"I have COVID! What should my kids and I take to reduce chances of severe illness and Long COVID?"

I get this question a lot. Here is some info that may help adults & children with COVID.

Here are some of my current best bets for speeding up COVID recovery and reducing the chances of Long Covid. I’m focusing on accessible pharmacological treatments with a good balance of safety, tolerability and (potential) efficacy, based on currently available information. This is not an exhaustive list, but a few select treatments that can, for the most part, be combined together if desired. At the end of each treatment review, I present dosing/brand information for both adults and children. If you just want to see a summary with a sample treatment/dosing schedule, scroll to the end.

NOTE: It goes without saying that REST is incredibly important during and after infection; these picks are not a substitute for good rest and restorative sleep! To start, I include some info on sleep supplements which also may inhibit SARS-CoV-2.

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SLEEP SUPPLEMENTS

Many have sleep troubles during acute SARS2 infection which very likely impedes recovery and increases the risk of Long COVID. Three sleep supplements that may not only aid sleep but also help reduce illness severity and post-acute sequelae via other mechanisms are listed below.

NOTE: I tend to recommend liquid formulations to allow for flexible dose titration and sublingual administration (in smaller volumes). Sublingual (under the tongue) administration increases systemic absorption, exerts faster onset of action, and limits drug interactions by avoiding first-pass metabolism.

Melatonin Drops (sublingual immediate release +/- oral time release)

• In addition to lengthening sleep duration, some studies in adults suggest 5 to 10 mg daily melatonin improves COVID outcomes, including thrombotic events and mortality.

• Melatonin may suppress platelet hyperactivation, microclot formation and even incidence of ischemic reperfusion injury—issues which many Long COVID sufferers experience. Some experts believe that ischemic reperfusion is related to post-exertional malaise (PEM). Relatedly, a recent pilot study (n=65) found that early treatment of 20 mg melatonin once daily for five days improved functional & neurological recovery in patients 30 to 90 days following acute ischemic stroke.

• If you’re having trouble staying asleep, consider adding 1 to 5 mg melatonin time release tablets. Start with 1 mg to assess tolerability. I do not recommend taking melatonin for nighttime awakenings.

• Adult dosing: KAL drops linked above contain 3 mg per 20 drops. These should help you fall asleep but you may have to experiment with dosing. A lot of people have success with just 0.3 mg sublingually for sleep, but 0.3 mg likely won’t exert many additional benefits at that low of a dose.

• For kids age 3+, I recommend staying around 0.3 to 0.5 mg, which would be 2 to 4 drops of KAL. Avoid in children younger than 3 yrs old. Another option is Mommy’s Bliss Kids’ Sleep Liquid, which combines 0.5 mg melatonin with a similar herbal concoction (chamomile, lemon balm, passionflower) as recommended above.

• Avoid gummies! Besides being bad for dental hygiene, gummies also involve a host of other issue, which you can read about in this article from Consumer Labs. Again, I prefer sublingual drops administration for superior absorption, faster action, & (generally) cleaner ingredients.

SLEEP Herbal tincture (drops)

• Contains valerian, passionflower, chamomile, hops strobile and anise. Shake before use.

• Help to fall asleep but not necessarily to stay asleep.

• These drops are especially helpful for nighttime awakenings — may help you fall back to sleep.

• Chamomile may exert antiviral and antioxidant activity through its beneficial flavonoids luteolin, quercetin and apigenin.

• Recently re-branded as kids’ formulation but is same concentration as before when it was marketed for adults. Thus can easily be administered for both kids and adults.

• For children over 1 year of age, dosed by weight. I recommend starting around 5 drops for all weights. In my experience, the maximum dose is not typically necessary if dosed sublingually.

  • Under 25 lbs: 5 to 10 drops maximum

  • 26-50 lbs: 5 to 15 drops maximum

  • 51-75 lbs: 5 to 20 drops maximum

  • 76-100 lbs: 5 to 25 drops maximum

• Adult dosing: Bottle recommends 30 drops but that high of dose likely not necessary, especially if administered sublingually. Place 10 drops under tongue and let absorb for a minute or so, then wash down the rest with water if desired. Repeat or titrate up as needed.

• For infants as young as 4 months, a similar option is Mommy’s Bliss Organic Baby Bedtime Drops + Immunity Support. It contains elderberry, chamomile, passionflower, and lemon balm. Comes with a dosing syringe, but may be easier to administer with a dropper.

DIPHENHYDRAMINE (last resort for sleep, NOT specifically for COVID treatment)

• Most people are familiar with diphenhydramine as an antihistamine, but it is also a sigma-1 receptor agonist. Sigma-1 receptor agonists have been shown to exert antiviral activity against SARS-CoV-2 by reducing replication. For example, the highly-touted fluvoxamine is a potent sigma-1 receptor agonist that has also shown benefit in COVID.

• One study found that histamine facilitates spike protein entry into endothelial cells. Thus it stands to reason that inhibiting histamine with an antihistamine might suppress the S protein from cell entry. Authors examined the H2 blocker famotidine, but it’s possible that H1 blockers like diphenhydramine exerts a similar effect. Whether it would be clinically significant is unknown at this point.

• Diphenhydramine’s antiviral activity appears synergistic with lactoferrin according to this in vitro study. The study looks quite exciting at first glance. However, the concentration studied was much higher than what is achievable in humans (54.25 µg/mL in study vs 0.066 µg/mL Cmax in humans). Nevertheless, it is possible this combination may still be beneficial somehow. I discuss lactoferrin next.

• Liquid formulations like Nytol (UK) or Genexa (US) may be administered by mouth or even under the tongue to optimize systemic absorption.

• If you prefer capsules, I recommend dye-free liqui-gels.

• Diphenhydramine’s duration of action is around 4-6 hours, so it may help you stay asleep longer than immediate-release melatonin or the herbal concoction, both of which are shorter-acting.

• Since diphenhydramine is sedating, I recommend only taking it at bedtime and not around the clock.

• Avoid in: ages 65+, glaucoma, Long QT Syndrome, cognitive dysfunction, or those taking other anticholinergic medications (amitriptyline, oxybutynin, hydroxyzine, clemastine, chlorpheniramine, et al). Check with pharmacist if unsure.

• Adult dosing: May be somnolent at doses as low as 10 mg but most may need 12.5 to 25 mg at bedtime with a maximum dose of 50 mg. With liquid formulations, one can titrate up or down easily as needed in small intervals.

• Children: Avoid use in children under 6 yrs old. Speak with pediatrician before using in kids 6+ for sleep. May cause paradoxical hyperactivity or insomnia.

MY FIVE BEST BETS:

LACTOFERRIN

Lactoferrin is an iron-binding glycoprotein with immunomodulating properties. It has been studied in both adults and children and has a good safety profile in all age groups, even infants. A 2020 RCT (n=290) found that lactoferrin significantly reduced duration of total infectious diseases compared to placebo. A 2021 meta-analysis backed up these results further.

This small study (n=92) compared three groups of COVID patients: 1) those treated with liposomal lactoferrin, 2) patients with no treatment, and 3) patients treated with the HIV antiviral Kaletra (lopinavir + ritonavir) plus [hydroxy]chloroquine. Those treated with lactoferrin showed both clinically & statistically significant improvements over the other two groups, including shorter time to test negative, superior symptom resolution, and reductions in ferritin, D-dimer and IL-6. See results compiled in chart below. Note that patients in the lactoferrin group achieved symptom remission across almost all symptoms monitored, in striking contrast to those taking Kaletra plus [hydroxy]chloroquine.

Another trial, COVID-LF, found no difference in COVID symptom severity between placebo and lactoferrin groups. Importantly, however, that study was not powered to assess this secondary endpoint—in other words, the sample size was not large enough to determine a difference if there was indeed one. Furthermore, the study was stopped early (63 days vs the planned 90) due to the availability of COVID vaccines.

It is well-established that COVID often leads to reactivation of latent pathogens. As a result, for some, Long COVID may actually involve symptoms caused by these reawakened pathogens. Lactoferrin may exert action against not only SARS-CoV-2 but also many other viruses and bacteria via several routes as noted below.

1. competes with SARS-CoV-2, HSV-1, HPV, and even HIV for cell receptor occupancy — namely HSPGs on cell membranes — thereby blocking viral docking and entrance into cells.

2. prevents iron utilization by many harmful pathogens—including SARS-CoV-2— which need iron for replication/growth

3. promotes innate immunity via natural killer cell recruitment

4. enhances humoral immunity by stimulating B and T cells (so if you’re getting a booster, lactoferrin may provide an added “boost” to the booster!)

5. may diminish cytokine storm

6. improves gut microbiome

   

Source for image

Note that lactoferrin is better absorbed with enteric coating and on an empty stomach. Unfortunately it is difficult to find enteric-coated lactoferrin. Liposomal formulations may also yield a more beneficial immunmodulatory response according to this small RCT comparing liposomal vs non-liposomal lactoferrin in ten healthy men. The only liposomal formulations I found can be purchased here, here, and here, but they are quite expensive. Lactyferrin Forte Defense is the same liposomal formulation used in clinical trials, but a 250 mL bottle contains just 64 mg lactoferrin per 20 mLs and would require more than one bottle per day to reach the desired total daily dose of 1000 mg! Since this is impractical and very expensive, another option may be to empty the contents of two 250 mg capsules of Jarrow’s and mix with liquid sunflower lecithin (phosphatidylcholine) or a small volume of liquid liposomal vitamin C to improve absorption. Even better, one could purchase empty delayed release capsules and transfer the contents of the lactoferrin inside these capsules.

Adults: Recommended dosing is 500 mg twice daily on an empty stomach for 28 days, then may reduce to 500 mg once daily or 250 mg twice daily for another 8 weeks minimum.

Children: 400 to 600 mg daily have been used in children (see case series below). Lactyferrin Forte Defense is a flexible option for younger kids who cannot swallow pills. For babies and toddlers, another option is Jarrow Baby’s Big Support, but it is very expensive ~$42) with only 30 doses at 100 mg per dose. One could attempt mixing in an additional 250 mg from the capsule of Jarrow’s lactoferrin capsules. Another options is to simply mix Jarrow’s 400-500 mg with milk as done in a recent case series described below. Adding a few drops of lecithin may improve absorption further, as cited above. Ask your pediatrician if appropriate and cite this small case series that treated persistent post-COVID GI symptoms in a baby and 6-yr-old child with lactoferrin. The contents of lactoferrin capsules were emptied and dissolved into water or milk for the boy (600 mg) and the 11-month-old baby (400 mg). Course of treatment was 90 days. The boy’s GI symptoms completely resolved after 2 weeks on lactoferrin, while the baby’s symptoms improved “considerably” after just 1 week. Anecdotally, authors also reported that while the 6-yr-old was on lactoferrin, he and his family (mom, dad, & baby) were all infected with coronavirus again, but the boy was the only family member who did not experience any symptoms.

EGCG

EGCG, a potent catechin & antioxidant found in green tea, inhibits both EBV and SARS-CoV-2. This in vitro study found that EGCG inhibits SARS2 replication via inhibition of M-protease—the same enzyme target as Paxlovid—and even more potently via other mechanisms. As can be seen from the images below, even at the low concentration of 1 µg/mL, EGCG appears to significantly reduce coronavirus replication and relative activity of M-protease. But is this concentration achievable in humans??

Yes!! After just one single 800 mg dose of EGCG, one pharmacokinetic study found that humans reached a mean maximum concentration of 2.3 µg/mL, and after 10 consecutive days, that increased to 2.8 µg/mL. This may reduce relative activity of M-protease by up to 25%! No serious adverse events or any other clinically relevant adverse events were reported. However, one of the twelve participants did show elevated ALT which resolved on its own within 2 weeks.

So is 800 mg considered safe? Sources say yes, but don’t go any higher than that. In 2018, the European Food Safety Authority presented its scientific opinion on the safety of green tea catechins and they concluded that green tea infusions in typical daily doses of up to 866 mg EGCG are generally considered to be safe, while EGCG supplements in doses above 800 mg/day may increase liver enzymes. Drinking several cups of EGCG-rich green tea daily plus EGCG supplements to target 800 mg during acute infection and up to 10 days may very well reduce viral load and , thereby attenuating or preventing progression to Long Covid.

Drug interactions: If you opt to take a higher dose of EGCG (≥300 mg), keep in mind some drug interactions are possible, but it’s unknown how clinically relevant they might be. EGCG is a CYP3A4, CYP2C9 and CYP1A2 inhibitor, so if you are taking any medications that are moderate to strong substrates of these enzymes, consult with your pharmacist or physician about potential dose adjustments. Some possible (but not necessarily clinical relevant) interactions with EGCG are listed in the table below:

You may search DailyMed for your medication(s) and then scroll down to Drug Interactions. If your medication is involved in clinically significant CYP interactions, it will say so there. For example, here is what ivabradine’s drug interaction section looks like:

Adults: Maximum dose 800 mg once daily for 10 days, then decrease to 200-400 mg once daily for 8-12 weeks. The chart below shows well-reputed brands of teas and supplements with higher EGCG content. I favor Teavigo because it has been used in clinical trials, but all other brands have been tested and approved by Consumer Labs. If I were to dose aggressively during acute illness, I might take 6 Teavigo capsules (700 mg EGCG) plus an additional cup or two of green tea to yield 800 mg EGCG. Please note in the study discussed above, the participants took 800 mg in one single dose on a completely empty stomach: they took first thing in the morning and did not eat for 4 hrs thereafter. They also only took this high dose for 10 days.

Children: EGCG in FontUp chocolate beverage was trialed in children age 6 to 12 years old with similar adverse effect profile to placebo. Dose was 10mg/kg/day in two divided doses which came out to 1 to 2 satchets total per day. Treatment continued for 6 months. However, this product seems difficult to procure. Older children aged 13-18 years old may drink decaffeinated green tea or take 10 mg/kg EGCG (max 500 mg daily in those over 50 kg) for up to 5 days.

TIPS: To improve absorption, drink green tea or take EGCG supplement on an empty stomach along with ≥10 mg of vitamin C. Vitamin C reportedly increases absorption of gallated tea catechins including EGCG “extraordinarily.” You can simply sprinkle a tiny bit of vitamin C powder directly into your water or tea or supplement with <100 mg (~1/4 tsp or 1.25mLs) of liposomal liquid vitamin C. I don’t recommend a higher dose of vitamin C on an empty stomach as it could cause nausea or even vomiting. Unfortunately, higher doses of EGCG also may cause nausea. This mouse study found that fish oil also improved EGCG absorption; moreover, fish oil and EGCG synergistically inhibited cerebral amyloid β deposits which are found in Alzheimer's Disease. Thus it’s possible this combination could be neuroprotective.

EPA (omega-3 fatty acid)

My last article delved deeply into EPA: if you haven’t ready this post yet, check it out. Currently high-dose EPA — or more accurately, the EPA derivative IPE — is being investigated for its use in preventing SARS-CoV-2 or reducing severity of COVID. The authors of this study noted that “preclinical data and clinical observations suggest that IPE may have pleiotropic effects including antiviral and anti-inflammatory properties that may prevent or reduce the downstream sequelae and cardiopulmonary consequences of viral [upper respiratory infections].” Anecdotally, one doctor reported to me that none of his ~160 acute COVID patients who took Vascepa (a high-dose brand of IPE) developed Long COVID.

Adults: Take at least 1 gram (max 2 g twice daily) with the fattiest meal(s) of the day to increase systemic absorption. Please be advised that in doses above 1 g, risk of atrial fibrillation & flutter slightly increases, especially in those with history of AFib or AFlutter. If you have a history of AFib or AFlutter, speak with your doctor before starting EPA or IPE.

Children age 12-17 yrs: Varies between individuals, but a maximum dose of 500 mg twice daily with fattiest meals of the day may be a good rule of thumb. Avoid in children with heart arrhythmias or speak with pediatrician first.

Children age 6-11 yrs: Varies between individuals, but a maximum dose of 750 mg total daily dose with the fattiest meal(s) of the day may be a good rule of thumb. Consult with pediatrician. Multiple trials have investigated EPA and EPA/DHA combos in children as young as 5 years old with good tolerability and safety. The doses studied were as high as 2 g daily with average doses hovering around 500 to 800 mg daily. Avoid in children with heart arrhythmias or speak with pediatrician first.

Children age 2-5 yrs: Consult with pediatrician. A maximum of 300 to 500 mg total daily dose with the fattiest meal(s) of the day may be a good rule of thumb. It is difficult to find palatable liquid EPA-dominant formulations for children. Most are DHA-only. Barlean’s Omega Pals is one possibility but the ratio of EPA:DHA is less than ideal at 3:2. Another albeit less convenient option involves drawing up milk or child’s favorite juice in a 5 mL dosing syringe (you can get these for free at most local pharmacies if you ask), then carefully poking a hole into the EPA softgel (VegEPA or PharmEPA may be perfect options dose-wise) and squeezing the oil into the syringe. Then administer to your child immediately. This ensures they get the full dose. Alternatively, you could skip the dosing syringe and directly add the oil from the softgel to a small volume of your child’s favorite smoothie. Try this approach only if you are confident your child will drink it within a few minutes of preparation to avoid fish oil oxidation. You could also add a few drops of lecithin to aid absorption further. Avoid in children with heart arrhythmias or speak with a pediatrician first.

PAXLOVID

According to this VA preprint, Paxlovid use within 5 days of testing positive for SARS-CoV-2 reduced the risk of Long Covid (PASC) by 26% (HR 0.74 95% CI (0.69, 0.81), ARR 2.32 (1.73, 2.91)). Based on human trials and the current available research (which is sadly limited), Paxlovid currently appears to be the best treatment available for preventing Long COVID.

While Paxlovid does involve drug interactions via CYP3A4, your dispensing pharmacist will review any potential interactions and discuss them with you and your doctor if warranted.

Children: Unfortunately, Paxlovid is not authorized for use in children younger than 12 years old or weighing less than 40 kg (88 lbs).

NATTOKINASE: a safer and more effective alternative to aspirin?

Microclots have been reported in both acute COVID and Long COVID. A 2021 study found anomalous amyloid microclots in Long Covid patients comparable to those in acute Covid patients. Nattokinase and lumbrokinase have been shown to degrade amyloid fibrils in vitro. These in vitro studies also found that amyloid degradation is pH-dependent and the fibrinolytic activity of nattokinase stops in pH<5 (gastric pH is normally ~2-3).

A study published in Thombosis and Hemostasis uncovered evidence of disordered clotting in Long Covid. Of the 330 patients, 26% had elevated Factor VIII, ranging from 2.1 to 5.1 IU/mL (normal range: 0.5-2 IU/mL), and 18% had elevated von Willebrand Factor (vWF), ranging from 1.7 to 3.3 IU/mL (normal range: 0.5-1.6 IU/mL). Both of these factors help the blood clot, and levels above the normal range suggest a higher risk for thrombosis. Importantly, trials in humans have shown that nattokinase reduces vWF and fVIII within normal ranges. One open-label human trial (n=45) found that nattokinase 4000 FU daily reduced Factors VIII & VII by 17-19% & 7-14%, respectively, after 2 months. A double-blind RCT (n=74) investigated the effects of nattokinase on von Willebrand Factor. Patients took NSK-SD (not enteric-coated) 2000 FU once daily for 8 weeks and on average their vWF reduced by 15%. I suspect that at higher doses with enteric coating, the reductions in vWF and Factors VIII & VII would be even greater.

A 2021 study found sustained pro-thrombotic (clot-promoting) changes in “recovered” COVID patients FOUR MONTHS after hospital discharge: Plasminogen-activator inhibitor type 1 (PAI-1) levels were significantly elevated (0.6 vs 3.15  ng/L, p<0.0001) while plasmin-antiplasmin (PAP) complexes were significantly lower compared with controls. Low PAP and high PAI-1 raise alarm bells for higher blood clot risk. Nattokinase has been shown to degrade PAI-1 and increase PAP. During acute COVID and even in the months after apparent “recovery,” nattokinase may help mitigate cardiovascular damage and/or complications.

Adults: For preventive measures during acute COVID, nattokinase doses ranging from 2000 to 5000 FU twice daily may be sufficient. Dose adjustments may be advised depending on individual’s medical history, risk factors, and other medications. Enteric coating ensures better absorption and fibrinolytic efficacy. For info on nattokinase potential drug interactions, see my write-up here. Info on lumbrokinase drug interactions is lacking but may be similar to nattokinase. For more info, see my FAQ.

Children: To my knowledge, there have been no nattokinase or lumbrokinase trials in children, but some physicians reportedly have treated children with nattokinase in half doses (~1000 FU daily). I personally wouldn’t recommend nattokinase in children younger than 12 years old, but they could eat natto. Best low-dose brands of supplements are Solaray NK 1250 FU and Naturally Vitamins NK 750 FU.

ALLERGY NOTE: For those with soy allergy or MCAS, consider that nattokinase is sourced from fermented soybeans. Some but not all with MCAS report have reported exacerbations. Healthy Origins makes a soy-free nattokinase but unfortunately it is not enteric-coated and may require higher doses for comparable efficacy. Some with MCAS report better tolerability with lumbrokinase, another fibrinolytic enzyme. More info on lumbrokinase in my FAQ.

HONORABLE MENTIONS:

Famotidine, Cromolyn, Palmitolyethanolamide (PEA), Metformin

Most are already well-aware of FAMOTIDINE’s ostensibly benefits in acute COVID, so I won’t spend much time on it. In this small RCT (n=56), rate of COVID symptom resolution but not time to symptom resolution was significantly improved: around 50% reduction of overall baseline symptom scores was achieved at 8.2 days (95% CI: 7 to 9.8 days) with famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) with placebo. Recall the dose in this study was 80 mg three times daily (240 mg total daily dose) which is sixfold higher than the typical dose of 20 mg twice daily (40 mg total daily dose).

Personally I am not particularly enthusiastic about blanket antihistamine treatments for everyone because I think they are tricky to dose. While some level of inflammation is needed to stave off infection, too much inflammation can be harmful, and it’s difficult to achieve that perfect balance of just the right amount. It may vary substantially between individuals. Therefore, I think it’s best to carefully consider histamine blockers on a case-by-case. In children, famotidine is typically dosed at 1 mg/kg divided into two doses (but never to exceed maximum adult doses), and if necessary, tablets may be crushed. Consult with pediatrician.

I discuss mast cell stabilizer CROMOLYN in this post. Check it out if interested. The nasal spray is generally safe and well-tolerated in ages 2 yrs old and up. It boasts very few drug interactions and offers nice dosing flexibility.

In vitro & animal studies have shown many promising features of PEA. Perhaps most importantly, PEA binds coronavirus S protein and dismantles lipid rafts used by SARS-CoV-2 for viral entry. Another in vitro study found that PEA reduced SARS-CoV-2 binding to ACE-2 receptors by 50% at 10µM and SARS-CoV-2 entry into cells at concentrations as low as 1 µM. But is that concentration reached in humans? Unfortunately, even a 1.75x more bioavailable formulation known as Levagen only reached a maximum concentration of 0.015 µM in adults per my calculations:

Nevertheless, a double-blind RCT found that compared to placebo, PEA reduced several inflammation biomarkers in non-hospitalized COVID patients. One of those biomarkers was P-selectin, a cell adhesion molecule expressed on activated endothelial cells and platelets.

Along with cromolyn (NasalCrom) and famotidine, PEA may be a good supplement to prevent mast cell activation syndrome (MCAS), a syndrome that seems to occur in many Long COVID sufferers and causes a host of troubling symptoms, including food intolerances, heart palpitations, brain fog, and hemostatic disruptions. While those with pre-existing MCAS may be predisposed to developing Long COVID, it also may be true that SARS-CoV-2 infection triggers new onset MCAS. This pre-COVID study found that PEA and luteolin can “work synergistically to reduce mast cell-mediated toxicity and elicit neuroprotection.” A Long COVID study found that PEA in combination with luteolin improved olfactory function and memory. Several human trials have found that PEA benefits Long COVID patients by attenuating neuroinflammation.

Adults: Doses used in Long COVID clinical trials were around 600 to 1200 mg total daily dose. Reputable brands include Mirica, Normast, Glialia, and Levagen. Take with fattiest meal(s) of the day to optimize absorption.

Children: PEA has been studied in children in ages as young as 8 years old and has shown good tolerability at an average dosage of 40 mg/kg/day (maximum 600 mg/day).

A preprint came out on December 24 that showed METFORMIN may reduce risk of Long COVID in overweight or obese adults aged 30 to 85. Unlike metformin which showed a statistically significant relative risk reduction, no benefit was found with ivermectin (3 days) or fluvoxamine (14 days). To aid tolerability, the metformin dose was titrated up, starting at 500 mg on day 1, then 500 mg twice daily for 4 days; then 500 mg mornings and 1000 mg evening through 14 days. The absolute risk reduction was 4.3%. For those curious, the relative risk reduction is calculated as follows:

Some have expressed concern that development of Long Covid was only a secondary endpoint of the original study whose primary endpoint investigated hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. (Results in that study found that none of the three medications prevented the occurrence of any endpoint.) Trials are powered for primary endpoints and not necessarily for secondary endpoints. Of course a larger sample size would be ideal, but I still believe this study looks promising, especially paired with the fact that metformin has shown anecdotal benefits in ME/CFS.

It’s certainly possible that a short course of metformin might help some people reduce their risk of Long Covid. While the study was not specifically powered to assess subgroups, authors noted that certain subgroups seemed to benefit more than others:

Metformin is a relatively safe prescription medication typically prescribed for type 2 diabetes. However, I wouldn’t recommend it for children as it hasn’t been studied in this population for COVID. Metformin has a low risk of hypoglycemia but does exert significant gastrointestinal side effects, especially diarrhea, nausea, and vomiting. Careful dose titration may reduce these adverse effects. Lactic acidosis is very rare but possible. While metformin may cause vitamin B12 deficiency, it is very unlikely to occur over a short 14-day course. However, one could supplement with B12 if concerned. Discuss metformin with your physician and ask if a standy-by prescription for a 14-day course might be appropriate for you.

One final note: Berberine and metformin share some similarities in several key mechanisms of action. For example, both activate AMP-activated protein kinase (AMPK) and inhibit mTOR. Berberine also has similar dosing and side effects as metformin. Could berberine reduce risk of Long COVID? It is certainly worth studying. However, a big concern is bioavailability—that is, what percentage of the dose reaches systemic circulation and thereby its therapeutic destination? Metformin has good oral bioavailability at around 40-60% whereas berberine’s is well under 1% due to extensive hepatic metabolism, P-glycoprotein efflux and poor intestinal absorption. If you decide to try berberine, combining it with nattokinase might help absorption due through P-gp inhibition.

SUMMARY

If one wanted to take all/most of the treatments above, here is how I might do it. These are ADULT doses below. Important: this is not medical advice nor is it a treatment protocol. This is based on current available research and my opinions as a pharmacist.

Days 1 - 5 for those who take Paxlovid:

1. 1 hr before breakfast: 1 cup of green tea with ≥10 mg vitamin C

   • Also may gargle green tea with honey

2. Paxlovid as prescribed

3. Saline nasal rinse and CPC mouthwash twice daily

   • Supervise use of CPC mouthwash in kids 6 to 12 years old. Advise kids practice swishing water without swallowing before trying CPC.

4. EPA or IPE 1-2 g twice daily with fattiest meals of the day

5. Melatonin sublingual drops

6. (if prescribed) Metformin 500 mg with breakfast and 1000 mg with dinner (titrate up) x 14 days

7. (if desired) Famotidine 80 mg three times daily

8. (if desired) PEA 600 mg twice daily with meals

Day 6 (or Day 1 if no Paxlovid): at least 4 weeks, preferably 8-12 weeks, except as noted:

>1 hr before breakfast (empty stomach):

1. 1-2 cups green tea

   • with ≥10 mg vitamin C to improve absorption

2. Lactoferrin 500 mg

3. Nattokinase 2000-4000 FU

4. Saline nasal rinse & CPC mouthwash twice daily for 14 days

   1. CPC mouthwash reduces salivary viral load.

5. EGCG capsules

   • Not to exceed 800 mg total daily dose including tea

   • 800 mg daily studied for treatment duration of 10 days. Since 800 mg is the max doses and liver enzymes could increase with longer administration, recommend dose decrease to 200-400 mg after 10 days.

   • Please note this may cause nausea in some - advise to start with just 1 capsule to test tolerability

   • Do not combine with famotidine! It will likely reduce absorption of EGCG due to increased gastric pH. Separate by at least 4 hrs. Consider that mast cell stabilizer cromolyn (e.g. Nasalcrom) does not affect gastric pH and has very few drug interactions, so can be taken at any time of day at ≥4-6 hour intervals.

With breakfast:

1. (if prescribed) Metformin 500 mg (14 days total)

With lunch:

1. EPA or IPE 500 mg to 2 g

   • Take at lunch or breakfast — whichever meal is fattier.

2. (If desired: famotidine and/or PEA)

With dinner:

1. EPA or IPE 500 mg to 2 g

   • total daily dose not to exceed 4 grams

2. Liposomal vitamin C** 1000 mg

3. (if prescribed) Metformin 1000 mg (14 days total)

4. (if desired) famotidine or PEA

≥2 hours after dinner OR 1 hr before bed (whichever is farther from food and/or more convenient):

1. Lactoferrin 500 mg

2. Nattokinase 2000-4000 FU

Bedtime (#1-#4 optional for insomnia; melatonin most promising of 3 for antiviral benefit):

1. Melatonin time-release 1 to 5 mg

   • doses ≥5 mg for antiviral benefit

2. Melatonin sublingual drops 0.3 to 3 mg

   • 2-8 drops for sleep, 20+ drops for antiviral benefit)

3. SLEEP drops

4. Diphenhydramine 10 to 25 mg last resort for insomnia in those for whom no contraindications

5. Saline nasal rinse & CPC mouthwash twice daily for 14 days

**I am aware of the L-arginine + liposomal vitamin C trials. I have some reservations about L-arg during active infection so did not include it on the list. If you plan to take L-arg, empty stomach is best. L-citrulline seems to be better absorbed and could be more effective, although it hasn’t been studied in COVID or Long COVID.

I hope this helps! 🌈

In Solidarity,

LongCovidPharmD