Group-DATATOP Investigators. Vitamin B12 and homocysteine levels predict different outcomes in early Parkinson’s disease. Mov Disord. 2018;33:762-770. doi:10.1002/mds.27301
41. Mizuno Y, Matuda S, Yoshino H, Mori H, Hattori N, Ikebe S. An immunohistochemical study on alpha-ketoglutarate dehydrogenase complex in Parkinson’s disease. Ann Neurol. 1994;35:204-210. doi:10.1002/ana.410350212
42. Munujos P, Coll-Cantí J, Beleta J, González-Sastre F, Gella FJ. Brain pyruvate oxidation in experimental thiamin-deficiency encephalopathy. Clin Chim Acta. 1996;253:13-25. doi:10.1016/0009-8981(96)06385-1
43. Lange K, Nakamura Y, Chen N, et al. Diet and medical foods in Parkinson’s disease. Food Sci Hum Wellness. 2019;8:10-16. doi:10.1016/j.fshw.2019.03.006
44. Sjöquist B, Johnson HA, Neri A, Lindén S. The influence of thiamine deficiency and ethanol on rat brain catecholamines. Drug Alcohol Depend. 1988;22:187-193. doi:10.1016/0376-8716(88)90017-8
45. Mousseau DD, Rao VL, Butterworth RF. Vesicular dysfunction during experimental thiamine deficiency is indicated by alterations in dopamine metabolism. Eur J Pharmacol. 1996;317:263-267. doi:10.1016/s0014-2999(96)00842-4
46. Jiménez-Jiménez FJ, Molina JA, Hernánz A, et al. Cerebrospinal fluid levels of thiamine in patients with Parkinson’s disease. Neurosci Lett. 1999;266:33-36. doi:10.1016/s0304-3940(99)00515-7
47. Yamashita H, Zhang YX, Nakamura S. The effects of thiamin and its phosphate esters on dopamine release in the rat striatum. Neurosci Lett. 1993;158:229-231. doi:10.1016/0304-3940(93)90271-l
48. Håglin L, Domellöf M, Bäckman L, Forsgren L. Low plasma thiamine and phosphate in male patients with Parkinson’s disease is associated with mild cognitive impairment. Clin Nutr ESPEN. 2020;37:93-99. doi:10.1016/j.clnesp.2020.03.012
49. Håglin L, Johansson I, Forsgren L, Bäckman L. Intake of vitamin B before onset of Parkinson’s disease and atypical parkinsonism and olfactory function at the time of diagnosis. Eur J Clin Nutr. 2017;71:97-102. doi:10.1038/ejcn.2016.181
50. Alizadeh M, Kheirouri S, Keramati M. What dietary vitamins and minerals might be protective against Parkinson’s disease? Brain Sci. 2023;13:1119. doi:10.3390/brainsci13071119
51. Brandis K, Holmes I, England S, Sharma N, Kukreja L, DebBurman S. α-Synuclein fission yeast model: concentration-dependent aggregation without plasma membrane localization or toxicity. J Mol Neurosci. 2006;28:179-191. doi:10.1385/jmn:28:2:179
52. Pan X, Sang S, Zhong C. Brain energy improvement as an emerging approach for Alzheimer’s disease treatment. Neurosci Bull. 2021;37:892-893. doi:10.1007/s12264-021-00679