Thread by @organichemusic

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. pubmed.ncbi.nlm.nih.gov/35508082/

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.
pubmed.ncbi.nlm.nih.gov/33129099/

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.
frontiersin.org/articles/10.33…

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. aacrjournals.org/clincancerres/…

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. link.springer.com/article/10.100…

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)! ncbi.nlm.nih.gov/pmc/articles/P…

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.
pubmed.ncbi.nlm.nih.gov/33753147/

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.”

In this single-dose study, authors observed that the exposure of baicalein began to plateau at 600 mg doses and speculated this was due to the saturation of baicalein absorption. Therefore, doses above 600 mg may not be useful. pubmed.ncbi.nlm.nih.gov/33753147/

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
journals.ashs.org/hortsci/view/j…

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
mdpi.com/1999-4915/14/5…

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
pubmed.ncbi.nlm.nih.gov/23813098

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👇🏼
ncbi.nlm.nih.gov/pmc/articles/P…

❗️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❌

❗️PEA double-blinded trial in Long Covid❗️
This RCT found that PEA combined with luteolin (PEA-LUT) attenuates neuroinflammation, significantly improving olfactory threshold, discrimination, & ID scores in Long Covid pts when compared to placebo.
pubmed.ncbi.nlm.nih.gov/35450527/

PEA

This wasn't the first time PEA + luteolin were studied together.

Previous studies also suggested PEA & luteolin work synergistically to reduce mast cell activation & elicit neuroprotection.

pubmed.ncbi.nlm.nih.gov/27423516/

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.
ncbi.nlm.nih.gov/pmc/articles/P…

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
Activity against:
1. SARS-CoV2: inhibits spike binding to ACE2 receptor
2. EBV: blocks lytic cycle
cellandbioscience.biomedcentral.com/articles/10.11… SARS2
sciencedirect.com/science/articl… EBV

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.
ncbi.nlm.nih.gov/pmc/articles/P…

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."
ncbi.nlm.nih.gov/pmc/articles/P…

MONOLAURIN

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

onlinelibrary.wiley.com/doi/10.1111/j.…

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
lauricidin.com/learn/intake-i…

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.

RESVERATROL

Activity against EBV, HSV, SARS-CoV-2, et al.

SARS2: Most notably, in silico analysis suggests potential inhibition of Mpro & RdRp plus ⬇️ binding of spike to ACE2 receptors
EBV: ⬇️ expression of EBV lytic proteins and ⬇️ virion production
ncbi.nlm.nih.gov/pmc/articles/P…

This double-blind placebo-controlled proof-of-concept RCT examined RESVERATROL for outpatient tx of mild COVID (n=105).
Primary outcome measure: hospitalization within 21 days of symptom onset
Secondary measures: ER visits and incidence of pneumonia & PE
nature.com/articles/s4159…

Dose was very HIGH: 1 g four times daily x ≥7 days, and up to 15 days if COVID-19 symptoms persisted

"Dosing was determined based upon published IC50 of resveratrol against MERS-COV and previously published pharmacokinetic literature of resveratrol plus its metabolites."

Despite the high dose, "no clinically significant adverse events were attributed to resveratrol."

Subjects took Vita-Age > 98% pure trans-resveratrol, which appears similar to this product available on Amazon. Note the addition of piperine, however.

amazon.com/Vita-Age-Certi…

The study was underpowered & results were NOT statistically significant:

-Hospitalization: 2% vs 6%, RR 0.33 (95% CI 0.04–3.10)
-COVID related ER visits: 8% vs 14%, RR 0.57 (95% CI 0.18–1.83)
-Pneumonia: 8% vs 16%, RR 0.5 (95% CI 0.16–1.55)
-One in each group developed PE.

RESVERATROL additional theoretical benefits relevant to #LongCovid:
1) improve endothelial function & flow-mediated
dilatation
2) scavenge reactive oxygen species
3) reduce inflammation
4) inhibit platelet aggregation
5) improve lipid profile
6) provide mitochondrial support

RESVERATROL is ~75% absorbed but is quickly metabolized➡️ low bioavailability.

This RCT found that trans-resveratrol PK showed circadian variation: bioavailability was best with MORNING administration.

Food does not appear to influence bioavailability. pubmed.ncbi.nlm.nih.gov/19194969/

Anti-EBV effects of RESVERATROL were significant at concentrations 25-50 µM (or as low a 5 µM in another study) in this in vitro study.

Is 25 µM achievable in humans?

doi.org/10.1371/journa…

My calculations suggest no👎🏼

Let's convert the Cmax of two highly-touted RESVERATROL (molar mass: 228) supplements to µM.
1) Evelor Cmax: 71 ng/mL ± 42 = ~113 ng/mL at best
= 0.5 µM❌
2) Vinia Cmax (per Vinia mfr): ~1400 ng/mL
= 6.1 µM❌
ncbi.nlm.nih.gov/pmc/articles/P…

However, resveratrol's metabolites may elicit benefits as well & Vinia is above the 5 µM threshold. These metabolites (glucuronide & sulfate conjugates) have been found in much higher plasma concentrations than free resveratrol in humans, but their effects are not well-studied.

DOSING
-complicated in part due to HORMESIS
-Typical dosing range = 100 to 1,000 mg/day
-food or empty stomach okay
-must consider CYP drug interactions (3A4, 2C9, 2D6)
-2 g/day & up has been associated with an increase in adverse effects such as diarrhea, nausea, headache

🚨Due to biphasic hormetic dose-dependent effects of resveratrol (see above), I have hesitated to write about this supplement. I feel like it's very tricky to dose properly and comes with unknown risks. However, many have requested a review.
ncbi.nlm.nih.gov/pmc/articles/P…

OTHER CAUTIONS WITH RESVERATROL:
-may be estrogenic or anti-estrogen: avoid in pregnancy or estrogen-sensitive conditions
-may affect thyroid: ⬆️ TSH in rat studies, but effects in humans not studied
-anti-platelet activity, so caution if on Plavix/aspirin
ncbi.nlm.nih.gov/pmc/articles/P…

Overall, RESVERATROL appears to have great potential in many diseases including Long Covid.

However, dosing is tricky & further complicated by inter-individual variability. Drug interactions must also be considered. Furthermore, bioavailability varies significantly b/t brands.