Drug Safety

, Volume 41, Issue 9, pp 859–869 | Cite as

Vitamin B6 in Health Supplements and Neuropathy: Case Series Assessment of Spontaneously Reported Cases

  • Florence van HunselEmail author
  • Sonja van de Koppel
  • Eugène van Puijenbroek
  • Agnes Kant
Original Research Article



In the literature, vitamin B6 has been linked to the development of polyneuropathy. Most often, these complaints were seen when taking high doses of vitamin B6 for a long time. Evidence as to whether a lower dosage range of vitamin B6 (< 50 mg/day) can also induce neuropathy is scarce.


We aim to comprehensively describe the cases of neuropathy associated with vitamin B6 received by the Netherlands Pharmacovigilance Centre Lareb and to assess the case series concerning the use of vitamin B6 and neuropathic complaints.


We describe the number and nature of the reported cases, including suspect product, dosage, duration of use, and vitamin B6 serum levels. In addition, we describe the causality for the individual cases (Naranjo Probability Scale) and for the entire case series (Bradford Hill criteria).


In total, 90 reports on products containing vitamin B6 included at least one adverse drug reaction in the standardized Medical Dictionary for Regulatory Activities (MedDRA®) query (SMQ; broad) ‘peripheral neuropathy’. The amount of vitamin B6 in the products varied between 1.4 and 100 mg per tablet. The serum vitamin B6 level was known in 36 cases (88–4338 nmol/l), and the mean serum vitamin B6 level was 907 nmol/l. However, no statistical correlation between dosage and vitamin B6 blood levels was found.

Discussion and Conclusion

Causality assessment of the case series of 90 reports to Lareb shows it is plausible for the vitamin B6 supplements to have caused complaints such as neuropathies. This is especially the case with higher dosages and prolonged use, but dosages < 50 mg/day also cannot be excluded.


Compliance with ethical standards

Conflict of interest

Florence van Hunsel, Sonja van de Koppel, Eugène van Puijenbroek and Agnes Kant have no conflicts of interest.


No sources of funding were used to assist in the preparation of this study.


  1. 1.
    Vrolijk MF, Opperhuizen A, Jansen EHJM, Hageman GJ, Bast A, Haenen GRMM. The vitamin B6 paradox: supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function. Toxicol In Vitro. 2017;44:206–12.CrossRefPubMedGoogle Scholar
  2. 2.
    van Rossum CTM, Fransen HP, Verkaik-Kloosterman J, Buurma-Rethans EJM, Ocke MC. Dutch National Food Consumption Survey 2007-2010: Diet of children and adults aged 7 to 69 years. RIVM Rapport 350050006, 1-144. 7-7-2012. RIVM. Ref Type: Report.Google Scholar
  3. 3.
    van der Watt JJ, Benatar MG, Harrison TB, Carrara H, Heckmann JM. Isoniazid exposure and pyridoxine levels in human immunodeficiency virus associated distal sensory neuropathy. Int J Tuberc Lung Dis. 2015;19(11):1312–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Porter K, Hoey L, Hughes CF, Ward M, McNulty H. Causes, consequences and public health implications of low B-vitamin status in ageing. Nutrients. 2016;8(11):725.CrossRefPubMedCentralGoogle Scholar
  5. 5.
    di Salvo ML, Safo MK, Contestabile R. Biomedical aspects of pyridoxal 5′-phosphate availability. Front Biosci (Elite Ed). 2012;4:897–913.Google Scholar
  6. 6.
    Steen G, Vlasveld LTH, Poot CC, Slot-Verhouven A, Castel AJ. Onderzoek naar referentiewaarden van laboratoriumonderzoek in een algemeen ziekenhuis: resultaten en bevindingen. Ned Tijdschr Klin Chem Labgeneesk. 2009;34(1):35–43.Google Scholar
  7. 7.
    Health Council of the Netherland. Dietary Reference Intakes: vitamin B6, folic acid, and vitamin B12. 2003/04. 2003. The Hague. Ref Type: Report.Google Scholar
  8. 8.
    Scientific Committee on Food, Scientific Panel on Dietetic Products NaA. Tolerable uptake levels for vitamins and minerals. http://www.efsaeuropaeu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf. 2006 [cited 8 Sept 2017].
  9. 9.
    de Kruijk JR, Notermans NC. Sensory disturbances caused by multivitamin preparations. Ned Tijdschr Geneeskd. 2005;149(46):2541–4.PubMedGoogle Scholar
  10. 10.
    Scott K, Zeris S, Kothari MJ. Elevated B6 levels and peripheral neuropathies. Electromyogr Clin Neurophysiol. 2008;48(5):219–23.PubMedGoogle Scholar
  11. 11.
    Kulkantrakorn K. Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited. Neurol Sci. 2014;35(11):1827–30.CrossRefPubMedGoogle Scholar
  12. 12.
    Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand. 1987;76(1):8–11.CrossRefPubMedGoogle Scholar
  13. 13.
    Ghavanini AA, Kimpinski K. Revisiting the evidence for neuropathy caused by pyridoxine deficiency and excess. J Clin Neuromuscul Dis. 2014;16(1):25–31.CrossRefPubMedGoogle Scholar
  14. 14.
    van Hunsel F, Venhuis BJ, Keizers PH, Kant A. A ‘natural’ weight loss product containing sibutramine. Drug Test Anal 2016;8(3–4):311–4.CrossRefPubMedGoogle Scholar
  15. 15.
    Bijwerkingencentrum Lareb. Vitamine B6 in (multi)vitamine preparaten en neuropathie. [cited 22 Feb 2018].
  16. 16.
    Bijwerkingencentrum Lareb. Vitamine B6 in (multi)vitamine preparaten en neuropathie - update. https://www.larebnl/media/2927/signals_2016_pyridoxine_neuropathie_update.pdf. 2017. [cited 22 Feb 2018].
  17. 17.
    Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities (MedDRA). Drug Saf. 1999;20(2):109–17.CrossRefPubMedGoogle Scholar
  18. 18.
    Bankowski Z, Bruppacher R, Crusius I. Reporting adverse drug reactions, definition of terms and criteria for their use. Council International Organizations of Medical Sciences (CIOMS). 32. 1999. Ref Type: Report.Google Scholar
  19. 19.
    CIOMS Working Group IV. Benefit-risk balance for marketed drugs: Evaluating safety signals. 1998. Geneva. Ref Type: ReportGoogle Scholar
  20. 20.
    Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45.CrossRefPubMedGoogle Scholar
  21. 21.
    Hill AB. The environment and disease: association or causation? Proc R Soc Med. 1965;58:295–300.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Fedak KM, Bernal A, Capshaw ZA, Gross S. Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology. Emerg Themes Epidemiol. 2015;12:14.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Noren GN, Hopstadius J, Bate A. Shrinkage observed-to-expected ratios for robust and transparent large-scale pattern discovery. Stat Methods Med Res. 2013;22(1):57–69.CrossRefPubMedGoogle Scholar
  24. 24.
    Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, et al. A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol. 1998;54(4):315–21.CrossRefPubMedGoogle Scholar
  25. 25.
    Mitwalli A, Blair G, Oreopoulos DG. Safety of intermediate doses of pyridoxine. Can Med Assoc J. 1984;131(1):14.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Brush MG, Bennett T, Hansen K. Pyridoxine in the treatment of premenstrual syndrome: a retrospective survey in 630 patients. Br J Clin Pract. 1988;42(11):448–52.PubMedGoogle Scholar
  27. 27.
    Williams MJ, Harris RI, Dean BC. Controlled trial of pyridoxine in the premenstrual syndrome. J Int Med Res. 1985;13(3):174–9.CrossRefPubMedGoogle Scholar
  28. 28.
    European Commissionhealth & Consumer Protection Directorate-GeneraL. Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin B. SCF/CS/NUT/UPPLEV/16 Final. 19-10-2000. 19-10-2000. Ref Type: Report.Google Scholar
  29. 29.
    Gdynia HJ, Muller T, Sperfeld AD, Kuhnlein P, Otto M, Kassubek J, et al. Severe sensorimotor neuropathy after intake of highest dosages of vitamin B6. Neuromuscul Disord. 2008;18(2):156–8.CrossRefPubMedGoogle Scholar
  30. 30.
    Morra M, Philipszoon HD, D’Andrea G, Cananzi AR, L’Erario R, Milone FF. Sensory and motor neuropathy caused by excessive ingestion of vitamin B6: a case report. Funct Neurol. 1993;8(6):429–32.PubMedGoogle Scholar
  31. 31.
    Foca FJ. Motor and sensory neuropathy secondary to excessive pyridoxine ingestion. Arch Phys Med Rehabil. 1985;66(9):634–6.PubMedGoogle Scholar
  32. 32.
    Peltier AC, Russell JW. Advances in understanding drug-induced neuropathies. Drug Saf. 2006;29(1):23–30.CrossRefPubMedGoogle Scholar
  33. 33.
    Visser NA, Notermans NC, Degen LA, de Kruijk JR, van den Berg LH, Vrancken AF. Chronic idiopathic axonal polyneuropathy and vitamin B6: a controlled population-based study. J Peripher Nerv Syst. 2014;19(2):136–44.CrossRefPubMedGoogle Scholar
  34. 34.
    Edwards IR. Causality assessment in pharmacovigilance: still a challenge. Drug Saf. 2017;40(5):365–72.CrossRefGoogle Scholar
  35. 35.
    Theophile H, Andre M, Miremont-Salame G, Arimone Y, Begaud B. Comparison of three methods (an updated logistic probabilistic method, the Naranjo and Liverpool algorithms) for the evaluation of routine pharmacovigilance case reports using consensual expert judgement as reference. Drug Saf 2013;36(10):1033–44.CrossRefPubMedGoogle Scholar
  36. 36.
    Kane-Gill SL, Kirisci L, Pathak DS. Are the Naranjo criteria reliable and valid for determination of adverse drug reactions in the intensive care unit? Ann Pharmacother 2005;39(11):1823–7.CrossRefPubMedGoogle Scholar
  37. 37.
    Teschke R, Schmidt-Taenzer W, Wolff A. Spontaneous reports of assumed herbal hepatotoxicity by black cohosh: is the liver-unspecific Naranjo scale precise enough to ascertain causality? Pharmacoepidemiol Drug Saf 2011;20(6):567–82.CrossRefPubMedGoogle Scholar
  38. 38.
    Rolfes L, Kolfschoten J, van Hunsel F, van Puijenbroek E. The validity and reliability of a signal impact assessment tool. Pharmacoepidemiol Drug Saf. 2016;25(7):815–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Russom M, Tesfai D, Gebregiorgis S, Usman A, Mihreteab S, Bahta I, et al. Artesunate/amodiaquine-induced acute extrapyramidal reactions in children and younger adults: case series assessment. Drug Saf. 2016;39(8):763–8.CrossRefPubMedGoogle Scholar
  40. 40.
    EFSA Panel on Dietetic Products NaAN. Dietary reference values for vitamin B6. EFSA J 2016;14(6):4485.Google Scholar
  41. 41.
    Dodge T, Kaufman A. What makes consumers think dietary supplements are safe and effective? The role of disclaimers and FDA approval. Health Psychol. 2007;26(4):513–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Netherlands Food and Consumer Product Safety Authority (NVWA). Vitamine B6 uit voedingssupplementen BuRO NVWA. 2016 [cited 4 July 2017]; Available from
  43. 43.
    Rijksoverheid. Schippers stelt maximum norm vitamine B6. https://www.rijksoverheidnl/actueel/nieuws/2016/12/16/schippers-stelt-maximum-norm-vitamine-b6. 2016 [cited 6 Oct 2017].
  44. 44.
    Bernstein AL. Vitamin B6 in clinical neurology. Ann N Y Acad Sci. 1990;585:250–60.CrossRefPubMedGoogle Scholar
  45. 45.
    van Hunsel F, Harmark L, Pal S, Olsson S, van Grootheest K. Experiences with adverse drug reaction reporting by patients: an 11-country survey. Drug Saf. 2012;35(1):45–60.CrossRefPubMedGoogle Scholar
  46. 46.
    Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983;309(8):445–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Dalton K. Pyridoxine overdose in premenstrual syndrome. Lancet. 1985;1(8438):1168–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Parry GJ, Bredesen DE. Sensory neuropathy with low-dose pyridoxine. Neurology. 1985;35(10):1466–8.CrossRefPubMedGoogle Scholar
  49. 49.
    de Zeghler F, Przyrembel H, Chalmers RA, Wolff ED, Huijmans JG. Successful treatment of infantile type I primary hyperoxaluria complicated by pyridoxine toxicity. Lancet. 1985;2(8451):392–3.CrossRefGoogle Scholar
  50. 50.
    Friedman MA, Resnick JS, Baer RL. Subepidermal vesicular dermatosis and sensory peripheral neuropathy caused by pyridoxine abuse. J Am Acad Dermatol. 1986;14(5 Pt 2):915–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Waterston JA, Gilligan BS. Pyridoxine neuropathy. Med J Aust. 1987;146(12):640–2.PubMedGoogle Scholar
  52. 52.
    Albin RL, Albers JW, Greenberg HS, Townsend JB, Lynn RB, Burke JM Jr, et al. Acute sensory neuropathy-neuronopathy from pyridoxine overdose. Neurology. 1987;37(11):1729–32.CrossRefPubMedGoogle Scholar
  53. 53.
    Santoro L, Ragno M, Nucciotti R, Barbieri F, Caruso G. Pyridoxine neuropathy. A four-year electrophysiological and clinical follow-up of a severe case. Acta Neurol (Napoli). 1991;13(1):13–8.PubMedGoogle Scholar
  54. 54.
    Berger AR, Schaumburg HH, Schroeder C, Apfel S, Reynolds R. Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. Neurology. 1992;42(7):1367–70.CrossRefPubMedGoogle Scholar
  55. 55.
    Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. BMJ. 1999;318(7195):1375–81.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Bacharach R, Lowden M, Ahmed A. Pyridoxine toxicity small fiber neuropathy with dysautonomia: a case report. J Clin Neuromuscul Dis. 2017;19(1):43–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Netherlands Pharmacovigilance Centre Lareb’s-HertogenboschThe Netherlands
  2. 2.Department of Pharmacy: Pharmacotherapy and Pharmaceutical CareUniversity of GroningenGroningenThe Netherlands

Personalised recommendations