MATH+ and Paul Marik's COVID-19 Treatment Protocols

Table of Contents

1. The Alliance and the Birth of MATH+
2. How Marik Described Severe COVID-19
3. The Four Core Drugs of MATH+
4. The “Plus”: Vitamin D, Melatonin, Quercetin and Minerals
5. Vitamin C and Vitamin D Levels in Critically Ill Patients
6. Spike Protein Lung Injury in Mice
7. Ivermectin and the I-MASK+ Protocol
8. The Case Against “Supportive Care Only”
9. Later Research: Corticosteroids in Hospitalised Patients
10. Later Research: Randomised Trials of Ivermectin
11. Key Research Papers
12. Connections
13. Featured Videos

1. The Alliance and the Birth of MATH+

When the pandemic reached hospitals in early 2020, Marik was running the critical-care division at Eastern Virginia Medical School. In a 2022 paper setting out the clinical and scientific rationale for the protocol, he and his co-authors — Pierre Kory, G. Umberto Meduri, Jose Iglesias, Joseph Varon and Flavio Cadegiani — described the situation they faced. Because COVID-19 was assumed to be a viral pneumonia with no anti-coronavirus therapy, they wrote, nearly all national and international health-care societies recommended “supportive care only”, steering clinicians away from other therapies outside randomised controlled trials, with “a specific prohibition against the use of corticosteroids”.

The authors wrote that early reports of COVID-19 respiratory failure showed unexpectedly high death rates and long periods on mechanical ventilation, even from centres expert in supportive care. Those reports, they said, led them to form a clinical expert panel, the Front-Line COVID-19 Critical Care Alliance. According to the paper, the approximately 20% of hospitalised patients who developed acute respiratory failure needing intensive care were where the disease had its greatest impact.

The panel reviewed the emerging clinical, radiographic and autopsy reports, and held discussions with front-line intensive-care doctors in the first outbreak areas — China, Italy and New York. Based on their shared early impressions of “what was working and what wasn’t working”, the growing journal literature and their own experience with patients, they built a hospital protocol around methylprednisolone, ascorbic acid, thiamine, heparin and non-antiviral co-interventions. The 2022 paper reviews laboratory, pre-clinical and clinical data for each medicine, with special emphasis on studies in viral syndromes and in COVID-19 itself.

A separate history of the protocols, written by the Finnish independent researcher Mika Turkia and published in Cureus in December 2020, describes the Alliance as “an alliance of established experts on critical care” that had by then published two protocols: MATH+ for hospital and intensive-care treatment, and I-MASK+ for prevention and early outpatient treatment. Turkia wrote that MATH+ received scarce attention at first because the World Health Organization had advised against corticosteroids early in the pandemic, and because randomised trials were demanded as a condition of adoption — trials the protocol’s authors considered unethical to run.

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2. How Marik Described Severe COVID-19

MATH+ rests on a particular picture of the illness. In the paper Marik wrote as first author with Kory, Varon, Iglesias and Meduri — “MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale”, published in Expert Review of Anti-Infective Therapy — the authors stated that COVID-19 moves through several distinct phases, and that each phase needs its own management.

The phase they focused on was the pulmonary phase. They described it as an organizing pneumonia (a pattern in which inflamed lung air spaces fill with plugs of repair tissue) with profound immune dysregulation, activation of blood clotting and severe injury to the smallest blood vessels, ending in severely low blood oxygen. In their view, this was not simply a virus attacking the lungs but the body’s own inflammatory and clotting response running out of control — which is why the treatments they chose aim at inflammation, oxidative stress and clotting rather than at the virus.

In 2021 Marik, Iglesias, Varon and Kory expanded this model in a scoping review of the pathophysiology of COVID-19 in the International Journal of Immunopathology and Pharmacology. They called severe COVID-19 “probably amongst the most complex of medical conditions known to medical science” and, drawing on clinical, protein, gene and autopsy studies, described it as the meeting of three basic processes:

• a pulmonary macrophage activation syndrome — immune cells in the lung driving uncontrolled inflammation;
• a complement-mediated endothelialitis — inflammation of the inner lining of blood vessels driven by the complement system, part of innate immunity;
• a procoagulant state with a thrombotic microangiopathy — a tendency to form clots in small vessels.

The review added that platelet activation with release of serotonin, and the activation and degranulation of mast cells, feed the hyper-inflammatory state, and that auto-antibodies found in a large number of hospitalised patients add to organ damage and clotting.

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3. The Four Core Drugs of MATH+

The 2020 rationale paper put the core of the protocol in one sentence: the treatment strategy for the pulmonary phase “includes the combination of methylprednisolone, ascorbic acid, thiamine, and heparin (MATH+ protocol)”. In their expert opinion, the authors wrote that while there is no single “Silver Bullet” to cure COVID-19, they believed the disturbed processes leading to respiratory failure would respond to methylprednisolone, ascorbic acid, thiamine and full anticoagulation with heparin. Each letter stands for one drug:

• M — methylprednisolone. A corticosteroid, given against the inflammation the authors saw at the heart of the organizing pneumonia. This was the component that ran against the early guidance on corticosteroids.
• A — ascorbic acid (vitamin C). Given intravenously; Turkia’s history describes it as a “high-dose vitamin C infusion”. It carried over from Marik’s earlier sepsis work, in which he combined vitamin C, hydrocortisone and thiamine (see his sepsis protocol of hydrocortisone, ascorbic acid and thiamine).
• T — thiamine (vitamin B1). Another carry-over from the sepsis protocol.
• H — heparin. An anticoagulant, aimed at the clotting and small-vessel injury the authors described. The 2020 paper speaks of “full anticoagulation” with heparin.

The authors stressed that the drugs are old, widely available and inexpensive. Turkia’s history describes the protocol as “based on affordable, commonly available components”.

The exact doses and timing were set out in the Alliance’s own protocol documents, which were revised several times as the pandemic went on; this page does not reproduce them. The 2022 paper in the Journal of Clinical Medicine Research is the authors’ fullest published statement of the rationale for each component.

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4. The “Plus”: Vitamin D, Melatonin, Quercetin and Minerals

The “+” in MATH+ stands for co-interventions. Turkia’s history lists the supplemental components as melatonin, vitamin D, elemental zinc and magnesium, alongside the antiparasitic drug ivermectin. Marik co-wrote several papers in 2020 on the reasoning behind these additions.

Quercetin with vitamin C

With Ruben Colunga Biancatelli, Matthew Berrill and John Catravas, Marik published “Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19)” in Frontiers in Immunology in June 2020. The authors described vitamin C as a vitamin crucial to the immune system that plays a role in the stress response and had shown promising results in the critically ill, and quercetin as a well-known flavonoid whose antiviral properties have been investigated in numerous studies. They wrote that there is evidence the two act synergistically, because of overlapping antiviral and immune-modulating effects and because vitamin C can recycle quercetin, increasing its efficacy. They argued that safe, cheap interventions with a sound biological rationale deserve priority for experimental use during a pandemic, and presented the evidence for the pair both for prevention in high-risk groups and as an add-on treatment.

Melatonin

In May 2020 Marik was a co-author, with first author Russel Reiter and colleagues in Spain, of “Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19” in Frontiers in Medicine. The authors proposed that melatonin be considered for prevention or treatment, alone or with other drugs. They pointed to its anti-inflammatory and antioxidant actions and its antiviral activity against other viruses, and described it as readily available, inexpensive, very safe and easily self-administered. They also noted that the body’s own melatonin production falls with age.

Vitamin D

In April 2020 Marik, Kory and Varon published a short paper in Medicine in Drug Discovery asking, in its title, “Does vitamin D status impact mortality from SARS-CoV-2 infection?”. Vitamin D became one of the protocol’s listed co-interventions.

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5. Vitamin C and Vitamin D Levels in Critically Ill Patients

Marik was the senior author of a small pilot study, led by Cristian Arvinte, that measured blood levels of vitamin C and vitamin D in critically ill COVID-19 patients. It included all 21 such patients admitted in May 2020 to the intensive care unit of a community hospital in Colorado in whose care the principal investigator was involved. The patients were 15 men and 6 women, with a median age of 61 years (range 20 to 94); 11 survived.

The authors reported that:

• blood levels of vitamin C and vitamin D were low in most of the patients;
• older age and a low vitamin C level appeared to be linked risk factors for death in this sample;
• insulin resistance and obesity were common in the group, but smoking was not.

The study used descriptive statistics only and was designed, in the authors’ words, to generate hypotheses. They concluded that the findings point to a need to explore whether care for COVID-19 patients ought routinely to include measuring and correcting vitamin C and vitamin D levels, and whether critically ill patients warrant intravenous vitamin C and vitamin D replacement. With 21 patients and no comparison group, it is a pilot observation, not a trial.

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6. Spike Protein Lung Injury in Mice

Marik also took part in laboratory work at Eastern Virginia Medical School and Old Dominion University. In a 2021 paper in the American Journal of Physiology – Lung Cellular and Molecular Physiology, led by Colunga Biancatelli with Catravas as senior author, the team asked whether part of the virus’s spike protein could injure the lungs on its own, without the virus.

They placed the S1 subunit of the spike protein directly into the airways of transgenic mice engineered to carry the human angiotensin-converting enzyme 2 (ACE2) receptor, the doorway the virus uses to enter cells, and examined the mice 72 hours later. The researchers reported, in these mice:

• weight loss, sharply increased white blood cells and protein in fluid washed from the lungs, and raised inflammatory signalling molecules in that fluid and in the blood;
• lung tissue injury under the microscope, and activation of two inflammatory switches in lung cells (signal transducer and activator of transcription 3 and nuclear factor kappa B);
• little or no lung injury in mice given salt water or the intact spike protein, and a milder illness in ordinary mice given the S1 subunit.

In cultured human lung blood-vessel cells, the S1 subunit — but not the intact spike protein — weakened the barrier the cells form. The authors called it the first demonstration of a COVID-19-like response to an essential protein of the virus in a living animal, and proposed the model as a tool for testing new treatments. These are findings in mice and in cell culture, not in patients.

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7. Ivermectin and the I-MASK+ Protocol

Ivermectin is an old antiparasitic drug whose discovery earned a share of the 2015 Nobel Prize (see the site’s ivermectin page). Within the Alliance’s protocols it moved from the margins to the centre during 2020.

Turkia’s history records the sequence. Ivermectin first appeared in MATH+ as an optional component. In October 2020 it was upgraded to an essential component. According to the protocol’s authors, as Turkia reported them, ivermectin was considered the first agent effective both for prevention of COVID-19 and for treatment of all its phases, including outpatient treatment of the early symptomatic phase. For that reason, at the end of October 2020 the Alliance published a separate ivermectin-based protocol, I-MASK+, for prevention and early outpatient treatment — leaving MATH+ as the hospital protocol.

Marik and Kory continued to argue for ivermectin in print. In 2021 they published a letter in the American Journal of Therapeutics titled “Ivermectin, A Reanalysis of the Data”, returning to the trial evidence on the drug.

Marik’s interest in ivermectin did not end with COVID-19. In his later book Cancer Care he discusses it as a repurposed drug in cancer, while stating plainly that cancer is not a parasitic disease (see Cancer Care: Paul Marik’s Book on Repurposed Drugs).

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8. The Case Against “Supportive Care Only”

The thread running through all of Marik’s COVID-19 writing is an ethical argument about waiting. The 2020 MATH+ rationale paper closes its expert opinion with this sentence:

“We believe that it is no longer ethically acceptable to limit management to ‘supportive care’ alone, in the face of effective, safe, and inexpensive medications that can effectively treat this disease and thereby reduce the risk of complications and death.” — Marik, Kory, Varon, Iglesias and Meduri, 2020

In 2021 Marik joined a large international group of clinicians, led by Brian Ngo, in a review titled “The time to offer treatments for COVID-19” in Expert Opinion on Investigational Drugs. The authors searched trial registries, PubMed and preprint servers and found, as of 15 February 2021, 111 publications on 14 classes of agents and 9 vaccines, including 62 randomised controlled studies; only 21 publications dealt with outpatient care. They noted that the pandemic is spread by the viral phase in people outside hospital, while treatments to date had focused on late disease in hospital and public-health strategy relied solely on vaccines. Because vaccines and antibodies are highly specific to the virus’s antigens and new variants were appearing, the authors called on public-health authorities to authorise treatments with known low risk and possible benefit for outpatients, in parallel with universal vaccination.

Turkia’s history adds that the protocol’s authors regarded withholding the protocol from patients in a placebo-controlled trial as unethical, and that later clinical trials run by other groups on corticosteroids and anticoagulants led to wider adoption of those two components.

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9. Later Research: Corticosteroids in Hospitalised Patients

The “M” of MATH+ — a corticosteroid for hospitalised patients — was tested in a large randomised trial in the United Kingdom while the protocol was being promoted. The RECOVERY trial, published in the New England Journal of Medicine (online July 2020; final report February 2021), compared dexamethasone, a different corticosteroid from the methylprednisolone in MATH+, with usual care.

According to the trial’s abstract:

• 2,104 patients were assigned to dexamethasone 6 mg once daily, by mouth or vein, for up to 10 days, and 4,321 to usual care alone;
• 22.9% of the dexamethasone group and 25.7% of the usual-care group died within 28 days (age-adjusted rate ratio 0.83);
• among patients on invasive mechanical ventilation, deaths were 29.3% with dexamethasone against 41.4% with usual care;
• among patients receiving oxygen without a ventilator, deaths were 23.3% against 26.2%;
• among patients receiving no respiratory support, there was no reduction (17.8% against 14.0%).

The investigators concluded that dexamethasone lowered 28-day mortality in hospitalised patients receiving invasive mechanical ventilation or oxygen alone, but not in those receiving no respiratory support. This is the later research Turkia refers to when he writes that trials by other groups led to wider adoption of corticosteroids.

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10. Later Research: Randomised Trials of Ivermectin

From 2021 onward, several large randomised trials tested ivermectin in people with COVID-19, mostly outpatients early in the illness — the setting of the I-MASK+ protocol. Each is described here as its own abstract states.

Cali, Colombia (JAMA, 2021)

A double-blind trial led by Eduardo López-Medina randomised 400 adults with mild COVID-19 to ivermectin 300 μg per kilogram of body weight daily for 5 days or placebo. The median time to resolution of symptoms was 10 days with ivermectin and 12 days with placebo, a difference that was not statistically significant (hazard ratio 1.07). By day 21, 82% of the ivermectin group and 79% of the placebo group had resolved symptoms. The authors wrote that the findings do not support ivermectin for mild COVID-19, although larger trials may be needed to understand effects on other outcomes.

I-TECH, Malaysia (JAMA Internal Medicine, 2022)

An open-label trial at 20 public hospitals and a quarantine centre enrolled 490 patients aged 50 or older with comorbidities and mild to moderate COVID-19. They received ivermectin 0.4 mg per kilogram daily for 5 days plus standard care, or standard care alone. Progression to severe disease occurred in 21.6% of the ivermectin group and 17.3% of the control group (relative risk 1.25, not statistically significant). None of the secondary outcomes differed significantly: mechanical ventilation in 1.7% against 4.0%, intensive-care admission in 2.4% against 3.2%, and 28-day in-hospital death in 1.2% against 4.0%. Diarrhoea was the most common adverse event (5.8% against 1.6%).

TOGETHER, Brazil (New England Journal of Medicine, 2022)

This double-blind, placebo-controlled platform trial recruited adults with symptoms for up to 7 days and at least one risk factor for progression from 12 public-health clinics. Patients received ivermectin 400 μg per kilogram once daily for 3 days (679 patients) or placebo (679). A primary-outcome event — hospital admission, or more than 6 hours of emergency observation, for worsening COVID-19 within 28 days — occurred in 14.7% of the ivermectin group and 16.3% of the placebo group (relative risk 0.90). The investigators reported that ivermectin did not lead to a lower incidence of hospital admission or prolonged emergency observation, and found no significant effects on secondary outcomes or adverse events.

ACTIV-6, United States (JAMA, 2022)

This decentralised, double-blind, placebo-controlled trial at 93 sites enrolled outpatients aged 30 and older with mild to moderate COVID-19; 817 received ivermectin 400 μg per kilogram daily for 3 days and 774 placebo. The median time to sustained recovery was 12 days with ivermectin and 13 days with placebo (hazard ratio 1.07). There were 10 hospitalisations or deaths in the ivermectin group and 9 in the placebo group (1.2% in each). The authors concluded that ivermectin did not significantly improve time to recovery.

COVID-OUT, United States (New England Journal of Medicine, 2022)

This double-blind trial tested three repurposed drugs — metformin, ivermectin and fluvoxamine — in 1,323 non-hospitalised adults aged 30 to 85 with overweight or obesity, enrolled within 3 days of diagnosis. For the primary end point (low blood oxygen on home oximetry, emergency visit, hospitalisation or death), the adjusted odds ratio was 1.05 with ivermectin. The investigators reported that none of the three medications prevented the primary outcome. In prespecified secondary analyses, the odds ratio for emergency visit, hospitalisation or death was 0.58 with metformin and 1.39 with ivermectin.

PRINCIPLE, United Kingdom (Journal of Infection, 2024)

This open-label community platform trial included 8,811 adults with a positive test and symptoms for up to 14 days; 2,157 received ivermectin (300–400 μg per kilogram once daily for 3 days) and 3,256 usual care. Time to self-reported recovery was shorter with ivermectin, by a median of about 2 days (hazard ratio 1.15), but the probability of the meaningful effect the trial had set in advance was 0.192. COVID-19-related hospitalisations or deaths were similar (odds ratio 1.02), as were serious adverse events, and 74.3% against 71.2% felt fully recovered at 6 months. The investigators concluded that ivermectin is unlikely to provide clinically meaningful improvement in recovery, hospital admission or longer-term outcomes.

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Key Research Papers

1. Marik PE, Kory P, Varon J, Iglesias J, Meduri GU. MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale. Expert Rev Anti Infect Ther. 2021;19(2):129-135. — PubMed PMID: 32809870
2. Kory P, Meduri GU, Iglesias J, Varon J, Cadegiani FA, Marik PE. “MATH+” Multi-Modal Hospital Treatment Protocol for COVID-19 Infection: Clinical and Scientific Rationale. J Clin Med Res. 2022;14(2):53-79. — PubMed PMID: 35317360
3. Turkia M. The History of Methylprednisolone, Ascorbic Acid, Thiamine, and Heparin Protocol and I-MASK+ Ivermectin Protocol for COVID-19. Cureus. 2020;12(12):e12403. — PubMed PMID: 33532161
4. Marik PE, Iglesias J, Varon J, Kory P. A scoping review of the pathophysiology of COVID-19. Int J Immunopathol Pharmacol. 2021;35:20587384211048026. — PubMed PMID: 34569339
5. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and Vitamin C: An Experimental, Synergistic Therapy for the Prevention and Treatment of SARS-CoV-2 Related Disease (COVID-19). Front Immunol. 2020;11:1451. — PubMed PMID: 32636851
6. Reiter RJ, Abreu-Gonzalez P, Marik PE, Dominguez-Rodriguez A. Therapeutic Algorithm for Use of Melatonin in Patients With COVID-19. Front Med (Lausanne). 2020;7:226. — PubMed PMID: 32574327
7. Marik PE, Kory P, Varon J. Does vitamin D status impact mortality from SARS-CoV-2 infection? Med Drug Discov. 2020;6:100041. — PubMed PMID: 32352080
8. Arvinte C, Singh M, Marik PE. Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study. Med Drug Discov. 2020;8:100064. — PubMed PMID: 32964205
9. Colunga Biancatelli RML, Solopov PA, Sharlow ER, Lazo JS, Marik PE, Catravas JD. The SARS-CoV-2 spike protein subunit S1 induces COVID-19-like acute lung injury in K18-hACE2 transgenic mice and barrier dysfunction in human endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2021;321(2):L477-L484. — PubMed PMID: 34156871
10. Marik PE, Kory P. Ivermectin, A Reanalysis of the Data. Am J Ther. 2021;28(5):e579-e580. — PubMed PMID: 34491955
11. Ngo BT, Marik P, Kory P, Shapiro L, Thomadsen R, Iglesias J, et al. The time to offer treatments for COVID-19. Expert Opin Investig Drugs. 2021;30(5):505-518. — PubMed PMID: 33721548
12. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021;384(8):693-704. — PubMed PMID: 32678530
13. López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, et al. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(14):1426-1435. — PubMed PMID: 33662102
14. Lim SCL, Hor CP, Tay KH, Mat Jelani A, Tan WH, Ker HB, et al. Efficacy of Ivermectin Treatment on Disease Progression Among Adults With Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial. JAMA Intern Med. 2022;182(4):426-435. — PubMed PMID: 35179551
15. Reis G, Silva EASM, Silva DCM, Thabane L, Milagres AC, Ferreira TS, et al. Effect of Early Treatment with Ivermectin among Patients with Covid-19. N Engl J Med. 2022;386(18):1721-1731. — PubMed PMID: 35353979
16. Naggie S, Boulware DR, Lindsell CJ, Stewart TG, Gentile N, Collins S, et al. Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2022;328(16):1595-1603. — PubMed PMID: 36269852
17. Bramante CT, Huling JD, Tignanelli CJ, Buse JB, Liebovitz DM, Nicklas JM, et al. Randomized Trial of Metformin, Ivermectin, and Fluvoxamine for Covid-19. N Engl J Med. 2022;387(7):599-610. — PubMed PMID: 36070710
18. Hayward G, Yu LM, Little P, Gbinigie O, Shanyinde M, Harris V, et al. Ivermectin for COVID-19 in adults in the community (PRINCIPLE): An open, randomised, controlled, adaptive platform trial of short- and longer-term outcomes. J Infect. 2024;88(4):106130. — PubMed PMID: 38431155

PubMed Topic Searches

1. MATH+ protocol and COVID-19
2. Paul E. Marik: COVID-19 papers
3. Methylprednisolone in COVID-19: randomised trials
4. Intravenous vitamin C in COVID-19
5. Ivermectin in COVID-19: randomised controlled trials

Further Reading

• Independent Medical Alliance (formerly the Front Line COVID-19 Critical Care Alliance) — the organisation Marik co-founded, which publishes its protocols online.

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Connections

• Dr. Paul Marik: Critical Care, Vitamin C and Repurposed Drugs
• Paul Marik: Life and Career
• The HAT Protocol: Vitamin C, Thiamine and Hydrocortisone in Sepsis
• Cancer Care: Paul Marik’s Book on Repurposed Drugs
• Paul Marik’s Metabolic Approach to Cancer
• Paul Marik’s Critical Care Research and Textbooks
• Contemporary Practitioners
• Ivermectin
• Vitamin C
• Vitamin B1 (Thiamine)
• Quercetin
• Melatonin

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