10 Natural Alternatives for Paxlovid (2022) - Evidence based Review

Paxlovid

In March 2022, the Biden administration launched the Test to Treat initiative. The initiative’s goal was to allow people to be tested for COVID-19 at pharmacies or health centers that have an on-site clinic, like CVS MinuteClinic. If you had a positive test, you’d then receive an antiviral prescription at the pharmacy before leaving the building.

While well-intentioned, there were many roadblocks that made the Test to Treat initiative difficult to roll out. One big barrier was the fact that most pharmacies don’t have clinics in the same building. In late May 2022, there were only about 2,500 Test to Treat locations in the entire U.S. This left many Americans still struggling to get a prescription from their healthcare providers in enough time to benefit from Paxlovid.

In response to this, the FDA updated Paxlovid’s EUA in July 2022. This change allows pharmacists to prescribe Paxlovid directly to people who have tested positive for COVID-19. This means that you might be able to head over to your local pharmacy for the medication without having to make other stops along the way. Keep in mind that not all pharmacies may offer this service.

To get Paxlovid from your pharmacist, you must bring the following documents with you to the pharmacy:

• Your current health records, which must be less than a year old (either electronic or printed records are fine)
• Your most recent liver and kidney function tests, which must be less than a year old
• A complete list of all medications that you take, including any over-the-counter (OTC) medications, vitamins, and supplements

If you don’t have all of this information available, or your records aren’t recent enough, there may be a delay in getting Paxlovid. A pharmacist can reach out to your provider by phone to get this information, but that takes time. In this case, pharmacist-prescribed Paxlovid might not be much faster than seeing your healthcare provider or visiting a Test to Treat location.

How much will Paxlovid cost? 

The U.S. will pay about $500 for each course of Pfizer’s treatment, which consists of three pills taken twice a day for five days. Two of the pills are Paxlovid and the third is a different antiviral that helps boost levels of the main drug in the body.

New Paxlovid Dose Pack Author​ized by FDA

On April 14, 2022, the U.S. Food and Drug Administration (FDA) revised the Emergency Use Authorization (EUA) for the COVID-19 oral antiviral therapeutic Paxlovid to authorize an additional dose pack presentation with appropriate dosing for patients with moderate renal impairment within the scope of the EUA. As a result, Paxlovid will soon be available in two package presentations:

1. ​The standard packaging that is currently in distribution: 300 mg nirmatrelvir;100 mg ritonavir - Each carton contains 30 tablets divided in 5 daily-dose blister cards. Each blister card contains 4 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each). Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.
2. The new packaging option that will be in distribution later this month: 150 mg nirmatrelvir; 100 mg ritonavir - Each carton contains 20 tablets divided in 5 daily-dose blister cards. Each blister card contains 2 nirmatrelvir tablets (150 mg each) and 2 ritonavir tablets (100 mg each). Nirmatrelvir tablets and ritonavir tablets are supplied in separate blister cavities within the same child-resistant blister card.

The updated provider Fact Sheet, Letter of Authorization, and Dear Healthcare Provider Letter​ are available for reference.

Precaution: PAXLOVID is not recommended (the appropriate dose has not been determined) in patients with severe renal impairment (<30 mL/min). (Source)

The COVID-19 Treatment Guidelines Panel’s Statement on Therapies for High-Risk, Non-hospitalized Patients With Mild to Moderate COVID-19 (Last Updated: Sept. 26, 2022)

This statement contains the Panel’s recommendations for treating these non-hospitalized patients using the currently available therapies.

For Patients Who Are at High Risk of Progressing to Severe COVID-19
Preferred therapies. Listed in order of preference:

• Ritonavir-boosted nirmatrelvir (Paxlovid)
• Remdesivir

Alternative therapies. For use ONLY when neither of the preferred therapies are available, feasible to use, or clinically appropriate. Listed in alphabetical order:

• Bebtelovimab
• Molnupiravir

Paxlovid Rebound

In late May 2022, the CDC issued a health advisory about “COVID-19 rebound” after Paxlovid treatment. The CDC described it as “a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative.”

At the same time, the CDC wrote, “a brief return of symptoms may be part of the natural history of [coronavirus] infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status.”

The CDC said there is no evidence for more treatment in rebound cases, though people should isolate again for at least 5 days so they won’t pass COVID-19 to others.

People who have a rebound after taking Paxlovid can report their cases to Pfizer’s adverse event reporting page.

However, according to a new study, this puzzling phenomenon can occur whether you take Paxlovid or not.

Researchers found that when patients received a placebo instead of treatment, a portion of them still experienced a rebound of their symptoms after they had initially improved.

“Symptom return is common,” said Dr. Davey Smith, the chief of infectious diseases and global public health at the University of California, San Diego School of Medicine, who led the study. “It doesn’t mean that things are going south. It’s just the natural way the disease goes.” What is surprising, however, is how many people may experience a rebound, he said. (Read More)

Paxlovid for long COVID

A report from the Veterans Affairs health system (now in preprint), the largest in the United States, is the first study to look at longer term effects. Dr. Ziyad Al -Aly and colleagues, who have published many of the important papers on Long Covid in leading peer review journals, now studied over 9,000 paxlovid treated patients (within 5 days of symptom onset; in March-June 2022 during Omicron and subvariant waves) and compared the results to ~47,000 controls. Their mean age was 65 years and 12% were female. 

In summary, the results show that in people with SARS-CoV-2 infection who had at least 1 risk factor for progression to severe COVID-19 illness, treatment with Paxlovid (nirmatrelvir) within 5 days of a positive SARS-CoV-2 test was associated with reduced risk of PASC (Post Acute Sequelae of COVID-19) regardless of vaccination status and history of prior infection. The totality of findings suggests that treatment with Paxlovid during the acute phase of COVID-19 reduces the risk of post-acute adverse health outcomes.

The U.S. National Institutes of Health's $1 billion RECOVER Initiative has picked Pfizer Inc's (PFE.N) antiviral drug Paxlovid as the first treatment it will study in patients with long COVID, organizers of the study said on Oct 27, 2022.

The complex medical condition involves more than 200 symptoms ranging from exhaustion and cognitive impairment to pain, fever and heart palpitations that can last for months and even years following a COVID-19 infection.

According to details of the study, posted on Clinicaltrials.gov, the randomized, placebo-controlled trial will test Pfizer's treatment or a placebo in 1,700 volunteers aged 18 and older.

The Duke Clinical Research Institute is supervising the study, which is scheduled to start on Jan. 1, 2023.

The trial will investigate a leading theory of the cause of long COVID, which holds that fragments of the virus persist in the tissues of some individuals, causing prolonged symptoms.

Patients in several case studies have reported improvements in their symptoms after taking Pfizer's antiviral treatment, and several physicians have called for the drug to be studied in a large, scientifically rigorous study in patients with long COVID.

Paxlovid, which combines a new Pfizer pill with the old antiviral ritonavir, is currently authorized for use in the first days of a COVID infection to prevent severe disease in high-risk patients.

Estimates of long COVID prevalence range from 5 to 50% of people who have had a COVID-19 infection. It affects people who have had both mild and severe COVID-19, including children, and can be severe enough to keep people out of work.

Paxlovid's Contraindications and Drug Interactions

Pfizer anti-COVID pill's interaction with common drugs will narrow its benefit, experts say | National Post:

The buzz around PAXLOVID™ has largely obscured one major downside of this treatment. Ritonavir can interact dangerously with a slew of commonly used medications, pumping up the potency of blood thinners, heart-arrhythmia therapies, epilepsy drugs and others. And the patients targeted for its use – those most at risk of serious COVID disease because of age and other health issues – are also the people most likely to be taking those “contraindicated” medications. 

In some cases, the interactions could be managed, but it’s clear the problem will limit the pool of potential recipients, experts say. “It has a utility, it has a use,” said Dr. Gerald Evans, head of the Infectious Diseases Division of the Queen’s University medical school. “(But) I certainly would not call it a game-changer.” “A patient on blood thinners could end up with spontaneous bleeding in the gastrointestinal tract or brain”, noted Evans. 

“Someone taking pills for hypertension might see their blood pressure fall so much they pass out”, said Dr. Andrew Hill, a pharmacology researcher at the U.K.’s Liverpool University. “There are all kinds of ways that PAXLOVID™ could cause serious harm,” he said. 

Ritonavir is also used in HIV treatments, so there is a wealth of knowledge about those potential drug interactions. The U.S. Food and Drug Administration (FDA) product monograph for PAXLOVID™ lists over 100 drugs that it says should not be taken with the COVID pills, or whose use ought to be carefully monitored. The figure below lists a few of these drugs as well as liver enzymes whose functions are impacted by Ritonavir.

See Sections 4 and 7 of the FACT SHEET FOR HEALTHCARE PROVIDERS and a publication on JAMA by Ross et al. Pharmacists as prescribers may be a problem since they are not authorized to manage, deprescribe and be responsible for the OTHER drugs.

There are many Paxlovid drug-interaction checkers, but the one we find most useful is from the University of Liverpool summarized in the Table below. For most, the interactions can be avoided by holding the 'medication of concern' until the 5-day treatment course is completed.

Natural Alternatives to Paxlovid

PAXLOVID is not recommended in patients with severe kidney impairment or severe liver impairment (See sections 2 of the FACT SHEET FOR HEALTHCARE PROVIDERS). In the event that you simply cannot get Paxlovid, there are viable natural alternatives. 

There is more than one way to manage COVID-19. Nutrients are natural alternatives that will benefit your body for optimal health.

We know there’s an ocean of information out there to navigate, so we’ve compiled and covered 10 best natural alternatives for Paxlovid.

We have perused hundreds of studies and identified multiple nutritional supplements that can be a game-changer in the alleviation and prevention of severe COVID-19.

This practical guide on nutritional supplements has more than 200 supporting studies that represent the best of science-backed strategies for nutritional interventions in the prevention and treatment of COVID-19. Various dietary supplements can be used in combination with other treatments of COVID-19. All these featured supplements have scientific studies to back up their claims. These natural alternatives can easily be purchased over the counter in most countries.

Nutrients and nutraceuticals tend to be agnostic to the COVID-19 virus i.e. it doesn't matter if the patient is down with the Indian, European, Delta, Omicron or Deltacron variants. The mode of actions tend to be multiple and do not have a specific target like targeting the spike protein alone.

Nutrients and supplements are also safer alternatives especially if your risk is low e.g. age below 50 and no other chronic illness. Discuss with your doctor on the benefit vs risk for each treatment. If you are on multiple medications, be aware of supplement-drug interactions that might enhance the possibilities of adverse effects.

The important key takeaway is that you should never attempt to self medicate without the guidance of a licensed medical provider. If you are not a medical doctor, you are likely to find the information below overwhelming. The aim of this article is to empower you with a better understanding of the options available and to discuss the options with your medical doctor as an informed patient.

We have provided the list below as a summary and followed by a summary explanation and references for each option/nutrient:

1. Vitamin D3
2. Quercetin
3. Zinc
4. Nigella Sativa (Black Seed Oil) 
5. Melatonin
6. Vitamin A 
7. Curcumin and Turmeric
8. Vitamin C
9. NAC and Glutathione
10. B Vitamins and NAD+

Nutraceutical Therapy by Mode of Action

1. Vitamin D3 - Anti-inflammatory and Anti-coagulant

At this point, there is simply no question that vitamin D optimization is a crucial component of COVID-19 prevention and treatment. In addition to the many studies published during 2020 and 2021, since December 2021, four large systematic meta-analyses (R, R, R, R) have been published, looking at either vitamin D levels, supplementation or both.

In a peer-reviewed study published in Nature (Nov 2022), treatment with Vitamin D can actually reduce the risk of severe COVID-19 infection.

In all cases, the data consistently show that low vitamin D levels raises your risk of COVID while higher baseline levels and/or supplementation lowers all risks by 1.5 to three times.

Vitamin D, as an immuno-modulator, is a perfect candidate for countering the immune dysregulation common with COVID-19. Vitamin D deficiency affects the body’s susceptibility to infection and has been associated with influenza, hepatitis C, human immunodeficiency virus (HIV) and other viral diseases [Source]. Surveys indicate that most people in the United States consume less than recommended amounts of vitamin D. Sun exposure, which increases serum 25(OH)D levels, is one of the reasons serum 25(OH)D levels are usually higher than would be predicted on the basis of dietary vitamin D intakes alone. Vitamin D deficiency is also known to enhance a process known as the “cytokine storm” (Marik 2020).

According to a July 2022 paper:

“Each 10 ng/mL increase in vitamin D levels was associated with a 45 % and 26 % lower risk of 45-day mortality (HR: 0.55, 95 % CI: 0.40–0.74) and ICU mortality due to COVID-19 (HR: 0.74, 95 % CI: 0.60–0.92), respectively.”

Since the outbreak of the pandemic, many vitamin D sufficiency studies have been conducted. Almost all of them show that an adequate vitamin D level reduces the chance of (a) getting ill, (b) ending up in the hospital, and (c) dying.

Almost all studies consider a vitamin D blood serum level of >30 ng/mL ‘adequate/good’. Several studies have shown that people with a blood serum level of >50 ng/mL hardly get sick at all. Results of a systematic review and meta-analysis (Nutrients 2021) suggested that COVID-19 mortality risk correlates inversely with vitamin D3 status, and a mortality rate close to zero could theoretically be achieved at 50 ng/ml 25(OH)D3.

In a June 2022 review paper titled “The Role of Diet and Supplements in the Prevention and Progression of COVID-19: Current Knowledge and Open Issues”​ published in the journal Preventive Nutrition and Food Science, researchers said:

"The consumption of vitamin C and D supplements, in addition to a healthy diet, could be promoted as a co-adjuvant therapy for COVID-19..."

For more evidence, check out the evidence tracker on vitamin D and COVID-19 from c19vitamind.com (constantly updated), with more than 100 published treatment studies and more than 130 sufficiency studies by more than 1,000 scientists.

Trusted Source

Vitamin D is higher than Paxlovid, ivermectin and hydroxychloroquine in this COVID-19 drug league table for 'early treatment study results':

Vitamin D has also been shown to have an anticoagulant effect. A decrease in 25-hydroxyvitamin D [25(OH)D] concentration has also been associated with an increased risk of venous thromboembolism (PubMed).

Safety: Daily intakes of up to 25–100 mcg (1,000 IU–4,000 IU) vitamin D in foods and dietary supplements are safe for children (depending on their age) and up to 100 mcg (4,000 IU) are safe for adults. These values, however, do not apply to individuals receiving vitamin D treatment under the care of a physician. Higher intakes (usually from supplements) can lead to nausea, vomiting, muscle weakness, confusion, pain, loss of appetite, dehydration, excessive urination and thirst, and kidney stones. In extreme cases, vitamin D toxicity causes renal failure, calcification of soft tissues throughout the body (including in coronary vessels and heart valves), cardiac arrhythmias, and even death.

Vitamin D and Omicron

Will Vitamin D Work Against Omicron BA4 and BA 5? Vitamin D is not variant specific because it's primary mode of action is to support the body’s immune system which reacts in a variety of ways against viral attack, not just in a specific antibody reaction to a specific spike protein. 

Related: Best Vitamin D3 Supplement

2. Quercetin - Anti-inflammatory, anti-coagulant, zinc ionophore and anti-viral

As of November 2022, there have been 9 published studies of quercetin and COVID-19 (c19quercetin.com). 

Quercetin is also no. 1 in this prevention studies league table:

Quercetin is a pigment that is found in plants, vegetables, and fruits, and serves as an immune nutrient offering many health benefits. Elderberry, red onions, white onions and cranberries are the richest sources of quercetin. It is a flavonoid and antioxidant that may help to reduce inflammatory cytokines, infections, allergies and anti-blood clot property. Research has found that quercetin may be particularly beneficial for viral respiratory infections.

Quercetin as a Zinc Ionophore

Quercetin is a zinc ionophore (J Agric Food Chem. 2014). A 2015 study found that that Quercetin shows inhibitory activity in the early stages of a wide range of influenza viruses, including H1N1 and H5N1 (Viruses 2016). Although influenza is not in the same family of viruses as the coronavirus, it’s plausible that a similar mechanism could apply here. There is actually some evidence that Quercetin has already proven effective at treating Ebola and Zika viruses.

Quercetin and Vitamin C

Incidentally, ascorbic acid (vitamin C) and the bioflavonoid quercetin (originally labeled vitamin P) were both discovered by the same scientist — Nobel prize winner Albert Szent-Györgyi. Quercetin and vitamin C also act as an antiviral drug, effectively inactivating viruses. 

Quercetin Dosage

The FLCCC I-MASK+ protocol recommends 250 mg daily for prevention and 250 mg twice daily for early treatment.

Quercetin works best when taken with vitamin C and Bromelain, as vitamin C helps activate it and bromelain helps with the absorption.

Precaution: Quercetin should be used with caution in patients with hypothyroidism (low thyroid hormone) and relevant thyroid hormone levels should be monitored.

Quercetin and ivermectin interactions? According to Drugs.com: "No interactions were found between ivermectin and Quercetin. This does not necessarily mean no interactions exist. Always consult your healthcare provider."

Quercetin and COVID-19

For an updated list of studies, check out c19quercetin.com. 

A word about quercetin: Some physicians are recommending this supplement to reduce viral illnesses because quercetin acts as a zinc ionophore to improve zinc uptake into cells. It is much less potent than HCQ (hydroxychloroquine) as a zinc transporter, and it does not reach high concentrations in lung cells that HCQ does. Quercetin may help reduce risk of viral illness if you are basically healthy. But it is not potent enough to replace HCQ for treatment of COVID once you have symptoms, and it does not adequately get into lung tissue unless you take massive doses (3-5 grams a day), which cause significant GI (gastrointestinal) side effects such as diarrhea.

Related: Best Quercetin Zinc Supplement

3. Zinc - Anti-viral 

Zinc is another powerful immune nutrient known for its benefits for providing immune health support and inflammation reduction as well as for improving cold and respiratory symptoms, wound healing, acne reduction, and lowering the risk of age-related diseases. This trace element is essential to to cell function and involved in over 100 enzymes. Research on atherosclerosis and diabetes mellitus suggests that zinc deficiency may contribute to low-grade systemic inflammation.

Aging is associated with compromised immunity, that just means that your immune response to pathogens and infections starts to slow and is less robust, including a reduced vaccine immune response/efficacy. ⁣
⁣
Improving zinc intake/zinc status improves/modulates/enhances immune function. The flip side is, while some aspects of immunity slow, others increase. Uncontrolled immune responses drive excess inflammation. Zinc helps to balance all of this. ⁣

The National Institutes of Health (NIH) states:

“Zinc is involved in numerous aspects of cellular metabolism. It is required for the catalytic activity of approximately 100 enzymes and it plays a role in immune function, protein synthesis, wound healing, DNA synthesis, and cell division. Zinc also supports normal growth and development during pregnancy, childhood, and adolescence and is required for proper sense of taste and smell.”

Zinc and COVID-19

The use of zinc for SARS-CoV-2 was a topic routinely flagged by COVID fact checkers as “misinformation,” so word didn’t really get out about its potential as an anti-COVID agent. However, research once again shows zinc’s promise for keeping people healthy if they get COVID.

A team of researchers with Fattouma Bourguiba University Hospital in Tunisia set out to determine zinc’s efficacy in treating adults with COVID-19. “Like in many other diseases, regulation of white blood cell production using immuno-nutrition is a novel concept that could be applied to COVID-19,” they noted. “Some molecules and nutrients such as zinc play central roles in keeping the function and integrity of the immune system.” (R)

They conducted a randomized, double-blind, placebo-controlled trial, during which patients who tested positive for COVID-19 — including 190 outpatients and 280 hospitalized patients (R) — received either oral zinc or a placebo twice daily for 15 days. Those taking zinc had a nearly 40% lower rate of death and admission to the intensive care unit (ICU). They also had shorter hospital stays and cut the number of days needed for their symptoms to resolve. (R)

Specifically, mortality after 30 days was 6.5% in the zinc group compared to 9.2% in the placebo group. ICU admission rate was 5.2% in the zinc group and 11.3% in the placebo group. Further, those in the zinc group had, on average, a 3.5-day shorter hospital stay while their symptoms resolved 1.9 days sooner than those who received a placebo. (R)

The beneficial effects of zinc were seen even in subgroups of patients, including those under 65, people with comorbidities and those who needed oxygen therapy at the start of the study. No severe adverse effects were seen. In fact, more minor adverse events occurred in the placebo group (7.1%) than in those taking zinc (3.9%). (R) The researchers concluded: (R)

“To our knowledge, this study is the first well powered, placebo-controlled clinical trial to report results of zinc for the treatment of patients with COVID-19.

When administered orally to patients hospitalized with COVID-19 without end-organ failure, zinc demonstrated its efficacy to prevent ICU admission and to reduce hospital length of stay; for outpatients, zinc reduced symptom duration. Zinc should be considered for the treatment of patients with COVID-19.”

For more evidence, check out the evidence tracker on zinc and COVID-19 from c19zinc.com (constantly updated). 

Foods that are high in zinc include oysters, crab, lobster, mussels, red meat, and poultry. Cereals are often fortified with zinc. Most multivitamin and nutritional supplements contain zinc.

Safety: Taking zinc long term is typically safe for healthy adults, as long as the daily dose is under the set upper limit of 40 mg of elemental zinc (PubMed). Be aware that typical daily doses of zinc provided by zinc lozenges generally exceed tolerable upper limits for zinc, and for this reason, they should not be used for longer than about a week. 

Excessive doses may interfere with copper absorption, which could negatively affect your immune system as it can cause copper deficiencies, blood disorders and potentially permanent nerve damage. Zinc can also impair the absorption of antibiotics, and use of zinc nasal gels or swabs has been linked to temporary or permanent loss of smell.

Zinc Form and Dosage

There are several types of zinc supplements. Supplements contain several forms of zinc, including zinc gluconate, zinc citrate and zinc picolinate. The percentage of elemental zinc varies by form. To find out the percentage of elemental zinc in each form, check out elemental zinc percentage.

Chelated zinc is a general form of supplementary zinc in which the zinc is chelated — or bound — to a compound to make it easier for the body to absorb. Zinc picolinate or zinc gluconate are formed when zinc is chelated to picolinic acid or gluconic acid, so the main difference between zinc gluconate and picolinate is what compound it is bound to.

To find out which zinc supplement to consider, check out best zinc supplement.

Most people do not lack an intake of zinc, but in disease state, there might be an increase in demand by the body. The FLCCC I-MASK+ protocol recommends 30 mg a day for prevention and 100 mg a day for early treatment of COVID-19. This should not be taken long term without evaluation of your zinc/copper ratios.

The ideal dose for prevention while the COVID-19 risk is high is 40-100 mg/d, a portion of which comes from zinc lozenges to spread the zinc through the tissues of the nose, mouth and throat. It should be accompanied by at least 1 mg copper from food and supplements for every 15 mg zinc.

Do take note that you should keep the dosage back to within 40 mg/d once the exposure risk is back to normal.

4. Nigella Sativa (Black Seed Oil) and Cytokine Storm - Anti-inflammatory

Nigella sativa (N. sativa) is a small flowering plant that grows in Southwest Asia, the Middle East, and Southern Europe (Source). This shrub produces fruit with tiny black seeds. Commonly referred to as black seed, N. sativa seeds go by many other names, such as black cumin, black caraway, nigella, fennel flower, and Roman coriander (Source).

Black seed oil is extracted from N. sativa seeds and has been used in traditional medicine for over 2,000 years due to its many therapeutic benefits.

Thymoquinone which is the active ingredient in N. sativa seeds has demonstrated effects in significantly reducing the cytokine storm chances and consequent mortalities (Source).

Summary results of 7 published clinical studies are available on this dedicated webpage: c19ns.com. The 4 RCTs (Randomized Controlled Trials) provide promising evidence that Nigella Sativa was associated with an average improvement of 69% in decreasing the likelihood of death and hospitalization if given as early treatment.

5. Melatonin- Anti-inflammatory and anti-viral

Melatonin is a hormone produced by the pineal gland in the brain, mainly during the night, that helps regulate circadian rhythms [Source]. Its levels decrease with aging. Most melatonin supplementation studies have evaluated its ability to control sleep and wake cycles, promote sleep, and reduce jet lag.

The potential utility of melatonin in treating COVID patients has not gone unnoticed, with a PubMed search combining melatonin and COVID producing more than 50 citations.

Check out the evidence tracker on melatonin and COVID-19 from c19melatonin.com (constantly updated).

As of September 2022, there are more than 15 published clinical studies of melatonin for treatment and prevention in COVID-19 and the results are promising even when it's given as a late treatment.

The 2 early treatment studies provide promising evidence that melatonin was associated with an average improvement of 78% (below).

Melatonin is a hormone synthesized in your pineal gland and many other organs. While it is most well-known as a natural sleep regulator, it also has many other important functions. For example, melatonin is a potent antioxidant (Antioxidants, 2020) with the rare ability to enter your mitochondria, where it helps “prevent mitochondrial impairment, energy failure and apoptosis of mitochondria damaged by oxidation.” It also helps recharge glutathione and glutathione deficiency has been linked to COVID-19 severity.

Production of melatonin diminishes with age, contributing to immune dysfunction and increasing oxidative stress, inflammation, and infection susceptibility (Ref). In addition, infectious viruses can suppress melatonin production, disrupting circadian controls and impairing immune function (Ref).

According to a review (Cardinali et al. 2020), melatonin might counteract the consequences of COVID-19 via salutary effects on the sleep/wake cycle and more generally on chronobiology, as well as through its antioxidant and anti-inflammatory effects.

Based on melatonin’s therapeutic potential and well-established safety profile, it has been suggested those at higher risk for severe illness and complications from viral respiratory infection, including the elderly and those with chronic medical conditions, may benefit most from regular use of 3–10 mg melatonin at bedtime (Ref). 

Fluvoxamine (Selective Serotonin Reuptake Inhibitor) might also exert beneficial effects in COVID patients through its well-characterized ability to substantially increase (~ 2–3-fold) night-time plasma levels of melatonin. This increase appears to result from fluvoxamine’s inhibition of the melatonin-metabolizing liver enzymes (von Bahr et al. 2000).

An Iranian randomised controlled trial (Arch Med Res 2021), studied 74 mild to moderate hospitalized patients. The study showed that adjuvant use of melatonin has a potential to improve clinical symptoms of COVID-19 patients and contribute to a faster return of patients to baseline health.

Some researchers have suggested high doses of melatonin, ranging from 50 to 200 mg twice daily, might help treat patients hospitalized for severe acute respiratory illness (Ref).

In a small Philippine case series study of 10 hospitalised COVID-19 patients, high dose melatonin (hdM) was given in addition (adjuvant) to standard therapy. According to the authors:

"High dose melatonin may have a beneficial role in patients treated for COVID19 pneumonia, in terms of shorter time to clinical improvement, less need for MV, shorter hospital stay, and possibly lower mortality."

Safety: If you take a melatonin supplement, be careful: Too much can cause daytime sleepiness. There is no federal RDA nor any formal advice on supplement dose ranges. Based on an on-going Spanish study, a 2 mg daily dose protocol is being investigated for prevention of COVID-19. Do take note that the dosage for 'prevention' and 'treatment' is different, For prevention or maintenance, a lower dosage is normally recommended whereas a 'treatment' or 'therapeutic' dosage is normally higher.

Typical doses of 1–10 mg/day melatonin appear to be safe for short-term use (Source). Reported side effects, which are usually minor, include dizziness, headache, nausea, upset stomach, rash, and sleepiness. However, some reports have linked high blood levels of melatonin with delayed puberty and hypogonadism.

Studies have not evaluated melatonin supplementation during pregnancy and breastfeeding, but some research suggests that these supplements might inhibit ovarian function (Source). Therefore, some experts recommend that women who are pregnant or breastfeeding avoid taking melatonin.

6. Vitamin A

Summary results of 10 vitamin A and COVID-19 studies are available on this dedicated webpage: c19early.com/va. 

Based on this early treatment mortality studies drug league table below, vitamin A might even out-perform vitamin D, ivermectin and hydroxychloroquine:

That said, most clinicians will use the multi-drug or combination approach to get the best outcome.

Scientists are also investigating if taking vitamin A could aid patients who have lost their sense of smell due to COVID-19. The 12-week 'Apollo study' would use nasal drops containing the vitamin to treat individuals who have lost or changed their sense of smell.

7. Curcumin and Turmeric - Anti-inflammatory and anti-viral

Curcumin, a yellow carotenoid from turmeric, is a nutritional therapeutic recommended as part of the FLCCC I-CARE early treatment protocol, and has antiviral, anti-inflammatory, antioxidant and immune modulating properties.

There are more than 20 completed studies of curcumin in COVID-19 that suggest that it improves clinical outcome of patients.

Curcumin also acts as natural zinc ionophores and can promote the cellular uptake of zinc and can be used with zinc to increase the effectiveness of these compounds in the inhibition of the virus (Ref).

Curcumin has been demonstrated (Ref) to suppress several inflammatory cytokines and mediators of their release such as tumor necrosis factor-alpha (TNF-alpha), IL-1, IL-8 and nitric oxide synthase.

8. Vitamin C - Anti-inflammatory

Vitamin C, which most of us reach for with any cold or flu, was used in high doses to great effect by COVID-19 early treatment doctors.

Vitamin C may be one of the most well-known immune nutrients that protect against immune deficiencies and which supports the prevention and recovery from the common cold and upper-respiratory issues, and also protects your cardiovascular system, eyes, skin, and other parts of your body. Research has found that vitamin C may help to optimize the immune system.

Do take note that the vitamin C dosages given in the hospitals intravenously are different from those over the counter vitamin C supplements. Therefore, when you come across studies on vitamin C, you need to differentiate those that are given intravenously vs oral vitamin C.

Vitamin C and COVID-19

 

Check out the evidence tracker on vitamin C and COVID-19 from c19vitaminc.com (constantly updated).

Safety: The U.S. Recommended Dietary Allowance (RDA) for vitamin C is 75 to 120 milligrams per day. Taking large doses of vitamin C (ascorbic acid) on a regular basis lowers your level of copper, so if you are already deficient in copper and take high doses of vitamin C, you can compromise your immune system.

While generally considered safe even in high doses, way too much vitamin C — anything above 2,000 milligrams daily—can cause headaches, insomnia, diarrhea, heartburn, and other issues.

Temporarily taking megadoses of vitamin C supplements to combat a case of the cold or flu is likely not going to cause a problem. 

Many vitamin C supplements that are above the US RDA are sold in the market. It’s important to seek a physician’s advice if you intend to take high dose vitamin C on a long term basis. To be on the safe side, you may also request for your kidney functions to be monitored.

For long-term, daily use, your best bet is to eat a diet that is full of high quality organic vegetables and fruits that are minimally processed. Not only will you get vitamin C, but you will get all the other accessory nutrients and micronutrients that are needed to optimize it. 

Vitamin C, Omicron and Deltacron

Will Vitamin C Work Against Omicron or Deltracron? Vitamin C is not variant specific because it's primary mode of action is to support the body’s immune system which reacts in a variety of ways against viral attack, not just in a specific antibody reaction to a specific spike protein. 

Related: Best Vitamin C Supplement

9. NAC, Glutathione and COVID-19 - Anti-inflammatory and anti-coagulant

N-acetylcysteine (NAC) is a precursor to glutathione. It is an antioxidant and increases glutathione levels in the body (Source). NAC has mucolytic activity, so it helps reduce respiratory mucus levels. Laboratory research suggests that NAC might boost immune system function and suppress viral replication. NAC also decreases levels of interleukin-6 and has other anti-inflammatory effects.

Much of the research on NAC has used an inhaled, liquid form of this compound. This form—which is classified as a drug, not a dietary supplement—is approved by the U.S. Food and Drug Administration (FDA) as a mucolytic agent and for decreasing respiratory secretion viscosity (Source). Products containing NAC are also sold as dietary supplements.

NAC and COVID-19

Considering many COVID-19 cases involve blood clots in addition to excessive oxidative stress, and NAC effectively addresses both, NAC should be seriously included in standard of care for COVID-19.

 

For a compilation of more than 10 studies of NAC and COVID-19, check out the list of studies here (constantly updated).

However, in terms of early treatment, the improvement rate is not as impressive as the other natural alternatives i.e. quercetin, black seed oil and vitamin A.

That said, NAC is a natural alternative for aspirin and an over-the-counter supplement that both prevents blood clots and breaks up existing ones i.e. anticoagulant effects. 

Studies have shown that NAC may protect against coagulation problems associated with COVID-19, as it has both anticoagulant (source) and thrombolytic effects (source), meaning it may both prevent clots and break up clots that have already formed.

A 2017 paper found NAC has potent thrombolytic effects, meaning it breaks down blood clots once they've formed.

Many COVID-19 patients experience serious blood clots, and NAC counteracts hypercoagulation, as it has both anticoagulant and platelet-inhibiting properties.

Consider taking around 500 milligrams/day of NAC, as it helps prevent blood clots and is a precursor for your body to produce the important antioxidant glutathione.

Why are some retailers and Amazon no longer selling NAC? The US FDA made it clear in 2020 that it considers NAC to be a drug and not a dietary supplement, so, for legal reasons, some companies have stopped selling it in United States.

Foods that have a positive impact on glutathione production include cruciferous vegetables such as broccoli, green tea, curcumin, rosemary and milk thistle. Getting quality sleep may also help.

Different types of exercise can influence your levels as well. In one study, researchers enrolled 80 healthy but sedentary volunteers to measure the type of exercise that may have the greatest effect. They found that aerobic training in combination with circuit weight training showed the greatest benefit.

What Is the Primary Cause of Severe COVID-19 Illness: Glutathione or Vitamin D Deficiency?

The hypothesis that vitamin D (VD) deficiency is responsible for severe manifestations and death in COVID-19 patients has been proposed and is actively being discussed by the scientific community. 

Several studies reported that glutathione levels positively correlate with active vitamin D. (PubMed, PubMed) 

Interestingly, a recent experimental study (PubMed) showed that Glutathione deficiency and the associated increased oxidative stress epigenetically alters vitamin D regulatory genes and, as a result, the suppressed gene expression decreases Vitamin D production, ultimately leading to a secondary deficiency of vitamin D. This study provides important information that glutathione is essential for the control of endogenous vitamin D production and demonstrates potential benefits of Glutathione treatment in reducing the deficiency of vitamin D. Taken together, these findings suggest that glutathione deficiency rather than vitamin D deficiency is a primary cause underlying biochemical abnormalities, including the decreased biosynthesis of vitamin D, and is responsible for serious manifestations and death in COVID-19 patients.

NAC (N-Acetyl Cysteine) vs Glutathione

N-acetyl L-cysteine (NAC), as a precursor of glutathione, helps to replenish intracellular glutathione, a vital cellular antioxidant. NAC has a low molecular weight and is well absorbed via oral administration as compared to glutathione.

NAC may also protect against coagulation problems associated with COVID-19, as it counteracts hypercoagulation and breaks down blood clots.

Glutathione and Zinc

To improve your glutathione, you need zinc, and zinc in combination with hydroxychloroquine (a zinc ionophore or zinc transporter) has been shown effective in the treatment of COVID-19.

Glutathione and Molecular Hydrogen 

One of the best ways to increase glutathione, though, is molecular hydrogen. Molecular hydrogen does so selectively and will not increase glutathione unnecessarily if you don’t need it. You can view Tyler LeBaron’s lecture on the details of how it does this in “How Molecular Hydrogen Can Help Your Immune System.”

Glutathione and Selenium

Selenium is also important, as some of the enzymes involved in glutathione production are selenium-dependent.

Safety: As an FDA-approved drug, the safety profile of NAC has been evaluated (Source). Reported side effects of oral NAC include nausea, vomiting, abdominal pain, diarrhea, indigestion, and epigastric discomfort. No safety concerns have been reported for products labeled as dietary supplements that contain NAC. (Source)

For NAC contra-indications, check out here.

Update: NAC supplements are now available on Amazon US. 

10. B Vitamins and COVID-19 - Anti-inflammatory

'B vitamins' as a topic is a complicated subject and that's probably why they are called 'B Complex'. 

B vitamins may constitute a long list, but each one is important for different reasons. B vitamins are especially effective in boosting your immunity when you combine the foods containing them so they can all work together for maximum effect. These include vitamin B1 (thiamin), B2 (riboflavin), B3 (niacin), B5 (pantothenic acid), B7 (biotin), B9 and B12.

B vitamins can be found in a variety of foods including red meat, beans, milk, cheese, broccoli, spinach, avocados and brown rice. Despite the availability of vitamin B-rich foods, many Americans may be deficient in this nutrient — and not even know it. According to a blog post from Harvard University, using the National Health and Nutrition Examination Survey, “3.2 percent of adults over age 50 have a seriously low B12 level” and “up to 20 percent may have a borderline vitamin B12 deficiency.”

Dr. Uma Naidoo, a nutrition expert at Harvard Medical School, explains that:

"In a poorly regulated immune system, the body's cytokine storm induced by COVID cause lots of inflammation in the body, just as if little grenades were being tossed around. This is what causes the worst outcomes and death in COVID.

It follows that anything that improves immune system function and decreases the chances that an infected person will have a catastrophic cytokine storm may improve the outcome of COVID-19 cases and decrease the overall death rate. Therefore, it’s quite feasible that B-vitamin supplementation could contribute to preventing the worst COVID outcomes.”

Thiamine (vitamin B1), a water-soluble B-complex vitamin, is rapidly depleted during times of metabolic stress, including severe illness. Thiamine deficiency is common in hospitalized patients, especially those with critical illness (Ref). Thiamine is needed for cellular energy production and helps regulate reduction-oxidation balance, immune function, nervous system function, and vascular function (Ref).

Thiamine, at 200 mg twice daily, reduced mortality in patients with septic shock and thiamine deficiency, and laboratory research suggests it may inhibit the hyper-inflammatory immune response that accompanies cytokine storm (Ref). It is a key therapeutic in the MATH+ protocol (methylprednisolone, ascorbic acid [vitamin C], thiamine, and heparin, plus other supportive nutrients and medications), a treatment strategy proposed for managing advanced stages of severe acute viral respiratory illness (Ref). Although high-quality clinical evidence is lacking, two US hospitals implementing the MATH+ protocol in patients with a severe acute viral respiratory illness reported mortality rates that were approximately one-quarter of those reported from other US hospitals using standard care (Ref).

In a study in Saudi Arabia (Al Sulaiman et al. Crit Care 2021), 738 critically ill COVID-19 patients from two centers were included in the study. The in-hospital death rate and 30-day death rate were significantly lower in the group that received thiamine as an adjunctive treatment (a therapy given in addition to standard therapy). In addition, the thiamine group also were less likely to have blood clot during ICU stay.

Another study of COVID-19 patients with severe symptoms found 26.3% among diabetics with COVID-19 were vitamin B1 deficient.

Niacin or vitamin B3 is a precursor to nicotinamide adenine dinucleotide (NAD+). There are three main forms of niacin, which are dietary precursors to nicotinamide adenine dinucleotide (NAD). These are nicotinamide riboside (NR), nicotinic acid and nicotinamide mono nucleotide (NMN).

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor in all living cells that is involved in fundamental biological processes.

Structurally, the closest molecule to NAD+ is NMN, requiring only one enzymatic step to be converted to NAD+. NR, which is two enzymatic steps away from NAD+, is also being studied clinically (David Sinclair. Trends Immunol. 2022).

Vitamin B9 and folic acid help repair tissues and aid in cell metabolism and immune support. They’re found in dark leafy greens, wild-caught, cold water fish like herring, mackerel, sardines, anchovies and wild-caught Alaskan salmon, and pastured, organic chicken.

B12, also known as cobalamin, is a powerful cold- and flu-fighting nutrient in your system, as is vitamin B6, another important, germ-combating vitamin that naturally benefits and strengthens your immune system and even protects against the damaging effects of air pollution.

Adequate amounts of folate, vitamin B6 and vitamin B12 are also needed for your body to make the amino acid cysteine. N-acetyl cysteine (NAC) is a supplement form of cysteine. Consuming adequate cysteine and NAC is important for a variety of health reasons — including replenishing the most powerful antioxidant in your body, glutathione.

Related: Niacin and COVID-19 - Is Niacin a Missing Piece of the COVID Puzzle?

Other Potential Treatments

There are over two dozen compounds that have shown effectiveness in treating COVID-19. For a list of COVID-19 early treatment studies, check out c19early.com (constantly updated).

Please check this page regularly for updates – new natural alternatives may be added and/or dose changes to existing alternatives may be made as further scientific studies emerge.

As you can see from the treatment league table above, some of the 'natural alternatives' (including diet (R) and exercise (R)) might even perform better than synthetic drugs.

Summary

The combination of vitamin D, quercetin, zinc, vitamin C, melatonin, black seed oil and vitamin A offer a high virus inhibiting and anti-inflammatory potential with a valuable degree of safety at a time of great uncertainty.

Nutrients and supplements are safer alternatives especially if your risk is low e.g. age below 50 and no other chronic illness. Discuss with your doctor on the benefit vs risk for each treatment. If you are on multiple medications, be aware of supplement-drug interactions that might enhance the possibilities of adverse effects.

However, if your risk is high e.g. age above 60, hypertensive, diabetic and obese; you might wish to consult a doctor and discuss more potent alternatives.

If you review most of the above studies, you will find a very common theme among most of the studies. A key highlight is that 'early treatment' results tend to be better than 'late treatment' results. Therefore, the most important takeaway is to get 'early treatment'. That said, you should never attempt to self medicate without the guidance of a licensed medical provider. If you are not a medical doctor, you are likely to find the information above overwhelming. 

Please also follow other precautions and measures (as advised by your local health authorities and doctors) in order to minimize your risk.

Treatments do not replace vaccines and other measures. All practical, effective, and safe means should be used. Elimination is a race against viral evolution. No treatment, vaccine, or intervention is 100% available and effective for all variants.

Related: Difference between paxlovid and molnupiravir