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.
Klara Rombauts, Arne Heyerick, CAM Cancer Consortium. Artemisia annua [online document], June, 2019.
Last revised in June 2019 by Barbara Wider.
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.
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 world1. 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.
The phytochemical composition of A. annua has been reviewed in great detail by Bhakuni et al2. 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 extracts3-5.
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 weight6. In addition, artemisinin and its semisynthetic derivatives are used in antimalarial treatment in artemisinin-based combination therapies, with daily doses between 100 and 200mg7.
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 urine8. In 1971, scientists demonstrated that the plant extracts had antimalarial properties in primate models9.
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 activity10,11. 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 therapy12,13. 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 cycle10,11,13,14. Artemisinin-related endoperoxides were found to significantly inhibit angiogenesis and also to induce apoptosis10,15. 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 lines10,15.
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 cells16.
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 one17.
Apart from malaria, A. annua is also used in cases of fever, headaches, infections and inflammations18. It has been claimed to kill cancer cells and to be especially effective in breast cancer and leukaemia19,20.
There are no data available on the prevalence of use of A. annua in the treatment of cancer.
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.
There are no clinical trials with A. annua preparations available. There is, however, one randomised clinical trial with the semisynthetic derivative artesunate.
One randomized clinical trial on artesunate in cancer treatment has been published21. 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 observed24.
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 cells2,6,10,18. 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.
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 days25. 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 encephalopathy26. 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 mice27,28.
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 count18. A 2019 study reported that in thirteen patients with metastatic breast cancer up to 200 mg/d long-term oral ART (2.3-4.1 mg/kg BW/d) in up to 1115 cumulative treatment days (37 months) did not result in any major safety concerns31.
Topical application of A. annua may cause dermatitis6.
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 symptoms7.
- Artemisia Annua, Wikipedia, the free encyclopedia 2012. Available online , accessed 27 July 2012.
- Bhakuni, R.S., Jain D.C., Sharma, Kumar. Secondary metabolites of Artemisia annua and their biological activity. Current Science, 2001 Jan 10;80(1):35-48.
- Carbonara T, Pascale R, Argentieri MP, Papadia P, Fanizzi FP et al. Phytochemical analysis of a herbal tea of Artemisia annua L. J Pharm Biomed Anal 2012;62:79-86.
- Iqbal S, Younas U, Chan KW, Zia-Ul-Haq M, Ismail M. Chemical composition of Artemisia annua L. leaves and antioxidant potential of extracts as a function of extraction solvents. Molecules 2012;17:6020-6032.
- Weathers PJ, Towler MJ. The flavonoids casticin and artemetin are poorly extracted and are unstable in an Artemisia annua tea infusion. Planta Med 2012;78(10):1024-6.26. McGovern PE, Christofidou-Solomidou M, Wang W, Dukes F, Davidson T and El-Deiry WS. Anticancer activity of botanical compounds in ancient fermented beverages (review). Int J Oncol 2010;37:5-14.
- Natural Standard. Monograph on Artemisia annua. Natural Standard 2010. Available online, accessed 27 July 2012.
- World Health Organization. WHO monograph on good agricultural and collection practices (GACP) for Artemisia annua L. 2006.
- McGovern PE, Christofidou-Solomidou M, Wang W, Dukes F, Davidson T, El-Deiry WS. Anticancer activity of botanical compounds in ancient fermented beverages (review). Int J Oncol. 2010 Jul;37(1):5-14.
- van Agtmael MA, Eggelte TA, van Boxtel CJ. Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. Trends Pharmacol Sci 1999 May;20(5):199-205.
- Firestone GL, Sundar SN. Anticancer activities of artemisinin and its bioactive derivatives. Expert Rev Mol Med 2009;11:e32.
- Efferth T. Molecular pharmacology and pharmacogenomics of artemisinin and its derivatives in cancer cells. Curr Drug Targets 2006 Apr;7(4):407-21.
- Li LN, Zhang HD, Yuan SJ, Yang DX, Wang L, Sun ZX. Differential sensitivity of colorectal cancer cell lines to artesunate is associated with expression of beta-catenin and E-cadherin. Eur J Pharmacol 2008 Jun 24;588(1):1-8.
- Huang XJ, Ma ZQ, Zhang WP, Lu YB, Wei EQ. Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor-1alpha activation in C6 glioma cells. J Pharm Pharmacol 2007 Jun;59(6):849-56.
- Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX. Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer 2007 Sep 15;121(6):1360-5.
- Chen HH, Zhou HJ, Wu GD, Lou XE. Inhibitory effects of artesunate on angiogenesis and on expressions of vascular endothelial growth factor and VEGF receptor KDR/flk-1. Pharmacology 2004 May;71(1):1-9.
- Zhai DD, Supaibulwatana K, Zhong JJ. Inhibition of tumor cell proliferation and induction of apoptosis in human lung carcinoma 95-D cells by a new sesquiterpene from hairy root cultures of Artemisia annua. Phytomedicine 2010;17:856-861.
- Efferth T, Herrmann F, Tahrani A, Wink M. Cytotoxic activity of secondary metabolites derived from Artemisia annua L. towards cancer cells in comparison to its designated active constituent artemesinin. Phytomedicine 2011;18(11):959-969.
- Memorial Sloan Kettering Cancer Center. MSKCC summary on Artemisia annua L. Memorial Sloan Kettering Cancer Center 2010Available from: URL: http://www.mskcc.org/mskcc/html/69126.cfm, accessed July 2012.
- Singh NP and Lai H. Selective cytotoxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. Life Sci 2001;70(1):49-56.
- Singh NP and Lai H. Synergistic cytotoxicity of artemesinin and sodium butyrate on human cancer cells. Anticancer Res 2005;25:4325-4332.
- Zhang ZY, Yu SQ, Miao LY, Huang XY, Zhang XP, Zhu YP, et al. [Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial]. Zhong Xi Yi Jie He Xue Bao 2008 Feb;6(2):134-8.
- Singh N.P., Verma K.B. Case report of a laryngeal squamous cell carcinoma treated with artesunate. Archive of Oncology 2002;10(4):279-80.
- Berger TG, Dieckmann D, Efferth T, Schultz ES, Funk JO, Baur A, et al. Artesunate in the treatment of metastatic uveal melanoma--first experiences. Oncol Rep 2005 Dec;14(6):1599-603.
- Singh NP, Panwar VK. Case report of a pituitary macroadenoma treated with artemether. Integr Cancer Ther 2006 Dec;5(4):391-4.
- Campos S, de la Cerda P, Rivera A. Fatal artesunate toxicity in a child. Journal of Pediatric Infectious Diseases 2008;3(1):69-75.
- Panossian LA, Garga NI, Pelletier D. Toxic brainstem encephalopathy after artemisinin treatment for breast cancer. Ann Neurol 2005 Nov;58(5):812-3.
- Gordi T, Lepist EI. Artemisinin derivatives: toxic for laboratory animals, safe for humans? Toxicol Lett 2004 Mar 1;147(2):99-107.
- Shen M, Ge HL, He YX, Song QL, Zhang HZ. Immunosuppressive action of Qinghaosu. Sci Sin B 1984 Apr;27(4):398-406.
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- von Hagens C, Walter-Sack I, Goeckenjan M, et al. Long-term add-on therapy (compassionate use) with oral artesunate in patients with metastatic breast cancer after participating in a phase I study (ARTIC M33/2). Phytomedicine. 2019 Feb 15;54:140-148.