Sweet wormwood

Sweet Wormwood (Artemisia annua L.): A Comprehensive Reference

1. Identity and Botanical Description

Nomenclature and Taxonomy

Artemisia annua L., also referred to as sweet wormwood, sweet Annie, sweet sagewort, and annual wormwood, is a member of the Asteraceae family with significant therapeutic and commercial value. It is a common type of wormwood native to temperate Asia, but naturalized in many countries including scattered parts of North America. Qinghao is the botanical name for the plant in the Chinese tradition. The Chinese character name Qing Hao is rendered variously in Western texts; its Chinese name Qing Hao means "green grass."

Morphology

Artemisia annua belongs to the plant family Asteraceae and is an annual short-day plant. Its stem is erect and brownish or violet-brown. The plant itself is hairless and naturally grows from 30 to 100 cm tall, although in cultivation plants can reach a height of 200 cm. The leaves consist of two or three leaflets which are divided by deep cuts and have quite an intense scent. The small green-yellow flowers appear in loose panicles and have no scent. Sweet Annie can be found at the edge of forests, on hillsides, and in wastelands.

Natural Source and Cultivation

Artemisia annua L., a plant belonging to the Asteraceae family, grows wild in Asia (mainly China, Japan and Korea) and it was introduced to Poland, Brazil, Spain, France, Italy, Romania, United States and Austria, where it became domesticated. As a source of artemisinin, found in the aerial portion of the plant, sweet Annie has been cultivated to treat malaria.

Common Forms and Preparations

Sweet wormwood is used in several distinct forms, each with different phytochemical profiles and applications:

• Dried leaf tea (infusion/decoction): Artemisia sp. phytochemicals also improve bioavailability of artemisinin and synergistically improve artemisinin therapeutic efficacy, especially when delivered as dried leaf Artemisia as a tea infusion or as powdered dry leaves in a capsule or compressed into a tablet.
• Powdered dried leaf capsules/tablets: Whole-plant preparations in capsule or compressed tablet form that preserve the full spectrum of secondary metabolites.
• Standardized extracts: A. annua extract, produced using a supercritical carbon dioxide extraction method and formulated with grapeseed oil, has been marketed in New Zealand as a natural product for joint health.
• Essential oil: Artemisia annua L. is well known as the source of the unique sesquiterpene endoperoxide lactone artemisinin. The essential oil is rich in mono- and sesquiterpenes and represents a by-product with medicinal properties.
• Isolated and semi-synthetic derivatives: Artemisia annua is the source of artemisinin and semisynthetic artemisinin derivatives (including dihydroartemisinin, artesunate, artemether, and arteether) used in the development of malaria combination treatments (ACTs = Artemisinin-based combination therapy).

2. Traditional and Historical Use

Earliest Records

Artemisia annua L. is commonly used in traditional Chinese medicine (TCM) and it has a history of more than 2,000 years. A. annua L. was firstly recorded in Prescriptions for Fifty-two Diseases (Wu Shi Er Bing Fang) written on a piece of silk treatise unearthed from the Mawangdui Han Dynasty tombs (168 BC), described as a treatment for hemorrhoids.

Artemisia annua L., with the ancient name of qinghao, is a traditional Chinese herbal medicine. It has appeared in many ancient Chinese medical manuscripts, which describe its uses to include treatment of wounds, alleviating intermittent fevers, as well as enhancing the brightness of eyes and even improving longevity.

Classical Chinese Materia Medica

A. annua has been then regularly recorded as a herbal medicine in many ancient Chinese materia medica and writings, including 〈Shang Han Lun〉 (On Cold Damage, 200–205), 〈Zhou hou bei ji fang〉 (Handbook of Prescriptions for Emergency Treatment, 4th century), 〈Shi liao ben cao〉 (Materia Medica for Successful Dietary Therapy, 721–739), 〈Zheng lei ben cao〉 (Materia Medica Corrected and Arranged into Categories, 1082), 〈Meng xi bi tan〉 (Dream Pool Essays, 1086), 〈Ben cao gang mu〉 (Classified Materia Medica, 1596), etc.

On the basis of these documents, the herbal medicine qinghao has been recommended for treating re lao (exhaustion due to heat/fevers), mie gu zheng lao re (eliminating bone steaming and heat/fevers arising from exhaustion), treating nüe (intermittent fevers) and shi zhu, gui qi, fu lian (disorders with acute convulsions).

The Pictorial Classic of Herbal described that qinghao "is the best medicine for treating bone-heat syndrome and fever in chronic consumptive diseases and was used alone in ancient prescriptions." A. annua can also be used for treating "ulcer," as documented in Shennong's Herbal Classic. According to the Newly Compiled Materia Medica of the Tang Dynasty, "crude stalks of Artemisia annua can be applied to incised (metal-inflicted) wounds, and effectively stop bleeding."

Traditional Chinese Medicine Theory

Artemisia annua is a commonly used Chinese herbal medicine, which is bitter in taste and cold in nature. Assigned to hepatic, biliary, and renal meridians, it has the traditional functions of clearing summer heat, removing hectic heat and antimalaria. Clinically, it is used for the treatment of symptoms such as fever due to Yin deficiency, affection due to exogenous summer heat, and malaria and jaundice due to dampness heat.

Based on the Pharmacopoeia of the People's Republic of China (PPRC), Sweet wormwood herb can be used to resolve summerheat-heat, and prevent malaria.

Traditional Range of Use

As a Traditional Chinese Medicine, Artemisia annua L. has been used for the treatment of various diseases since ancient times, including intermittent fevers due to malaria, bone steaming and heat/fever arising from exhaustion, tuberculosis, lice, wounds, scabies, dysentery et al.

Fourth-Century Clinical Recommendation

In the fourth century CE, Ge Hong recommended qinghao (A. annua, sweet wormwood) for treating intermittent fever. This recommendation in the Zhou Hou Bei Ji Fang is notable for its instruction to prepare the herb as a cold-water infusion rather than a decoction — a preparation method that Tu Youyou later identified as critical for preserving artemisinin's heat-labile structure.

Archaeological Evidence

A sheaf of plant remains, including stalks and inflorescence intentionally placed in the corner of a tomb, have been recovered from the Shengjindian cemetery (about 2,400–2,000 BP on the basis of 14C dating), Turpan, Xinjiang, China. The morphology of these materials was examined using a stereomicroscope and a scanning electron microscope. Ancient DNA was also extracted from these remains. By comparing the morphological and DNA characteristics with modern specimens, these plant remains were identified to belong to Artemisia annua L.

Rediscovery in the Modern Era

In 1967, a national research project against malaria was initiated in China. More than 380 herbal extracts were evaluated by Chinese scholar Tu Youyou for their anti-malarial activities and A. annua was found to be the most active herb. Discovery of artemisinin and its antimalarial properties made the Chinese scientist Tu Youyou recipient of the 2011 Lasker Prize and 2015 Nobel Prize in Physiology or Medicine.

3. Key Constituents and Active Compounds

Overall Phytochemical Complexity

It contains 251 different compounds under the groups of sesquiterpene, monoterpene, phenol, flavonoid and others. Artemisia ssp. primarily contain sesquiterpenoid lactones, coumarins, flavonoids, and phenolic acids.

Artemisinin and Sesquiterpene Lactones

Artemisinin is an endoperoxide sesquiterpene lactone isolated from Artemisia annua and is often used to treat malaria. Artemisinin's peroxide bridge is the key structure behind its antimalarial action. The compound was named "qinghaosu" in Chinese, with the Western designation artemisinin adopted subsequently.

Artemisia annua L. synthesizes artemisinin, which is known as qinghaosu, and is considered a unique sesquiterpene endoperoxide lactone. Artemisinin is poorly soluble in water and oil but readily soluble in most aprotic solvents. This property coupled with its short half-life, as well as desire to improve more potent derivatives, led to the efforts for chemically modifying its structure and synthesizing new artemisinin derivatives.

Key sesquiterpene-related compounds beyond artemisinin itself include arteannuin B (also called artemisinin B), artemisinic acid (the biosynthetic precursor to artemisinin), dihydroartemisinic acid, and artemisitene. Research has shown that compatibility of artemisinin, scopoletin, arteannuin B and arteannuic acid has antimalarial effect. Artemisia annua tea, which contains a mixture of active constituents including dihydroartemisinic acid, artemisinic acid, and artemisinin, may be more effective than artesunate in treating malaria.

Semi-Synthetic Derivatives

Scientists have created dihydroartemisinin, artemether, artesunate, and other derivatives preserving artemisinin's peroxide bridge to increase its clinical utility value. The most important derivatives of Artemisia annua L. are arteether, artemether, artemiside, artemisinin, artemisone, artesunate, and dihydroartemisinin.

Flavonoids and Phenolic Compounds

Phenolics from Artemisia annua consist of coumarins, flavones, flavonols, phenolic acids, and miscellaneous compounds. While artemisinin is the main therapeutically active component, emerging evidence demonstrates that the other phytochemicals in this genus are also therapeutically active. Those compounds include flavonoids, other terpenes, coumarins, and phenolic acids. A key flavonoid found in tea preparations is isovitexin; HPLC and mass spectrometric analyses detected concentrations of artemisinin (47.5±0.8 mg L⁻¹), dihydroartemisinic acid (70.0±0.3 mg L⁻¹), arteannuin B (1.3±0.0 mg L⁻¹), isovitexin (105.0±7.2 mg L⁻¹) and a range of polyphenolic acids in a representative tea preparation.

Compatibility of scopoletin, arteannuin B and arteannuic acid is conducive to resolving summerheat-heat, suggesting that the coumarin scopoletin also contributes meaningfully to traditional bioactivity beyond pure antimalarial effects.

Essential Oil Constituents

The essential oil is rich in mono- and sesquiterpenes. Significant variations in its percentage and composition have been reported: major constituents can be camphor (up to 48%), germacrene D (up to 18.9%), artemisia ketone (up to 68%), and 1,8-cineole (up to 51.5%).

Analysis of A. annua essential oils revealed the presence of mainly monoterpenoids and sesquiterpenes, and the profiles showed great differences in the three main components — artemisia ketone, 1,8-cineole, and camphor — depending on the global phytogeographic origin. Oils can be grouped into: Vietnamese oil with 3.3–21.8% camphor and 0.3–18.9% germacrene D; Chinese oil with high content of artemisia ketone (64%); Indian oil with 11.5–58.8% artemisia ketone; French oil with 2.8–55% artemisia ketone, 1.2–11.6% 1,8-cineole, and 15% germacrene D; North American oil with 35.7–68% artemisia ketone and 22.8–31.5% 1,8-cineole; and Iranian oil with 48% camphor and 9.4% 1,8-cineole.

Chemical constituents in A. annua vary significantly according to geographical locations, and distribution of A. annua may play a key role in the characteristics of efficacy and chemical constituents of Sweet wormwood herb.

4. Established Mechanisms of Action

Antimalarial Mechanism: Endoperoxide Activation

Artemisinin is an endoperoxide sesquiterpene lactone. Artemisinin's peroxide bridge is the key structure behind its antimalarial action. The dominant mechanistic model holds that the endoperoxide bridge is activated by intraparasitic iron:

A two-step mechanism has been proposed for the antimalarial action of artemisinin and other related endoperoxides. In the first step, the endoperoxide bridge in artemisinin is cleaved by free heme or iron, leading to the generation of an unstable radical of the drug.

Heme and iron produced by hemozoin can activate artemisinin to produce free radicals. The activated artemisinin disrupts the physiological functions of Plasmodium by targeting proteins, lipids, and nucleic acids, leading to the parasites' death.

In the first step, the endoperoxide bridge in artemisinin is cleaved by free heme or iron, leading to the generation of an unstable radical of the drug. This subsequently causes selective alkylation of malarial proteins. Additionally, these drugs, at least in part, exert their effect by interfering with the plasmodial hemoglobin catabolic pathway and inhibition of heme polymerization.

As artemisinin is active during the intraerythrocyte stage of infection and contains an endoperoxide function that is essential for its activity, a reasonable hypothesis for the mechanism of action of artemisinin is the reductive activation of its endoperoxide bridge by Fe(II) heme resulting from the digestion of hemoglobin by Plasmodium species.

Heterolytic cleavage of the endoperoxide bridge and subsequent capture of water leads to the formation of an unsaturated hydroperoxide, capable of irreversibly modifying protein residues by direct oxidation. Subsequent Fenton degradation of the hydroperoxide produces a hydroxyl radical, a species that can subsequently oxidize target amino acid residues.

Anticancer Mechanisms (Preclinical)

The main anticancer components of Artemisia annua L. are artemisinin and its derivatives, quercetin, and polyphenols (pKAL). These compounds inhibit cancer cell proliferation, invasion, and metastasis, and induce apoptosis by regulating pathways like PI3K/AKT, JAK-STAT, p53, and GPX4. They also modulate the immune and tumor microenvironment, enhancing chemotherapeutic drug efficacy.

Following the discovery that artemisinin and its derivatives are active against a host of human cancer cell lines in 2001, preclinical and clinical evidence has been obtained to make a strong case for significant anticancer activity for artemisinin derivatives such as artesunate. However, the pharmacological challenges such as short half-life and poor bioavailability may limit anticancer activity.

Anti-inflammatory and Immunosuppressive Mechanisms

Among the long list of rheumatic disorders, artemisinin derivatives (artemisinin, artesunate, artemether, dihydroartemisinin, and the semisynthetic derivatives DC32, SM 903, and SM934) have been investigated in rheumatic arthritis, osteoarthritis, and osteoporosis as well as lupus erythematosus and gout.

Pharmacokinetic Auto-Induction

Due to auto-induction metabolism, declining plasma concentrations after repeated dosing have been reported for artemisinin (qinghaosu) and artemether. Induction of CYP2B6 and CYP3A4, which are involved in the metabolism of artemisinin, has been implicated as the underlying mechanism of their time-dependent pharmacokinetics. This auto-induction property is clinically significant as it can reduce the drug's own bioavailability with repeated dosing.

Whole-Plant Synergy and Bioavailability Effects

The antimalarial effect of whole A. annua extracts (nACTs) was about 10-fold higher than that of artemisinin alone when administered at the same dosage. A. annua extracts exhibited significantly enhanced oral bioavailability, longer half-life as well as extended mean retention time in rats. Components including deoxyartemisinin (DEART), artemisinic acid (AA), and dihydroartemisinic acid (DHAA) inhibited the efflux and translocation of P-glycoprotein and facilitated the reduction of artemisinin efflux.

5. Scientific Evidence by Area of Use

5.1 Malaria (Plasmodium falciparum and Other Species)

Evidence strength: Strong — WHO-endorsed standard of care for semi-synthetic derivatives; whole-plant preparations: preliminary-to-moderate clinical evidence.

The artemisinins have antimalarial activity in vitro and in vivo and are believed to act by release of free radicals into the parasite vacuoles. Artemisinin derivatives are currently the most active antimalarial drugs available and have been introduced around the world as an integral part of therapy of active malaria, always in combination with other antimalarials to prevent resistance such as amodiaquine, lumefantrine and mefloquine.

The chemical compound artemisinin, which is isolated from A. annua, is a medication used to treat malaria due to Plasmodium falciparum, the deadliest species of malarial parasite.

Artemisinin compounds exhibit excellent efficacy, quick action, and minimal toxicity in malaria treatment and have greatly contributed to malaria control.

Regarding the whole-plant (tea) form specifically: Artemisia annua tea, which contains a mixture of active constituents including dihydroartemisinic acid, artemisinic acid, and artemisinin, may be more effective than artesunate in treating malaria. A randomized, placebo-controlled clinical trial enrolling 957 patients with malaria compared Artemisia annua tea to artesunate-amodiaquine therapy.

Artemisinin Resistance

Emergence of artemisinin resistance has been identified in Cambodia and the border of Thailand. The resistance of Plasmodium falciparum to artemisinin-based (ART) drugs, the front-line drug family used in artemisinin-based combination therapy (ACT) for treatment of malaria, is of great concern. Mutations in the kelch13 (k13) gene (for example, those resulting in the Cys580Tyr [C580Y] variant) were identified as genetic markers for ART-resistant parasites.

K13 mutations allow a subset of early ring-stage parasites to survive cell-cycle arrest brought on by ART exposure, enabling those parasites to reinitiate transcription and complete their intraerythrocytic developmental cycle once ART is no longer present at inhibitory concentrations.

5.2 Anti-Cancer Activity

Evidence strength: Preliminary. Mechanistic and preclinical data are extensive; robust human clinical trial evidence remains limited.

Network pharmacology-based analysis showed that the hit Artemisia annua constituents related to cancer targets include compounds active at NFKB1, MAP2K1 and AR. Sixty-eight significant signaling KEGG pathways with p < 0.01 were recognized, the most enriched of which were prostate cancer, breast cancer, melanoma and pancreatic cancer.

Artemisinin is also used against some cancers such as liver cancer, brain glioma, leukemia, nasopharyngeal cancer, gallbladder cancer, gastric cancer, cervical cancer, lung cancer, breast cancer and colon cancer — though it is important to note this refers to in vitro, animal, and early-phase human studies rather than established clinical indications. Since there are no published works regarding the use of Artemisia genus extracts specifically for cancer treatment in completed trials, the presented clinical investigations in this section were carried out with compounds present in the genus and with their analogs — more specifically, artemisinin extracted from A. annua and its analogs artesunate, dihydroartemisinin, and artemether.

5.3 Parasitic Diseases: Schistosomiasis, Leishmaniasis, Trypanosomiasis

Evidence strength: Moderate for schistosomiasis prophylaxis (based on meta-analysis of clinical trial data); preliminary for other parasites.

Artemether, artesunate and dihydroartemisinin share common antischistosomal therapeutic characteristics. In vivo studies have demonstrated that these artemisinins are highly effective against juvenile infections and only moderately effective against adult infections.

This observation suggests that these drugs particularly show clinical benefit when used as prophylactic treatments. As calculated by a recent meta-analysis, administration of multiple low doses of artemether or artesunate over a 1–2 week period achieved a protection rate of 65–97% against schistosomiasis japonicum.

Results from in vitro, and in vivo animal and human studies have been summarized and critically discussed for mainly malaria, but also other diseases susceptible to artemisinin and Artemisia sp. including schistosomiasis, leishmaniasis, and trypanosomiasis.

5.4 Anti-inflammatory Use: Osteoarthritis

Evidence strength: Preliminary. A single small RCT exists; findings were mixed across dose groups.

In a randomized double-blind clinical trial, oral treatments of 42 patients by Arthrem (supercritical CO₂-extracted A. annua) at doses 150 mg and 300 mg or placebo twice daily for 12 weeks were tested for their efficacy on stiffness, pain, and functional limitations in osteoarthritis of the hip and knees. Results showed a significant decrease in visual analogue scale (VAS) score and improvement in WOMAC total score only at the low dose of 150 mg. Afterwards, an open-label 6-month extension trial was proceeded to examine the safety of Arthrem in the long run.

The safety and efficacy of a dietary supplement derived from Artemisia annua was investigated in osteoarthritis of the hip or knee. This plant was shown to have potential as an anti-inflammatory/analgesic in OA. Decrease in pain over 12 weeks with ART 150 mg is clinically confirmed. These findings require replication in larger trials before conclusions can be drawn.

5.5 Autoimmune Diseases: Lupus and Rheumatoid Arthritis

Evidence strength: Preliminary. Primarily preclinical and small clinical series; no large RCTs for the whole-plant extract.

Among the long list of rheumatic disorders, artemisinin derivatives have been investigated in rheumatic arthritis, osteoarthritis, lupus erythematosus and gout. The sesquiterpene lactone artemisinin from Artemisia annua L. is well established for malaria therapy, but its bioactivity spectrum is much broader.

Lupus nephritis, the most common manifestation in patients with SLE, represents a primary risk factor for both morbidity and mortality. Wen et al. (2024) found that artesunate (15 mg·kg⁻¹·day⁻¹) suppressed serum autoantibody levels, including serum ANA, anti-dsDNA antibodies, and IgG. This data point is from an animal model, not a clinical trial.

5.6 Essential Oil: Antimicrobial and Antioxidant

Evidence strength: In vitro only. No controlled human clinical trials.

The essential oil derived from the leaves has been shown to have antioxidant, antibacterial, and antifungal properties — but this evidence is based on in vitro laboratory studies. Both gram-positive bacteria (Enterococcus, Streptococcus, Staphylococcus, Bacillus, and Listeria spp.) and gram-negative bacteria (Escherichia, Shigella, Salmonella, Haemophilus, Klebsiella, and Pseudomonas spp.) and other microorganisms (Candida, Saccharomyces, and Aspergillus spp.) have been investigated. The essential oil has revealed strong antimicrobial properties towards numerous bacterial strains, both gram-positive and gram-negative, and diverse fungal strains.

5.7 Skin Diseases

Evidence strength: Preliminary, mostly in vitro and small clinical studies.

Recent research has suggested that artemisinin and its derivatives may have therapeutic effects on parasites, viruses, tumors, inflammation and skin diseases. A scoping review published in 2023 examined clinical research on artemisinin and its derivatives across these areas.

6. Body Systems and Health Areas

Based on the available evidence, sweet wormwood and its constituents have been studied in connection with the following body systems:

• Hematopoietic / Blood (antimalarial): Heme and iron activate artemisinin to produce free radicals that disrupt the physiological functions of Plasmodium by targeting proteins, lipids, and nucleic acids, leading to the parasite's death.
• Hepatobiliary (liver): Assigned to hepatic and biliary meridians in TCM, it has the traditional functions of clearing summer heat, removing hectic heat and antimalaria.
• Immune system: Artemisia annua is commonly used for its anti-malarial, immunosuppressive anti-inflammatory properties.
• Musculoskeletal (joints): Investigated clinically in osteoarthritis of the hip and knee, as described in the RCT above.
• Oncological (multiple cancer types): Recent research has suggested that artemisinin and its derivatives may have therapeutic effects on tumors.
• Integumentary (skin): Artemisinin and its derivatives may have therapeutic effects on skin diseases.
• Parasitology / Infectious Disease: A. annua has been revealed to show inhibitory effects against parasites (e.g. Plasmodium, Toxoplasma gondii, Leishmania, Acanthamoeba, Schistosoma), viruses.

7. Dosage Forms and Reported Dosages

The following dosages are drawn directly from cited studies and should not be interpreted as clinical recommendations:

• Arthrem® capsules (supercritical CO₂ extract, for osteoarthritis): Oral treatments of 42 patients by Arthrem at doses 150 mg and 300 mg or placebo twice daily for 12 weeks were tested. Arthrem® is available as 150 mg capsules for twice-daily dosing.
• Rectal artemisinin derivatives (for severe malaria): Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin.
• Oral artemisinin-based combination therapies (ACTs): The present forms of ACT contain artemether plus lumefantrine (Coartem®), artesunate plus either amodiaquine, mefloquine or sulphadoxine-pyrimethamine, and dihydroartemisinin plus piperaquine (Artekin®).
• DHA-piperaquine (Artekin®, for malaria): Fourteen healthy Chinese subjects received four recommended oral doses of Artekin, an ACT containing DHA (80 mg/dose) and piperaquine (PQ; 640 mg/dose), at 0, 6, 24 and 32 h.
• Whole-plant dried leaf preparations: Therapeutic efficacy appears to be enhanced especially when delivered as dried leaf Artemisia as a tea infusion or as powdered dry leaves in a capsule or compressed into a tablet. Exact standardized dosages for tea infusions vary across studies and no WHO-endorsed dose for tea preparations is established.

8. Safety Considerations and Interactions

Hepatotoxicity Signal (Extracted Form)

A case series of hepatotoxicity associated with an extract of Artemisia annua L. was identified through the New Zealand spontaneous adverse drug reaction reporting system. A. annua extract, produced using a supercritical carbon dioxide extraction method and formulated with grapeseed oil, has been marketed in New Zealand as a natural product for joint health. As of 31 January 2019, the New Zealand Pharmacovigilance Centre had received 29 reports of hepatic adverse reactions occurring in patients taking A. annua extract in grapeseed oil.

Jaundice, often with pruritus and dark urine, was experienced by 16 patients. There was considerable consistency across case reports from various reporters. The case reports were assessed using the Bradford Hill guidelines for causal inference, and concluded that there was a safety signal of a causal association between the A. annua extract and hepatotoxicity sufficient to be communicated and investigated further.

Twenty-seven patients were reported to have recovered or improved on stopping A. annua extract. Nine patients required hospital admission.

Of the 28 subjects randomized to Arthrem®, one of 14 participants receiving high-dose Arthrem® (300 mg twice daily) developed hepatitis, considered possibly related to the study medicine by the investigator.

In February 2018, Medsafe, the New Zealand medicines regulator, issued a safety communication regarding 14 reports of hepatotoxicity in patients taking A. annua extract. Following the communication, a further 11 reports were received, including one report of hepatic cirrhosis, prompting a further communication in November 2018.

Possible explanations for the hepatotoxic effects observed in this case series include involvement of toxic constituents other than artemisinin, production of a toxic artifact during the extraction process, and/or adulterated or contaminated product.

Liver Injury from Isolated Artemisinin

Cases of artemisinin hepatotoxicity have been characterized by rapid onset within a few days to 3 weeks of starting therapy and a hepatocellular pattern of serum enzyme elevations, but without signs of hypersensitivity such as rash, fever or eosinophilia. The cause of the injury is unknown, but it has many features of hypersensitivity such as short latency and occurrence upon reexposure. Fatal instances have been reported.

Complicating the interpretation of these reports, however, is that most severe cases of liver injury occurred in patients who were also receiving other antimalarial agents, some of which are known to be hepatotoxic (amodiaquine, sulfamethoxazole, sulfadiazine/pyrimethamine).

One case was distinctive in that the patient was taking artemisinin not for malaria, but as a part of an herbal medication for gastrointestinal complaints. Artemisinin was taken in very high doses and for a longer period than is typical for acute malaria (active therapy of which is typically for 3 days).

CYP Enzyme Interactions and Auto-Induction

Pharmacogenomic resources indicate that artemisinin, artemether, and DHA can induce CYP3A activity and up-regulate CYP2B6 and CYP2C19. This raises the possibility of drug–drug interactions with CYP-metabolized immunomodulators, endocrine medications, or other chronic therapies.

Conversely, Artemisia annua extracts and some formulations may inhibit CYP2B6 or CYP3A4, underscoring the need to distinguish purified chemotypes from botanical products.

A study showed that Artemisia teas inhibit activity and artemisinin autoinduction of CYP2B6 and CYP3A4 post transcription, a response likely the effect of other phytochemicals in these teas. This finding suggests that the CYP interaction profile differs meaningfully between isolated artemisinin and whole-plant preparations.

The alternative common three-day regimen for artemisinin-piperaquine combinations could probably lead to lower bioavailability of artemisinin and higher potential of drug-drug interaction caused by the induction of drug-metabolizing enzymes.

Concomitant Medications Implicated in Case Reports

Among the concomitant medicines reported alongside A. annua extract hepatotoxicity cases were several drugs that are known to be hepatotoxic, including atorvastatin (3 reports), diclofenac (1 report), cyproterone acetate (1 report), mesalazine (1 report), and paracetamol (3 reports). These co-medications complicate causality attribution.

Essential Oil Safety

The essential oil constituents consist of 6–76% artemisia ketone, up to 44% camphor, up to 33% germacrene D, up to 16% alpha-pinene, and up to 15% alpha-guaiene. As ketones are considered a possible toxin, essential oils high in ketones are used with great care or often avoided by aromatherapists.

Precautions in Sustained Use

The uncontrolled use of artesunate and other antimalarial drugs is becoming disturbing; there is evidence of self-medication and free purchase of antimalarial drugs in endemic areas, and such practices can contribute to the intoxication and injury of vital organs. Toxicological investigations on artesunate have reported acute nephrotoxicity, testis damage, neurotoxicity and hepatotoxicity.

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