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FOR IMMEDIATE RELEASE

Orthomolecular Medicine News Service, Apr 23, 2020

Vitamin C Evidence for Treating Complications of COVID-19 and other Viral Infections



by Magnus P. F. Rasmussen

(OMNS Apr 23, 2020) - For medical professionals, COVID-19 patients and their relatives/families and anyone willing to learn more about vitamin C. A bit of information on vitamin D3, zinc and melatonin is included, too.



L-Ascorbic Acid molecular structure 3D and electron microscope photography of SARS-CoV-2 virus.

Licensing:

This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at Creative Commons' website: https://creativecommons.org/licenses/by/4.0/legalcode This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Legal Disclaimer:

This document does NOT provide medical advice. This document acts SOLELY for informational purposes and nothing stated in this document, including but not limited to text, URL link, scientific studies and other sources provided, should be considered medical advice.

Nor is it intended to be a substitute for ANY professional medical advice, including but not limited to the professional medical advice, diagnosis or treatment of a physician and/or a medical provider.

Do NOT disregard any professional medical advice or delay in seeking it because of anything you have read in this document. ALWAYS seek the advice of your physician or other qualified health care providers with any questions you may have regarding a medical condition and/or treatment before undertaking a new health care regimen.

Neither is this document to be taken as a reason to stop self isolating and social distancing amid the pandemic.

- Reliance on any information appearing in this document is SOLELY at your own discretion.

Read this before reading:

The document does not substitute reading the sources provided herein. Most of the document is a reading guide for most relevant sources on vitamin C and D for prevention and treatment of complications from COVID-19 and other viral infections.

I also highly encourage anyone reading this document, especially the medical professionals, to keep an open mind. I'm therefore hoping you will search for information about other micronutrients, supplements and/or pharmaceutical drugs that play an important role in immune function and possible prevention and treatment of COVID-19 and or other viral respiratory illnesses.

A nonexhaustive list of these micronutrients: vitamin C, D, E and A, zinc, selenium, magnesium, vitamin B6, iron and copper.

The Google Docs document this article is based on will receive regular updates and can be accessed with the following link: https://docs.google.com/document/d/1uLormkjoKO5JMkQh80-nGiKk-X5Ik5idi3gWqwd_Up4/edit

Abbreviations used:

IV-C: Intravenous Vitamin C

HDIV-C: High Dose Intravenous Vitamin C

NIH: National Institute of Health

CAM: Complementary and Alternative Medicine

RCT: Randomized Controlled Trial

HAT therapy/protocol: Hydrocortisone, Vitamin C and Thiamine therapy/protocol

SA: Sodium Ascorbate

AA: L-Ascorbic Acid

LEV-C: Liposomal Encapsulated Vitamin C

IV: Intravenous

Table of Contents

1. Vitamin C Safety Oral and Intravenous

1.1. Safety of Oral Vitamin C

1.2. Safety of IV-C

1.3. Vitamin C and Kidney Stones

1.4. G6PD Deficiency and Vitamin C

1.5. Vitamin C and Hemochromatosis

1.6. A Final Note

2. Efficacy and Benefits of IV vs Oral Vitamin C

3. IV-C Protocols, Administration, Cost and Dosing

4. Significant RCT's, Reviews, Meta-analyses and Articles on Vitamin C

4.1. RCT's and Studies

4.2. Meta-analyses

4.3. Reviews

4.4. Miscellaneous Articles

5. Studies and Trials on Vitamin C for Treatment of COVID-19

6. Orthomolecular Clinical Experience, Studies and Articles on Vitamin C

6.1. Clinical Experience and Observational Studies

6.2. Miscellaneous Research Papers, Articles and Slideshows on Vitamin C

6.3. Large Folders (ZIP), Link Collections and Comprehensive Articles on Multifaceted Orthomolecular Treatment of Viral Diseases

7. Alan Smith H1N1 Story and an Enterovirus Case Report

8. Immunoregulatory and Antiviral Properties of Vitamin D, Zinc and Melatonin 31

References

1. Vitamin C Safety Oral and Intravenous

This section contains carefully selected and compiled information on the safety of oral and intravenous (IV) vitamin C.

1.1. Safety of Oral Vitamin C

Oral supplementation of vitamin C is safe and well tolerated when not taken beyond bowel tolerance. Bowel tolerance is indicated by mild gastrointestinal symptoms such as: flatulence, belching, mild rumbling from the gastrointestinal tract, increased bowel movement and loose stools. Bowel tolerance is not indicated by severe gastrointestinal issues like diarrhea, abdominal pain, cramping and bloating and nausea. That's taking vitamin C past bowel tolerance, and it's not recommended unless the goal is to cleanse the gastrointestinal tract.

When taking very large and frequent (many times per day) oral dosages of vitamin C it could be potentially dangerous not to follow Dr. Robert F. Cathcart's advice on the symptoms of bowel tolerance and titrating vitamin C to bowel tolerance [1].

The original 1981 research paper by Cathcart discussed titrating to bowel tolerance with l-ascorbic acid (AA) - this was Cathcart's preferred variant of vitamin C. Cathcart said AA was the only form of oral vitamin C that could achieve a "clinical ascorbate effect".

According to Cathcart the usual bowel tolerance dosage depends on the severity of the disease. The dosage required to hit this level could be anything from 15g/day to +200g/day [1]. The severity of the disease is measured as the amount of inflammation and oxidation caused by reactive oxygen and nitrogen species (ROS/RNS). A 2007 literature review titled "Vitamin C may affect lung infections" reported this about the high bowel tolerance vitamin C dosages Cathcart had observed in his clinical practice [71]:

"Furthermore, it has been stated that patients with pneumonia can take up to 100 g/day of vitamin C without developing diarrhoea, possibly because of the changes in vitamin C metabolism caused by the severe infection."

1.2. Safety of IV-C

For nearly all people high dose intravenous vitamin C (HDIV-C) appears to be remarkably safe, well tolerated and without any serious adverse events in clinical trials and clinical practice of practitioners using it.

One of the lead National Institute of Health (NIH) nutrient researchers Sebastian J. Padayatty and colleagues came to the following conclusion in a study from 2010 about use of IV-C by integrative medicine practitioners [2]:

"Other than the known complications of IV vitamin C in those with renal impairment or glucose 6 phosphate dehydrogenase deficiency, high dose intravenous vitamin C appears to be remarkably safe"

The NIH - National Cancer Institute's article titled "High-Dose Vitamin C (PDQ(r))-Health Professional Version" about HDIV-C treatment for cancer had this to say about side effects [3]:

"Intravenous (IV) high-dose ascorbic acid has been generally well tolerated in clinical trials. [1-8] Renal failure after ascorbic acid treatment has been reported in patients with preexisting renal disorders. [9]

Case reports have indicated that patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency should not receive high doses of vitamin C because of the risk of developing hemolysis. [10-12]

Vitamin C may increase bioavailability of iron, and high doses of the vitamin are not recommended for patients with hemochromatosis. [13]"

The article's section "Human/Clinical Studies" appears to indicate that the NIH has not yet been able to establish an upper limit for dosing & infusion rate for HDIV-C. This applies only to people without existing renal disorders, hemochromatosis or G6PD deficiency, since people suffering from any of these illnesses were excluded from the clinical trials.

The current largest dosage and infusion rate investigated for cancer patients in clinical trials is 1.5g/kg/day and infusion rate of 1g/minute. They did not appear to cause any serious adverse events [3]. Hence, no upper limit on dose and infusion rate for vitamin C has been established in clinical trials.

A review about critically ill patients with septic shock Markos G. Kashiouris, Alpha A. Fowler and colleagues reported the following about intravenous vitamin C (IV-C) and side effects:[4]

"In all the sepsis trials mentioned above, HDIVC was found to be safe and no significant side-effects were identified. Additionally, two studies in non-medical patients did not report adverse side effects."

The trials mentioned in the review excluded those with renal impairment, hemochromatosis & G6PD deficiency [4].

1.3. Vitamin C and Kidney Stones

A prospective case series study conducted by Melissa Prior et al., which was the first long term study to examine the relationship between IV-C administration and renal stones, reported the following [5]:

"No renal stones were reported by any patients in the study, despite 8% of the patients having a history of renal stones. In addition, the majority of patients investigated had stable renal function during the study period as evidenced by little change in serum creatinine levels and estimated glomerular filtration rate (eGFR) following IVC. In conclusion, IVC therapy was not associated with patient-reported renal stones."

In the previously mentioned septic shock article the researchers reported that vitamin C hasn't caused renal stones or hyperoxaluria in any clinical trials [4]:

"One proposed side effect of HDIVC is an increased propensity for oxalate kidney stone production, but this has not been shown in any clinical trials to date."

In addition, case reports of vitamin C therapy causing renal stones or renal failure are rare [2].

The limited evidence in the medical literature on vitamin C induced renal stones suggests vitamin C will only cause renal stones in patients with renal insufficiency.

It's therefore plausible to conclude it's highly unlikely for HDIV-C or daily multigram oral supplementation to cause renal stone precipitation in people without renal insufficiency.

1.4. G6PD Deficiency and Vitamin C

While IV-C is usually not recommended for patients with G6PD deficiency Ron Hunninghake of the Riordan Clinic Research Institute has said IV-C appears to be safe for patients with G6PD deficiency at moderate infusion dosages of 25g [6] (s. 4 p. 14):

"Hemolysis has been reported in patients with G6PD deficiency when given high-dose IVC (Campbell, et al., 1975). The G6PD level should be assessed before beginning IVC. (At the Riordan Clinic, G6PD readings have yielded five cases of abnormally low levels. Subsequent IVC at 25 grams or less showed no hemolysis or adverse effects.)"

This evidence, while limited, seems to indicate IV-C at moderate infusion dosages of 25g appears to be safe and well tolerated in patients with G6PD deficiency.

The Riordan Clinic recommends checking red blood cell G6PD levels prior to onset of IV-C therapy [6] (s. 3 p. 13.).

1.5. Vitamin C and Hemochromatosis

The relationship between vitamin C and hemochromatosis appears to be based on the theory of "iron overload" as stated here by the NIH [3]:

"Vitamin C may increase bioavailability of iron, and high doses of the vitamin are not recommended for patients with hemochromatosis. [13]"

While there are reports of vitamin C therapy causing "iron overload", these are rare. In addition, no studies on vitamin C supplementation in people with hemochromatosis have been conducted to date. Some evidence from the Riordan Clinic seems to conflict with the theoretical premise of vitamin C and "iron overload". Ron Hunninghake, MD from the Riordan Clinic reported the following [6] (s. 9 p. 15):

"There have been some reports of iron overload with vitamin C therapy. We have treated one patient with hemochromatosis with high-dose IVC with no adverse effects or significant changes in the iron status."

Steve Hickey PhD had the following to say about high dose vitamin C and hemochromatosis [7]:

"There is a theoretical danger but the actual reports are sparse and unclear. I expect that if vitamin C really did have such a side-effect, its detractors would have had a field day. Having read much of the available evidence, I consider the benefits of high dose vitamin C to exceed greatly any (largely theoretical) side-effects." - from the book "Ascorbate: The Science of Vitamin C", by Hickey S and Roberts H.

The limited evidence in the medical literature on megadose vitamin C and hemochromatosis suggests vitamin C is fairly safe, and the evidence to discourage its use appears to be weak, largely unfounded and based on theory, not reality.

Despite this, caution is still advised for patients with hemochromatosis using IV-C therapy, and blood levels should be monitored during treatment.

Another word of caution for oral supplementation: People with hemochromatosis taking large multigram daily doses of oral vitamin C should be taking it between meals. Additionally, they should take measures to lower blood ferritin levels like blood donation or lowering dietary iron intake.

1.6. A Final Note

We can conclude that vitamin C is a very safe biomolecule, and it can be used in massive dosages by those not suffering from G6PD deficiency, hemochromatosis or renal insufficiency. It also appears vitamin C will only cause renal stones in people with renal insufficiency.

For patients with G6PD deficiency, limited patient data from the Riordan Clinic showed that: "Subsequent IV-C at 25 grams or less showed no hemolysis or adverse effects"

For people with hemochromatosis, while caution is still advised vitamin C appears to be fairly safe, and the evidence to discourage its use appears to be weak, largely unfounded and based on theory, not reality.

Science has proven that Frederick Robert Klenner was right when he said: "Vitamin C is the safest substance available to the physician."

2. Efficacy and Benefits of IV vs Oral Vitamin C

In mainstream medicine and some of the integrative and orthomolecular medicine community there's a strong consensus that oral vitamin C cannot achieve the clinical effects associated with pharmacological ascorbate (1-100mM/L) blood levels but at most blood concentrations of 0.2mM/L. This notion is based on research that investigated vitamin C blood levels following oral supplementation [8].

In mainstream medicine there's also another widely accepted notion that only 200-250mg/day of oral vitamin C can be absorbed. However clinical experience from Robert F. Cathcart, a prominent practitioner advocating for oral megadoses of vitamin C, and new research seems to contradict this notion [9].

Owen Fonorow did a case study on a diabetic 61 year old male. He monitored blood vitamin C concentrations every minute following ingestion - something that's never been done before. Because vitamin C uses the same cell membrane transporters as glucose, a diabetic study participant is ideal.

Based on findings from the second experiment Fonorow estimated 4000mg of AA absorption in a short time frame (250mg/minute for 40 minutes) is possible. The paper mentioned that AA absorption was efficient [9]:

"Indeed, the initial oral measurements appear slightly greater than were obtained with the IV/C suggesting an efficient absorption through the stomach wall."

In a third experiment absorption and blood levels were monitored following ingestion of a 10g gulp of AA or 11.3g of SA. AA had rapid absorption and achieved remarkably high vitamin C blood levels in the millimolar range (>1mM/L), peaking as high as >5mM/L at 3-7 minutes. This effect was not seen for SA which had significantly slower absorption - that was more like a timed release.

Fonorow ended the article by stating the following about Cathcart [9]: "Cathcart also reported that he could only obtain 'a clinical ascorbate effect' orally with ascorbic acid, not mineral ascorbates. We might speculate that an increased stomach acidity in the sick can at least in part explain Cathcart's observations."

The rapid and early absorption and utilization of AA presented here may help explain what Cathcart reported. While the sample size from this case study is tiny, the remarkable pharmacokinetics of AA observed does seem to confirm the clinical observations of Dr. Cathcart [9] [1].

Some practitioners who have used LEV-C, including Thomas E. Levy, claim that in some instances it can have effects that are similar or superior to IV-C.

This could be due to the following unique features of LEV-C [10]:

It can be transported into the cells through the cell membrane without any energy consumption. It has a high bioavailability. The majority of LEV-C gets directly into the cell cytoplasm. This doesn't happen with oral non-LEV-C and IV-C, where only a small amount reaches cell cytoplasm and the majority gets excreted in urine before reaching cell cytoplasm. It's absorbed and transported through the lymphatic system.

While the oral AA findings from the case study and the unique features of LEV-C sound impressive, HDIV-C can achieve much higher and more stable vitamin C blood levels (>20mM/L) than oral vitamin C [3]. Furthermore IV-C is more viable than oral SA and AA for hospitalized patients for multiple reasons.

First, titrating to bowel tolerance isn't possible for many ICU patients, some of whom are in critical condition. Second, it could be more convenient for hospitalized patients than oral vitamin C. Third, IV-C allows for higher and more effective doses of vitamin C. Fourth, the uptake into the bloodstream is 100%, and the rate of infusion can be controlled and fine tuned. And fifth, IV-C can be given to patients no matter how sick they're as long as they don't suffer from renal failure or preexisting renal disorders.

In addition, as previously mentioned, one 25g IV-C infusion can safely be used in patients with G6PD deficiency.

Many integrative medicine vitamin C advocates have recommended combining IV-C with oral supplementation when possible. The LEV-C - because of its aforementioned unique features - seems to be the best candidate for hospitalized patients [10]. Oral AA is the second best candidate.

If the clinician wants to use massive doses of vitamin C orally as an adjunct til IV-C, AA should be used instead of SA due to its superior pharmacokinetics and nonexistent sodium load, which makes titrating to bowel tolerance an easier and more effective strategy [9].

A word of caution: Hospitalized patients should not take oral vitamin C past bowel tolerance.

3. IV-C Protocols, Administration, Cost and Dosing

Given the relatively novel nature of IV-C in mainstream medical research, most of the information in the articles listed here is based on clinical experience of medical practitioners using megadose vitamin C. The safety aspect of vitamin C was explained in a previous section titled "1. Vitamin C Safety Oral and Intravenous".

The recommended IV-C dosages for treating COVID-19 infection in hospitalized patients varies. The lowest dosages are 6gram/day, 50-100mg/kg/day [11] [12] [17]. Moderate dosages are 200mg/kg/day, 12gram/day and 25gram/day [11] [12] [14] [17]. The HDIV-C are 30-60g/day [18], and as high as >1g/kg/day for mild and moderate cases and >3g/kg/day for severe cases [14].

The IV-C administration strategies are different in other aspects. Some protocols have used multiple hour continuous infusion of IV-C two times per day [85], while others have used 1-2x 30-60minute infusions per day [14]. Most of the protocols use IV-C infusions every 6-8 hours [14] [17].

The duration of IV-C treatment and dosages required depends on the severity and progression of the COVID-19 infection. Hence, the course of the illness should be closely monitored and IV-C dosages should be adjusted accordingly.

Below are included some IV-C articles explaining how to best administer it. Articles with useful information about how to make IV-C solutions and dosage recommendations for treating COVID-19 in hospitalized patients are listed too:

Shanghai Expert Group on Clinical Treatment of New Coronavirus Diseases. Expert Consensus on Comprehensive Treatment of Coronavirus Diseases in Shanghai 2019 [J / OL], Chinese Journal of Infectious Diseases, 2020,38 (2020-03-01) , doi: 10.3760 / cma.j.issn.1000-6680.2020.0016. [Pre-published online]

Description [11]: This is the official Shanghai Expert Group on Clinical Treatment of New Coronavirus Diseases and Shanghai Medical Association consensus pre-published. This is a treatment plan for COVID-19. It recommends 50-100mg/kg/day of IV-C for mild to moderate cases of hospitalized COVID-19 and 100-200mg/kg/day of IV-C as part of a multifaceted protocol for prevention and treatment of "cytokine storms".

- Most of the article can be found translated by Dr. Richard Cheng on his website [12]. Intravenous Ascorbic Acid (IVAA) for COVID-19 Supportive Treatment in Hospitalized COVID-19 Patients (Based on use in China and US settings), Dr. Paul S. Anderson, Isom.ca, March 24, 2020.

Description [13]: This is a medical document for health professionals on IV-C and the rationale for using it to treat hospitalized COVID-19.

It includes pharmacy and nursing details and an approximation of drug cost of IV-C dosages recommended in the Shanghai treatment plan. Role of Ascorbic Acid in Covid 19 Management, Dr Yuen Chuen Fong Raymond, Doctoryourself.com.

Description [14]: This is a comprehensive slideshow answering the most important questions about vitamin C. It provides evidence and rationale for using vitamin C in treatment and prevention of many different diseases, including COVID-19.

- Slides concerning "Protocol - High Dose AA for Covid19" is at slide no. 116-120. This is the previously mentioned protocol using >1g/kg/day for mild and moderate cases and >3g/kg/day for severe cases.

- The recommendations made by the Japanese College of Intravenous Therapy (JCIT) are at slide no. 115. JCIT recommends IV-C 1-2x per day of 12.500-25.000mg per day for treatment of acute viral infections. Medical Information/COVID Care Protocol, EVMS Medical Group, Eastern Virginia Medical School, EVMS.edu.

Description [17]: This is medical information about COVID-19 and the COVID Care Protocol provided by the EVMS Medical Group led by Dr. Paul E. Marik. The resources and protocol are frequently updated and thus, subject to change.

- The COVID Care Protocol is a comprehensive protocol, and it's explained in great detail in a downloadable PDF document. It recommends the clinician consider various nutritional and pharmaceutical compounds for treatment of COVID-19. The compounds and dosages recommended depends on the severity of COVID-19.

- A one page PDF summary of the protocol is provided, too. Rationale for Vitamin C Treatment of COVID-19 and Other Viruses, Orthomolecular Medicine News Service Editorial Review Board, Orthomolecular Medicine News Service, Orthomolecular.org, April 3, 2020.

Description [18]: This article is urging "The world's political, scientific, medical and industrial leaders need to consider this (vitamin C) very carefully". Different dosages and route of administration (oral or IV) are listed, and a short note on Vitamin D and zinc is provided, too.

- They recommend the following for treatment of "cytokine storm":

"In severe lung infections, a "cytokine storm" generates reactive oxygen species (ROS) that can be effectively treated with doses of 30-60 g of vitamin C. At the same time the relatively high level of vitamin C can promote an enhanced chemotaxis of white blood cells (neutrophils, macrophages, lymphocytes, B cells, NK cells)."

- The article has a section on IV-C side effects and precautions that's useful for medical professionals. The Riordan IVC Protocol for Adjunctive Cancer Care Intravenous Ascorbate as a Chemotherapeutic and Biological Response Modifying Agent, Ron Hunninghake et al., Riordan Clinic Research Institute, 2014.

Description [6]: This is a thorough research document describing the Riordan Clinic's IV-C protocol for cancer.

- Check "Precautions and Side Effects" at page 14-15 and the concise "cheat sheets" for IV-C solutions at page 15-16.

- A website version of the PDF is available here at the Riordan Clinic website [15]. A Guide to the Optimal Administration of Vitamin C, Thomas E. Levy, MedFox Publishing.

Description [16]: Here is an exhaustive guide on IV-C administration. It is written by Thomas E. Levy, MD. He is hailed as the "vitamin C expert" in orthomolecular and integrative medicine circles.

- Contains information on the "Important Factors in the Effective Administration of Vitamin C". These are: Dose, route, rate, frequency, duration of treatment period, type of vitamin C, adjunct therapies, safety and quality of overall protocol. Preparation of Sodium Ascorbate for IV and IM Use, Robert F. Cathcart III, M.D, Edited 2011 by Owen Fonorow, Vitamin C Foundation, VitaminCFoundation.org.

Description [19]: This is a useful document for hospital pharmacies willing to make their own IV-C SA solutions and bags. In this document Robert F. Cathcart outlines how to make IV-C SA solutions and bags.

- The document contains information about dosage guidelines (Dr. Levy), rate of infusion and hypoglycemia. The following comment about dosage is important:



"Dosage is always empirical, as in give more if the clinical response, especially in infections or poisonings, is not adequate." - Thomas Levy, MD.

- Dr. Cathcart's video instructions can be found here on the Vitamin C Foundation's YouTube Channel [20].

4. Significant RCT's, Reviews, Meta-analyses and Articles on Vitamin C

Note: Research material by integrative and orthomolecular medicine practitioners and advocates have been excluded from this section. These studies can be found under the section titled "6. Orthomolecular Clinical Experience, Studies and Articles on Vitamin C". Ongoing research announced investigating IV-C for treating COVID-19 can found under the section titled "5. Studies and Trials on Vitamin C for Treatment of COVID-19".

For articles on safety, efficacy and administration of vitamin C go to references or the previous sections titled: "1. Vitamin C Safety Oral and Intravenous", "2. Efficacy and Benefits of IV vs Oral Vitamin C" and "3. IV-C Protocols, Administration, Cost and Dosing".

It should be noted that the vitamin C research listed here is built upon a mountain of in vitro and in vivo studies and clinical research. In addition, it builds upon decades of clinical experience from medical doctors who at some point began using orthomolecular medicine in their clinical practice. These doctors were Frederick R. Klenner, Robert F. Cathcart, Archie Kalokerinos, Hugh Riordan, Ron Hunninghake, Thomas E. Levy and many more.

4.1. RCT's and Studies

Alpha A. Fowler III et al., Effect of vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure - The CITRIS-ALI Randomized Clinical Trial, Journal of the American Medical Association (JAMA), 2019;322(13):1261-1270 (Epub 2019 October 1), doi:10.1001/jama.2019.11825

Description [21]: This is the first RCT to date to investigate the effects of moderate dosages (>200mg/kg/day) of IV-C on patients with sepsis and severe acute respiratory failure (ARDS). The trial could not detect any significant or noticeable differences in the primary end point outcomes between the vitamin C and placebo group. Primary end points were: SOFA scores, C-reactive protein levels and thrombomodulin levels.

However, there were some encouraging results in of many of the secondary end point outcomes. Some of these were statistically significant:

28-day mortality: "At day 28, mortality was 46.3% (38/82) in the placebo group vs 29.8% (25/84) in the vitamin C group (X2 = 4.84; P = .03; between-group difference, 16.58% [95% CI, 2% to 31.1%])" Kaplan-Meier survival curves: "The Kaplan-Meier survival curves for the 2 groups were significantly different by the Wilcoxon test (X21 = 6.5; P = .01)." Ventilator-free days: "The number of ventilator-free days was 13.1 in the vitamin C group vs 10.6 in the placebo group (mean difference, 2.47; 95% CI, -0.90 to 5.85; P = .15)" ICU-free days: "The number of ICU-free days to day 28 was 10.7 in the vitamin C group vs 7.7 in the placebo group (mean difference, 3.2; 95% CI, 0.3 to 5.9; P = .03)" Transfer out of the ICU by hour 168: "Transfer out of the ICU by hour 168 or less occurred in 25% of patients in the vitamin C group (21/84) vs 12.5% in the placebo group (10/83) (X2 = 4.63; P = .03; difference, 12.95% [95% CI, 1.16% to 24.73%; P = .31])" Hospital free days: "The number of hospital-free days in the vitamin C group vs the placebo group was 22.6 vs 15.5, respectively (mean difference, 6.69; 95% CI, 0.3 to 13.8; P = .04)"

- This RCT faced criticism due to alleged survivorship bias.

- Dr. Fowler presents the study findings on JAMA Network's YouTube channel [22].

Alpha A. Fowler et al., Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis, Journal of Translational Medicine, 2014; 12: 32 (Epub 2014 January 31), doi: 10.1186/1479-5876-12-32

Description [23]: This was the first RCT to investigate IV-C for severe sepsis (septic shock). It detected significant IV-C dose dependent reductions in SOFA scores and no adverse events in patients receiving IV-C.

Following quote is from the abstract:

"No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury."

Mohadeseh H. Zabet et al., Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock, Journal of Research in Pharmacy Practice, 2016 Apr-Jun: 5(2): 94-100, doi: 10.4103/2279-042X.179569

Description [24]: This small RCT (28 participants) investigated the impact of administering 100mg/kg/day IV-C for 72 hours in surgical critically ill patients with septic shock. The researchers reported the following results:

"Mean dose of norepinephrine during the study period (7.44 ± 3.65 vs. 13.79 ± 6.48 mcg/min, P = 0.004) and duration of norepinephrine administration (49.64 ± 25.67 vs. 71.57 ± 1.60 h, P = 0.007) were significantly lower in the ascorbic acid than the placebo group. No statistically significant difference was detected between the groups regarding the length of ICU stay. However, 28-day mortality was significantly lower in the ascorbic acid than the placebo group (14.28% vs. 64.28%, respectively; P = 0.009)."

Paul E. Marik et al., Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study, Chest, 2017 Jun;151(6):1229-1238 (Epub December 6, 2016), doi: 10.1016/j.chest.2016.11.036

Description [25]: Retrospective study conducted by Dr. Paul E. Marik and colleagues. It investigated their HAT protocol for treatment of septic shock. The study reported massive reductions in the vasopressor duration and hospital mortality in the vitamin C group. The following is from the abstract:

"The hospital mortality was 8.5% (4 of 47) in the treatment group compared with 40.4% (19 of 47) in the control group (P <0.001)" and "All patients in the treatment group were weaned off vasopressors, a mean of 18.3 ± 9.8 h after starting treatment with the vitamin C protocol. The mean duration of vasopressor use was 54.9 ± 28.4 h in the control group (P <0.001)."

Eric Wald et al., Hydrocortisone-Ascorbic Acid-Thiamine Use Associated with Lower Mortality in Pediatric Septic Shock, American Journal of Respiratory and Critical Care Medicine, 2020 April 1, Volume 201, Issue 7 (Epub January 9, 2020), doi: 10.1164/rccm.201908-1543LE

Description [26]: Retrospective study conducted at the Ann & Robert H. Lurie Children's Hospital of Chicago investigating HAT therapy for treating pediatric septic shock.

The following is from a study report published on the hospital's website (see link below):

"They found that while controls had mortality of 28 percent at 30 days, mortality in patients treated with the vitamin C combination protocol dropped to 9 percent in the same period. Treatment with hydrocortisone alone did not improve mortality (30 percent at 30 days). Similar reductions in mortality were seen at 90 days (14 percent with vitamin C protocol vs. 35 percent in controls and 37 percent in the hydrocortisone only group)."

- Here's a link to the study report on the hospital's website [27].

Tomoko Fujii et al., Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock - The VITAMINS Randomized Clinical Trial, Journal of the American Medical Association (JAMA), 2020;323(5):423-431 (Epub 2020 January 17), doi:10.1001/jama.2019.22176

Description [28]: This is the largest RCT (216 participants) to date to study HAT therapy for septic shock. The trial did not detect any significant or noticeable differences between the vitamin C and placebo group. The abstract reports these results:

"Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported."

- Comment [29]: This RCT faced criticism from Dr. Paul E. Marik during the presentation of the trial at CCR Belfast 2020. Marik claimed that it did not replicate real life clinical experience, because the treatment was delayed too much (median 12 hours past meeting eligibility criteria of septic shock). According to Marik this delay in treatment rendered the HAT therapy ineffective.

Two ICU doctors using HAT therapy in their ICU's, one from Wisconsin (Pierre D. Kory, MD), and one from Norway (Dr. Eivind H. Vinjevoll), agreed with Marik's assessment of the trial.

Marik said HAT therapy should be initiated <6 hours past presentation for optimal results, and the doctor from Wisconsin affirmed that if HAT therapy is initiated >12 hours past presentation, it has an insignificant effect on mortality.

The <6 and >12 hour figures are based on accepted (Critical Care and Shock) and soon to be published research conducted by Pierre D. Kory and colleagues.

- Here's a video of VITAMINS trial presentation at CCR 2020 in Belfast on JAMA Network's YouTube channel [29].

Ping Chang et al., Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock (HYVCTTSSS): A randomized controlled clinical trial, Chest, 2020 Mar 31. pii: S0012-3692(20)30552-3, doi: 10.1016/j.chest.2020.02.065.

Description [83]: This is the most recent RCT to date to investigate IV-C (HAT therapy) as a treatment for sepsis and septic shock. The trial is single-blinded, randomized and placebo controlled, and it had 80 participants. The researchers reported the following results in the abstract:

"No difference in 28-day all-cause mortality was observed (27.5% vs. 35%; P = 0.47), although treatment was associated with a significant improvement of 72-h ΔSOFA score (P = 0.02)."

"In prespecified subgroup analysis, patients of the treatment subgroup diagnosed with sepsis within 48 h showed lower mortality than those in the control subgroup (p = 0.02)."

- The subgroup analysis showed that those diagnosed with sepsis <48 hours past ICU admission fared much better than the rest of the IV-C study participants; some of the secondary outcome endpoints were statistically significant. The mortality was significantly lower in the IV-C group "(13.6% vs.47.6%; RR, 0.29; 95% CI, 0.09 to 0.90; p = 0.02)", and 72 hour PCT clearance was significantly lower in the IV-C group "(p = 0.02; 75.6% (62.3-92.0) vs. 58.9% (16.0-79.5)".

The reported difference in survival rate of IV-C was extremely close to the one reported in Paul Marik's 2017 Chest paper (34% vs 37.9%).

- Comment [83]: The subgroup analysis, the first of its kind in a RCT investigating HAT therapy, strongly suggests that Marik's assertions on the importance of timely administration of the protocol are correct, and that HAT therapy is only effective in the early stages of septic shock.

Won-Young Kim et al., Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: Propensity score-based analysis of a before-after cohort study, Journal of Critical Care, 2018 Oct;47:211-218 (Epub 2018 July 5). doi: 10.1016/j.jcrc.2018.07.004

Description [73]: This is a significant "Propensity score-based analysis of a before-after cohort study" investigating HAT therapy as a treatment for severe pneumonia requiring ICU admission.

The following results was reported in the abstract:

"In the propensity-matched cohort (n = 36/group), the treated patients had significantly less hospital mortality than the control group (17% vs. 39%; P = 0.04). The vitamin C protocol associated independently with decreased mortality in propensity score-adjusted analysis (adjusted odds ratio = 0.15, 95% confidence interval = 0.04-0.56, P = 0.005). Relative to the control group, the treatment group had a significantly higher median improvement in the radiologic score at day 7 compared with baseline (4 vs. 2; P = 0.045). The vitamin C protocol did not increase the rates of acute kidney injury or superinfection."

Anitra C. Carr et al., Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes, Critical Care, 2017 Dec 11;21(1):300, doi: 10.1186/s13054-017-1891-y

Description [30]: Study about the widespread hypovitaminosis C and scurvy in critically ill patients. The following is from the abstract:

"Critically ill patients have low vitamin C concentrations despite receiving standard ICU nutrition. Septic shock patients have significantly depleted vitamin C levels compared with non-septic patients, likely resulting from increased metabolism due to the enhanced inflammatory response observed in septic shock."

Tae K. Kim et al., Vitamin C supplementation reduces the odds of developing a common cold in Republic of Korea Army recruits: randomised controlled trial, BMJ Military Health, 2020 Mar 5. pii: bmjmilitary-2019-001384 (Epub ahead of print), doi: 10.1136/bmjmilitary-2019-001384

Description [31]: This is the first large scale RCT (1444 participants) to investigate if a high 6,000mg/day dose of oral vitamin C per day reduces the odds of developing a common cold. The researchers reported the following in the abstract:

"The vitamin C group had a 0.80-fold lower risk of getting a common cold than did the placebo group. Subgroup analyses showed that this effect was stronger among subjects in camp A, among never smokers and among those in physical rank 3."

H. Clay Gorton and Kelly Jarvis, The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infections, Journal of Manipulative and Physiological Therapeutics, 1999 Oct;22(8):530-3, DOI: 10.1016/s0161-4754(99)70005-9

Description [32]: This is a "prospective controlled study of students in a technical training facility" investigating vitamin C's usage and efficacy for "preventing and relieving the symptoms of virus-induced respiratory infections". The following is from the abstract:

"Overall, reported flu and cold symptoms in the test group decreased 85% compared with the control group after the administration of megadose vitamin C."

Clare Hunt et al., The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections, International Journal for Vitamin and Nutrition Research, 1994;64(3):212-9., PMID: 7814237

Description [33]: This small (57 participants) randomized double-blind trial reported 80% fewer deaths in the 200mg/day vitamin C group than placebo. This RCT was included in the 1999 review "Vitamin C and acute respiratory infections" and the 2017 review "Vitamin C and Infections". These reviews can be found under the subsection titled "4.3. Reviews".

Imran M. Khan et al., Efficacy of Vitamin C in Reducing Duration of Severe Pneumonia in Children, Journal Of Rawalpindi Medical College (JRMC), 2014;18(1):55-57, at Journalrmc.com.

Description [34]: This is a descriptive and placebo controlled trial of children under the age of 5 with pneumonia. 200mg/day of oral vitamin C was administered and control group received placebo drops matching color and taste.

The researchers reported the following results:

"Among 222 children, majority (61.71%) were male and 85(38.28%) were female. Majority (58.55%) were infants, 29.72% were between 1-3 years and 11.71% were between 4-5 years (15.14+7.76 months). Oxygen saturation was improved in < 01 day (p=0.003) and respiratory rate was improved in < 04 days (p=0.03) in vitamin C group".

They concluded that: "Vitamin C is effective in reducing duration of severe pneumonia in children less than five years of age."

- Available as a PDF here on Rawalpindi Medical College's website [35].

Ren Shiguang et al., Observation on the therapeutic effect of intravenous large dose of vitamin C on infants and young children with viral pneumonia, Hebei Medicine, 1978,4:1-3.

Description [36] [37]: This is an observational study on high dose vitamin C for treating infantile viral pneumonia. The researchers reported that high doses of vitamin C reduced mortality and shortened duration of the illness compared to no vitamin C.

4.2. Meta-analyses

Harri Hemilä and Elizabeth Chalker, Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis, Journal of Intensive Care, 2020; 8: 15 (Epub 2020 February 7), doi: 10.1186/s40560-020-0432-y

Description [38]: This meta-regression analysis investigated the effect of vitamin C on duration of mechanical ventilation. It was based in part on their earlier meta-analysis "Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis". These results were reported in abstract:

"...vitamin C shortened the length of mechanical ventilation on average by 14% (P = 0.00001). However, there was significant heterogeneity in the effect of vitamin C between the trials. Heterogeneity was fully explained by the ventilation time in the untreated control group. Vitamin C was most beneficial for patients with the longest ventilation, corresponding to the most severely ill patients. In five trials including 471 patients requiring ventilation for over 10 h, a dosage of 1-6 g/day of vitamin C shortened ventilation time on average by 25% (P < 0.0001)."

The researchers concluded the following:

"We found strong evidence that vitamin C shortens the duration of mechanical ventilation, but the magnitude of the effect seems to depend on the duration of ventilation in the untreated control group."

Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis, Harri Hemilä and Elizabeth Chalker, Nutrients, 2019 Apr; 11(4): 708 (Epub 2019 March 27), doi: 10.3390/nu11040708.

Description [39]: This meta-analysis investigated vitamin C's impact on length of stay in the ICU, and it reported the following:

"In 12 trials with 1766 patients, vitamin C reduced the length of ICU stay on average by 7.8% (95% CI: 4.2% to 11.2%; p = 0.00003). In six trials, orally administered vitamin C in doses of 1-3 g/day (weighted mean 2.0 g/day) reduced the length of ICU stay by 8.6% (p = 0.003).". The authors concluded: "Given the insignificant cost of vitamin C, even an 8% reduction in ICU stay is worth exploring. The effects of vitamin C on ICU patients should be investigated in more detail."

- It should be noted that none of the IV-C studies included in the calculation of the 7.8% figure used IV-C dosages >3g/day. In fact, only two IV-C studies used dosages >1g; one 3g/day and the other 2g/day. Three studies used 1 gram/day, and one used 0.5 gram/day, yielding a 1.42g/day average of IV-C. This was not mentioned in meta-analysis, and in future clinical trials much higher IV-C dosages should be investigated.

Harri Hemilä and Elizabeth Chalker, Vitamin C for preventing and treating the common cold, Cochrane Database of Systematic reviews, 2013 Jan 31;(1):CD000980, doi: 10.1002/14651858.CD000980.pub4.

Description [40]: This meta-analysis investigated the role of vitamin C for prevention and treatment of the common cold. The researchers reported the following results:

"In adults the duration of colds was reduced by 8% (3% to 12%) and in children by 14% (7% to 21%). In children, 1 to 2 g/day vitamin C shortened colds by 18%. The severity of colds was also reduced by regular vitamin C administration. Seven comparisons examined the effect of therapeutic vitamin C (3249 episodes). No consistent effect of vitamin C was seen on the duration or severity of colds in the therapeutic trials."

They concluded the following in the abstract:

"Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them."

- It should be noted that the abstract of the meta-analysis did not mention the two and only placebo controlled trials using high dose oral vitamin C (Karlowski (1975) and Anderson (1974)). These were later included in the abstract of a review from 2017 titled "Vitamin C and infections". This review can be found under the next sub-section "4.3. Reviews".

- A report of the meta-analysis can be found here on Cochrane's website [41].

4.3. Reviews

Markos G. Kashiouris et al.,The Emerging Role of Vitamin C as a Treatment for Sepsis, Nutrients, 2020 Feb; 12(2): 292 (Epub 2020 January 22), doi: 10.3390/nu12020292

Description [4]: Review on IV-C as a treatment for sepsis. It contains a comprehensive explanation of vitamin C's mechanisms of action relevant in ARDS and sepsis. This can be found in the article under a section titled "2.3 Vitamin C's Mechanism of Action in Sepsis and ARDS".

Harri Hemilä, Vitamin C and Infections, Nutrients, 2017 Apr; 9(4): 339 (Epub 2017 March 29), doi: 10.3390/nu9040339

Description [42]: This is an in-depth review investigating the evidence and importance of vitamin C for treatment and prevention of infections. The following is from the abstract:

"Two controlled trials found a statistically significant dose-response, for the duration of common cold symptoms, with up to 6-8 g/day of vitamin C. Thus, the negative findings of some therapeutic common cold studies might be explained by the low doses of 3-4 g/day of vitamin C. Three controlled trials found that vitamin C prevented pneumonia. Two controlled trials found a treatment benefit of vitamin C for pneumonia patients."

- The high dose vitamin C trials (Karlowski (1975) and Anderson (1974) used 3/6g and 4/8g of oral vitamin C a day respectively. In the high dosage vitamin C group the trials reported a 17% (Karlowski 1975) and 19% (Anderson 1974) reduction in the duration of cold infections vs placebo. It should be noted that "In the Anderson (1974) trial, vitamin C was administered only on the first day of the common cold".

Anitra C. Carr and Silvia Maggini, Vitamin C and Immune Function, Nutrients, 2017 Nov; 9(11): 1211 (Epub 2017 November 3), doi: 10.3390/nu9111211

Description [43]: Comprehensive review investigating vitamin C's role in and importance for immune function. In the abstract the researchers reported:

"In contrast, treatment of established infections requires significantly higher (gram) doses of the vitamin to compensate for the increased inflammatory response and metabolic demand."

The following was said about vitamin C and pneumonia:

"There was also a positive effect on the normalization of chest X-ray, temperature, and erythrocyte sedimentation rate [255]. Since prophylactic vitamin C administration also appears to decrease the risk of developing more serious respiratory infections, such as pneumonia [256], it is likely that the low vitamin C levels observed during respiratory infections are both a cause and a consequence of the disease."

Harri Hemilä and Robert M. Douglas, Vitamin C and acute respiratory infections, International Journal of Tuberculosis and Lung Disease, 1999 Sep;3(9):756-61, PMID: 10488881

Description [44]: Review investigating vitamin C's role for treatment and prevention of respiratory infections. The vast majority of the research in this review can be found in a newer review from 2017 titled "Vitamin C and infections". The following was reported in the abstract:

"In the four largest studies the duration of colds was reduced only by 5%. In two of these studies, however, absence from school and work was reduced by 14-21% per episode, which may have practical importance. Three controlled studies recorded a reduction of at least 80% in the incidence of pneumonia in the vitamin C group, and one randomised trial reported substantial treatment benefit from vitamin C in elderly UK patients hospitalized with pneumonia or bronchitis."

Harri Hemilä and Pekka Louhiala, Vitamin C may affect lung infections, Journal of the Royal Society of Medicine, 2007 Nov; 100(11): 495-498, doi: 10.1258/jrsm.100.11.495

Description [71]: Short literature review on vitamin C and lung infections. The paper reviews vitamin C's importance for immune function and the clinical research on vitamin C and lung infections. Most of the information in the review can be found in a newer review from 2017 titled "Vitamin C and Infections".

Harri Hemilä and Pekka Louhiala, Vitamin C for preventing and treating pneumonia, Cochrane Database Systematic Review, 2013 Aug 8;(8):CD005532, doi: 10.1002/14651858.CD005532.pub3.

Description [72]: Systematic review on the evidence on vitamin C for prevention and treatment of pneumonia. The following was reported in the abstract:

"We identified two therapeutic trials involving 197 community-acquired pneumonia patients. Only one was satisfactorily randomised, double-blind and placebo-controlled. That trial studied elderly patients in the UK and found lower mortality and reduced severity in the vitamin C group; however, the benefit was restricted to the most ill patients. The other therapeutic trial studied adults with a wide age range in the former Soviet Union and found a dose-dependent reduction in the duration of pneumonia with two vitamin C doses."

Yin Li and Guoping Li., Is Vitamin C Beneficial to Patients with CAP, Current Infectious Disease Reports, 2016 Aug;18(8):24. doi: 10.1007/s11908-016-0530-0.

Description [74]: Review investigating if vitamin C is beneficial to patients with community-acquired pneumonia (CAP). The following was reported in the abstract: "First, we reviewed recent advances about the role of oxidative stress in CAP. Oxidative stress is a crucial component of the host defense system and inflammatory response. However, excessive oxidative stress can cause a systemic inflammatory response leading to tissue damage. The degree of oxidative stress has been associated with the severity of CAP." "Administration of vitamin C decreases the duration of mechanical ventilation by decreasing oxidative stress."

Pramath Kakodkar et al., A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19), Cureus, Cureus 12(4): e7560, 2020 April 6, doi: 10.7759/cureus.7560

Description [76]: This article is highly recommended for medical professionals. It's a concise overview on the current knowledge about COVID-19. A section near the end is dedicated to the following experimental treatments for COVID-19: Vitamin C and D, remdesivir, lopinavir, ritonavir, umifenovir, chloroquine, antepyretics, ACEi, ARBs and systemic corticosteroids.

The article lists some of vitamin C's mechanisms of action relevant for COVID-19:

"vitamin C reinforces the maintenance of the alveolar epithelial barrier and transcriptionally upregulates the protein channels (CFTR, aquaporin-5, ENaC, and Na+/K+ ATPase) regulating the alveolar fluid clearance [37]. HDIVC has been implicated in reducing plasma cell-free DNA formed from the neutrophil extracellular trap (NET) which is the facilitator of systemic inflammation in sepsis-induced multi-organ failure [38,39]. Interestingly, elevated levels of syndecan-1 in the plasma correlate with increased mortality in severe sepsis and ARDS, and this endothelial glycocalyx can be reduced significantly by HDIVC [39]."

Sebastian J. Padayatty and Mark Levine, Vitamin C physiology: the known and the unknown and Goldilocks, Oral Diseases, 2016 Sep; 22(6): 463-493 (Epub 2016 April 14), doi: 10.1111/odi.12446

Description [45]: Comprehensive review investigating vitamin C's physiology. Recommended for medical professionals.

4.4. Miscellaneous Articles

Michael A. Matthay et al., Treatment of severe acute distress syndrome from COVID-19, The Lancet Respiratory Medicine, 2020 March 20, doi: https://doi.org/10.1016/S2213-2600(20)30127-2

Description [80]: A comment written by prominent researchers at The University of California and published in the prestigious medical journal The Lancet. It contains brief information on the "Treatment for severe acute respiratory distress syndrome from COVID-19". Furthermore, it includes a recommendation of vitamin C being used as a rescue therapy based on the mortality reduction (IV-C: 29.8% vs placebo: 46.3%) AA Fowler and colleagues observed in the CITRIS-ALI RCT. The vitamin C recommendation reads as follows: "Rescue therapy with high-dose vitamin C can also be considered."

iSepsis - Vitamin C, Hydrocortisone and Thiamine - The "Metabolic Resuscitation Protocol", Paul Marik, EMCrit.org - iSepsis Project (EMCrit), July, 16 2017.

Description [46]: In this article at EMCrit.org Paul E. Marik explains the rationale for HAT therapy. He lists the decades of evidence it builds upon and details the Hydrocortisone, Vitamin C and Thiamine (HAT) protocol.

Adnan Erol, High-dose intravenous vitamin C treatment for COVID-19, preprint (not yet peer reviewed), 2020 February, doi: 10.31219/osf.io/p7ex8.

Description [92]: In this detailed research article, researcher Adnan Erol investigates the non-clinical research on the pathology of and immune response to SARS-CoV-2 virus. Furthermore, he describes the proposed action of vitamin C as an immunomodulatory, -regulatory and -suppressant, and he discusses IV-C treatment of COVID-19.

Paul E. Marik and Michael H. Hooper, Doctor-your septic patients have scurvy!, Critical Care, 2018 Jan 29;22(1):23, doi: 10.1186/s13054-018-1950-z

Description [47]: Editorial by Paul E. Marik and Michael H. Hooper written in response to the study "Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes". They provide evidence for why this antioxidant depletion occurs in critically ill patients, and they detail what happens if the deficiency is not corrected.

Salim Surani and Munish Sharma, Revisiting the Role of Vitamin C in Sepsis. Is it a Forlorn Hope or is there Still Dearth of data?, The Open Respiratory Medicine Journal, Bentham Open, Benthamopen.com, 2019 Dec 31;13:55-57, doi: 10.2174/1874306401913010055

Description [48]: Editorial on vitamin C for treating sepsis. It's written in response to the CITRIS-ALI randomized controlled trial.

5. Studies and Trials on Vitamin C for Treatment of COVID-19

As of today (April 15, 2020) 6 trials on vitamin C have been announced, and three of them are currently recruiting patients. Four are active, while two have been cancelled. A brief overview of the current vitamin C trials can be found under the section "Nutrients" in the following document from the Danish Medicines Agency titled "Overview of planned or ongoing studies of drugs for the treatment of COVID-19" [84].

ZhiYong Peng, Vitamin C Infusion for the Treatment of Severe 2019-nCoV Infected Pneumonia, Date of registration: February 11, 2020, ClinicalTrials.gov.

Description [85]: Look below.



Study identifier: NCT04264533

Study design: Phase II randomized triple-blinded placebo controlled trial (140 participants, experimental (n=70), control (n=70)).

Description of participants: Serious or critical COVID-19 patients.

Treatment protocol: Experimental group: 12g IV-C in 50mL sterile water solution q12h, 12mL/h (4.17h infusion), IV-C 24g/day. Placebo control group: 50mL sterile water solution q12h, 12mL/h (4.17h infusion). Administered for 7 days for both groups.

Study location: Zhongnan Hospital, Hubei, China.

Status of trial: Recruiting.

Primary completion date: September 30, 2020.

Study completion date: September 30, 2020.

Jun Lin, A randomized, open, controlled trial for diammonium glycyrrhizinate enteric-coated capsules combined with vitamin C tablets in the treatment of common novel coronavirus pneumonia (COVID-19) in the basic of clinical standard antiviral treatment to evaluate the safety and efficiency, Date of registration: February 12, 2020, Chinese Clinical Trial Registry, Chictr.org.cn.

Description [86]: Look below.



Study identifier: ChiCTR2000029768

Study design: Randomized open controlled trial (60 participants, experimental (n=30), control (n=30)).

Description of participants: COVID-19 patients.

Treatment protocol: Experimental group: Vitamin C 0.5 g (3x day) + diammonium glycerrhizinate enteric coated capsules 150 mg 4x/day + and standard clinical antiviral treatment. Control: Standard clinical antiviral treatment. Duration of treatment not stated.

Study location: Zhongnan Hospital, Hubei, China.

Status of trial: Recruiting.

Primary completion date: May 12, 2020.

Study completion date: n/a

Gao Defeng, An observational study of high-dose vitamin C in the treatment of severe and critical patients with novel coronavirus pneumonia (COVID-19), Date of registration: February 17, 2020, Chinese Clinical Trial Registry, Chictr.org.cn.

Description [87]: Look below.



Study identifier: ChiCTR2000029957

Study design: Case series, observational study (66 participants).

Description of participants: Severe or critical COVID-19 patients.

Treatment protocol: High dose vitamin C (dose: n/a) + standard care. Dosages used reported by Dr. Richard Cheng: 6.000-12.000mg/day [91]. Duration of treatment not stated.

Study location: Shaanxi and Hubei, China.

Status of trial: Not yet recruiting, canceled by ethics committee on March 14, 2020.

Primary completion date: ---||---

Study completion date: ---||---

Gao Defeng, A randomized controlled trial for high-dose vitamin C in the treatment of severe and critical novel coronavirus pneumonia (COVID-19) patients, Date of registration: February 24, 2020, Chinese Clinical Trial Registry, Chictr.org.cn.

Description [88]: Look below.



Study identifier: ChiCTR2000030135

Study design: Randomised controlled trial, blinding not stated (40 participants, experimental (n=26), control (n=13)).

Description of participants: Severe or critical COVID-19 patients.

Treatment protocol: Experimental group: high dose vitamin C (dose = n/a.). Control group: routine treatment. Duration of treatment not stated.

Study location: Shaanxi and Hubei, China.

Status of trial: Not yet recruiting, cancelled by ethics committee on March 14, 2020.

Primary completion date: ---||---

Study completion date: ---||---

Salvatore Corrao, Use of Ascorbic Acid in Patients With COVID 19, Date of registration: March 26, 2020, ClinicalTrials.gov.

Description [89]: Look below.



Study identifier: NCT04323514

Study design: Single arm, open label (500 participants).

Description of participants: Hospitalized patients with COVID-19.

Treatment protocol: 10 grams IV-C, appears to be a single infusion.

Study location: University of Palermo, Palermo, Sicily, Italy.

Status of trial: Recruiting.

Primary completion date: March 13, 2021.

Study completion date: March 13, 2021.

Markos. G. Kashiouris and Alpha A. Fowler, Early Infusion of Vitamin C for Treatment of Novel COVID-19 Acute Lung Injury (EVICT-CORONA-ALI), Date of registration: April 14, 2020, ClinicalTrials.gov.

Description [90]: Look below.



Study identifier: NCT04344184

Study design: Quadruple blind randomized placebo controlled trial (200 participants, experimental (n=100), control (n=100))

Description of participants: Patients with hypoxemia and suspected COVID-19.

Treatment protocol: Experimental group: 100mg/kg/q8h (300mg/kg/24h) IV-C infusion. 12mL/h (4.17h infusion), IV-C 24g/day. Placebo control group: Dextrose 5% water q8h. Administered for up to 72 hours for both groups.

Study location: Virginia Commonwealth University, Virginia, USA.

Status of trial: Not yet recruiting

Primary completion date: n/a

Study completion date: n/a

6. Orthomolecular Clinical Experience, Studies and Articles on Vitamin C

Below is a compilation of articles relevant to the current COVID-19 pandemic. This includes the clinical experience medical doctors, who are/were using orthomolecular medicine, have had with vitamin C and viral infections. Other miscellaneous articles from orthomolecular medicine practitioners and advocates are provided, too.

6.1. Clinical Experience and Observational Studies

Frederick R. Klenner reported remarkable results using IV-C and high dose oral vitamin C. Here are some of the papers he published and a detailed article about his research:

Clinical Guide to the Use of Vitamin C, Lendon H. Smith. M.D, AscorbateWeb, 1988.

Description [49]: This is a comprehensive article about "The Clinical Experiences of Frederick R. Klenner, M.D." and it's "abbreviated, sumarized and annotated by Lendon H. Smith, M.D.". Lendon H. Smith went through Frederick R. Klenner's over 27 papers from the 1940's to 1970's. The article is an adaption of the book "Vitamin C as a Fundamental Medicine: Abstracts of Dr. Frederick R. Klenner, M.D.'s Published and Unpublished Work". The book is written by Lendon H. Smith, too.

- The article details Frederick R. Klenner's observations on vitamin C's dosage, antitoxin, antiviral and antimicrobial properties and the many illnesses and ailments Klenner said he cured with megadose vitamin C.

Frederick R. Klenner, M.D, The Treatment of Poliomyelitis and Other Virus Diseases with Vitamin C, Southern Medicine & Surgery, Volume 111, Number 7, July, 1949, pp. 209-214.

Description [50]: This is an observational report on vitamin C being used to treat poliomyelitis and other viral diseases. In this paper Klenner reported curing many viral illnesses with IV-C and megadose oral vitamin C. During a poliomyelithis epidemic in North Carolina in 1948 Klenner reported curing 60 out of 60 cases of poliomyelitis with megadose vitamin C:

"With these precautions taken, every patient of this series recovered uneventfully within three to five days."

Frederick R. Klenner, M.D, Observations On the Dose and Administration of Ascorbic Acid When Employed Beyond the Range Of A Vitamin In Human Pathology, Journal of Applied Nutrition, Vol. 23, No's 3 & 4, Winter 1971.

Description [51]: This is a detailed research article in which Dr. Klenner laid out his thoughts and observations on vitamin C's mechanisms of action in many diseases. Furthermore, the article includes observational evidence from hundreds of treated patients from Klenner's own practice and other practitioners and researchers using megadose vitamin C.

- It includes a case report of a dying cyanotic patient (due to a toxin) being saved by 12 grams vitamin C IV push (extremely rapid infusion). In addition, there are hundreds of case reports of IV-C being successful in treatment of mononucleosis, viral encephalitis and many other illnesses.

And here are two important articles, one by Robert F. Cathcart, MD and one by Thomas E. Levy, MD:

Robert F. Cathcart, M.D, VITAMIN C, TITRATING TO BOWEL TOLERANCE, ANASCORBEMIA, AND ACUTE INDUCED SCURVY, Medical hypotheses, 1981, 7:1359-1376, Vitamin C Foundation.

Description [1]: This is the famous research article by Robert F. Cathcart, III, MD where he introduced the concept of titrating to bowel tolerance. It also includes the clinical observations made by Cathcart on the remarkably high daily vitamin C dosages required for certain illnesses to hit bowel tolerance. Cathcart reported sometimes +200g/day of oral AA was required to reach bowel tolerance. Cathcart estimated bowel tolerance doses for a wide variety of illnesses based on his clinical experience, too. - And all the other publications by Robert F. Cathcart can be found on the Vitamin C Foundation's webpage [52].

The Clinical Impact of Vitamin C: My Personal Experience as a Physician, Thomas E. Levy, Orthomolecular Medicine News Service, Orthomolecular.org, September 3, 2014. Description [53]: In this commentary Thomas E. Levy, MD compiled what he considered to be the most dramatic anecdotes about the power of megadose vitamin C. The majority of these were from his own practice.

6.2. Miscellaneous Research Papers, Articles and Slideshows on Vitamin C

Rationale for Vitamin C Treatment of COVID-19 and Other Viruses, Orthomolecular Medicine News Service Editorial Review Board, Orthomolecular Medicine News Service, Orthomolecular.org, April 3, 2020.

Description [18]: This article urges "The world's political, scientific, medical and industrial leaders need to consider this (vitamin C) very carefully". It provides the evidence and rationale for vitamin C in treatment of COVID-19 and other viral infections.

Vitamin C's mechanisms of action are explained, and a short note on vitamin D and zinc is provided. Different dosage recommendations and route of administration (oral or IV) are outlined, too.

Richard Z. Cheng, Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?, Medicine in Drug Discovery, 2020 March 26, doi: 10.1016/j.medidd.2020.100028

Description [54]: Editorial by Richard Z. Cheng on the mounting evidence indicating vitamin C could be useful in treatment of COVID-19.

Coronavirus Coverup - Vitamin C Dramatic Help against Infection in China, South Korea - Why Aren't We Told, Mara Leverkuhn, Medium.com, March 17, 2020.

Description [81]: This is an article translated from Romanian, which contains an interview with medical researcher and biophysicist Virgiliu Gheorghe on the topic of vitamin C. The interview contains information on the reports from China and South Korea and the censorship of these. Furthermore, Mr. Gheorghe answers additional miscellaneous questions about the safety of vitamin C and dosages.

Case for Vitamin C for COVID-19, Patrick Halford, PatrickHolford.com, Mar 29, 2020.

Description [77]: Short article by Patrick Holford on the "...five compelling reasons why high dose oral (6gram+) and intravenous vitamin C (IVC) should be trialled on critically ill COVID-19 patients to speed up recovery time spent in ICU and reduce mortality".

And here's a transcript of a video conference where Dr. Enqiang Mao shared his experience with IV-C for treating hospitalized COVID-19 patients:

Successful High-Dose Vitamin C Treatment of Patients with Serious and Critical COVID-19 Infection, Richard Cheng, MD, PhD, Orthomolecular Medicine News Service, March 18, 2020.

Description [56]: This article is a transcribed online video conference, where a group of medical doctors, healthcare providers and scientists discussed vitamin C for the treatment of moderate to severe hospitalized cases of COVID-19.

- The key guest was Dr. Enqiang Mao. He had successfully treated 50 moderate to severe COVID-19 patients with 10,000-20,000mg/day IV-C for 7-10 days. The mortality rate was 0%.

- A report of a rapidly deteriorating patient given a bolus of 50,000mg IV-C over 4 hours is included, too. The patient's oxygenation was reportedly improved in real time following initiation of HDIV-C therapy.

This is a useful article on how to get IV-C administered to a hospitalized patient:

How to Get Intravenous Vitamin C Given to a Hospitalized Patient: A Checklist, Andrew W. Saul, DoctorYourself.com, 2019.

Description [57]: For hospitalized patients and their families and relatives. It has all the information needed on "How to Get Intravenous Vitamin C Given to a Hospitalized Patient". The document is not legal advice. If legal advice and action is required, contacting a lawyer is recommended.

And here are some interesting slideshows:

Role of Ascorbic Acid in Covid 19 Management, Dr Yuen Chuen Fong Raymond, DoctorYourself.com.

Description [14]: This is a comprehensive slideshow answering most questions about vitamin C. It provides evidence and rationale for using vitamin C in the treatment and prevention of various diseases, including COVID-19.

Colds, Flus and COVID-19: Can Supplements Help?, Prof Kylie O'Brien PhD and Prof Ian Brighthope, Australasian College Of Nutritional And Environmental Medicine (ACNEM), ACNEM.org, 2020.

Description [58]: Slide show from ACNEM presenting multiple research findings about the efficacy of vitamin C, D and zinc for treating colds, flus and respiratory illnesses. The research findings suggest that IV-C could play an important role in treatment of COVID-19.

- The slide show has been presented in three video presentations: Part 1 - Vitamin C, Part 2 - Vitamin D and Part 3 - Zinc. These can be found on ACNEM's webpage [58].

And furthermore, here's some in-depth research material on COVID-19 by Doris Loh:

STOP ARDS NOW WITH ASCORBIC ACID, Doris Loh, Evolutamente.it, March 28, 2020.

Description [60]: Detailed slideshow explaining the mechanisms of action of oral AA and IV-C and their potential importance for treating COVID-19. It contains excerpts from the five text articles by Doris Loh listed here.

- The article puts a great emphasis on the unique mechanisms of action of AA.

COVID-19, ARDS & CYTOKINE STORMS - THE RECYCLING OF ASCORBIC ACID BY MACROPHAGES, NEUTROPHILS AND LYMPHOCYTES, Doris Loh, Evolutamente.it, April 5, 2020.

Description [79]: Detailed slideshow explaining SARS-CoV-2's virulent destruction of hemoglobin and red blood cells leading to a surge in cytotoxic cell-free hemoglobin. The slide show investigates vitamin C's importance for preventing and treating destruction and extracellular release of hemoglobin.

Furthermore, the slide show provides evidence for vitamin C's importance for treatment and prevention of ARDS and "cytokine storms".

MITOCHONDRIA & THE CORONAVIRUS - THE VITAMIN C CONNECTION (PART 3), Doris Loh, Evolutamente.it, February 1, 2020.

Description [61]: Detailed article on the mechanisms of vitamin C for mitochondrial function and its potential for prevention of "cytokine storm" and ARDS. ARDS and "cytokine storm" are strongly associated with severe cases of COVID-19.

COVID-19, FURINS & HYPOXIA - THE VITAMIN C CONNECTION, Doris Loh, Evolutamente.it, February 29, 2020.

Description [62]: In-depth article explaining the connection between vitamin C and COVID-19, furins and hypoxia. The significance of furins and HIF1a in COVID-19 are explained in great detail, too.

COVID-19 MUTATIONS, VACCINES & NITRIC OXIDE - THE VITAMIN C CONNECTION, Doris Loh, Evolutamente.it, March 7, 2020.

Description [63]: In-depth article investigating mechanisms of action of nitric oxide and vitamin C important for COVID-19. SARS-CoV-2 mutations and how they impact vaccine R&D are explored, too. Furthermore, the viruses SARS-CoV (SARS 2003) and SARS-CoV-2 (COVID-19) are compared.

COVID-19, PNEUMONIA & INFLAMMASOMES - THE MELATONIN CONNECTION, Doris Loh, Evolutamente.it, March 14, 2020.

Description [64]: In-depth article investigating the relationship between COVID-19, inflammasomes and pneumonia. The important role the mechanisms of action of melatonin play in COVID-19 is discussed, too.

- The article reports that melatonin, nitric oxide and ascorbic acid inhibit NLRP3 inflammasomes. NLRP3 inflammasomes play a significant role in the "cytokine storm" associated with severe COVID-19.

- A simple guide for melatonin and ascorbic acid supplementation is provided near the bottom of the article.

COVID-19, ARDS & CELL-FREE HEMOGLOBIN - THE ASCORBIC ACID CONNECTION, Doris Loh, Evolutamente.it, March 24, 2020.

Description [65]: Comprehensive article explaining the relationship between ARDS, cell-free hemoglobin and COVID-19 in great detail. The important role vitamin C plays in preventing and treating cell-free hemoglobin and ARDS is investigated.

- Furthermore, the article explains why oral AA is superior to oral SA.

- Near the end it gives an oral supplementation protocol for COVID-19.

6.3. Large Folders (ZIP), Link Collections and Comprehensive Articles on Multifaceted Orthomolecular Treatment of Viral Diseases

BRIGHTHOPE CORONAVIRUS SHARE GENERAL, Dr. Ian Brighthope, available at Dropbox.com.

Description [82]: This is a storehouse of information (+70 PDF documents) from Australian physician Dr. Ian Brighthope about vitamin C, D, COVID-19 and viruses. The folder "VITAMIN C D AND VIRUSES" contains information on viral disease and vitamin C. In addition, the folder provides plenty of evidence from experimental and clinical research that strongly supports vitamin C's efficacy as a treatment of viral disease.

Safe and Effective Modalities For COVID-19 That Can Not Be 'Proven'", Dr. Charles Chun-En Hsu, M.D, Afternoon Health, April 1, 2020.

Description [55]: In-depth article explaining the potential benefits of magnesium, zinc, vitamin C and D, melatonin and NAC for prevention and treatment of COVID-19. The majority of the sources provided are in vitro and in vivo research papers on the mechanisms of action of the previously mentioned compounds.

- All these mechanisms of action play an important role in COVID-19. Hence, the compounds are speculated to be potentially beneficial for treatment and prevention of COVID-19

Published Research and Articles on Vitamin C as a Consideration for Pneumonia, Lung Infections, and the Novel Coronavirus (SARS-CoV-2/COVID-19), Graham Player, PhD et al., March 22, 2020, Orthomolecular Medicine News Service, Orthomolecular.org.

Description [101]: A comprehensive compilation of "Published Research and Articles on Vitamin C as a Consideration for Pneumonia, Lung Infections, and the Novel Coronavirus (SARS-CoV-2/COVID-19)". A majority of the research of the extant articles is referenced in this document.

7. Alan Smith H1N1 Story and an Enterovirus Case Report

Alan Smith, a New Zealand farmer with severe H1N1 Swine Flu resulting in coma and ECMO intubation, saved by HIDV-C and LEV-C. Watch Part 1 [66] and 2 [67].

Description [66] [67]: Alan Smith's H1N1 infection quickly worsened, and ECMO intubation was necessary. After a few weeks his condition was deteriorating, and the hospital doctors felt they had no recourse but to take him off ECMO and let him die.

Smith's family, however, contacted Dr. Thomas E. Levy and pushed for IV-C to be given to him. The hospital doctors reluctantly allowed HDIV-C to be administered. Massive dosages of 25g, 50g, 75g and 100 g/day of IV-C were given, and Smith's "whitened lungs" cleared within days. Following that, the treatment dose was lowered to only a few thousand milligrams. Then treatment stopped and was resumed again at a smaller dose. This caused his condition to quickly worsen. The family decided to intervene by giving large doses of LEV-C, and the patient's condition improved. He made a full recovery and resumed his farmer life. Alan Smith continues to take high-doses of oral vitamin C daily.

Alpha A. Fowler et al., Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome, World Journal of Critical Care Medicine, 2017 Feb 4; 6(1): 85-90 (Epub 2017 February 4), doi: 10.5492/wjccm.v6.i1.85

Description [68]: A case report of severe ARDS caused by enterovirus/rhinovirus and resulting in ECMO intubation. The researchers used their 200mg/kg/day IV-C protocol, and "ECMO decannulation and extubation from ventilation occurred on ECMO day 7". The IV-C dose was gradually lowered on the two days following ECMO day 7: From 200mg/kg/day to 50mg/kg/day. The patient was sent home on hospital day 12. In the abstract the authors concluded:

"The patient's recovery was rapid. ECMO and mechanical ventilation were discontinued by day-7 and the patient recovered with no long-term ARDS sequelae. Infusing high dose intravenous vitamin C into this patient with virus-induced ARDS was associated with rapid resolution of lung injury with no evidence of post-ARDS fibroproliferative sequelae."

8. Immunoregulatory and Antiviral Properties of Vitamin D, Zinc and Melatonin

This section will list important sources for vitamin D and melatonin, and it will include a piece of text on zinc's antiviral properties.

Antiviral and immunoregulatory effects of vitamin A, NAC, magnesium and other compounds won't be discussed here or in any other section of this document. Reference no. 55 talks about magnesium and NAC and can be found under subsection "6.3. Large Folders (ZIP), Link Collections and Comprehensive Articles on Multifaceted Orthomolecular Treatment of Viral Disease".

Here are four sources on vitamin D3 and COVID-19:

Covid-19 and Vitamin D Information, Dr Gareth Davies (PhD), Dr Joanna Byers (MBChB), Dr Attila R Garami (MD, PhD), Google Docs.

Description [69]: In-depth article on the rationale of vitamin D for COVID-19. It explains how and why "...Vitamin D supplements could be effective in preventing Covid-19, and play a key role in treating patients if added to existing treatment plans, especially if this is done early in the disease progression." - from the document's front page.

- This document is for medical professionals only.

Jaykaran Charan et al., Vitamin D for prevention of respiratory tract infections: A systematic review and meta-analysis, Journal of Pharmacology & Pharmacotherapeutics, 2012 Oct-Dec; 3(4): 300-303, doi: 10.4103/0976-500X.103685

Description [75]: Systematic review and meta-analysis on the role of "Vitamin D for prevention of respiratory tract infections". Here are the results from the meta-analysis:

"Events of respiratory tract infections were significantly lower in vitamin D group as compared to control group [Odds ratio = 0.582 (0.417 - 0.812) P = 0.001] according to random model. Results were similar in fixed model. On separate analysis of clinical trials dealing with groups of children and adults, beneficial effect of vitamin D was observed in both, according to fixed model [Odds ratio = 0.579 (0.416 - 0.805), P = 0.001 and Odd ratio = 0.653 (0.472 - 0.9040, P = 0.010 respectively]."

Mihnea Zdrenghea et al., Vitamin D modulation of innate immune responses to respiratory viral infections, Reviews in Medical Virology, 2017 Jan;27(1) (Epub 2016 Oct 7), doi: 10.1002/rmv.1909

Description [93]: Comprehensive review about "Vitamin D modulation of innate immune responses to respiratory viral infections". Contains information about vitamin D's immunomodulatory and antiviral activity, its role in acute respiratory infections and the impact of vitamin D deficiency and supplementation in preventing and treating acute viral infections (ARIs) and more.

Former CDC Chief. Dr. Tom Frieden: Coronavirus infection risk may be reduced by Vitamin D, Op-ed by Tom Frieden, M.D, Fox News, March 2020.

Description [70]: Op-ed written by former CDC chief Tom Frieden. He explains how and why vitamin D could play an important role in the current COVID-19 pandemic.

And here's a comprehensive piece of research on melatonin as a treatment for COVID-19:

Rui Zhang et al., COVID-19: Melatonin as a potential adjuvant treatment, Life Sciences, 2020 June 1; 250: 117583 (Epub 2020 March 23), doi: 10.1016/j.lfs.2020.117583

Description [78]: This is a comprehensive research article that "...summarizes the likely benefits of melatonin in the attenuation of COVID-19 based on its putative pathogenesis".

And now a short word on zinc: Zinc is likely an effective and potent SARS-CoV-2 antiviral. It has been proven in multiple in vitro studies to inhibit viral replication [94] [95] [96] [97]. It's been proven in vitro to inhibit SARS-CoV (2003) [97]. The mechanism of action for zinc in viral infections is similar to remdesivir, because they both inhibit the RNA polymerase enzyme [97]. Zinc on its own won't have the same antiviral effect as when combined with a carrier ionophore. A carrier ionophore catalyzes ion transport across the cell membrane, leading to rapid intracellular ion accumulation and high intracellular concentrations of zinc ions. There are multiple known zinc ionophores, but the ones that get the greatest attention for COVID-19 are the pharmaceutical drugs hydroxychloroquine, chloroquine and the flavonol quercetin [98] [99] [100].

An excellent preprint research hypothesis by Martin Scholz and Roland Derwand from April 8, 2020 titled "Does Zinc Supplementation Enhance the Clinical Efficacy of Chloroquine/Hydroxychloroquine to Win Todays Battle Against COVID-19?" explains this in greater detail [100].

Disclaimer:

This document does not provide medical advice. This document acts solely for informational purposes and nothing stated in this document, including but not limited to text, URL link, scientific studies and other sources provided, should be considered medical advice.

Nor is it intended to be a substitute for any professional medical advice, including but not limited to the professional medical advice, diagnosis or treatment of a physician and/or a medical provider.

Do not disregard any professional medical advice or delay in seeking it because of anything you have read in this document. Always seek the advice of your physician or other qualified health care providers with any questions you may have regarding a medical condition and/or treatment before undertaking a new health care regimen.

Neither is this document to be taken as a reason to stop self isolating and social distancing amid the pandemic.

Reliance on any information appearing in this document is solely at your own discretion.

(Magnus P. F. Rasmussen lives in Copenhagen, Denmark. Already as an undergraduate, he is especially interested in compiling and reviewing research, particularly on the value of orthomolecular medicine to fight COVID-19.)

1. Robert F. Cathcart, M.D, VITAMIN C, TITRATING TO BOWEL TOLERANCE, ANASCORBEMIA, AND ACUTE INDUCED SCURVY, Medical hypotheses, 1981, 7:1359-1376, Vitamin C Foundation.

Link URL: https://vitamincfoundation.org/www.orthomed.com/titrate.htm

2. Sebastian J. Padayatty et al., Vitamin C: Intravenous use by complementary and alternative medicine practitioners and adverse effects, PloS One, 2010; 5(7): e11414 (Epub 2010 Jul 7), doi: 10.1371/journal.pone.0011414

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2898816/

3. High-Dose Vitamin C (PDQ(r))-Health Professional Version, NIH - National Cancer Institute, Adverse Effects section, Cancer.gov.

Link URL: https://www.cancer.gov/about-cancer/treatment/cam/hp/vitamin-c-pdq#_18

4. Markos G. Kashiouris et al.,The Emerging Role of Vitamin C as a Treatment for Sepsis, Nutrients, 2020 Feb; 12(2): 292 (Epub 2020 January 22), doi: 10.3390/nu12020292

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070236/

5. Melissa Prier et al., No Reported Renal Stones with Intravenous Vitamin C Administration: A Prospective Case Series Study, Antioxidants (Basel), 2018 May; 7(5): 68 (Epub 2018 May 21), doi: 10.3390/antiox7050068

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981254/

6. The Riordan IVC Protocol for Adjunctive Cancer Care Intravenous Ascorbate as a Chemotherapeutic and Biological Response Modifying Agent, Ron Hunninghake et al., Riordan Clinic Research Institute, 2014.

Link URL: https://riordanclinic.org/wp-content/uploads/2014/11/Riordan_IVC_Protocol.pdf

7. Hemochromatosis and vitamin C, Andrew W. Saul, DoctorYourself.com.

Link URL: http://www.doctoryourself.com/hemochrom.html

8. Sebastian J. Padayatty et al., Vitamin C Pharmacokinetics: Implications for Oral and Intravenous use, Annals of Internal Medicine, 2004;140(7):533-537, doi:10.7326/0003-4819-140-7-200404060-00010Link URL:

Link URL: https://annals.org/aim/fullarticle/717329/vitamin-c-pharmacokinetics-implications-oral-intravenous-use

9. Unexpected Early Response in Oral Bioavailability of Ascorbic Acid, Owen Fonorow, Townsend Letter, TownsendLetter.com, March 13, 2020.

Link URL: https://www.townsendletter.com/article/online-unexpected-oral-vitamin-c-response/

10. Exposing the truth about liposomal nutrients, Dr. Thomas Levy, PeakEnergy.com, April 11, 2014.

Link URL: https://www.peakenergy.com/articles/nh20140411/Exposing-the-truth-about-liposomal-nutrients/

11. Shanghai Expert Group on Clinical Treatment of New Coronavirus Diseases. Expert Consensus on Comprehensive Treatment of Coronavirus Diseases in Shanghai 2019 [J / OL], Chinese Journal of Infectious Diseases, 2020,38 (2020-03-01) , doi: 10.3760 / cma.j.issn.1000-6680.2020.0016. [Pre-published online]

Link URL: http://rs.yiigle.com/yufabiao/1183266.htm

12. Shanghai Expert Consensus on Covid-19 treatment, Dr. Cheng, Cheng Integrative Health Center Blog, Drwlc.com, March 21, 2020.

Link URL: https://www.drwlc.com/blog/2020/03/21/shanghai-expert-consensus-on-covid-19-treatment/

13. Intravenous Ascorbic Acid (IVAA) for COVID-19 Supportive Treatment in Hospitalized COVID-19 Patients (Based on use in China and US settings), Dr. Paul S. Anderson, Isom.ca, March 24, 2020.

Link URL: https://isom.ca/wp-content/uploads/2020/03/IVAA-COVID19-Hospital-Use-Anderson-03.24.2020.pdf

14. Role of Ascorbic Acid in Covid 19 Management, Dr Yuen Chuen Fong Raymond, DoctorYourself.com.

Link URL: http://www.doctoryourself.com/role%20of%20AA%20in%20covid%2019.pdf

15. IVC Protocol, Riordan Clinic, RiordanClinic.org.

Link URL: https://riordanclinic.org/research-study/vitamin-c-research-ivc-protocol/

16. Levy TE (2017) A Guide to the Optimal Administration of Vitamin C. Appendix C in "Hidden Epidemic," MedFox Publishing. ISBN-13: 978-0983772873



Link URL: https://d2taktuuo4oqx.cloudfront.net/2019/imm19/bonus/purchase/Thomas-Levy-Guide-To-The-Optimal-Administration-of-Vitamin-C.pdf

17. Medical Information/COVID Care Protocol, EVMS Medical Group, Eastern Virginia Medical School, EVMS.edu.

Link URL: https://www.evms.edu/covid-19/medical_information_resources/#d.en.140202

18. Rationale for Vitamin C Treatment of COVID-19 and Other Viruses, Orthomolecular Medicine News Service Editorial Review Board, Orthomolecular Medicine News Service, Orthomolecular.org, April 3, 2020.

Link URL: http://orthomolecular.org/resources/omns/v16n21.shtml

19. Preparation of Sodium Ascorbate for IV and IM Use, Robert F. Cathcart III, M.D, Edited 2011 by Owen Fonorow, Vitamin C Foundation, VitaminCFoundation.org.

Link URL: https://vitamincfoundation.org/pdfs/civprep.pdf

20. Cathcart's Instructions on the Preparation of Vitamin C for I.V. Use, vitamincfoundation, February 2, 2011, YouTube.com.

Link URL: https://www.youtube.com/watch?v=Zgi-7xPrCAg

21. Alpha A. Fowler III et al., Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure - The CITRIS-ALI Randomized Clinical Trial, Journal of the American Medical Association (JAMA), 2019;322(13):1261-1270 (Epub 2019 October 1), doi:10.1001/jama.2019.11825

Link URL: https://jamanetwork.com/journals/jama/fullarticle/2752063

22. Vitamin C for Sepsis and Severe ARDS, JAMA Network, YouTube, October 28, 2019.

Link URL: https://www.youtube.com/watch?v=-3_aYNT1KNA

23. Alpha A. Fowler et al., Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis, Journal of Translational Medicine, 2014; 12: 32 (Epub 2014 January 31), doi: 10.1186/1479-5876-12-32

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937164/

24. Mohadeseh H. Zabet et al., Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock, Journal of Research in Pharmacy Practice, 2016 Apr-Jun: 5(2): 94-100, doi: 10.4103/2279-042X.179569

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843590/

25. Paul E. Marik et al., Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study, Chest, 2017 Jun;151(6):1229-1238 (Epub December 6, 2016), doi: 10.1016/j.chest.2016.11.036

Link URL: https://www.ncbi.nlm.nih.gov/pubmed/27940189

26. Eric Wald et al., Hydrocortisone-Ascorbic Acid-Thiamine Use Associated with Lower Mortality in Pediatric Septic Shock, American Journal of Respiratory and Critical Care Medicine, 2020 April 1, Volume 201, Issue 7 (Epub January 9, 2020), doi: 10.1164/rccm.201908-1543LE

Link URL: https://www.atsjournals.org/doi/10.1164/rccm.201908-1543LE

27. Vitamin C-B1-Steroid Combo Linked to Lower Septic Shock Mortality in Kids, Ann & Robert H. Lurie Children's Hospital of Chicago, LurieChildrens.org, January 21, 2020.

Link URL: https://www.luriechildrens.org/en/news-stories/vitamin-c-b1-steroid-combo-linked-to-lower-septic-shock-mortality-in-kids/

28. Tomoko Fujii et al., Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock - The VITAMINS Randomized Clinical Trial, Journal of the American Medical Association (JAMA), 2020;323(5):423-431 (Epub 2020 January 17), doi:10.1001/jama.2019.22176

Link URL: https://jamanetwork.com/journals/jama/article-abstract/2759414

29. VITAMINS Trial: Vitamin C and Thiamine for Sepsis and Septic Shock, JAMA Network, YouTube, January 17, 2020.

Link URL: https://www.youtube.com/watch?v=sF2ktY00dqs

30. Anitra C. Carr et al., Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes, Critical Care, 2017 Dec 11;21(1):300, doi: 10.1186/s13054-017-1891-y



Link URL: https://ccforum.biomedcentral.com/articles/10.1186/s13054-017-1891-y

31. Tae K. Kim et al., Vitamin C supplementation reduces the odds of developing a common cold in Republic of Korea Army recruits: randomised controlled trial, BMJ Military Health, 2020 Mar 5. pii: bmjmilitary-2019-001384 (Epub ahead of print), doi: 10.1136/bmjmilitary-2019-001384

Link URL: https://www.ncbi.nlm.nih.gov/pubmed/32139409

32. H. Clay Gorton and Kelly Jarvis, The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infections, Journal of Manipulative and Physiological Therapeutics, 1999 Oct;22(8):530-3, DOI: 10.1016/s0161-4754(99)70005-9

Link URL: https://www.ncbi.nlm.nih.gov/pubmed/?term=10543583

33. Clare Hunt et al., The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections, International Journal for Vitamin and Nutrition Research, 1994;64(3):212-9., PMID: 7814237

Link URL: https://www.ncbi.nlm.nih.gov/pubmed/?term=1994+hunt+c+vitamin+c

34. Imran M. Khan et al., Efficacy of Vitamin C in Reducing Duration of Severe Pneumonia in Children, Journal Of Rawalpindi Medical College (JRMC), 2014;18(1):55-57, at Journalrmc.com.

Link URL: https://www.journalrmc.com/index.php/JRMC/article/view/381

35. Imran M. Khan et al., Efficacy of Vitamin C in Reducing Duration of Severe Pneumonia in Children, Journal Of Rawalpindi Medical College (JRMC), 2014;18(1):55-57, at Journalrmc.com.

Link URL: https://www.journalrmc.com/index.php/JRMC/article/view/381/290

36. Ren Shiguang et al., Observation on the therapeutic effect of intravenous large dose of vitamin C on infants and young children with viral pneumonia, Hebei Medicine, 1978,4:1-3., at China National Knowledge Infrastructure, Cnki.com.cn.

Link URL: http://www.cnki.com.cn/Article/CJFDTOTAL-HBYZ197804000.htm

37. Ren Shiguang et al., Observation on the therapeutic effect of intravenous large dose of vitamin C on infants and young children with viral pneumonia, Hebei Medicine, 1978,4:1-3., at Hebei Medical Journal, Hbyz.chinajournal.net.cn.

Link URL: http://hbyz.chinajournal.net.cn/WKD/WebPublication/paperDigest.aspx?paperID=c9874a37-7d84-4d9b-8eeb-07bc95a55d7f

38. Harri Hemilä and Elizabeth Chalker, Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis, Journal of Intensive Care, 2020; 8: 15 (Epub 2020 February 7), doi: 10.1186/s40560-020-0432-y

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006137/

39. Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis, Harri Hemilä and Elizabeth Chalker, Nutrients, 2019 Apr; 11(4): 708 (Epub 2019 March 27), doi: 10.3390/nu11040708.

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521194/

40. Harri Hemilä and Elizabeth Chalker, Vitamin C for preventing and treating the common cold, Cochrane Database of Systematic reviews, 2013 Jan 31;(1):CD000980, doi: 10.1002/14651858.CD000980.pub4.

Link URL: https://www.ncbi.nlm.nih.gov/pubmed/23440782/

41. Vitamin C for preventing and treating the common cold, Hari Hemilä and Elizabeth Chalker, Cochrane, Cochrane.org, January 31, 2013.

Link URL: https://www.cochrane.org/CD000980/ARI_vitamin-c-for-preventing-and-treating-the-common-cold

42. Harri Hemilä, Vitamin C and Infections, Nutrients, 2017 Apr; 9(4): 339 (Epub 2017 March 29), doi: 10.3390/nu9040339

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409678/

43. Anitra C. Carr and Silvia Maggini, Vitamin C and Immune Function, Nutrients, 2017 Nov; 9(11): 1211 (Epub 2017 November 3), doi: 10.3390/nu9111211

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707683/

44. Harri Hemilä and Robert M. Douglas, Vitamin C and acute respiratory infections, International Journal of Tuberculosis and Lung Disease, 1999 Sep;3(9):756-61, PMID: 10488881

Link URL: https://www.researchgate.net/publication/12811097_Vitamin_C_and_acute_respiratory_infections

45. Sebastian J. Padayatty and Mark Levine, Vitamin C physiology: the known and the unknown and Goldilocks, Oral Diseases, 2016 Sep; 22(6): 463-493 (Epub 2016 April 14), doi: 10.1111/odi.12446

Link URL: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4959991/

46. iSepsis - Vitamin C, Hydrocortisone and Thiamine - The "Metabolic Resuscitation Protocol", Paul Marik, EMCrit.org - iSepsis Project (EMCrit), July, 16 2017.

Link URL: https://emcrit.org/isepsis/isepsis-vitamin-c-hydrocortisone-thiamine-metabolic-resuscitation-protocol/

47. Paul E. Marik and Michael H. Hooper, Doctor-your septic patients have scurvy!, Critical Care, 2018 Jan 29;22(1):23, doi: 10.1186/s13054-018-1950-z

Link URL: https://ccforum.biomedcentral.com/articles/10.1186/s13054-018-1950-z

48. Salim Surani and Munish Sharma, Revisiting the Role of Vitamin C in Sepsis. Is it a Forlorn Hope or is there Still Dearth of data?, The Open Respiratory Medicine Journal, Bentham Open, Benthamopen.com, 2019 Dec 31;13:55-57, doi: 10.2174/1874306401913010055

Link URL: https://benthamopen.com/FULLTEXT/TORMJ-13-55

49. Clinical Guide to the Use of Vitamin C, Lendon H. Smith. M.D, AscorbateWeb, 1988.

Link URL: https://www.seanet.com/~alexs/ascorbate/198x/smith-lh-clinical_guide_1988.htm

50. Frederick R. Klenner, M.D, The Treatment of Poliomyelitis and Other Virus Diseases with Vitamin C, Southern Medicine & Surgery, Volume 111, Number 7, July, 1949, pp. 209-214.

Link URL: https://www.seanet.com/~alexs/ascorbate/194x/klenner-fr-southern_med_surg-1949-v111-n7-p209.htm

51. Frederick R. Klenner, M.D, Observations On the Dose and Administration of Ascorbic Acid When Employed Beyond the Range Of A Vitamin In Human Pathology, Journal of Applied Nutrition, Vol. 23, No's 3 & 4, Winter 1971.

Link URL: http://www.doctoryourself.com/klennerpaper.html

52. Publications by Robert F. Cathcart, Orthomed.com (Cathcart's website), Vitamin C Foundation, VitaminCFoundation.org.

Link URL: https://vitamincfoundation.org/www.orthomed.com/publications1.html

53. The Clinical Impact of Vitamin C: My Personal Experience as a Physician, Thomas E. Levy, Orthomolecular Medicine News Service, Orthomolecular.org, September 3, 2014.



Link URL: http://www.orthomolecular.org/resources/omns/v10n14.shtml

54. Richard Z. Cheng, Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?, Medicine in Drug Discovery, 2020 March 26, doi: 10.1016/j.medidd.2020.100028

Link URL: https://www.sciencedirect.com/science/article/pii/S2590098620300154

55. Safe and Effective Modalities For COVID-19 That Can Not Be 'Proven'", Dr. Charles Chun-En Hsu, M.D, Afternoon Health, April 1, 2020.

Link URL: https://www.afternoonhealth.com/2020/04/01/safe-effective-modalities-for-covid-19-that-can-never-be-proven/

56. Successful High-Dose Vitamin C Treatment of Patients with Serious and Critical COVID-19 Infection, Richard Cheng PhD, Orthomolecular Medicine News Service, March 18, 2020.

Link URL: http://www.orthomolecular.org/resources/omns/v16n18.shtml

57. How to Get Intravenous Vitamin C Given to a Hospitalized Patient: A Checklist, Andrew W. Saul, DoctorYourself.com, 2019.

Link URL: http://www.doctoryourself.com/strategies.html

58. Colds, Flus and COVID-19: Can Supplements Help?, Prof Kylie O'Brien PhD and Prof Ian Brighthope, Australasian College Of Nutritional And Environmental Medicine (ACNEM), ACNEM.org, 2020.Link URL:

Link URL: https://www.acnem.org/sites/default/files/pdf/2020/Key%20Supplements%20for%20Protecting%20Against%20&%20Treating%20Colds,%20Flus%20&%20COVID-19.pdf

59. Colds, Flus and COVID-19: Can Supplements Help?, Prof Kylie O'Brien PhD and Prof Ian Brighthope, Australasian College Of Nutritional And Environmental Medicine (ACNEM), ACNEM.org, 2020. - This is a placeholder since the page is currently restricted.

Link URL: https://www.acnem.org/videos/Supplements-Flus-COVID-19

60. STOP ARDS NOW WITH ASCORBIC ACID, Doris Loh, Evolutamente.it, March 28, 2020.

Link URL: https://www.evolutamente.it/stop-ards-now-with-ascorbic-acid/

61. MITOCHONDRIA & THE CORONAVIRUS - THE VITAMIN C CONNECTION (PART 3), Doris Loh, Evolutamente.it, February 1, 2020.

Link URL: https://www.evolutamente.it/mitochondria-the-coronavirus-the-vitamin-c-connection-part-3/

62. COVID-19, FURINS & HYPOXIA - THE VITAMIN C CONNECTION, Doris Loh, Evolutamente.it, February 29, 2020.

Link URL: https://www.evolutamente.it/covid-19-furins-cancer-a-tale-of-vitamin-c-hif/

63. COVID-19 MUTATIONS, VACCINES & NITRIC OXIDE - THE VITAMIN C CONNECTION, Doris Loh, Evoluta