Article | Published:

Minerals, trace elements, Vit. D and bone health

Vitamin D supplementation has no effects on progression of motor dysfunction in amyotrophic lateral sclerosis (ALS)



To investigate the effects of cholecalciferol supplementation on the progression of motor disability in a cohort of amyotrophic lateral sclerosis (ALS) patients with low blood 25-hydroxyvitamin D3 [25(OH)D] levels, on the basis of the hypothesis of potential neuroprotective effects of vitamin D supplementation.


Forty-eight ALS patients, 34 with deficient (<20 ng/mL) and 14 with insufficient (20–29 ng/mL) serum levels of 25(OH)D, were randomized and treated by 3 different doses of cholecalciferol [50.000, 75.000 and 100.000 international units (IU) /month] and evaluated after 6-months. Assessment of motor dysfunction at baseline and after 6 months included ALS Functional Rating Scale-Revised (ALFRS-R) and upper motor neuron (UMN) scores and blood samples for 25(OH)D levels.


Clinical data of 33 patients were available after 6 months. Analysis of Covariance (ANCOVA), with pre-treatment measurements included as covariate, did not show statistically significant differences in the ALSFRS-R (p > 0.05) and UMN (p > 0.05) among the patient groups who underwent 3 different doses of cholecalciferol. Conversely, the treatment with 75.000 IU/month or 100.000 IU/month induced a significant increase in serum levels of 25(OH)D in comparison with the supplementation with 50.000 IU/month; no significant differences were found between 75.000 IU/month and 100.000 IU/month.


Our findings highlighted that 6-month supplementation of vitamin D in ALS patients had no significant effects on motor dysfunction. However, it is recommended to prevent medical complications of vitamin D deficiency in ALS patients as well as in other populations of neurodegenerative patients, characterized by low mobility and decreased sun exposure.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Lin AM, Chen KB, Chao PL. Antioxidative effect of vitamin D3 on zinc-induced oxidative stress in CNS. Ann N Y Acad Sci. 2005;1053:319–29.

  2. 2.

    Durk MR, Han K, Chow EC, Ahrens R, Henderson JT, Fraser PE, et al. 1α,25-Dihydroxyvitamin D3 reduces cerebral amyloid-β accumulation and improves cognition in mouse models of Alzheimer’s disease. J Neurosci. 2014;34:7091–101.

  3. 3.

    Gianforcaro A, Hamadeh MJ. Dietary vitamin D(3) supplementation at 10x the adequate intake improves functional capacity in the G93A transgenic mouse model of ALS, a pilot study. CNS Neurosci Ther. 2012;18:547–57.

  4. 4.

    Gianforcaro A, Solomon JA, Hamadeh MJ. Vitamin D3 at 50x the adequate intake attenuates functional decline in the G93A mouse model of amyotrophic lateral sclerosis, but is toxic in females. PLoS ONE. 2013;8:e30243.

  5. 5.

    Di Somma C, Scarano E, Barrea L, Zhukouskaya VV, Savastano S, Mele C, et al. Vitamin D and Neurological Diseases: An Endocrine View. Int J Mol Sci. 2017;18:E2482.

  6. 6.

    Iacopetta K, Collins-Praino LE, Buisman-Pijlman FTA, Liu J, Hutchinson AD, Hutchinson MR. Are the protective benefits of vitamin D in neurodegenerative disease dependent on route of administration? A systematic review. Nutr Neuroscience. 2018; e-pub ahead of print 9 July 2018;

  7. 7.

    Moghimi E, Solomon JA, Gianforcaro A, Hamadeh MJ. Dietary vitamin D3 restriction exacerbates disease pathophysiology in the spinal cord of the G93A mouse model of amyotrophic lateral sclerosis. PLoS ONE. 2015;10:e0126355.

  8. 8.

    Solomon JA, Gianforcaro A, Hamadeh MJ. Vitamin D3 deficiency differentially affects functional and disease outcomes in the G93A mouse model of amyotrophic lateral sclerosis. PLoS ONE. 2011;6:e29354.

  9. 9.

    Lương K, Nguyễn LTH. Roles of vitamin D in amyotrophic lateral sclerosis: possible genetic and cellular signaling mechanisms. Mol Brain. 2013;6:16.

  10. 10.

    Atif F, Sayeed I, Ishrat T, Stein DG. Progesterone with vitamin D affords better neuroprotection against excitotoxicity in cultured cortical neurons than progesterone alone. Mol Med. 2009;15:328–36.

  11. 11.

    Garcion E, Sindji L, Leblondel G, Brachet P, Darcy F. 1,25-dihydroxyvitamin D3 regulates the synthesis of γ-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J Neurochem. 1999;73:859–66.

  12. 12.

    Byers S, Shah S. Vitamin D and the regulation of Wnt/beta-catenin signaling and innate immunity in colorectal cancer. Nutr Rev. 2007;65:S118–20.

  13. 13.

    Sato Y, Honda Y, Asoh T, Kikuyama M, Oizumi K. Hypovitaminosis D and decreased bone mineral density in amyotrophic lateral sclerosis. Eur Neurol. 1997;37:225–9.

  14. 14.

    Paganoni S, Macklin EA, Karam C, Yu H, Gonterman F, Fetterman KA, et al. Vitamin D levels are associated with gross motor function in amyotrophic lateral sclerosis. Muscle Nerve. 2017;56:726–31.

  15. 15.

    Karam C, Barrett MJ, Imperato T, Macgowan DJ, Scelsa S. Vitamin D deficiency and its supplementation in patients with amyotrophic lateral sclerosis. J Clin Neurosci. 2013;20:1550–3.

  16. 16.

    Camu W, Tremblier B, Plassot C, Alphandery S, Salsac C, Pageot N, et al. Vitamin D confers protection to motoneurons and is a prognostic factor of amyotrophic lateral sclerosis. Neurobiol Aging. 2014;35:1198–205.

  17. 17.

    Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169:13–21.

  18. 18.

    Blasco H, Madji Hounoum B, Dufour-Rainfray D, Patin F, Maillot F, Beltran S, et al. Vitamin D is not a protective factor in ALS. CNS Neurosci Ther. 2015;21:651–6.

  19. 19.

    Libonati L, Onesti E, Gori MC, Ceccanti M, Cambieri C, Fabbri A, et al. Vitamin D in amyotrophic lateral sclerosis. Funct Neurol. 2017;32:35–40.

  20. 20.

    Woodford HJ, Barrett S, Pattman S. Vitamin D: too much testing and treating? Clin Med (Lond). 2018;18:196–200.

  21. 21.

    Aspray TJ, Bowring C, Fraser W, Gittoes N, Javaid MK, Macdonald H, et al. National Osteoporosis Society vitamin D guideline summary. Age Ageing. 2014;43:592–5.

  22. 22.

    Brooks BR, Miller RG, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Mot Neuron Disord. 2000;1:293–9.

  23. 23.

    Turner MR, Cagnin A, Turkheimer FE, Miller CC, Shaw CE, Brooks DJ, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [(11)C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15:601–9.

  24. 24.

    O’Connell NS, Dai L, Jiang Y, Speiser JL, Ward R. Methods for analysis of pre-post data in clinical research: a comparison of five common methods. J Biom Biostat. 2017;8:2.

  25. 25.

    Suzuki M, Yoshioka M, Hashimoto M, Murakami M, Noya M, Takahashi D, et al. Randomized, double-blind, placebo- controlled trial of vitamin D supplementation in Parkinson disease. Am J Clin Nutr. 2013;97:1004–13.

  26. 26.

    Stein MS, Scherer SC, Ladd KS, Harrison LC. A randomized controlled trial of high-dose vitamin D2 followed by intranasal insulin in Alzheimer’s disease. J Alzheimer’s Dis. 2011;26:477–84.

  27. 27.

    Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman CH, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014;71:306–14.

  28. 28.

    Gangwar AK, Rawat A, Tiwari S, Tiwari SC, Narayan J, Tiwari S. Role of vitamin-D in the prevention and treatment of Alzheimer’s disease. Indian J Physiol Pharmacol. 2015;59:94–9.

  29. 29.

    Munger KL, Kochert K, Simon KC, Kappos L, Polman CH, Freedman MS, et al. Molecular mechanism underlying the impact of vitamin D on disease activity of MS. Ann Clin Transl Neurol. 2014;1:605–17.

  30. 30.

    Bhargava P, Gocke A, Calabresi PA. 1,25-Dihydroxyvitamin D3 impairs the differentiation of effector memory T cells in vitro in multiple sclerosis patients and healthy controls. J Neuroimmunol. 2015;279:20–4.

  31. 31.

    Simpson S Jr, Taylor B, Blizzard L, Ponsonby AL, Pittas F, Tremlett H, et al. Higher 25-hydroxyvitamin D is associated with lower relapse risk in multiple sclerosis. Ann Neurol. 2010;68:193–203.

  32. 32.

    Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, et al. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76:540–8.

  33. 33.

    Sotirchos ES, Bhargava P, Eckstein C, van Haren K, Baynes N, Ntranos A, et al. Safety and immunologic effects of high- vs low-dose cholecalciferol in multiple sclerosis. Neurology. 2016;86:382–90.

  34. 34.

    Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermatoendocrinol. 2015;6:e983401.

  35. 35.

    Yang J, Park JS, Oh KW, Oh SI, Park HM, Kim SH. Vitamin D levels are not predictors of survival in a clinic population of patients with ALS. J Neurol Sci. 2016;367:83–8.

  36. 36.

    Finamor DC, Sinigaglia-Coimbra R, Neves LC, Gutierrez M, Silva JJ, Torres LD, et al. A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. Dermatoendocrinol. 2013;5:222–34.

  37. 37.

    Rolland Y, de Souto Barreto P, Abellan Van Kan G, Annweiler C, Beauchet O, Bischoff-Ferrari H, et al. Vitamin D supplementation in older adults: searching for specific guidelines in nursing homes. J Nutr Health Aging. 2013;17:402–12.

  38. 38.

    Zittermann A, Prokop S, Gummert JF, Borgermann J. Safety issues of vitamin D supplementation. Anticancer Agents Med Chem. 2013;13:4–10.

  39. 39.

    Hackman KL, Gagnon C, Briscoe RK, Lam S, Anpalahan M, Ebeling PR. Efficacy and safety of oral continuous low-dose versus short-term high-dose vitamin D: a prospective randomised trial conducted in a clinical setting. Med J Aust. 2010;192:686–9.

  40. 40.

    Ding H, Dhima K, Lockhart KC, Locascio JJ, Hoesing AN, Duong K, et al. Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study. Neurology. 2013;81:1531–7.

  41. 41.

    Zhao Y, Sun Y, Ji HF, Shen L. Vitamin D levels in Alzheimer’s and Parkinson’s diseases: a meta-analysis. Nutrition. 2013;29:828–32.

  42. 42.

    Wicherts IS, van Schoor NM, Boeke AJ, Visser M, Veeg DJ, Smit J, et al. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab. 2007;92:2058–65.

  43. 43.

    Fraser WD, Milan AM. Vitamin D assays: past and present debates, difficulties, and developments. Calcif Tissue Int. 2013;92:118–27.

  44. 44.

    Littlejohns TJ, Henley WE, Lang IA, Annweiler C, Beauchet O, Chaves PH, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 2014;83:920–8.

  45. 45.

    Chun RF, Peercy BE, Orwoll ES, Nielson CM, Adams JS, Hewison M, et al. Vitamin D and DBP: the free hormone hypothesis revisited. J Steroid Biochem Mol Biol. 2014;144:132–7.

Download references


The authors are grateful to all patients with ALS who kindly agreed to take part in this research.

Author information

FT, MS, GS, MRM, and GT conceived and designed the experiments; FT, MS, CP, AB, AR, LL, SE, and DR performed the experiments; FT, MS, CP, and GS analyzed the data; FT, MS, CP, AB, AR, LL, SE, DR, MRM, and GT contributed reagents/materials/analysis tools; FT, MS, GT, and GS wrote and/or revised the paper.

Correspondence to Francesca Trojsi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Table 1

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3