Artemisinin From Sweet Wormwood Inhibits SARS-CoV-2
October 20, 2021
- An antimalarial treatment made from the plant Artemisia annua (Sweet Wormwood) shows promise as a COVID-19 treatment
- The drug artesunate — which contains two compounds found in Artemisia annua: artemisinin and dihydroartemisinin — is a first-line treatment for malaria
- In a recent in vitro study, both pretreatment and treatment with artemisinin extracts, synthetic artemisinin and the drug artesunate were able to inhibit SARS-CoV-2 infection. However, artesunate was the most potent in terms of treatment, and from a clinical perspective may be the only one worth pursuing
- Artesunate’s mechanism of action against SARS-CoV-2 is as yet unknown, but artemisinin does have confirmed antiviral activity
- The World Health Organization has come out in opposition to artemisinin-based products, warning their use can bolster drug-resistant strains of malaria parasites. For this reason, people living in malaria-prone areas should be cautious about using this plant remedy
This article was previously published January 4, 2021, and has been updated with new information.
A second antimalarial treatment is now being seriously considered and evaluated for its efficacy against COVID-19. The treatment is made from the plant Artemisia annua, which most people know as Sweet Wormwood. Other names for this plant include Annual Sagewort and Sweet Annie.
Research over the past few decades has revealed multiple health benefits from this medicinal herb, which has a centuries-long history of use in folk medicine. In 2015, Chinese scientist Tu Youyou received a partial Nobel Prize in Physiology or Medicine for his discovery of artemisinin and dihydroartemisinin,1 both of which have potent malaria-fighting properties.
As reported by the University of Kentucky,2 “The popular malaria drug artesunate was developed from those compounds and is still used as a first-line treatment for the disease today.”
Artemisinin — A Viable COVID-19 Remedy?
Interestingly, in addition to having a long-standing history of being used as a highly effective antiparasitic, it also has anticancer properties. Additionally, artemisia annua has antiviral activity that might be helpful against SARS-CoV-2.
In an April 8, 2020, SEC filing, Mateon Therapeutics reported3 that “Artemisinin is highly potent at inhibiting the ability of the COVID-19 causing virus (SARS-CoV-2) to multiply while also having an excellent safety index.”
After testing the plant’s antiviral effects in a laboratory setting for a couple of years, University of Kentucky researchers are also exploring its use for the treatment of COVID-19,4 as are researchers in Denmark and Germany.5 According to the University of Kentucky:6
“Surprisingly, results showed that the plant’s leaves, when extracted with absolute ethanol or distilled water, provided more antiviral activity than the actual drug itself — meaning that an Artemisia annua-blended coffee or tea could possibly be more effective than taking the drug.”
Based on these findings, researchers have decided to test artemisinin in patients diagnosed with COVID-19. Some of the first human studies, set to investigate both the extract blended into coffee and tea, as well as the drug artesunate, were implemented by UK HealthCare.
University of Kentucky researchers have founded a company called ArtemiFlow to develop and manufacture the drug, in collaboration with the Kentucky Tobacco Research & Development Center.7 A sister company, ArtemiLife, is marketing Artemisia tea and coffee to raise research funds.
Mechanism of Action Remains Unknown
As for its mechanism of action, such details still remain to be discovered. C&EN explains:8
“When countering malaria, artemisinin exploits the parasite’s taste for hemoglobin in its host’s blood. As the parasite digests hemoglobin, it frees the iron-porphyrin heme complex from the protein.
Because this heme is toxic to the parasite, the organism normally converts the complex to a more benign crystalline form. ‘But artemisinin corrupts this heme-detoxification pathway,’ says Paul O’Neill, a medicinal chemist at the University of Liverpool.
If artemisinin does have any effect against SARS-CoV-2, though, it likely relies on a completely different mechanism than the one it uses against the malaria parasite, Harvard’s [malaria researcher Dyann F.] Wirth says.”
In Vitro Study Reports Positive Results
An in vitro study9,10 looking at the efficacy of artemisinin-based treatments against SARS-CoV-2, posted on the prepublication server bioRxiv, October 5, 2020, report promising results.
The study was a collaboration between researchers from Germany, Denmark and Hong Kong, led by Kerry Gilmore, Ph.D., from the Max Planck Institute for Colloids and Interfaces in Potsdam, Germany.
Three artemisinin extracts, as well as pure, synthetic artemisinin, artesunate and artemether were evaluated. During the initial screening for antiviral activity, a German SARS-CoV-2 strain obtained from Munich was used.
Later on, during the concentration-response phase of the trial, they used a Danish SARS-CoV-2 strain from Copenhagen. These two strains are said to be “more closely related to the majority of SARS-CoV-2 strains circulating worldwide than the Wuhan strain.”11,12
In summary, they found that both pretreatment and treatment with artemisinin extracts, synthetic artemisinin and the drug artesunate were able to inhibit SARS-CoV-2 infection of Vero E6 cells and human hepatoma Huh7.5 cells. That said, artesunate was the most potent in terms of treatment, and from a clinical perspective may be the only one worth pursuing.13,14
World Health Organization Warns Against Its Use
While the world is eager to add another remedy to its COVID-19 treatment list, the World Health Organization has come out in opposition to artemisinin-based products. In a May 27, 2020, article, C&EN reported:15
“One of the most high-profile advocates for using the herbal remedy against the novel coronavirus is Madagascar president Andry Rajoelina, who has been touting Covid-Organics, a tonic containing A. annua that the Malagasy Institute of Applied Research developed …
But health officials are deeply concerned about the promotion and use of these herbal remedies for three principal reasons. First, no evidence exists that A. annua extracts can prevent or cure COVID-19 …
Second, A. annua preparations such as teas, tonics, or herbal capsules also contain a cocktail of bioactive compounds in addition to artemisinin that can have side effects such as dizziness, hearing problems, and vomiting.
Third, and perhaps most worrying of all, widespread use of A. annua herbal extracts could bolster drug-resistant strains of malaria parasites such as Plasmodium falciparum.16
For people living in regions where malaria is endemic, exposure to subtherapeutic doses of artemisinin in A. annua may be enough to kill off some of the parasites in their bodies, but not all of them. Clearing out weakling parasites leaves more room for drug-resistant siblings to proliferate, rendering vital ACTs [artemisinin-based combination therapies] ineffective.”
According to Pascal Ringwald, who heads up the drug resistance and response unit of the WHO Global Malaria Program, artemisinin resistance is a significant problem in Southeast Asia, where Artemisia readily grows and is commonly used.17
That said, this risk is bound to be slight for Americans and people in many other Western countries where malaria is exceedingly rare. According to C&EN,18 “Scientists interviewed by C&EN agree that although this use is against WHO recommendations, it does not risk accelerating resistance because there are so few cases of malaria in the U.S.”
- 1 NobelPrize.org Tu Youyou
- 2, 4, 6 University of Kentucky August 11, 2020
- 3 SEC Database April 8, 2020
- 5, 7, 8, 15, 17, 18 C&EN May 27, 2020
- 9, 11, 13 bioRxiv October 5, 2020 DOI: 10.1101/2020.10.05.326637
- 10, 12, 14 News-medical.net October 6, 2020
- 16 WHO.int Use of Non-Pharmaceutical Forms of Artemisia October 10, 2019
Two New Studies Test Quercetin And COVID Outcomes
October 14, 2021
- Two recently published studies confirm quercetin is useful as an adjunct therapy in the early outpatient treatment of mild SARS-CoV-2 infection
- In one study, COVID patients who received quercetin in addition to analgesics and an antibiotic cleared the virus faster than those who only received analgesics and antibiotics, and a greater number of patients reported reduced symptoms
- In the second study, daily quercetin supplementation for one month reduced the frequency and length of hospitalization, the need for noninvasive oxygen therapy, intensive care and deaths
- Quercetin has antiviral, anti-blood clotting, anti-inflammatory and antioxidant properties, all of which are important in the treatment of SARS-CoV-2 infection
- Quercetin also inhibits binding of specific spike proteins to your ACE2 receptors, thereby blocking the virus’ ability to infect your cells. It’s also been shown to directly neutralize viral proteins that are critical in the replication of SARS‐CoV‐2
In an August 21, 2021, newsletter,1 Dr. Michael Murray discussed the use of quercetin for respiratory infection symptoms. In November 2020, he’d suffered a “very mild and brief bout of COVID-19.”
He also recounts an anecdotal story of a friend who developed suspicious respiratory symptoms. His friend had been taking a number of supplements said to offer protection, but was still feeling awful.
As it turns out, the one thing he’d not taken was quercetin, and as soon as he did, that same day, his symptoms started to dissipate. This experience, Murray says, “is consistent with the results from two clinical trials” that were recently published.
Quercetin seems to be a safe, far less expensive, and easier-to-obtain and it works by a similar mechanism, driving zinc into the cells to stop viral replication.
Statistical Improvement in Clinical Outcomes
In the first study,2 42 COVID-19 outpatients were divided into two groups. One group of 21 patients received standard medical therapy consisting of analgesics and an antibiotic (acetaminophen 500-milligram (mg) to 1,000-mg dose if body temperature was higher than 37.5 degrees C — 99.5 F — with a maximum daily dosage of 3 grams, and 500 mg azithromycin for three consecutive days).
The other group of 21 patients received standard therapy plus the equivalent of 600 mg of quercetin per day (divided into three doses) for seven days, followed by another seven-day course of 400 mg of quercetin per day (divided into two doses).
The quercetin was used with sunflower lecithin, which has been demonstrated to increase absorption in the gut by as much as 20 times, compared to pure quercetin formulations.
The main outcomes being evaluated were virus clearance and symptoms. After one week of treatment, 16 of the 21 patients in the quercetin group tested negative for SARS-CoV-2 and 12 reported that all symptoms had diminished.
In the standard care group, only two tested negative and four had partially improved symptoms. By the end of Week 2, the five remaining patients in the quercetin group tested negative. In the standard care group, 17 of the 19 remaining patients tested negative and one had died.
“These results are impressive and hopefully additional studies will be conducted on hospitalized patients to see how quercetin might be helpful in more severe cases,” Murray wrote in his newsletter.
Can Quercetin Reduce Hospitalizations and Deaths?
The second study3 — a prospective, randomized, controlled and open-label trial — gave 152 COVID-19 outpatients a daily dose of 1,000 mg of quercetin for 30 days to evaluate its adjuvant effects in the treatment of early symptoms and the prevention of severe infection. According to the authors:
“The results revealed a reduction in frequency and length of hospitalization, in need of non-invasive oxygen therapy, in progression to intensive care units and in number of deaths. The results also confirmed the very high safety profile of quercetin and suggested possible anti-fatigue and pro-appetite properties.
QP (Quercetin Phytosome®) is a safe agent and in combination with standard care, when used in early stage of viral infection, could aid in improving the early symptoms and help in preventing the severity of COVID-19 disease. It is suggested that a double-blind, placebo-controlled study should be urgently carried out to confirm the results of our study.”
Mechanisms of Action
As noted in the first study4 above, quercetin was chosen based on the fact that it has antiviral, anti-blood clotting, anti-inflammatory and antioxidant properties, all of which are important in the treatment of SARS-CoV-2 infection. In the second study, more detailed mechanisms of action are reviewed. According to the authors:5
“SARS-CoV-2 proteases, like 3-chymotrypsin-like protease (3CLpro), papain-like pro-tease (PLpro), RNA-dependent RNA polymerase, spike (S)protein and human angiotensin-converting enzyme 2 (hACE2) are considered possible targets for developing effective anti-COVID-19 drugs.
Recently, molecular docking studies have suggested the possible binding interaction of quercetin with the 3CLpro, PLpro, and S-hACE2 complex. Some recent results, obtained by biophysical techniques, appear to support the results of the molecular docking studies.
Quercetin, a flavonol not naturally present in the human body, is the most abundant polyphenol in fruits and vegetable and is widely used as a dietary supplement to boost the immune system and promote a healthy lifestyle.
Quercetin is characterized by three crucial properties: antioxidant, anti-inflammatory and immunomodulatory. The combination of these actions allows quercetin to be a potential candidate to support all unhealthy conditions where oxidative stress, inflammation and immunity are involved.”
Initially, quercetin gained attention because it’s a zinc ionophore, meaning it shuttles zinc — which has well-known antiviral effects — into your cells just like the drug hydroxychloroquine.
Some proposed the primary reason hydroxychloroquine and quercetin worked was because of this feature. Of course, you also had to take zinc along with either of them. To effectively act as a zinc ionophore, the quercetin also needs vitamin C.
Since then, other studies, including the two reviewed here, have shown quercetin has other actions that makes it useful against SARS-CoV-2 as well. As reported by Murray in his newsletter:
“In particular, quercetin exerts significant inhibition on the binding of specific spike proteins to ACE-2 receptors, thereby blocking the ability of the virus to infect human cells. Quercetin has also been shown to directly neutralize viral proteins the are critical in the replication of SARS-CoV-2.”
In some studies, quercetin has also been shown to inhibit the release of inflammatory cytokines, which could help alleviate infection-related symptoms and suppress excessive inflammatory responses from occurring. Its antioxidant effects may also help prevent tissue damage caused by scavenging free radicals, thereby aiding in the recovery process of viral infections.6
Quercetin’s Antiviral Properties
Quercetin’s antiviral properties have been attributed to three main mechanisms of action:
- Inhibiting the virus’ ability to infect cells
- Inhibiting replication of already infected cells
- Reducing infected cells’ resistance to treatment with antiviral medication
For example, research7 funded by the U.S. Defense Advanced Research Projects Agency (DARPA), published in 2008, found it lowers your risk of viral illness such as influenza and boosts mental performance following extreme physical stress, which might otherwise undermine your immune function and render you more susceptible to infections.
Here, cyclists who received a daily dose of 1,000 mg of quercetin in combination with vitamin C (which enhances plasma quercetin levels8,9) and niacin (to improve absorption) for five weeks were significantly less likely to contract a viral illness after bicycling three hours a day for three consecutive days, compared to untreated controls. While 45% of the placebo group got sick, only 5% of the treatment group did.
Quercetin Works Against Many Common Viruses
Before the COVID-19 pandemic struck, several studies had highlighted quercetin’s ability to prevent and treat the common cold and seasonal influenza.10,11,12,13,14,15,16,17,18 By attenuating oxidative damage, it also lowers your risk of secondary bacterial infections,19 which is actually the primary cause of influenza-related deaths.
Importantly, quercetin increases mitochondrial biogenesis in skeletal muscle, which suggests part of its antiviral effects are due to enhanced mitochondrial antiviral signaling.20 Quercetin also works against other viruses, as demonstrated in the following studies:
• A 1985 study found quercetin inhibits infectivity and replication of herpes simplex virus type 1, polio-virus type 1, parainfluenza virus type 3 and respiratory syncytial virus (RSV).21
• A 2016 animal study22 found quercetin inhibited mouse dengue virus and hepatitis virus.
• Other studies have confirmed quercetin’s power to inhibit both hepatitis B23 and C24 infection.
• A March 2020 study25 found quercetin provides “comprehensive protection” against Streptococcus pneumoniae infection, both in vitro and in vivo, primarily by neutralizing pneumolysin (PLY),26 one of the toxins released from pneumococci that encourages S. pneumoniae infection to blossom in the first place.
Streptococcus pneumoniae is responsible not only for pneumonia, but can also be involved in some ear and sinus infections, meningitis and certain blood infections.27 As reported by the authors of this study:28
“The results indicated that quercetin significantly reduced PLY-induced hemolytic activity and cytotoxicity via repressing the formation of oligomers.
In addition, treatment with quercetin can reduce PLY-mediated cell injury, improve the survival rate of mice infected with a lethal dose of S. pneumoniae, alleviate the pathological damage of lung tissue and inhibit the release of cytokines (IL-1β and TNF-α) in bronchoalveolar lavage fluid.
Considering the importance of these events in antimicrobial resistant S. pneumoniae pathogenesis, our results indicated that quercetin may be a novel potential drug candidate for the treatment of clinical pneumococcal infections.”
How Quercetin Combats Inflammation and Boosts Immunity
Aside from its antiviral activity, quercetin is also known for boosting immunity and combating inflammation. As noted in a 2016 study29 in the journal Nutrients, mechanisms of action include (but is not limited to) the inhibition of:30
- Lipopolysaccharide (LPS)-induced tumor necrosis factor α (TNF-α) production in macrophages. TNF-α is a cytokine involved in systemic inflammation, secreted by activated macrophages, a type of immune cell that digests foreign substances, microbes and other harmful or damaged components
- LPS-induced mRNA levels of TNF-α and interleukin (IL)-1α in glial cells, which results in “diminished apoptotic neuronal cell death”
- The production of inflammation-producing enzymes
- Calcium influx into the cell, which in turn inhibits pro-inflammatory cytokine release, as well as histamine and serotonin release from intestinal mast cells31
According to this paper, quercetin also stabilizes mast cells, has cytoprotective activity in the gastrointestinal tract, and “a direct regulatory effect on basic functional properties of immune cells,” which allows it to inhibit “a huge panoply of molecular targets in the micromolar concentration range, either by down-regulating or suppressing many inflammatory pathways and functions.”32
While quercetin does have potent antiviral effects, in order for it to work effectively you need sufficiently high dosages to raise the level of quercetin in your body’s tissues.
The relatively low absorption rate of quercetin is why a sunflower lecithin formulation was used.
Research33 published in the July-December 2021 issue of the Journal of Natural Health Products Research, found a quercertin matrix has the same total absorption rate as quercetin phytosome — and higher peak blood levels.
“Since both of these forms of quercetin produce similar blood levels, they should produce the same effects at equal dosages based upon quercetin content,” Murray wrote in his newsletter, adding:
“My dosage recommendation as part of a nutritional supplement program to support immune function is 250 mg twice daily.
And in patients with active Infection, my recommendation is … six capsules twice a day providing a total of 3,000 mg of quercetin. This high dosage should be taken for at least 10 days and then reduced to a maintenance dosage of 250 mg twice daily …
[This] high dosage may not be necessary. But my dosage calculations are based upon likely tissue concentrations needed to exert the strongest antiviral effects. And given the safety of quercetin, there is no harm at this level.”
Protocol Using Quercetin
One doctor who early brought quercetin into the limelight was Dr. Vladimir Zelenko. As hydroxychloroquine became difficult to obtain, Zelenko switched to recommending quercetin instead, as it’s readily available as an over-the-counter supplement. For a downloadable “cheat sheet” of Zelenko’s protocol for COVID-19, visit VladimirZelenkoMD.com.
Other Health Benefits of Quercetin
There are also other lesser known benefits and uses for quercetin, including the prevention and/or treatment of:34
|High blood pressure35,36|
|Obesity38 and metabolic syndrome39 (a cluster of conditions including high blood pressure, high blood sugar, high triglyceride levels and fat accumulation around the waist that raise your risk for Type 2 diabetes, heart disease and stroke)|
|Certain kinds of cancer, in particular leukemia, and to a lesser degree breast cancer40|
|Nonalcoholic fatty liver disease (NAFLD)41|
|Aluminum-induced neurodegenerative changes, such as those seen in Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS).45|
|Longevity, thanks to its senolytic benefits (clearing out damaged and worn-out cells)46,47|
Research has also highlighted quercetin’s epigenetic influence and ability to:48
- Interact with cell-signaling pathways
- Modulate gene expression
- Influence the activity of transcription factors
- Modulate microRNAs
MicroRNAs used to be considered “junk” DNA. But far from being useless, research has revealed so-called “junk” DNA is actually microRNA and plays a crucial role in regulating genes that make the proteins that build your body.
The microRNA function as “on/off” switches for the genes. Depending on the microRNA input, a single gene can code for any of more than 200 protein products. Quercetin’s ability to module microRNA may also help explain its cytotoxic effects, and why it appears to improve cancer survival (at least in mice).
- 1 Drmurray.com
- 2, 4 International Journal of General Medicine June 2021; 14: 2807-2816
- 3 International Journal of General Medicine June 8, 2021; 14: 2359-2366
- 5 International Journal of General Medicine June 8, 2021; 14: 2359-2366 (Full)
- 6 Journal of Natural Health Product Research July-December 2021; 3(2) Rationale for Quercetin as a Potential Supplement to Increase Resistance to COVID
- 7 American Journal of Physiology August 1, 2008
- 8 Journal of the American Dietetic Association 2011 Apr;111(4):542-9
- 9, 10, 19, 20 Journal of Infectious Diseases and Preventive Medicine May 24, 2014; 2: 111
- 11 Antiviral Research June 2012; 94(3): 258-271
- 12 Journal of Ancient Diseases & Preventive Remedies 2014
- 13 Viruses 2016 8(1), 6
- 14 European Journal of Pharmaceutical Sciences June 28, 2009; 37(3-4): 329-333
- 15 Antiviral Research 2010 Nov;88(2):227-35
- 16 Experimental Lung Research 2005; 31(5)
- 17 Journal of Agricultural and Food Chemistry 2016; 64(21): 4416-4425
- 18 Viruses 2016 Jan; 8(1): 6
- 21 Journal of Medical Virology January 1985 DOI: 10.1002/jmv.1890150110
- 22 Asian Pacific Journal of Tropical Medicine January 2016; 9(1): 1-7
- 23 Virologica Sinica August 2015; 30(4): 261-268
- 24 Hepatology 2009 Dec;50(6):1756-64
- 25, 28 Microbial Pathogenesis March 2020; 140: 103934
- 26 Clinical & Experimental Immunology November 2004; 138(2): 195-201
- 27 CDC Pneumococcal Disease
- 29 Nutrients 2016 Mar; 8(3): 167, 5.2.1 Animal Models
- 30, 32 Nutrients 2016 Mar; 8(3): 167, 5.1.2 Mechanism of Action
- 31 Nutrients 2016 Mar; 8(3): 167, Table 1: Mast cell
- 33 Journal of Natural Health Product Research July-December 2021; 3(2)
- 34 Genetic Lifehacks December 17, 2019
- 35 J Am Heart Assoc. 2016 Jul 12;5(7). pii: e002713
- 36 Nutrition Reviews January 6, 2020 DOI: 10.1093/nutrit/nuz071
- 37 Int J Mol Sci. 2019 Dec 3;20(23). pii: E6093
- 38 Obesity (Silver Spring). 2008 Sep;16(9):2081-7
- 39 Phytotherapy Research March 8, 2019; 33(5)
- 40 Scientific Reports April 12, 2016; 6 Article Number: 24049
- 41 Phytotherapy Research August 26, 2019 DOI: 10.1002/ptr.6486
- 42 Br J Nutr. 2016 Mar 14;115(5):800-6
- 43 J Am Coll Nutr. 2017 Jan;36(1):9-15
- 44 Fitoterapia 2015 Oct;106:256-71
- 45 Neuroscience 2016 Jun 2;324:163-76
- 46 EBioMedicine. 2019 Sep;47:446-456
- 47 BMB Rep. 2019;52(1):47–55
- 48 Molecules 2019 Dec 23;25(1). pii: E63