The MATH+ Protocol has been updated: August 1st PDF file from EVMS.edu

Please note that the author of this article is not a physician or medical professional. The article reviews a set of recommendations from physicians. However, consult your health care provider before following this or any other medical recommendations.

The Front Line Covid-19 Critical Care Working Group (or FLCCC Working Group) is comprised of ten physicians at the forefront of the battle against Covid-19. They have devised a set of recommendations for fighting Covid-19. It is called the MATH+ Protocol.

“The world is desperate to find a treatment that will save the lives of COVID-19 patients who come into the ER or hospital with low oxygen levels or struggling to breathe. As a working group with over 200 years of combined experience in Critical Care and Emergency Medicine, we designed the MATH+ COVID-19 Early Intervention Treatment Protocol and, to date, are having remarkable success using it to treat patients in hospitals that permit its use. We are in the process of gathering patient data to scientifically prove that point.”

The Working Group is comprised of ten physicians. See the team list here, which includes their qualifications and background. They are professors of medicine, critical care chiefs, pulmonary specialists, etc. Here are the links to the MATH+ protocol and the associated websites:
* The latest MATH+ Protocol (June 17th, 2020; PDF file)
* The Eastern Virginia Medical School site which hosts the Protocol (evms.edu)
* The FLCCC Working Group’s own website (covid19criticalcare.com)

Much of the Protocol is concerned with advising other physicians about treatment of severe cases of Covid-19. But this review will focus on two common situations addressed by MATH+:
* What to take while you are well.
* What to take if you have a mild case of Covid-19 and you are sick at home.

And this section of the Protocol is important. Many persons are worried that Covid-19 might cause suffering or death to themselves and to their family and friends. But there is as yet no vaccine. And physicians are not giving out prescription medications for Covid-19 unless you are actually have Covid-19.

Caution

The supplements discussed in the MATH+ Protocol are for adults only. Check with your child’s pediatrician before giving any type of supplement to children.

For adults, check with your doctor before taking any supplements or medications, other than vitamin D. Zinc can cause nausea in higher doses (above 20 mg or so per dose). Quercetin can conflict with many different medications. Be careful not to take a supplement that might not be compatible with some prescription medication you are taking.

Prevention

Can certain medications prevent you from getting Covid-19? Well, yes and no. Nothing, not even a vaccine, will entirely eliminate your risk of getting Covid-19. The flu vaccine, for example, varies in effectiveness from 19% to 60%. CDC However, some medications or supplements may possibly reduce your risk of getting Covid-19. There is sufficient data at present to make that “may possibly” assertion, but be aware that the studies on reduction of risk are not yet definitive. Let’s review the “prophylaxis” portion of the MATH+ Protocol

PROPHYLAXIS

Prophylaxis

While there is extremely limited data, the following “cocktail” may have a role in the prevention/mitigation of COVID-19 disease. This cocktail is cheap, safe, and widely available.
• Vitamin C 500 mg BID and Quercetin 250-500 mg BID
• Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1 month, reduce the dose to 30-50 mg/day.
• Melatonin (slow release): Begin with 0.3 mg and increase as tolerated to 2 mg at night
• Vitamin D3 1000-4000 IU/day
• Optional: Famotidine 20-40 mg/day
[Full Protocol Here]

See the full protocol for the studies they cite in support of the recommendations, 140 references at the end of the document here: PDF file. A shorter two-page summary is here: PDF file.

Vitamin D

Out of all the supplements recommended by MATH+, the greatest body of evidence for a preventative medication is for vitamin D. More than twelve studies have been done so far. See the Covid.us.org Review of those studies here and here. “Recent and historical data are highly consistent with a causal protective role for Vitamin D in respiratory disease risk and especially in the case of COVID-19 [2].” According to those twelve studies, Vitamin D may possibly reduce the risk of Covid-19: infection [7, 8, 9, 11, 12], a severe case [1, 3, 4, 5], need for ICU care [2], need for mechanical ventilation [10], and death [4, 6, 7, 9, 12, 47]. The now-13 studies are listed in the endnotes to this article [1 – 12, 47].

So it is not surprising that the MATH+ Protocol recommends vitamin D for all patients and even for persons who are not symptomatic.

Vitamin D Dosage

Although the Protocol recommends vitamin D at 1000 to 4000 IU/day, some studies on vitamin D are tending toward a higher level of supplementation. For a faster correction of possible vitamin D deficiency, Grant et al. recommended 10,000 IU/day for a few weeks, followed by 5,000 IU/day [13].

Is 10,000 IU of vitamin D per day safe? Yes. The Calgary Vitamin D Study gave participants either 400 or 4,000 or 10,000 IU of vitamin D every day for 3 years [26]. They found that even the highest dose was safe for that period of time. And it was an RCT. Here is a recent secondary analysis of that data.

Garland et al. found that 10,000 IU/day would be required to achieve the blood level of vitamin D that, in their study, represented the optimum level for lower risk of cancer [14]. The Endocrine Society’s Clinical Practice Guidelines state that “vitamin D deficiency is very common in all age groups” and that up to 10,000 IU of vitamin D may be necessary in adults to correct vitamin D deficiency [27].

The current tolerable upper limit for vitamin D is 4,000 IU/day.

Other Benefits of Vitamin D

In addition to reducing various types of risk related to Covid-19, vitamin D has other health benefits. Studies have shown that a high intake of vitamin D reduces risk of stroke,[28] multiple sclerosis,[29] rheumatoid arthritis,[30] type 2 diabetes,[31] breast cancer,[32] prostate cancer,[33] colon cancer,[34] and all-cause mortality.[35]

By comparison, a vitamin D deficiency increases the risk of death from cardiovascular disease, respiratory disease, and all-cause mortality [36]. Correcting a vitamin D deficiency reduces that risk of death. How common is vitamin D deficiency?

A 2018 study published in the British Journal of Nutrition found that 28.9% of U.S. adults had a vitamin D deficiency (<20 ng/ml, which is <50 nmol/L), and 41.4% had a vitamin D insufficiency (20 to 29 ng/ml, or ~50 to 75 nmol/L). This means that 70.3% of the U.S. population had below normal levels of vitamin D in their blood (<30 ng/ml, or <75 nmol/L). The Alipio study [1] found that persons with blood levels of 30 ng/ml or higher had the lowest risk of a severe case of Covid-19.

So there are clearly lots of benefits to following the MATH+ Protocol on vitamin D.

Melatonin

Another MATH+ recommended supplement, for prophylaxis and for mild Covid-19 cases at home is melatonin. There is a good review of all the possible ways that melatonin might benefit Covid-19 patients here: Can melatonin reduce the severity of COVID-19 pandemic? [15] web page | PDF file. And here’s a quote from that melatonin review:

“Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin.” [15]

Melatonin is also an inhibitor of the SARS-CoV-2 Main protease (3CLpro; Mpro) [16]. However, the effectiveness of melatonin needs to be confirmed by an RCT. The reason for using this supplement without definitive clinical evidence is that melatonin is safe, inexpensive, widely available, and has the above discussed benefits on the immune system.

The dose for melatonin under prophylaxis starts at 0.3 milligrams (which is 300 micrograms) and gradually goes up to 2 mg at night, “as tolerated”. If taking the melatonin causes any problem with sleep or otherwise, reduce the dose or stop taking it.

MATH Plus

The same is true for any of the supplements in the MATH+ protocol as for melatonin. If it causes side effects or any type of problems, reduce the dosage or stop taking the supplement, and consult your healthcare provider.

Note that the “M” in MATH+ is not melatonin, but methylprednisolone, a steroid used only in severe Covid-19 cases. The “A” stands for Ascorbic Acid (vitamin C) which is used by IV. The use of vitamin C as a prophylaxis is by mouth and has a different basis of action. The “T” is thiamine, which is used in high doses to treat severe cases, but again may have a use in prophylaxis. The use of thiamine (vitamin B1) in prophylaxis has been suggested by other researchers [17], but is not included in the MATH+ protocol.
MATHplus
The “H” stands for heparin, an anticoagulant. Heparin prevents coagulation. Severe Covid-19 often includes blood clots that lodge in the deep veins, or in the arteries, or — most commonly — in the small blood vessels of the lungs. Anticoagulants are used to counter or prevent clotting. Again, this is for severe cases of Covid-19.

The Plus in MATH+ is all the other recommendations, especially those for prophylaxis or for mild stay-at-home cases. But these supplements have the goal of preventing infection with Covid-19 or preventing a severe case. If you can’t avoid getting Covid-19, you at least want to avoid the severe version of the disease. That is what the prophylactic supplements hope to accomplish.

Vitamin C

Covid-19 can cause Acute Respiratory Distress Syndrome (ARDS), due to the cytokine storm with its excesses of inflammation and fluids in the lungs. A common treatment for ARDS is vitamin C by IV. This dosage given is very high, much higher than could safely be taken by mouth. Furthermore, the limit to the amount of vitamin C that can be absorbed with taken by mouth is perhaps 400 mg/day [18].

For prophylaxis, that is, for persons who are not yet ill, vitamin C has a different goal. It strengthens the immune system, in case of subsequent infection with Covid. Read an overview of vitamin C’s role in immunity at the Linus Pauling Institute here. Vitamin C also protects the body from oxidative damage by functioning as an antioxidant.

In addition to its general benefits on health, Vitamin C (ascorbic acid) is an inhibitor of the SARS-CoV-2 proteases PLpro [19, 20, 21], and Mpro [22, 23] as well as an inhibitor of the surface receptor ACE2 [23]. By its binding with ACE2, vitamin C helps to protect the receptor from SARS-CoV-2, preventing infection of the cell. By binding to the two proteases, it both slows replication of the virus within cells and protects the immune system from attack by those proteases (as detailed in this article). The inhibition of these proteins by vitamin C is mild to moderate.

Vitamin C also helps the body absorb the flavonoid quercetin, which is another MATH+ recommended supplement for prophylaxis, and for stay-at-home mild cases of Covid-19.

Quercetin

Flavonoids are healthy compounds found in certain foods. They are a subtype of a micronutrient found in plants called phytochemicals. Many flavonoids have been shown to improve or protect the health of the human body. Quercetin is a flavonoid found in blueberries, capers, kale, peppers, and onions. However, a therapeutic dose of quercetin cannot be obtained by food, but only by a quercetin supplement.

The MATH+ protocol recommends 250 or 500 mg of quercetin, twice a day, for a total of 500 to 1000 mg per day. This recommendation is the same for prophylaxis (while you are well) and for at-home mild cases of Covid-19 in the protocol.

How does quercetin work? First, quercetin is a viral inhibitor; it binds to certain components of SARS-CoV-2 (the virus) to inactivate those components. Quercetin inhibits the following Covid-19 viral components: the Spike protein, the Main protease (Mpro), Replicase, the N-protein (wraps and protects viral RNA), and a couple of other viral targets (NSP3, NSP15), as indicated by molecular docking studies [24, 37, 38, 39, 40]. This broad spectrum inhibition of SARS-CoV-2 is expected to be more effective than an inhibitor that only targets one or two viral components.

Second, quercetin binds to ACE2, the natural receptor on the surface of lung cells (and other important human cells), so as to protect that receptor from the viral Spike. When the ACE2 has quercetin binding to it, the Spike cannot dock with the ACE2, and this protects the cell from infection.

Third, quercetin is a zinc ionophore, meaning that quercetin carries zinc ions into cells of the human body [41]. Once inside the cell, the zinc ions attack the virus by binding to Replicase, the enzyme that makes copies of viral RNA.

Why isn’t quercetin widely prescribed for Covid-19? So far, there are no completed clinical studies on quercetin as a treatment for Covid-19. The evidence is from studies on computer, in which a three dimensional model of the viral protein is tested against various compounds to find those which will bind to the right place on the protein to shut it down.

At least one clinical trial of quercetin is underway right now [25]. It is expected to be completed by August 31, 2020. That study uses 500 mg quercetin per day for prophylaxis, and 1000 mg/day for treatment of Covid-19.

Despite the limited evidence, the physicians who designed the MATH+ protocol recommend quercetin for those who are well, and for mild stay-at-home cases of Covid-19. Quercetin is available over-the-counter, and it is an FDA-approved medication (though not for Covid-19).

Important: quercetin can have serious side effects, listed here: Drugs.com Quercetin, Side Effects. Quercetin can also conflict with different medications. If you are taking any kind of prescription medication, check with your healthcare provider before taking quercetin. Read more about quercetin here.

Zinc

Zinc has two ways to fight the Covid-19 virus. First, it strengthens the immune system generally. This is beneficial against any type of viral or bacterial infection. Second, once inside a cell infected by SARS-CoV-2, zinc ions bind to the virus’ Replicase enzyme. This binding prevents replicase from making copies of the viral RNA.

In order to get into an infected cell, past the lipid bilayer which comprises the wall of cells in the human body, zinc ions need a ride. A charged ion can’t go through a lipid bilayer, as the lipid (fat) is hydrophobic and therefore resists ions dissolved in water (or blood). So the zinc ions need something to carry them into the cell: a zinc ionophore. Zinc ionophores include quercetin or EGCG (found in green tea extract) [41], hydroxychloroquine or chloroquine, or doxycycline. Any one or more of these will greatly increase the amount of zinc ions that enter the cell.

You don’t need or want to take a high dose of zinc. That could do more harm than good. Notice the dose recommended in the Protocol: “Zinc 75-100 mg/day (acetate, gluconate or picolinate). Zinc lozenges are preferred. After 1 month, reduce the dose to 30-50 mg/day” [MATH+ protocol, June 17th update].

Too much zinc can reduce the amount of copper in your system. Zinc and copper are both essential minerals; and they are antagonists. The more you take of one, the less you have of the other. Some supplements have zinc with copper for that reason, such as 50 mg zinc with 2 mg copper, or 20 mg zinc with 1 mg copper. That’s about the right proportion also. Zinc can cause nausea in too high a dose. If you have nausea from zinc, reduce the dosage to the 30 mg as 15 mg twice a day, with food.

Famotidine

The next recommendation in MATH+ is: “Optional: Famotidine 20-40 mg/day”. Famotidine is an acid-reducer, which can be purchased under the generic name “famotidine”, or under the brand name Pepcid AC. Check the label for the amount of famotidine per pill.

The generic version I have is 10 mg/pill and the label says not to take more than 2 pills, which would be 20 mg total per 24 hours. I would say, to my readers, not to take famotidine unless you check with your healthcare provider first. Taking vitamin D and vitamin C is safer than almost any over-the-counter medication. And I certainly would not exceed the labeled dose of anything without a physician’s approval.

The reason famotidine is being considered for use against Covid-19 is a particular study, titled: “Famotidine use is associated with improved clinical outcomes in hospitalized COVID-19 patients.” This was peer-reviewed and approved for publication in Gastroenterology (22 May 2020); it was published online ahead of print publication. The study found a 70% decrease in risk of death for patients who used famotidine as compared to patients who did not use it, and a 57% decreased risk of intubation (ventilation) and/or death [42]. This is a substantial benefit from an OTC medication that millions of persons take merely for stomach acid.

As stated earlier, the use of famotidine for prophylaxis is optional. The study was in hospitalized patients, and was not a randomized clinical trial.

SYMPTOMATIC PATIENTS (AT HOME)

The next set of recommendations in the MATH+ Protocol is for persons who have tested positive for Covid-19, or who otherwise have been diagnosed with the disease, yet who are sent home. These patients have symptoms of Covid-19, but they are not sick enough to be hospitalized.

Notice that one of the recommendations is Ivermectin, a prescription medication. The MATH+ protocol is directed mainly at physicians. On the other hand, adults who wish to take OTC vitamins and supplements can make their own decisions. That is why some medications are OTC, so that you can decide what to take without necessarily having a doctor’s order.

“Symptomatic patients (at home):
• Vitamin C 500 mg BID and Quercetin 250-500 mg BID
• Zinc 75-100 mg/day
• Melatonin 6-12 mg at night (the optimal dose is unknown)
• Vitamin D3 2000-4000 u/day
• Optional: ASA 81 -325 mg/day
• Optional: Famotidine 20-40mg/day
• Optional: Ivermectin 150-200 ug/kg (single dose) [26-28]
• In symptomatic patients, monitoring with home pulse oximetry is recommended. Ambulatory
desaturation < 94% should prompt hospital admission. [29]
• Not recommended: chloroquine and hydroxychloroquine. The use of these agents is extremely
controversial. Notwithstanding, the retraction of the Lancet paper,[30] there is a paucity of data
to support the use of these drugs. [31-35] It is possible that the efficacy of these drugs requires
the co-administration of Zinc. [36,37]"

Notice that many of the recommendations are the same as for prophylaxis. Vitamin C, quercetin, and famotidine are the same. Vitamin D changes from 1000 to 4000 IU/day to 2000 to 4000 IU/day. So they are stressing the higher dose when someone is symptomatic. The same is true for the zinc. The protocol for symptomatic at-home patients is the higher end of the dosing from the prophylaxis, 75 to 100 mg/day, while you are sick.

And then melatonin increases to as much as 6 to 12 mg at night; however, “the optimal dose is unknown”. See if melatonin works for you, to help you sleep; find the right dose based on your own response to the supplement. Or you can omit this supplement, if it causes any side effects or sleep problems.

The recommendations found in the Symptomatic Patients at home protocol, but not found in the Prophylaxis protocol are “ASA” (acetyl salicylic acid; which is just aspirin) and “Ivermectin”, both of which are optional. If you have been diagnosed with Covid-19, and therefore are a symptomatic patient at home, consult with your physician before taking any of these supplements or medications. The ivermectin requires a prescription from a doctor. The aspirin does not.

NSAIDs

But perhaps you should still check with a doctor before using aspirin as one study [43] found that NSAIDs (which include aspirin) increased risk of poor outcomes in Covid-19 patients. An NSAID is a non-steroidal anti-inflammatory drug; these include Advil (ibuprofen), Aleve (naproxen), and aspirin, but not Tylenol. In the study, the use of NSAIDS in Covid-19 patients increased risk of the primary composite outcome, which was “death, intensive care unit admission, mechanical ventilation use, and/or sepsis” by 56% (OR 1.56). That’s an Odds Ratio of 56% more than expected if there was no effect (1.00 would mean no change). Then the use of NSAIDs in Covid-19 patients also more than doubled the risk of “cardiovascular or renal complications” (OR 2.64). The odds ratio of 2.64 means the risk increased by a multiple of 2.64. Cardiovascular complications are heart or blood vessel problems and renal complications are kidney problems. Tylenol (paracetamol) did not have the same risk.

Ivermectin

Ivermectin is a medication usually used to treat parasitic infections. The main side effects are caused by lots of parasites all dying at once when you take this med. If you take ivermectin for Covid-19, you don’t have the possibility of those types of side effects (unless you unknowingly had a parasitic infection also). So ivermectin is relatively safe. And the usual dose for Covid-19 is a one-time low dose. However, there is not much clinical evidence at the present time. See this Covid.us.org article on a Bangladeshi study.

Now, several molecular docking studies have shown that ivermectin can inhibit viral components: helicase [44], Mpro [45], as well as the Spike, N-protein, Nsp10, and Replicase (RdRp) [46]. That is an impressive list of targets for inhibition by ivermectin. However, inhibitors required a sufficient concentration of the drug in a cell (or outside for the Spike). But the low dosage of ivermectin does not seem to provide that concentration. Therefore, it is likely that the effectiveness of the drug is due to a different modality. Ivermectin is believed to work so well against Covid-19 because it prevents the virus from being able to access the nucleus of the cell. And this modality does not require a high concentration, as inhibition would.

Hydroxychloroquine?

Hydroxychloroquine and chloroquine are no longer recommended in the MATH+ protocol. Previously, they were “optional”. Recent studies have shown that these drugs are not as effective as we would like.

Pulse-Ox Meter

Finally, we have this note: “In symptomatic patients, monitoring with home pulse oximetry is recommended. Ambulatory desaturation < 94% should prompt hospital admission." You've probably seen a Pulse-Ox meter. It's that device the nurse puts on your finger to take your pulse. It gives two numbers, the pulse (or heart rate), and the percent of oxygenation of your blood. A typical good reading is 98 or 99%. A low reading, below 90%, may indicate a problem in the lungs, such as fluid preventing oxygen from reaching the bloodstream.

The idea for using a pulse-ox meter in Covid-19 patients is to detect if the disease worsens, and there is a build-up of fluid in the lungs, reducing oxygenation. The phrase "ambulatory desaturation" means that the person is able to walk around (they are ambulatory), but their blood is not saturated with oxygen; it has less oxygen than it can or should. If you are at home with Covid-19, ask your physician what Pulse-Ox reading should cause you to either call or go to the hospital. A normal healthy person can sometime have a Pulse-Ox reading below 94%. The reading can be artificially low for various reasons.

Stay safe and healthy.

Ronald L. Conte Jr.
Covid.us.org
Note: the author of this article is not a doctor, nurse, or healthcare provider.

Endnotes:

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3. Daneshkhah, Ali, et al. “The Possible Role of Vitamin D in Suppressing Cytokine Storm and Associated Mortality in COVID-19 Patients.” medRxiv (2020).

4. Davies, Gareth, Attila R. Garami, and Joanna C. Byers. “Evidence Supports a Causal Model for Vitamin D in COVID-19 Outcomes.” medRxiv (2020).

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6. Raharusun, Prabowo, et al. “Patterns of COVID-19 Mortality and Vitamin D: An Indonesian Study.” (2020).

7. Ilie, Petre Cristian, Simina Stefanescu, and Lee Smith. “The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality.” Aging Clinical and Experimental Research (2020): 1.

8. D’Avolio, Antonio, et al. “25-hydroxyvitamin D concentrations are lower in patients with positive PCR for SARS-CoV-2.” Nutrients 12.5 (2020): 1359.

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PDF file of Study | Tables Link

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25. Effect of Quercetin on Prophylaxis and Treatment of COVID-19

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