Written by Klara Rombauts, Arne Heyerick and the CAM-Cancer Consortium.
Updated January 29, 2015

Artemisia annua

Abstract and key points

  • Artemisia annua is a plant containing chemical compounds considered to have anti-cancer activity.
  • There is currently no evidence in humans to support the use of A. annua against cancer.
  • Artemisia annua is generally considered to be safe but cases of severe adverse effects with higher doses have been reported.

Artemisia annua L. is a common type of wormwood that belongs to the family of the Asteraceae. It is native to temperate Asia but naturalized throughout the world.

Artemisinin is an ingredient of A. annua. Artemesin and its semi-synthetic artemisinin derivatives (including dihydroartemisinin, artesunate, artemether and arteether) are used for the production of combination therapies for treatment of malaria (ACTs = Artemisinin-based Combination Therapy).

Animal studies suggested that artemisinin and related compounds inhibit tumour growth and metastasis. However, there is no evidence from clinical trials at the moment that the anticancer effects from animal studies translate into benefits for cancer patients. No clinical trials of A. annua and only one randomised clinical trial of artesunate are available.

Experiences from malaria treatment indicate a good tolerability of artemisinin-based drugs. However, there are two case reports with severe adverse effects when artemisinin-based drugs were used at higher doses.

Read about the regulation, supervision and reimbursement of herbal medicine at NAFKAMs website CAM Regulation.

What is it?

Artemisia annua, also known as sweet wormwood, sweet annie, sweet sagewort and annual wormwood (Chinese: qīnghāo), is a common type of wormwood that is native to temperate Asia but naturalized throughout the world.1 It belongs to the family of Asteraceae and has fern-like leaves, bright yellow flowers and a camphor-like scent. Glandular structures (trichomes) producing a wide range of bioactive compounds (mostly terpenoids) can be found on the surface of leaves, stems and flowers.

Ingredient(s)

The phytochemical composition of A. annua has been reviewed in great detail by Bhakuni et al.2 The most relevant compounds are sesquiterpenoids (ex. artemisinin), triterpenoids, flavonoids (polymethoxylated flavonoids), chromenes1 and essential oil components. The content of an A. annua extract depends on the solvent used for extraction. Aqeous extracts seem to contain less polymethoxylated flavonoids than alcohol extracts, but they do contain a high amount of mono-caffeoyl- and mono-feruloyl-quinic acids, di-caffeoyl- and di-feruloyl-quinic acids. Alcoholic extracts seem to contain the highest antioxidant potential. Also the flavonoids casticin and artemetin that have shown synergism with artemisinin against malaria are less extracted in aqeous extracts.3-5

Besides A. annua itself, this summary also reviews current literature on artesunate, dihydroartemisinin and artemether, which are semi-synthetic derivatives of artemisinin. Far more research has been published on the effect of these compounds than on artemisinin itself. Arteether, another semisynthetic derivative that has been used in antimalarial treatment has not been the focus of anticancer research to date.

Application and dosage

There is no documented safe or effective dose for the possible use of A. annua derived products for the treatment of cancer in adults or children. The Chinese pharmacopoeia lists the dry herb as a remedy for fever and malaria. The daily dose described is 4.5 to 9 grams of dried herb to be prepared as a tea infusion with boiling water. The artemisinin content varies from 0.02% to 1.1% of the dry weight.6 In addition, artemisinin and its semisynthetic derivatives are used in antimalarial treatment in artemisinin-based combination therapies, with daily doses between 100 and 200mg.7

History

Artemisia annua was used by Chinese herbalists in ancient times to treat specific fevers, but had fallen out of common use until it was rediscovered in 1970 when the Chinese Handbook of Prescriptions for Emergency Treatments (340 AD) was recovered. This ancient pharmacopeia contained a recipe for a tea from the dried leaves of A. annua to be used in case of specific fevers. In 2010 it was discovered that A. annua has already been cited in the earliest Chinese medical prescriptions, the Mawagndui tomb texts dating back to 168 B.C. There, it is prescribed for female haemorrhoids and as a sexual tonic, being mixed with other herbs, including cinnamon and ginger, and administered in boiled urine.8 In 1971, scientists demonstrated that the plant extracts had antimalarial properties in primate models.9

Mechanism of anti-cancer action

Artemisinin, the natural endoperoxide of A. annua, and its semisynthetic derivates dihydroartemisinin, arthemether, artheether and artesunate are considered to be the primary active constituents for antimalarial and anti-cancer activity.10,11 Also the polymethoxyflavonoids are indicated as important compounds with potential anticancer activity. Cancer cell lines show a differential sensitivity as well as resistance to this group of compounds. Different genes which influence the sensitivity or the resistance to treatment have been identified. These genes could potentially function as markers indicating the expected efficacy of a clinical therapy.12,13 In contrast to popular belief that the cytotoxic activities would only be due to the non-specific generation of reactive oxygen species, it has become clear that artemisinin-related endoperoxides additionally have various specific molecular targets and can significantly influence the expression of key regulatory proteins of the cell cycle.10,11,13,14 Artemisinin-related endoperoxides were found to significantly inhibit angiogenesis and also to induce apoptosis.10,15 Iron plays a crucial role in the cytotoxic activities of artemisinin-related endoperoxides through the generation of both ROS and carbon-centred radicals. In general, the addition of iron has been shown to enhance both the cytotoxicity and selectivity of the treatment, but not in all cell lines.10,15

AMDT is a sesquiterpene found in the hairy roots of A. annua. It has been demonstrated that it induces apoptosis through the mitochondrial dependent pathway in human lung 95-D cells. Cytotoxicity of this compound was also found in ovary, liver, and cervix cancer cells.16

No cross-resistance has been found between the artemisinin-related as well as the unrelated compounds, so cells resistant to one compound retain sensitivity to another one.17

Alleged indications

Apart from malaria, A. annua is also used in cases of fever, headaches, infections and inflammations.18 It has been claimed to kill cancer cells and to be especially effective in breast cancer and leukaemia.19,20

Prevalence

There are no data available on the prevalence of use of A. annua in the treatment of cancer.

Legal issues

There are no A. annua derived drugs that are approved for cancer treatment.

Cost(s) and expenditures

Prices available on the internet for artesunate range between US $0.30 and 0.70 for a 100mg tablet or capsule, i.e. the price for a one-month supply ranges from US$ 9 to 21 at a daily dose of 100mg.

Does it work?

There are no clinical trials with A. annua preparations available. There is, however, one randomised clinical trial with the semisynthetic derivative artesunate.

Controlled study

One randomized clinical trial on artesunate in cancer treatment has been published.21 In this open label 2-arm study, at least 2 cycles of chemotherapy (vinorelbine/cisplatin) were applied with or without artesunate in 120 Chinese patients with unresectable non-small lung cancer. The authors found no significant differences between the groups in mean survival time, 1-year survival rate and quality of life. However, the artesunate group had a significant higher disease control rate (88,2% vs. 72,7% [complete + partial response + stable disease]) and a significant longer time to progression (24 vs 20 weeks). As there was an imbalance in the disease stages between the groups (more stage IV diseases in the control group) and an unblinded outcome assessment, the risk of bias in this study is high.

Published case reports

There are two case reports published with artesunate, both reporting stabilization or regression of tumour growth during treatment with additional artesunate, while the tumour was progressing under standard treatment alone.22,23 In a third report of a patient who received artemether, a reduction in density of the tumour and improved quality of life was observed.24

Preclinical studies

Animal studies suggest that artemisinin and related compounds inhibit tumour growth and metastasis and prolong survival upon administration of 10-100mg/(kg day) in xenografts of a wide variety of cancer cells.2,6,10,18 The dosages applied are much higher than those used in anti-malaria treatment. Intermittent higher dosage therapy appears to be more efficient than daily dosing.

Is it safe?

Toxicology

Artemisinin derived drugs are available for the treatment of malaria. Except for two case reports, no major side effects have been reported in humans at doses used for the treatment of malaria but it is still unknown whether the higher doses required for the treatment of cancer patients could cause major side effects. In vivo studies showed that doses of artemisinin-related endoperoxides of at least 5 times higher than those used for antimalaria therapy are required in order to induce an effect. The safety of such doses has not yet been evaluated in Phase I clinical trials.

A first case report describes a boy who received artesunate suppositories and died 13 days.25 He had received a dose 7-fold higher than the maximum recommended dose which reportedly led to toxicity of the brain stem.

In a second case report a woman with recently resected early breast carcinoma described symptoms of toxic brainstem encephalopathy.26 Since this neurotoxicity has also been seen in animals, the authors of the case report ascribe the toxicity to artemisinin consumption, although she received also chemotherapy and a mixture of other herbs on top.

On the other hand, a review of the toxicity of artemisinin derivatives suggested that the toxicity seen in laboratory animals does not necessarily occur in humans due to the differences in pharmacokinetic profile after different routes of administration. The oral administration used in humans is unlikely to cause the neurotoxicity seen after intramuscular administration in mice.27,28

Adverse events

It has been reported that the oral intake of A. annua may cause abdominal pain, bradycardia (abnormally slow heartbeat), diarrhoea, nausea, vomiting, decreased appetite, flu-like symptoms, fever, and decreased reticulocyte count.18

Topical application of A. annua may cause dermatitis.6

Interactions

Experimental studies showed additive or synergistic activities with antineoplastics, antibiotics, antifungals, sodium butyrate, and chloroquine, where it could become more effective in fever subsidence and disappearance of malarial symptoms.7

Citation

Klara Rombauts, Arne Heyerick, CAM-Cancer Consortium. Artemisia annua [online document]. http://cam-cancer.org/The-Summaries/Herbal-products/Artemisia-annua. January 29, 2015.

Document history

Assessed as up to date in January 2015 by Barbara Wider.
Summary assessed as up to date in August 2013 by Barbara Wider.

Summary fully revised and updated in August 2012 by Klara Rombauts.

Summary first published in March 2011, authored by Klara Rombauts and Arne Heyerick.

References

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