SUPPLEMENTS WITH ANTIVIRAL ACTIVITY🧵 Some are finding benefit from fibrinolytic supplements like nattokinase which directly break down clots & biofilms. Once those clots degrade, however, pro-inflammatory molecules & viral debris may be released into circulation. ⬇️

This may cause temporary adverse effects — Herxheimer-like reactions — especially in those too ill or weak to clear out the debris. Therefore, it may be helpful to take supplements with antiviral activity.⬇️

Note that those with Long Covid may have not only persistent SARS-CoV-2 infections but also additional reactivated viruses or bacteria, all of which must be targeted! Among the most common reactivated viruses are EBV, VZV, HSV-1, HSV-6, & CMV.⬇️

Ideally, you would get tested for these viruses and if appropriate start prescription antivirals. But that isn’t feasible for everyone. Antiviral supplements may help, so let’s highlight some of the most promising ones: Curcumin PEA + luteolin Baicalein Monolaurin EGCG

I. CURCUMIN Curcumin exhibits antiviral, anti- inflammatory, anticoagulant, antiplatelet, and cytoprotective activity. This July 2022 in silico study found that curcumin inhibits the Omicron S protein and may also destabilize the ACE2-complex.

CURCUMIN A 2020 study found that IL-1ß and IL-6 significantly decreased in acute COVID patients on nanocurcumin vs placebo. Other studies found that curcumin may interfere with other viral pathways as well.

CURCUMIN An added bonus in #longcovid is that curcumin inhibits platelet aggregation. Studies suggest an association with LC & hyperactivated platelets. Those on aspirin or fibrinolytic enzymes need to watch out for and sign of bleeding.

CURCUMIN DOSING Depends on formulation Generally, 500 mg to 2,000 mg daily However, up to 8,000 mg daily x 18 months was tolerated with no reported toxicities in one population of pancreatic cancer patients.

CURCUMIN DOSING Curcumin has poor bioavailability & water solubility. Take with a fatty meal and/or 2.5 - 10 mg piperine to increase absorption. Caution with drug interactions involving cyp3a4. Notably, piperine also inhibits platelet aggregation.

CURCUMIN Theracurmin is curcumin dispersed w/ colloidal submicron particles, the size of which are much smaller than conventional curcumin particles (0.19 µm vs 22.75 µm). Theracurmin is 20x more bioavailable than regular curcumin formulations; thus doses are ~30-60 mg.

Curcumin Cautions: Avoid in gallbladder or liver disease. Curcumin could elevate liver enzymes. Since some pwLC may already have ⬆️ liver enzymes, this may be one supplement to limit for very short term use. If prone to kidney stones, get oxalate-free curcumin.

II. BAICALIN (aka huáng qín) Baicalin, a flavonoid derived from skullcap, is the main metabolite of baicalein. It is purported to exert antiviral, antibacterial & antioxidant effects via multiple pathways. Studies suggest it also ⬇️ IgE & thus histamine.

BAICALIN This in vitro study found that baicalein & GCG--a catechin found in green tea--have high affinity for binding Mpro, the same enzyme target of Paxlovid. This inhibitory activity was potent, showing strikingly low IC50 values (~5-13 µM)!

Is 5-13 µM feasible in humans? This study examined safety & PK of baicalein in healthy humans. Subjects took 200, 400, & 600 mg baicalein or placebo QD day 1 & 10 & TID days 4–9. Cmax at 600 mg was close to 2 µg/mL = 4.48 µM, suggesting 5 µM is feasible.

BAICALEIN DOSING Is 600 mg a safe dose? Authors investigated parameters including liver enzymes, urinalysis, SCr, TG, & CRP & concluded, “All drug‐related AEs were mild & resolved during the study w/o further treatment. The frequency of drug‐related AEs was not a/w ⬆️ dosage.”

BAICALEIN SAFETY Despite authors finding no significant toxicities, proteinuria stood out to me (600 mg: 5 out of 10 w/ proteinuria). In those w CKD or reduced GFR, I would consult with a TCM expert before initiating baicalein supplements, or consider a reduced dose.

BAICALIN CAVEATS -Problems with consistency of composition & biological activity of commercially available products -Important to choose supplement w/ standardized % of baicalin -in TCM, often combined w/ other herbs for ⬆️ benefit - best to consult expert

III. PALMITOYLETHANOLAMIDE (PEA) In vitro & animal studies have shown many promising features of PEA: -⬆️ macrophage activation & phagocytosis -binds coronavirus S protein -dismantles lipid rafts used by SARS-CoV-2 for viral entry

PEA Added bonuses of PEA: -prevents endothelial damage -antagonizes NK-KB signalling pathway -decreases TNF-alpha, IL-1ß -regulates fatty acid metabolism -reduces lipoperoxidation -downmodulates mast cell activation

PEA The in vitro study above found that PEA: -⬇️ SARS-CoV-2 binding to ACE-2 receptors by 50% at *10µM* -decreased SARS2 entry into Calu-3 cells in concentrations as low as *1 µM*! Long Covid PEA studies discussed below👇🏼

❗️PEA retrospective Long Covid study❗️ -600 mg BID x 3 months -33 patients -Post-COVID-19 Functional Status (PCFS) assessed before & after treatment -No side effects reported✅ -few drug interactions✅ -PCFS score sig improved in most pts ✅ -no placebo or control group❌

LUTEOLIN SARS-CoV-2 uses RNA-dependent RNA polymerase (RdRp) for viral replication. This in vitro study found that luteolin inhibited RdRp at an IC50 of just 4.6µM. Another study found that luteolin also inhibited Mpro (Paxlovid target) at IC50 of 20 µM.

LUTEOLIN DOSING -100 mg per 10 kg body weight = aggressive dosing that's been shown safe in one clinical trial in children -take w/ fatty meal -Liposomal formulations using olive pomace oil increase bioavailability -More details 👇🏼

EGCG DOSE: Empty stomach is best. Max safe dose of EGCG supplements = 800 mg daily. Teavigo = clinically tested brand ~140-150 mg/cap. 2-3 caps QAM + 2 caps QPM max dose Duration: high dose x 4 weeks, then decrease dose 8-12 wks

EGCG DOSING, cont Fish oil enhanced oral bioavailability of EGCG, significantly elevating plasma and brain levels of free EGCG in mice. Interestingly, fish oil is also associated with better covid outcomes - another reason to add this to one's arsenal.

Fish oil study: "Omega 3 was considered to reduce the risk of positive for SARS-CoV-infection and the duration of symptoms, overcome the renal and respiratory dysfunction, and increase survival rate in COVID-19 patients."

MONOLAURIN Less studied, but may help degrade viral envelopes of viruses including coronavirus, HSV-1&2, and EBV.

MONOLAURIN DOSE: Take with fattiest meal of day. Dosing ranges from 500 mg to 2000 mg BID Reputable brand Lauricidin recommends starting at a lower dose (750 mg BID), then titrating up gradually. Duration: 12 weeks minimum

DISCLAIMER: Some of these supplements may interact w/ other meds. Caution & review with pharmacist before starting. Examples: EGCG, curcumin & piperine inhibit an enzyme (cyp3a4) that metabolizes many Rx meds, so could ⬆️ (or less often⬇️) absorption.

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