Intravenous ascorbic acid

In patients suffering from malnutrition or malabsorption, intravenous ascorbic acid can be used to treat deficiency. For people who are receiving all of their nutrient requirements via total parenteral nutrition there are vitamin products that include ascorbic acid.[8]

Ascorbic acid operates as an anti-oxidant and essential enzyme cofactor in the human body. In in vitro studies, the primary mechanism of high dosage intravenous ascorbic acid can be related to ascorbic acid's pro-oxidant activity, whereby hydrogen peroxide is formed.[3][4][5] In the extracellular fluid of cells, ascorbic acid dissociates into an ascorbate radical upon the reduction of transition metal ions, such as ferric or cupric cations.[3] These transition metal ions will then reduce dissolved oxygen into a superoxide radical- this will then react with hydrogen to form hydrogen peroxide.[4]

Furthermore, according to Fenton chemistry, these transition metal ions can be further oxidised by hydrogen peroxide to generate a highly reactive hydroxyl radical.[6] The formation of hydrogen peroxide and hydroxyl radicals is believed to induce cytotoxicity and apoptosis of cancer cells.[6] Although many in vitro studies have studied hydrogen peroxide generation by ascorbic acid, the pharmacological mechanism of intravenous ascorbic acid in vivo is still unclear.[6]

Although the pharmacology of ascorbic acid had been studied since its discovery in the 1930s,[11] the method of administration and its medicinal potential to human patients was not investigated until the 1940s.[12] In 1949, American physician, Frederick Klenner, published his scientific report, “The Treatment of Poliomyelitis and Other Virus Diseases with ascorbic acid”,[13] which detailed the use of intravenous ascorbic acid to treat polio in children.[12] Although Klenner's attempts were unsuccessful, his research pioneered future studies investigating the medicinal role of intravenous ascorbic acid. Klenner's work was recognised by Linus Pauling in the foreword to the Clinical Guide: "Dr. Fred Klenner's early research reports provide much information on the use of high-dose ascorbic acid for the prevention and cure of many diseases, and these reports are still important."[14]

Nobel Prize winner, Linus Pauling, is recognised as one of the early pioneers of ascorbic acid research

Nobel Prize winner and biochemist, Linus Pauling, was pivotal in the re-emergence of intravenous ascorbic acid research. Over the course of the 1970s, Pauling would begin a long-term collaboration with fellow physician, Ewan Cameron, on the medical potential of intravenous ascorbate acid as cancer therapy in terminally ill patients. In 1976, Pauling and Cameron co-authored a study whereby a group of 100 terminal cancer patients underwent supplementary ascorbic acid therapy (10g/day by intravenous infusion and oral thereafter) and the control group of 1,000 patients did not.[15] Their findings reported that the survival rate of the terminal cancer patients increased by four-fold, compared to the control group, stating that: "the treatment of ascorbate in amounts of 10g/day or more is of real value in extending the life of patients with advanced cancer."[15]

Subsequent studies by Pauling and Cameron hypothesised that ascorbic acid's role in enhanced collagen production would lead to the encapsulation of tumours and thus, protect normal tissue from metastasis.[16] Following these findings, Pauling became a strong advocate for vitamin megadosing and continued to investigate the medicinal potential of intravenous ascorbic acid across a range of illnesses, including: HIV transmission, the common cold, atherosclerosis, and angina pectoris.[17][18][19]

The efficacy of intravenous ascorbic acid therapy came under scrutiny of the medical and science community, following the numerous high-profile studies authored by Linus Pauling in the 1970s.[5] The experimental design of Pauling and Cameron's 1976 publication, "Supplemental ascorbate in the supportive treatment of cancer",[15] had garnered considerable criticism as it was neither randomised nor placebo controlled. To test the validity of Pauling and Cameron's findings, the Mayo Clinic conducted three independent experiments in 1979, 1983 and 1985, whereby terminal cancer patients were given doses of oral ascorbic acid under randomised, double bind and placebo-controlled conditions.[20][21][22] All studies concluded that high doses of oral ascorbic acid were not effective against cancer.

In the 2000s, new research highlighted the important pharmacokinetic differences between intravenous infusions of ascorbic acid and oral supplementation; ultimately, these findings indicated that oral supplementation produces lower serum concentrations of ascorbic acid, as opposed to intravenous administration.[23]

The use of intravenous ascorbic acid in the treatment of cancer is a contentious issue. There is no evidence to indicate that intravenous ascorbic acid therapy can cure cancer.[24][22] However, reviews suggest therapeutic value to cancer patients undergoing treatment.[2][3][4][5][7][6][16] According to the U.S. Food and Drug Administration (FDA), high-dose vitamin C (such as intravenous ascorbic acid therapy) has not been approved as a treatment for cancer or any other medical condition.[25]

Cancer patients often have a compromised ascorbic acid status due to oxidative stress and chronic inflammation caused by the “metabolic state of the malignancy and its effects on host metabolism, the catabolic effects of antineoplastic therapy, and the physiologic stresses of disease processes”.[26] Therefore, high-dosages of ascorbic acid are administered intravenously to supplement these deficiencies.[1] The use of intravenous ascorbic acid in cancer patients has been shown to reduce inflammation, improve nutrient deficiencies and also, reduce post-oncological side effects related to chemotherapy or radiation therapy.[1]

As intravenous ascorbic acid therapy is currently used as a complementary treatment for cancer patients, there many been multiple studies devoted to investigating the medicinal properties of ascorbic acid. The use of high-dosage intravenous ascorbic acid as a cancer treatment was first promoted by Linus Pauling and Ewan Cameron in the 1970s;[15][16] however, these findings were not reproduced using oral administration by subsequent Mayo Clinic studies in the 1980s.[20][21][22] Nonetheless, the turn of the 21st century saw a renewed interest in the medical potential of intravenous ascorbic acid therapy. In the early 2010s, in vitro preclinical and clinical trials were undertaken to investigate the pharmacological mechanism of action of intravenous ascorbic acid therapy.[27][28] These findings demonstrated ascorbic acid's pro-oxidant capabilities to produce hydrogen peroxide and thus, proposed a possible pharmacological mechanism of action against cancer cells. Nonetheless, ascorbic acid's potential as an anti-tumour therapy is still dubious, as other pro-oxidant substances (such as menadione[29][30]) have been unsuccessful in the treatment of cancer patients.[31]

In 2010, an academic review which detailed 33 years of ascorbic acid and cancer research stated: "we still do not know whether Vitamin C has any clinically significant anti-tumor activity. Nor do we know which histological types of cancers, if any, are susceptible to this agent. Finally, we don't know what the recommended dose of Vitamin C is, if there is indeed such a dose, that can produce an anti-tumor response".[32]

As of April 2020, there are ten ongoing clinical trials of intravenous vitamin C for people who are hospitalized and severely ill with COVID-19; two placebo controlled (China, Canada) and one with no control (Italy).[33]