by James Odell, OMD, ND, L.Ac.
Artemisia annua has been used in China for more than 2000 years to treat fevers and more recently used in the treatment of the chloroquine-resistant and cerebral malaria (Plasmodium falciparum). Much focus has now been paid to its effectiveness in the treatment of SARS-CoV-2 (Covid-19). Its ancient Chinese name Qing Hao literally means “green herb.” Qing Hao was mentioned in the ancient text (168BC) Wu Shi Er Bing Fang or “Recipes for Fifty-Two Ailments”, as a remedy for fevers. The genus Artemisia consists of over 400 species, many of which have an aromatic, bitter taste. Herbal extracts of Artemisia annua have been used for thousands of years in other parts of the world, particularly Southeast Asia, Africa, India, and South America, to treat malaria and a variety of infectious diseases. Apart from its anti-malarial properties, Artemisia annua has been used in traditional Chinese medicine to stimulate hair growth, to promote longevity, as a food additive, as an anti-inflammatory, as well as a treatment for numerous external illnesses including hemorrhoids, lice and boils.
Botanical Aspects
Artemisia is a large, diverse plant genus with between 200 and 400 species and consists of hardy herbs and shrubs belonging to the Magnoliopsida class of flowering plants. Artemisia annua is an annual shrub of 50–150 cm in height. The shrub grows in temperate climates and is most widespread in China and Vietnam, but is also cultivated in East Africa, the United States, Russia, India, Brazil, and several other countries.1, 2 The reproduction of the shrub occurs by insects, self-pollination, and wind distribution.3
Artemisia annua Chemical Properties
The essential oil of Artemisia annua is rich in mono- and sesquiterpenes with numerous medicinal properties. Significant variations in its percentage and composition have been identified (main constituents may be camphor (up to 48%), germacrene D (up to 18.9%), artemisia ketone (up to 68%), and 1,8 cineole (up to 51.5%)). The oil has been subjected to numerous studies supporting exciting antiparasitic, antibacterial, antiviral, and antifungal activities. One of the more medicinal components found in Artemisia annua is artemisinin, first isolated in China in 1971.4
Artemisinin is the constituent with the greatest antimalarial activity. Up to 42% of the total artemisinin content is found in the upper leaves, where it accumulates in the glandular trichomes of the leaves. Artemisinin has been found in only two other species, Artemisia apiacea and Artemisia lance 5, and since that time its efficacy against malaria has been amply demonstrated.6, 7, 8, 9, 10, 11
The total amount of artemisinin found in different varieties of Artemisia annua varies slightly depending on extraction methods, different collection periods, different sample preparation, and different environmental influences.12 The artemisinin content in the plant exhibits the highest quantities usually just before flowering. Except for Artemisia annua, artemisinin is also present in Artemisia apiacea and Artemisia lancea, but only in minor quantities.13
Nowadays, many researchers are still investigating the effect of artemisinin and its analogues on the malarial parasite (Plasmodium) by modifying the structure of peroxides, ethers and ozonides in artemisinin. This improves the killing rate of plasmodium parasites for both in vitro and in vivo models as well as a faster clinical response for humans.14
Antimalarial Mechanism of Action of Artemisia annua
Malaria is one of the most severe public health problems worldwide. It is a leading cause of death and disease in many developing countries, where young children and pregnant women are the groups most affected. Worldwide an estimated 450,000 deaths annually (around 1200 per day) are attributed to malaria. This infection is caused primarily by the Plasmodium falciparum parasite, which largely reside in red blood cells and contains iron-rich heme-groups (in the form of hemozoin). Such hematophagous organisms digest hemoglobin and release high quantities of free heme, which is the non-protein component of hemoglobin. As a result, hemozoin pigment and other toxic factors such as glycosylphosphatidylinositol (GPI) are also released into the blood. These products, particularly the GPI, activate macrophages and endothelial cells to secrete cytokines and inflammatory mediators such as tumor necrosis factor, interferon-γ, interleukin-1, IL-6, IL-8, macrophage colony-stimulating factor, and lymphotoxin, as well as superoxide and nitric oxide. These inflammatory cytokines and mediators can cause significant damage to organs and tissues.15, 16, 17
The parasite is fairly shielded from attack by the body's immune system since it resides within the liver and blood cells for much of its human life cycle and is relatively invisible to immune surveillance. However, circulating infected blood cells are destroyed in the spleen. To avoid this fate, the Plasmodium falciparum parasite displays adhesive proteins on the surface of the infected blood cells, causing the blood cells to stick to the walls of small blood vessels, thus sequestering the parasite from passage through the general circulation and the spleen. Sequestered red blood cells can breach the blood-brain barrier and cause cerebral malaria. Artemisinin is also active against other parasite species such as Toxoplasma and Babesia that do not contain hematin.
Chemically, artemisinin is a sesquiterpene lactone that contains an unusual peroxide bridge. This 1, 2, 4-trioxane ring of endoperoxide is responsible for the drug's mechanism of action. Thus, the proposed antimalarial mechanism of action of artemisinin involves cleavage of endoperoxide bridges by iron, producing free radicals (hypervalent iron-oxo species, epoxides, aldehydes, and dicarbonyl compounds) which damage biological macromolecules causing oxidative stress in the cells of the parasite.18, 19
Artemisinins have also been investigated for their anti-proliferative activity against a wide range of cancer cell lines. Artemisinin results in decreased proliferation, increased levels of oxidative stress, induction of apoptosis and inhibition of angiogenesis in cancer cells. Artemisinins have also been shown to inhibit the falcipains, a papain family cysteine protease that aids hemoglobin degradation.20
Cultivation
Over the last ten years as the worldwide demand for artemisinin has become evident, Chinese, Vietnamese, African, and Indian plant breeding institutes have developed high-yielding Artemisia hybrids. Factories were developed in all three countries to extract artemisinin and manufacture its anti-malarial compounds. East African factories are currently exporting artemisinin to pharmaceutical factories in India and Europe, where the final products are made.
Drug resistance is a growing issue for the treatment of malaria in the 21st-century. Resistance is now common against all classes of antimalarial drugs except for artemisinins. Artemisinin treatment of resistant drug strains has therefore become increasingly popular. Unfortunately, while the cost of cultivation and production of artemisia is lower than that of other competitive pharmaceuticals, politics involving the pharmaceutical industry have restricted their use in the developing world.
From Quinine to Chloroquine to Hydroxychloroquine to Artemisinin
In 1820, the first antimalarial drug quinine was extracted from cinchona bark by French pharmacists Pelletier and Caventou.21 In the 1940s, limited by the raw materials for quinine extraction, German scientists synthesized chloroquine, which is similar to natural quinine in chemical structure.
In 1950, chemists Alexander Surrey and Henry Hammer published the synthesis of hydroxychloroquine which was even more effective with less toxicity.
By the mid-20th century, malaria was gradually controlled in China. However, parts of Africa still suffer high epidemic proportions of malaria. In the 1960’s an epidemic broke out which spread rapidly in Southeast Asia and South America. In addition, the plasmodium falciparum parasite was developing a resistance to chloroquine and hydroxychloroquine. Inspired by ancient books of traditional Chinese medicine, Youyou Tu, a Chinese scientist, successfully extracted artemisinin from Artemisia annua. With a 100% inhibition rate against plasmodium, artemisinin is now used for chloroquine and hydroxychloroquine resistant malaria. For her work, Tu was awarded the 2011 Lasker Award in clinical medicine and the 2015 Nobel Prize in Physiology or Medicine jointly with William Campbell and Satoshi Ōmura. Tu is the first Chinese Nobel laureate in physiology or medicine and the first female citizen of the People's Republic of China to receive a Nobel Prize in any category.22
Antiviral Effects of Chloroquine and Hydroxychloroquine
To better understand the therapeutic antiviral similarities of chloroquine derivatives and Artemisia annua extracts it is beneficial to review the antiviral background of chloroquine. Chloroquine has been confirmed to be effective during epidemics of various infectious diseases, especially Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome Coronavirus (MERS). In 2003, SARS broke out in China. According to the World Health Organization, a total of 8,098 people worldwide became sick with SARS during this outbreak, of whom 774 died. In 2004, MarcVan Ranst and colleagues found that chloroquine effectively inhibited SARS coronavirus replication in vitro.23
In 2005, Stuart Nichol and colleagues found that chloroquine suppressed SARS virus replication both before and after infection, suggesting a preventative and therapeutic role of chloroquine against SARS.24
In 2014 Eric Snijder and colleagues successfully inhibited MERS coronavirus replication by chloroquine in monkeys, with similar suppressive effect against SARS and human coronavirus.25 Additionally, chloroquine has also been reported to inhibit Human Immunodeficiency Virus (HIV), Zika virus (ZIKV), and dengue virus (DENV).26 Chloroquine phosphate was also reported to alleviate lung autophagy induced by avian influenza A (H5N1) and reduce alveolar injury in mice.27
February 2020, Wuhan Virus Research Institute of the Chinese Academy of Sciences and other units jointly published the results on cell research, which showed that chloroquine phosphate effectively inhibited SARS-Cov-2 and such inhibition was superior as compared to Remdesivir.28 Other recent studies have validated those findings.29, 30
The antiviral mechanisms of chloroquine and hydroxychloroquine on SARS-Cov-2 is proposed as follows:
1) To weaken the binding of the virus to the receptor by interfering with the terminal glycosylation of the receptor protein angiotensin 2 receptor invertase of coronavirus.
2) As an alkaline drug, chloroquine increases pH value inside endosomes which was not conducive for virus-cell fusion.
3) Inhibits cell autophagy and regulates host immune reaction to suppress viral infection and replication.
4) Suppresses transcription and translation of virus protein by binding to viral protease; and
5) Alleviates cytokine storm through inhibiting the production and release of TNF-α and IL-6.
In June 2020, the U.S. Food and Drug Administration revoked the emergency use authorization that allowed for chloroquine phosphate and hydroxychloroquine sulfate to be used to treat certain hospitalized patients with COVID-19 when a clinical trial was unavailable, or participation in a clinical trial was not feasible. More than 35 states have now restricted prescriptions for hydroxychloroquine, and at least five of those have rules specifically prohibiting prescribing the drug as a preventive measure. Fortunately, we still have artemisia extracts and other immunological nutrients (vitamin D3, zinc, vitamin C) available – for now.
Artemisia annua Extracts Effective Against Viruses
Due to its similar history to chloroquine in the treatment of malaria and viruses, scientists at several institutions have researched whether extracts of Artemisia annua - pure artemisinin and related derivatives - may be effective against the COVID-19 virus. These compounds would be attractive candidates for immediate use as they have an excellent safety profile, are readily available, and are relatively inexpensive.
Numerous in vitro studies have reported that artemisinins have antiviral properties. Artemisinins reduce replication rates of hepatitis B and C viruses 31, 32, a range of human herpes viruses 33, 34, 35, HIV-1 36, influenza virus A 37, 38, and a bovine viral diarrhea virus39, in the low micromolar range.
Like chloroquine, Artemisia annua extracts have even shown significant activity against the SARS coronavirus. In 2003, Li and colleagues showed that artemisinin was effective in treating SARS-CoV in vitro.40 Since the beginning of the COVID-19 pandemic, formulations of Artemisia annua have been used in Africa, Madagascar, and China for both COVID-19 prevention and treatment.41
Last June 2020, chemists at the Max Planck Institute of Colloids and Interfaces (Potsdam, Germany) in close collaboration with virologists at Freie Universität Berlin demonstrated in laboratory studies that aqueous and ethanolic extracts Artemisia annua are active against the SARS-CoV-2 (COIVID-19) virus. Human clinical trials to test the efficacy of both teas and coffee containing Artemisia annua are about to begin at the University of Kentucky’s academic medical center.42 Artemisia annua leaves, from a cultivated seed line grown by ArtemiLife Inc.in Kentucky, USA, when extracted with absolute ethanol or distilled water produces the strongest antiviral activity. The addition of either ethanolic or aqueous Artemisia annua extracts prior to the introduction of the virus resulted in significantly reduced plaque formation. The most active extract of both Artemisia annua and coffee was found to be ethanolic. However, artemisinin alone does not present much antiviral activity. “I was surprised to find that A. annua extracts worked significantly better than pure artemisinin derivatives and that the addition of coffee further enhanced the activity” says Klaus Osterrieder, Professor of Virology at Freie Universität Berlin who conducted all activity assays.
In SARS-CoV-2 (COVID-19), cellular adaptive immunity is primarily involved, in particular, CD8 and CD4 lymphocytes that stimulate the B lymphocytes responsible for the production of antibodies targeting the coronavirus. In addition, there is a cytokine storm in patients infected with SARS-CoV-2 which is responsible for a major inflammatory response and their very severe progressive clinical state. The increase in interleukin-10 and TNF alpha reduces CD4 counts, causes functional exhaustion of immune cells, and induces, at their site of action (liver, vascular endothelium), runaway production and action of inflammatory proteins, resulting in secondary aggravation of COVID-19 patients.
Artemisia annua has extensively recognized antiviral activity (anti HSV1, Poliovirus, RSV, hepatitis C anti-virus, type 2 dengue virus, hantavirus, human cytomegalovirus) and anti-HIV in vitro, due in partto the artemisinin, flavonoids, quercetin and dicaffeoylquinic acids it contains. These molecules have been shown to inhibit the enzymatic activity of CLPro (Chymotrypsin-like protease), an enzyme produced by SARS-CoV-2.
The antiviral action of Artemisia annua, which is achieved by stimulating adaptive immunity, regulating the production of the pro-inflammatory cytokines prostaglandin E2 (PGE2), IL-6, IL-10, TNF alpha, and increasing the genesis of CD4, CD8 and interferon gamma, involves many minerals and biomolecules: the properties of flavonoids, polyphenols, triterpenes, sterols, saponins, polysaccharides, artemisinin and its derivatives, the concentration of zinc, gallium and selenium in the plant play a role in the immune, antiviral, antioxidant and anti-inflammatory response.
The plant is rich in vitamins A and E, of which one, when supplemented, is known to reduce morbidity and mortality in viral infections, notably HIV among others, and the other is a powerful antioxidant. Therefore the combination of these biomolecules and the intake of Artemisia annua may strengthen the exhausted adaptive immunity and modulate the runaway inflammatory response during COVID-19 infection, as has already been demonstrated in other serious viral and parasitic infections.
As more research develops it is likely that Artemisia annua extracts will take their place as a first-line defense against coronaviruses. Given that this plant has been extensively used for more than 2000 years in traditional Chinese medicine for treatment of fever, viruses, and malaria, the evidence argues for the inclusion of inexpensive Artemisia annua dried leaf tablets, capsules, or teas into the arsenal of remedies to combat coronavirus.
Lastly, malaria treatment is more complicated for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) patients. Malaria and HIV co-infection represents a major health burden in Africa, primarily because it is now well known that HIV infection results in a higher incidence and more severe manifestations of malaria. With a compromised immune system, AIDS patients are more susceptible to malaria and respond slower to malaria therapy. In several studies and in clinical observation, Artemisia annua has demonstrated anti-HIV activity.43, 44 Hence, the use of Artemisia annua not only treats malaria but should also enhance the well-being of HIV/AIDS patients.
Preparation and Dosage
Artemisia annua is typically prepared as a tea extracted with water according to the rules of traditional Chinese medicine. There have been few well-controlled studies investigating the extraction, recovery, and stabilization of artemisinin and other compounds in Artemisia annua tea infusions. A systematic study of preparations of Artemisia annua therapeutic tea infusion was performed by van der Kooy and colleagues.45 This study showed that nearly 93% of available artemisinin was extracted from dried Artemisia annua leaves, but only under certain conditions. The best preparation method was: 9 g dried leaves/L, for 5 min at 100 °C. Subsequent storage of the tea infusion at room temperature showed that the concentration of artemisinin was stable for more than 24 hours. This is important for malaria-endemic locations where there is no refrigeration. Other studies using the same extraction protocol also measured the extraction and stability of artemisinin and certain key flavonoids in the tea. Artemisinin was found to be stable at room temperature for up to 48 hours.46 However, some flavonoids were poorly extracted and not stable at room temperature, therefore it may be best to refrigerate after the infusion is complete.47
Clearly, if a tea infusion is to be a therapeutic option, it must be prepared and consumed consistently and reliably. Artemisia annua is also available commercially in extracts such as capsules and tinctures. As with all herbal remedies, the correct dosage depends on a variety factors such as the illness treated, the age of the person, health status, and number of other conditions.
Herb-Drug Reactions
Artemisinin has no reported toxicity if taken in recommended doses for a limited period of time.51 In animal studies, artemisinin has been used in high oral doses in dogs and rabbits52 and at 200-300 mg/kg BW in mice53 without toxicity. Artemisinin has been effective against Plasmodium in humans at doses of approximately 30 mg/kg BW, but it has poor bioavailability and a short half-life that is quickly eliminated from the body.54, 55 Artemisinin derivatives (dihydroartemisinin, artesunate, artemether, arteether) present better bioavailability and antimalarial activity than artemisinin, but have different safety margins than artemisinin. The bioavailability and half-lives also vary with the delivery mechanism (intramuscular, intravenous, intraperitoneal, oral).
Conclusion
Evidence is mounting for the therapeutic effectiveness of the use of Artemisia annua not only in the treatment of malaria, but also for various viruses, including coronaviruses. The complex mixture of antiparasitic compounds in the plant appears to account for its therapeutic activity with the animal and human trials supporting this claim. It is also clear that the cost of using Artemisia annua is a fraction of that for any other existing or potential antimalarial or antiviral treatment. Considering that for more than 2000 years this plant was used in traditional Chinese medicine for the treatment of fever with little to no significant toxicity and no clear signs of artemisinin drug resistance. Thus, the cumulative evidence argues for the inclusion of Artemisia annua extracts,tinctures, and teas into the arsenal of remedies to not only combat malaria, but also numerous other diseases, particularly viruses.
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