Written by Luc Geeraert and the CAM-Cancer Consortium.
Updated July 9, 2014

Intravenous high-dose vitamin C

Is it safe?

Adverse events

Vitamin C itself is essentially non-toxic. In general, adverse events after high-dose intravenous vitamin C were mild, and consistent with side effects occurring due to rapid infusion of any high-osmolarity solution, and were preventable by drinking fluids before and during the infusion.1,35,38

Contraindications

Patients with glucose 6-phosphate dehydrogenase deficiency were found to be at risk to experience haemolysis (breakdown of red blood cells) following administration of high doses of vitamin C.53,54 Therefore patients should be screened for this metabolic deficiency before initiation of therapy.

Oxalic acid is an end product of metabolic oxidation of vitamin C. Oxalate nephropathy has been reported after administration of intravenous vitamin C in subjects with renal dysfunction.55-57 However, in people with normal renal function, the risk of oxalate crystallization in the kidney was not increased.58 Therefore, high-dose intravenous vitamin C is contraindicated in people with renal dysfunction, and a history of kidney stones should be reviewed.

Another concern is life-threatening bleeding (haemorrhage) and rapid necrosis of tumours.59 Authors therefore advised gradual increase of intravenous vitamin C whilst monitoring the patient.

Interactions

As vitamin C at physiological concentrations has antioxidant properties, it is conceivable that it may attenuate the anti-cancer activity of therapies generating increased reactive oxygen species, e.g. radiation and some chemotherapeutics.

Several studies on interactions of vitamin C and anti-cancer therapies have been performed, both in vitro and in vivo.36-37,60-68 Vitamin C was found to reinforce the action of radiation and several chemotherapeutics, while it has no influence or even diminishes the effects of other chemotherapeutics. In this respect, the results of Heaney et al. are worth mentioning.69 When comparing the therapeutic efficacy of a range of anticancer agents in cell lines and tumour-bearing mice with and without pretreatment with dehydroascorbic acid (the oxidized form of vitamin C), it was found that the latter caused a dose-dependent reduction of cytotoxicity; however, later studies questioned the relevance of these findings when using pharmacological concentrations of vitamin C.63 Also, several studies showed that vitamin C could abrogate the effects of bortezomib when taken simultaneously.70

In conclusion, negative interactions may occur when adding vitamin C to conventional anti-cancer therapy, making the conventional therapy less potent. 

Citation Luc Geeraert, CAM-Cancer Consortium. Intravenous high-dose vitamin C [online document]. http://ws.cam-cancer.org/The-Summaries/Other-CAM/Intravenous-high-dose-vitamin-C. July 9, 2014.

References

  1. Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, Rousseau C, Robitaille L, Miller WH Jr. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann. Oncol. 2008 November;19(11):1969-74.
  2. Stephenson CM, Levin RD, Spector T, Lis CG. Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer. Cancer Chemother Pharmacol. 2013 Jul;72(1):139-146.
  3. Riordan HD, Hunninghake RB, Riordan NH, Jackson JJ, Meng X, Taylor P, Casciari JJ, González MJ, Miranda-Massari JR, Mora EM, Rosario N, Rivera A. Intravenous ascorbic acid: protocol for its application and use. P R Health Sci. J. 2003 September;22(3):287-90.
  4. Allwood MC, Kearney MC. Compatibility and stability of additives in parenteral nutrition admixtures. Nutrition. 1998 September;14(9):697-706.
  5. Dupertuis YM, Morch A, Fathi M, Sierro C, Genton L, Kyle UG, Pichard C. Physical characteristics of total parenteral nutrition bags significantly affect the stability of vitamins C and B1: a controlled prospective study. JPEN J. Parenter. Enteral. Nutr. 2002 September-October;26(5):310-316.
  6. Lavoie JC, Chessex P, Rouleau T, Migneault D, Comte B. Light-induced byproducts of vitamin C in multivitamin solutions. Clin. Chem. 2004 January;50(1):135-140.
  7. Cabanillas F. Vitamin C and cancer: what can we conclude - 1,609 patients and 33 years later? P R Health Sci. J. 2010 September;29(3):215-217.
  8. Szent-Györgyi, A. Observations on the function of peroxidase systems and the chemistry or the adrenal cortex: description of a new carbohydrate derivative. Biochem. J. 1928;22:1387-1409.
  9. Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim. Biophys. Acta. 2012 Dec;1826(2):443-457.
  10. Cameron E, Pauling L, Leibovitz B. Ascorbic acid and cancer: a review. Cancer Research. 1979 March;39(3):663-681.
  11. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. USA. 1976;73:3685-3689.
  12. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc. Natl. Acad. Sci. USA. 1978;75:4538-4542.
  13. Creagan ET, Moertel CG, O’Fallon JR, Schutt AJ, O’Connel MJ, Rubin J, Frytak S. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. New Engl. J. Med. 1979 September;301(13):687-690.
  14. Moertel CG, Fleming TR, Creagan ET, Rubin J, O’Connel MJ, Ames MM. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. New Engl. J. Med. 1985 January;312(3):137-141.
  15. Wittes RE. Vitamin C and cancer. New Engl. J. Med. 1985 January;312(3):178-179.
  16. Golde DW. Vitamin C in cancer. Integr. Cancer Ther. 2003 June;2(2):158-159.
  17. Levine M, Espey MG, Chen Q. Losing and finding a way at C: new promise for pharmacologic ascorbate in cancer treatment. Free Rad. Biol. Med. 2009 July;47(1):27-29.
  18. Levine M, Conry-Cantilena C, Wang Y, Welch RW, Washko PW, Dhariwal KR, Park JB, Lazarev A, Graumlich JF, King J, Cantilena LR. Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci. USA. 1996 April;93:3704-3709.
  19. Levine M, Wang Y, Padayatti SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc. Natl. Acad. Sci. USA. 2001 August;98(17):9842-9846.
  20. Graumlich JF, Ludden TM, Conry-Cantilena C, Cantilena Jr LR, Wang Y, Levine M. Pharmacokinetic model of ascorbic acid in healthy male volunteers during depletion and repletion. Pharm. Res. 1997 September;14(9):1133-1139.
  21. Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann. Intern. Med. 2004 April;140(7):533-537.
  22. Casciari JJ, Riordan NH, Schmidt TL, Meng XL, Jackson JA, Riordan HD. Cytotoxicity of ascorbate, lipoic acid, and other antioxidants in hollow fibre in vitro tumours. Br. J. Cancer. 2001 June;84(11):1544-50.
  23. Duconge J, Miranda-Massari JR, González MJ, Taylor PR, Riordan HD, Riordan NH, Casciari JJ, Alliston K. Vitamin C pharmacokinetics after continuous infusion in a patient with prostate cancer. Ann. Pharmacother. 2007 June;41(6):1082-1083.
  24. Padayatty SJ, Levine M. Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity. J. Am. Coll. Nutr. 2000 August;19(4):423-425.
  25. Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999;13:1007-1024.
  26. Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. USA. 2005 September;102(38):13604-13609.
  27. Frei B, Lawson S. Vitamin C and cancer revisited. Proc. Natl. Acad. Sci. USA. 2008 August;105(32):11037-11038.
  28. Chen Q, Espey MG, Sun AY, Lee JH, Krishna MC, Shacter E, Choyke PL, Pooput C, Kirk KL, Buettner GR, Levine M. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. USA. 2007 May;104(21):8749-8754.
  29. Chen Q, Espey MG, Sun AY, Pooput C, Kirk KL, Krishna MC, Khosh DB, Drisko J, Levine M. Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice. Proc. Natl. Acad. Sci. USA. 2008 August;105(32):11105-11109.
  30. Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic. Biol. Med. 2009 July;47(1):32-40.
  31. Oberley TD, Oberley LW. Antioxidant enzyme levels in cancer. Histol. Histopathol. 1997 April;12(2):525-535.
  32. Pollard HB, Levine MA, Eidelman O, Pollard M. Pharmacological ascorbic acid suppresses syngeneic tumor growth and metastases in hormone-refractory prostate cancer. In Vivo. 2010 May-June;24(3):249-255.
  33. Chen P, Yu J, Chalmers B, Drisko J, Yang J, Li B, Chen Q. Pharmacological ascorbate induces cytotoxicity in prostate cancer cells through ATP depletion and induction of autophagy. Anticancer Drugs. 2012 April;23(4):437-444.
  34. Mamede AC, Pires AS, Abrantes AM, Tavares SD, Gonçalves AC, Casalta-Lopes JE, Sarmento-Ribeiro AB, Maia JM, Botelho MF. Cytotoxicity of ascorbic acid in a human colorectal adenocarcinoma cell line (WiDr): in vitro and in vivo studies. Nutr Cancer. 2012;64(7):1049-57.
  35. Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010 July 7;5(7):e11414.
  36. Wilson MK, Baguley BC, Wall C, Jameson MB, Findlay MP. Review of high-dose intravenous vitamin C as an anticancer agent. Asia Pac J Clin Oncol. 2014 Mar;10(1):22-37.
  37. Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014 Feb 5;6(222):222ra18.
  38. Riordan HD, Casciari JJ, González MJ, Riordan NH, Miranda-Massari JR, Taylor P, Jackson JA. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. P R Health Sci. J. 2005;24(4):269-276.
  39. Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients' health-related quality of life after high dose vitamin C administration. J. Korean Med. Sci. 2007 February;22(1):7-11.
  40. Monti DA, Mitchell E, Bazzan AJ, Littman S, Zabrecky G, Yeo CJ, Pillai MV, Newberg AB, Deshmukh S, Levine M. Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. PLoS One. 2012;7(1):e29794.
  41. Welsh JL, Wagner BA, van't Erve TJ, Zehr PS, Berg DJ, Halfdanarson TR, Yee NS, Bodeker KL, Du J, Roberts LJ 2nd, Drisko J, Levine M, Buettner GR, Cullen JJ. Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. Cancer Chemother Pharmacol. 2013 Mar;71(3):765-775.
  42. Cameron E, Campbell A. The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem. Biol. Interact. 1974;9:285-315.
  43. Riordan H, Jackson J, Schultz M. Case Study: High Dose intravenous Vitamin C in the Treatment of a Patient with Adrenocarcinoma of the Kidney. J. Orthomol. Med. 1990;5:5-7.
  44. Jackson JA, Riordan HD, Hunninghake RE, Riordan N. High dose intravenous vitamin C and long time survival of a patient with cancer of head of the pancreas. J. Orthomol. Med. 1995;10:87-88.
  45. Riordan N, Jackson J, Riordan HD. Intravenous vitamin C in a terminal cancer patient. J. Orthomol. Med. 1996;11:80-82.
  46. Riordan HD, Jackson JA, Riordan NH, Schultz M. High-dose intravenous vitamin C in the treatment of a patient with renal cell carcinoma of the kidney. J. Orthomol. Med. 1998;13:72-73.
  47. Riordan NH, Riordan HD, Casciari, JJ. Clinical and experimental experiences with intravenous vitamin C. J. Orthomolec. Med. 2000;15(4):201-213.
  48. Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J. Am. Coll. Nutr. 2003 April;22(2):118-123.
  49. Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ. 2006 March;174(7):937-942.
  50. Cameron E, Campbell A. Innovation vs. quality control: an 'unpublishable' clinical trial of supplemental ascorbate in incurable cancer. Med. Hypotheses. 1991 November;36(3):185-189.
  51. Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J. Intravenous vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo. 2011 November-December;25(6):983-990.
  52. Mikirova N, Casciari J, Rogers A, Taylor P. Effect of high-dose intravenous vitamin C on inflammation in cancer patients. J Transl Med. 2012 Sep 11;10:189.
  53. Campbell GD Jr, Steinberg MH, Bower JD. Letter: Ascorbic acid-induced hemolysis in G-6-PD deficiency. Ann. Intern. Med. 1975 June;82(6):810.
  54. Rees DC, Kelsey H, Richards JD. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ. 1993 March;306(6881):841-842.
  55. McAllister CJ, Scowden EB, Dewberry FL, Richman A. Renal failure secondary to massive infusion of vitamin C. JAMA. 1984 October;252(13):1684.
  56. Lawton JM, Conway LT, Crosson JT, Smith CL, Abraham PA. Acute oxalate nephropathy after massive ascorbic acid administration. Arch. Intern. Med. 1985 May;145(5):950-951.
  57. Wong K, Thomson C, Bailey RR, McDiarmid S, Gardner J. Acute oxalate nephropathy after a massive intravenous dose of vitamin C. Aust. N. Z. J. Med. 1994 August;24(4):410-411.
  58. Robitaille L, Mamer OA, Miller WH Jr, Levine M, Assouline S, Melnychuk D, Rousseau C, Hoffer LJ. Oxalic acid excretion after intravenous ascorbic acid administration. Metabolism. 2009 February;58(2):263-269.
  59. Campbell A, Jack T. Acute reactions to mega ascorbic acid therapy in malignant disease. Scott. Med. J. 1979 April;24(2):151-153.
  60. Espey MG, Chen P, Chalmers B, Drisko J, Sun AY, Levine M, Chen Q. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med. 2011 June 1;50(11):1610-1619.
  61. Verrax J, Calderon PB. The controversial place of vitamin C in cancer treatment. Biochem. Pharmacol. 2008 December;76(12):1644-1652.
  62. Lamson DW, Brignall MS. Antioxidants and cancer therapy II: quick reference guide. Altern. Med. Rev. 2000 April;5(2):152-163.
  63. Frömberg A, Gutsch D, Schulze D, Vollbracht C, Weiss G, Czubayko F, Aigner A. Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs. Cancer Chemother Pharmacol. 2011 May;67(5):1157-1166.
  64. Shinozaki K, Hosokawa Y, Hazawa M, Kashiwakura I, Okumura K, Kaku T, Nakayama E. Ascorbic acid enhances radiation-induced apoptosis in an HL60 human leukemia cell line. J Radiat Res. 2011;52(2):229-237.
  65. Herst PM, Broadley KW, Harper JL, McConnell MJ. Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic. Biol. Med. 2012 Apr 15;52(8):1486-1493.
  66. Park JH, Davis KR, Lee G, Jung M, Jung Y, Park J, Yi SY, Lee MA, Lee S, Yeom CH, Kim J. Ascorbic acid alleviates toxicity of paclitaxel without interfering with the anticancer efficacy in mice. Nutr Res. 2012 Nov;32(11):873-83.
  67. Vuyyuri SB, Rinkinen J, Worden E, Shim H, Lee S, Davis KR. Ascorbic acid and a cytostatic inhibitor of glycolysis synergistically induce apoptosis in non-small cell lung cancer cells. PLoS One. 2013 Jun 11;8(6):e67081.
  68. Wei Y, Song J, Chen Q, Xing D. Enhancement of photodynamic antitumour effect with pro-oxidant ascorbate. Lasers Surg Med. 2012 Jan;44(1):69-75.
  69. Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, O'Connor OA. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res. 2008 October 1;68(19):8031-8038.
  70. Perrone G, Hideshima T, Ikeda H, Okawa Y, Calabrese E, Gorgun G, Santo L, Cirstea D, Raje N, Chauhan D, Baccarani M, Cavo M, Anderson KC. Ascorbic acid inhibits antitumor activity of bortezomib in vivo. Leukemia. 2009 September;23(9):1679-1686.