Table 2.
Natural compounds and supplements with plausible mechanisms of action against spike protein-related pathologies.
| Compound | Mechanism | Reference | Clinical Trials | Evidence Summary |
|---|---|---|---|---|
| Vitamin D | Immunomodulatory | [225] | NCT05356936 | Proxy (C19 severity) [226] |
| Vitamin C | Immune support, antioxidant | [227] | NCT05150782 | Reduction in fatigue (not long-COVID-19 related) [227] improved oxygenation, decrease in inflammatory markers, and a faster recovery were observed in initial COVID-19 infection (proxy measure for long-COVID-19) [228] Improvement in general fatigue symptoms when combined with l-arginine [229] Significant improvement [230] |
| Vitamin K2 | Immunomodulatory | [231] | NCT05356936 | Proxy evidence (severity of COVID-19 infection) [231] |
| N-Acetyl Cysteine (NAC) | Antioxidant, anti-inflammatory, cellular metabolism, blocks S-ACE2 interface (IS [232]) |
[233,234,235,236] |
NCT05371288 NCT05152849 |
Proxy evidence (severity of COVID-19 infection) [234] |
| Glutathione | Antioxidant, anti-inflammatory, cellular metabolism | [237,238,239] | NCT05371288 | Proxy (severity of COVID-19 infection) [239,240] |
| Melatonin | Antioxidant, anti-inflammatory, cellular metabolism | [241] | Proxy (higher rate of recovery, lower risk of intensive care unit admission) [242] | |
| Quercetin | Anti-inflammatory spike-ACE2 interaction [243,244] |
[243,245,246,247] | Proxy (faster time to negative PCR test when combined with Vitamin D and curcumin) [248] | |
| Emodin | Blocks spike-ACE2 interaction [249] | [249] | ||
| Black cumin seed extract (nigella sativa) |
Anti-inflammatory | [250,251,252] | ||
| Resveratrol | Anti-inflammaotry, anti-thrombotic | [253,254,255] | Proxy (lower rates of hospitalization) [256] | |
| Curcumin | Inhibits spike–ACE2 interaction, inhibits virus encapsulation [257], binds SC2 proteins (IS) [258] |
[259,260,261] | NCT05150782 | Proxy (lowers inflammatory cytokines) [261,262] |
| Magnesium | Multifactorial, nutritional support | [263,264] | Proxy (low magnesium–calcium ratio associated with higher C19 mortality [265], low magnesium associated with higher risk of infection [266]) | |
| Zinc | Nutritional support | [267,268,269] | NCT04798677 * | Proxy (possibe better acute C19 outcomes [270], other meta-analysis did not confirm efficacy [271]) |
| Nattokinase | Anti-coagulant, degrades spike (IVT) [203] |
[202,203] | Proxy: degrades spike protein in vitro [203] | |
| Fish Oil | Anti-coagulant | [272,273,274] | NCT05121766 | Proxy (lowered hospital admission and mortality [272]) |
| Luteolin | Decreases inflammation [275] | [275,276,277] | NCT05311852 | Faster recovery of olfactory dysfunction when combined with ultramicronized palmitoylethanolamide and olfactory training [278] |
| St. John’s Wort | Decrease inflammation [279] | [279,280] | ||
| Fisetin | Senolytic [281] Binds SARS-CoV-2 main protease (IS) [282] Binds spike protein (IS) [283] |
[281,283,284] | ||
| Frankincense | Binds to Furin | [285] | NCT05150782 | Positive impact [286] |
| Apigenin | Binds SARS-CoV-2 spike (IS [244]), antioxidant [287] | [288,289] | ||
| Nutmeg | Anti-coagulant | [290] | ||
| Sage | Inhibits replication (IVT) [291] | [291,292] | ||
| Rutin | Binds spike [293] | [294] | NCT05387252 † | |
| Limonene | Anti-inflammatory | [295] | Antiviral in in vitro assays as whole bark product [296] | |
| Algae | Immunomodulatory [297] | [298,299,300] |
NCT05524532 NCT04777981 |
|
| Dandelion leaf extract | Blocks S1–ACE2 interaction (IS + IVT [301] | [301] | Proxy (reduction in sore throat in combination with other extracts [302] | |
| Cinnamon | Immunomodulatory [303,304] | [305,306] | ||
| Milk thistle extract (Silymarin) | Antioxidant, anti-inflammatory [307] Endothelial protective (IVO [308]) Blocks spike [308] |
[308] | Evidence for mechanism, but not treatment, as of October 2022 [307] | |
| Andrographis | Binds ACE2 (IVT), reduction in viral load (IVT) [309] | [310,311] | Proxy (no decrease in C19 severity [312] | |
| prunella vulgaris | Blocks spike [313] | [313] | ||
| Licorice | Immunomodulatory, anti-inflammatory [314] | [315,316,317,318] | Proxy (inhibits virus in vitro [319]) | |
| Cardamom | Anti-inflammatory (IVO [320] | [320] | Proxy (lowers inflammatory markers) [320] | |
| Cloves | Antithrombotic, anti-inflammatory [321], Blocks S1–ACE2 interaction (IS, CFA) [322], stimulates autophagy [323] |
[321] | Prevents post-COVID-19 cognitive impairment [324] | |
| Ginger | Unknown | Proxy. Reduced the hospitalization period in SC2 infection [325] | ||
| Garlic | Immunomodulatory [326] | [326,327,328] | Proxy (faster recovery from C19) [329] | |
| Thyme | Antioxidant, nutrient rich, anti-inflammatory [330] | [331] | Positive impact on energy levels [289] | |
| Propolis | ACE2 signalling pathways (IS [332], IVT, IVO) [333,334] Immunomodulation [335] |
[333,336,337] | Meta-analysis reveals propolis and honey could probably improve clinical COVID-19 symptoms and decrease viral clearance time [332] |
Clinical trials were conducted for a long period, unless otherwise stated. Clinical trials are for long COVID-19, unless otherwise stated. * Vaccine immune response. † Adverse reactions to vaccination adverse reaction. Under mechanism. IS: in silico. IVT: in vitro. IVO: in vivo.