THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINEVolume 15, Number 2, 2009, pp. 101109 Mary Ann Liebert, Inc.DOI: 10.1089/acm.2008.0327

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Artemisia Species: From Traditional Medicines to Modern Antimalarialsand Back AgainMerlin Willcox,* B.A., B.M., B.Ch., M.R.C.G.P., M.C.P.P., D.C.H., D.T.M.&H.

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Research Initiative on Traditional Antimalarial Methods (RITAM), Oxford, UK.*In consultation with Elizabeth Hsu, M.A. (Oxon), Ph.D. (cantab), Dipl.Natwiss.E.T.H. (Zurich), P.D. (habil., Heidelberg), a reader in

social anthropology at the Institute of Social and Cultural Anthropology, University of Oxford, Oxford, UK.

Artemisia annua L (Asteraceae) (Photo by Merlin Willcox).

Introduction

The genus Artemisia (Asteraceae) comprises over 400species, many of which have an aromatic, bitter taste.Some say that it is named after the Greek Artemis (Fig. 1),who was goddess of the hunt, of forests, and of childbirth.1,2

Plants of this genus, as for instance A. absinthium, wereused to control pain in childbirth and to induce abortions.Most importantly, however, the species Artemisia annua L isnow known worldwide for its antimalarial properties. OtherArtemisia species have also been used for the treatment offevers and malaria. A. absinthium and A. abrotanum were usedto treat malaria in Europe, and A. afra in Africa.35

The species A. annua L and Artemisia apiacea Hance are na-tive to China. There has been some confusion over their an-cient Chinese names. In older texts, qing hao (bluegreenherb) and cao hao (herbaceous herb) were used interchange-ably. The polymath Shen Gua (10311095) of the Song dy-nasty described two different varieties of qing hao, one withbluegreen leaves, the other with yellowishgreen leaves inautumn. Based partly on his description, the famous physi-cian and natural historian Li Shizhen (15181593), whoseencyclopaedic Classified Materia Medica (Ben cao gang mu) waspublished posthumously in 1596, differentiated between qinghao (bluegreen herb) and huang hua hao (yellow blossomherb).6 Modern botanists have identified the former as A. api-acea, the latter as A. annua (Fig. 2).

A. annua is so named because it is almost the only mem-ber of the genus with an annual cycle. It is a shrub, oftengrowing over 2 m high (Fig. 3), and is native not only toChina but also to Japan, Korea, Vietnam, Myanmar, North-ern India, and southern Siberia through to Eastern Europe.7

It has been introduced to many other countries in Europe,North America, and the tropics.8 Seed varieties have beenadapted by breeding for lower latitudes, and cultivation hasbeen successfully achieved in many tropical countries, forexample in the Congo,9 India,10 and Brazil.1113 In contrastA. apiacea is less common and is rarely grown outside China.

A. annua and Related Species as Traditional Antimalarials

The earliest record of the medicinal use of qing hao datesback to 168 BC in the Fifty-two prescriptions (Fig. 4),14

which recommended it for the treatment of hemorrhoids,15

which were said to resemble cow lice (possibly ticks). Inthe classic of the Chinese materia medica (Shennong ben caojing), which is thought to have been compiled in the first cen-tury AD but is now lost, cao hao is recommended as a foodadditive for killing lice and lingering heat between bonesand joints.16,17

Ge Hong was the first to recommend qing hao for thetreatment of intermittent fevers (many of which wereprobably malaria). His Handbook of Prescriptions for EmergencyTreatment (Zhouhou Beiji Fang), written in 340 AD, recom-mends the following preparation: Take a bunch of qing haoand two sheng (two times 0.2 L) of water for soaking it, wringit out to obtain the juice and ingest it in its entirety.6,18

Different preparations have subsequently been recom-mended in different texts. The current pharmacopoeia of thePeoples Republic of China officially lists the dried herb ofA. annua as a remedy for fever and malaria, at a daily doseof 4.59 g of dried herb prepared as an infusion.19 This is theherbal preparation that has been used for clinical trials.

Development of Artemisinin as a Modern Pharmaceutical

During the Vietnam war, malaria was a problem for allarmed forces, so military research institutions on both sidesof the Pacific started to screen substances for their anti-malarial properties. The Maoist Chinese government estab-lished a nationwide campaign called taskforce 523, andone of the many institutions approached was the Academyof Traditional Chinese Medicine. This employed not only tra-

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FIG. 1. Artemis (Diana), goddess of the forests and hills.Roman statue, 1st2nd century AD (Arundel Collection, Ash-molean Museum, Oxford). (Photo by Merlin Willcox).

only a few hours.23,27 Hence, it cannot be used as a prophy-lactic.

The World Health Organization now recommends the useof artemisinin combination therapies (Fig. 7) for the first-linetreatment of uncomplicated malaria,28 to reduce the risk ofparasite resistance and recrudescence. There is widespreadresistance to older and cheaper drugs such as chloroquineand sulfadoxine-pyrimethamine, which have until now beenthe first-line treatments in most countries. Artemisinin ispoorly soluble in oil or water, so is usually administeredorally, although it can be given rectally29 and, when sus-pended in oil, intramuscularly.30

For patients with severe malaria (who are often uncon-scious and so cannot swallow), the treatment needs to begiven by injection or suppository (Fig. 8). Synthetic deriva-tives that are water-soluble (artesunate) and oil-soluble(artemether) have been developed to allow intravenous andintramuscular administration, respectively.31 A meta-analy-sis of trials, with data on 1919 patients, has shown thatartemether is at least as effective as quinine for the treatmentof severe malaria, and is associated with fewer serious ad-verse effects.32,33 The SEAQUAMAT (2005)34 trial has shownthat intravenous artesunate is not simply equivalent, but iseven more effective than quinine for the treatment of severemalaria.

Artemisinin cannot be synthesized cost-effectively, so isstill extracted from A. annua aerial parts. Therefore, the sci-ence of commercial cultivation of Artemisia annua, to maxi-mize artemisinin yields, is already well-developed.8,35 Dif-

ditional Chinese practitioners but also chemists, pharma-cognosists, and pharmacologists. A. annua was among thefirst 10 plants to be screened but no antimalarial propertieswere found, because the most active antimalarial substancein the plant extract, artemisinin, is soluble in neither waternor ether. Only 23 years later (in 1971) was a successful ex-traction method developed. A specially prepared ether ex-tract of A. annua, when fed to mice infected with malaria,was effective in 95100% of cases.20

Artemisia annua contains many different classes of com-pounds: at least 28 monoterpenes, 30 sesquiterpenes, 12triterpenoids and steroids, 36 flavonoids, 7 coumarins, and4 aromatic and 9 aliphatic compounds.21 Several of thesehave some antimalarial activity (Table 1), but the most ac-tive is undoubtedly the sesquiterpene lactone artemisinin(Fig. 5). This is found in the leaves and flowers of A. annua.Artemisinin has been found in only two other species,Artemisia apiacea and A. lancea.22

Artemisinin and its synthetic derivatives (e.g., artesunate,artemether, dihydroartemsinin) are the most potent andrapidly acting antimalarial drugs ever discovered: The par-asite biomass is reduced by 10,000-fold per asexual life cycle, compared to 1001,000-fold for other antimalarials.23

The pharmacologic and clinical evidence is well docu-mented.24,25 These drugs are unusual in also killing game-tocytes, the sexual stage of the malaria parasite (Fig. 6), andthus reducing transmission of malaria.26 However,artemisinin does not kill the liver stages of the parasite, ismetabolized rapidly, and remains in the bloodstream for

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FIG. 2. Artemisia apiacea (left) andArtemisia annua (right), from the Great Dic-tionary of the Chinese Materia Medica(Zhongyao dacidian, 1986, eds.: Jiangsu xihyixuey yuan).

ferent genetic varieties contain widely varying amounts ofartemisinin, and it is believed to be important to choose avariety with a high artemisinin content (1%) and a highbiomass. One of the best is the hybrid Artemis (produced byMediplant Inc., Conthey, Switzerland) which contains up to1.4% artemisinin.35

However, the endproducts (the pure compoundartemisinin or its derivatives) are often unaffordable for thepoor, especially as they are recommended only to be usedin combination with other drugs.28 Furthermore, its valuemakes it an attractive target for forgery. A survey in20002001 in Southeast Asia found that 38% of shop-boughtoral artesunate samples were fake and contained no arte-sunate,36 some indistinguishable from the genuine ones.37

Return to Artemisia annua as an Herbal Medicine

Several nongovernmental organizations (NGOs) recom-mend developing and perfecting A. annua as an herbal rem-edy. ANAMED (Action for NAture and MEDicine) is an NGO promoting the use of traditional medicines(www.anamed.org). It distributes seeds of a recently devel-oped artemisinin-rich genetic variety of A. annua (DelabaysN, 1997, unpublished thesis; De Magalhes, 1996, unpub-

lished thesis) for cultivation and preparation as an herbal an-timalarial. Two hundred and forty (240) partner organiza-tions in developing countries are participating in this pro-gram, and their feedback has helped the organization torefine its recommendations.

The recommended doses are based on the Chinese phar-macopoeia: an infusion of 5 g dried leaves on which 1 L boil-ing water is poured and left to cool for 15 minutes, of which250 mL is taken every 6 hours for 7 days. A reduced dose is

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TABLE 1. IN VITRO ANTIMALARIAL ACTIVITY OFCONSTITUENTS OF ARTEMISIA ANNUA49

Constituent IC50 (mol/L)

Artemisinin 0.03Artemetin 26Casticin 24Chrysoplenetin 23Chrysosplenol-D 32Cirsilineol 36Eupatorin 65

FIG. 4. The manuscript of the Fifty-two prescriptions dis-covered in one of the Han Dynasty tombs in Mawangdui,the first reference to the medicinal use of qinghao in 168 BC(Mawangdui Hanmu boshu zhengli xiaozu, 1985). The charac-ters for qinghao are circled. See ref 14.

FIG. 3. Artemisia annua var Artemis hybrid growing inBrazil ( Pedro Melillo de Magalhes; reprinted with per-mission).

recommended for children, according to weight.38 Thismethod can extract up to 86% of the artemisinin into the wa-ter, whereas as little as 30% is extracted in a decoction (whenthe plant is boiled in water for several minutes), becauseartemisinin is not heat-stable.20 Using full fat milk ratherthan water can increase the proportion of artemisinin ex-tracted.39 As artemisinin reacts with iron,25 herbal prepara-tions should not be made in iron pots.

The Research Initiative on Traditional Antimalarial Meth-ods (RITAM, www.gifts-ritam.org) has established anArtemisia annua Task Force, to investigate the feasibility ofusing a traditional formulation of Herba Artemisia annua asa more affordable and accessible option for the early treat-ment of malaria in poor and remote areas of developingcountries.40

Clinical Research on Whole Plant ExtractsClinical trials have examined the efficacy of the whole herb

for the treatment of malaria, but not of the juice expressedfrom the fresh plant. The best results were reported from

studies in China on alcohol extracts of the plant.41,42 How-ever, these are not practical to prepare in the field, so theyare not discussed further here. Table 2 summarizes the re-sults of studies on teas prepared from A. annua: one com-paring an infusion with a decoction9 and one comparing in-fusions of different strengths.43

These results suggest that the infusion is more effective thanthe decoction, and that there is no benefit in increasing thestrength of the infusion. The apparently better results in thefirst trial by Mueller et al.9 can mostly be explained by the factthat patients had low parasite counts, and were not followedup beyond 7 days. In the 2004 study, patients all had 2000parasites per microliter of blood, and were followed up for 28days. Because the definition of cure was taken to be para-site clearance at day 7, it would have been much easier toachieve this in patients with fewer parasites. Unfortunately,clinical outcome measures were not used, so the conclusionsare probably too pessimistic.44 Mueller et al.43 showed that re-crudescence rates were high. However, they also showed thatthe A. annua infusion was significantly more effective thanchloroquine in an area of chloroquine resistance.

None of the above studies adhere to an ideal design. Noneincluded children, who are at greatest risk of severe malariaand death in sub-Saharan Africa. Nevertheless, they all sug-gest that an herbal infusion of A. annua can be effectiveagainst malaria in humans, although its artemisinin contentis much lower than the World Health Organization (WHO)recommended dosage. More research is needed to determinethe optimal preparation method and dosage.

How Can the Whole Herb Be Effective?A. annua infusion is significantly more effective than the

equivalent dose of pure artemisinin for reducing parasitemiain animal experiments (Plaizier-Vercammen, personal com-munication). How can this be possible?

First, the oral dose of 500 mg artemisinin daily, recom-mended by WHO, may be unnecessarily high.29 The mini-mum concentration needed to inhibit the growth of Plas-modium falciparum in vitro is 9 ng/mL. This concentration is

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O

O

H

O

O

O

FIG. 5. The artemisinin molecule contains a unique en-doperoxide bond, which is responsible for its activity.

FIG. 6. Gametocyte of Plasmodium falciparum. Its shape has given the parasite its name (falx sickle in Latin). Gameto-cytes are swallowed by the mosquito and breed inside its stomach to make the infective stage, which is injected in the mos-quitos saliva. (Photo by Merlin Willcox).

present in the plasma for at least 4 hours after a dose of A.annua infusion.19

Second, artemisinin may boost the human immune re-sponse to malaria. It stimulates the phagocytic activity ofmacrophages in the mouse abdominal cavity in vivo, and im-proves their destruction of infected erythrocytes in vitro.45

Third, the whole plant contains other constituents with antimalarial activity (Table 1). The callus of the plant hassome antimalarial activity even though it contains noartemisinin.46 The water-soluble fraction of A. annua, af-ter extraction of artemisinin, has an antipyretic effect.41

Some Artemisia species, such as A. absinthium, A. abrotanum(Fig. 9), and A. afra (Fig. 10), have antimalarial activitywithout containing artemisinin.4,47,48 Perhaps some of thesame phytochemicals also contribute to the activity of A.annua.

Fourth, other constituents of A. annua synergize the ac-tivity of artemisinin.

There are 28 other sesquiterpenes, some in much greaterconcentrations than artemisinin in wild strains of the plant:arteannuin B (24) and artemisinic acid (78). Arteann-uin B used alone is ineffective and toxic in rat malaria, butit potentiates the effect of artemisinin.41 A. annua also pro-duces at least 36 flavonoids. Many of these have anti-malarial activity in vitro, although the IC50 is much higherthan that of artemisinin (Table 1). Five of these, artemetin,casticin, chrysoplenetin, chrysosplenol-D, and cirsilineol,have been shown selectively to potentiate the in vitro ac-tivity of artemisinin against Plasmodium falciparum.49 Cas-ticin, at a concentration of 5 mol/L, induced a 35-fold re-duction in the IC50 for artemisinin.50 Chrysosplenol-D hasthe strongest potentiating effect, and this is also the mostabundant flavone in plant material.51 The effect of all theflavones in combination with artemisinin has not been in-vestigated. Other flavones, and indeed other componentsof A. annua, may have a similar effect; they have not all

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FIG. 7. Artesunateamodiaquine, one of the artemisinincombination therapies promoted by the World Health Or-ganization. (Photo by Merlin Willcox).

FIG. 8. Dr. Moussa Dicko prescribes intramuscular artemether for a child with severe malaria at Sikasso Hospital, Mali.This treatment is more practical than intravenous quinine because it is often difficult to find veins in severely ill young chil-dren. Furthermore, the treatment can be given once daily rather than four times a day and carries less risk of toxicity. (Photoby Merlin Willcox).

been tested, because it is difficult to purify them. The anti-malarial properties of the traditional preparation of A. an-nua most probably reside in the combination of many con-stituents, not just artemisinin.

Modern drug combinations may unwittingly be mimick-ing the combinations of phytochemicals (and sometimesplant species) with synergistic activities contained in the tra-ditional preparations of A. annua. Indeed, the pharmaceuti-cal industry may find it beneficial to further investigate com-binations of artemisinin with other compounds produced byA. annua, which may improve its antimalarial efficacy, andreduce the risk of resistance.43

ControversyThere has been much debate as to whether it is appro-

priate to recommend the use of A. annua herbal teas for the treatment of malaria. At one end of the spectrum, commercial growers of A. annua and manufacturers ofartemisinin have claimed that it would be criminal to pro-mote the use of A. annua teas because they contain sub-therapeutic doses of artemisinin, which in theory couldlead to the evolution of parasites resistant to artemisinin.There is little evidence to support or refute this hypothe-sis, and further research is needed.43 Jansen51 writes thatThe herbal tea approach to artemisinin as a therapy formalaria is totally misleading and should be forgotten assoon as possible. His argument is based on the lowartemisinin content of the teas and the assumption thattherefore the teas cannot be effective, an assumption thatmay be incorrect.52 Furthermore, preliminary experimentalresearch that tests the ancient Chinese recommendationssuggests that more artemisinin can be extracted by prepar-ing juice from fresh A. annua plants (Elizabeth Hsu andColin W. Wright, personal communication).

At the other end of the spectrum, Anamed replies that itwould be criminal not to provide A. annua to remote com-munities that do not have any other treatment for malaria.Health care infrastructure is lacking in most of the areasworst affected by malaria, making it impossible to distributedrugs to those who most need them. For example, in theBrazilian Amazon, patients commonly have to travel for 2days before reaching a modern health facility. Although re-crudescence can occur after treatment with A. annua infu-sion, it can still be effective as a first aid measure to keepthe patient alive while they travel to the health center. Animperfect treatment given rapidly, to prevent deterioration

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TABLE 2. CLINICAL TRIALS OF ARTEMISIA ANNUA TEAS FOR PATIENTS WITH MALARIA

Recrudescence Totalrate at dose

Efficacy day 28 Na Species Preparation (g) Days Reference

93% 13% 254 Falciparum Aqueous 35 g 7 Hirt & Lindsey others infusion 2000b

100% ? 5 Falciparum Aqueous 20 g 5 Mueller etinfusion al., 20009

92% ? 48 Falciparum Aqueous 20 g 4 Mueller etinfusion al., 20009

77% 37% 39 Falciparum Aqueous 35 g 7 Mueller etinfusion al., 200443

70% 39% 33 Falciparum Aqueous 63 g 7 Mueller etinfusion al., 200443

aN, number of subjects.bHirt HM, Lindsey K. Natural Medicine in the Tropics: Experiences. Winnenden, Germany: Anamed 2000. Online document at:

www.anamed.org. Accessed January 31, 2009.

FIG. 9. Artemisia abrotanum is used to treat fevers in Turkey,and has antimalarial activity despite the lack of artemisinin.(Photo by Merlin Willcox).

to severe malaria and death, may be preferable to the goldstandard modern treatment if there is a significant delay inobtaining it.

Priorities for future research, proposed by the RITAMArtemisia task force, are summarized below.

Priorities for Future Research on Artemisia species as AntimalarialsPriorities are:

1. To determine the best species and genetic variety ofArtemisia to cultivate in each region of interest (in func-tion of its environmental characteristics).

2. To determine the most effective method of preparation(including combinations with other plants), dose, andlength of treatment.

3. To test the clinical effectiveness of this preparation fortreating falciparum malaria in nonimmune patients.

4. To determine whether use of this preparation increasesthe risk of P. falciparum developing resistance toartemisinin.

5. To test whether the use of this preparation reduces mor-tality from malaria.

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FIG. 10. Artemisia afra. Its antimalarial activity is attributable to a complex mixture of flavonoids and sesquiterpene lac-tones, rather than to a single compound. (Photo by Merlin Willcox).

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Address reprint requests to:Merlin Willcox, B.A., B.M., B.Ch., M.R.C.G.P.,

M.C.P.P., D.C.H., D.T.M.&H.Research Initiative on Traditional Antimalarial Methods

(RITAM)66 Lye Valley

Oxford OX3 7ERUnited Kingdom

E-mail: merlinwillcox@doctors.org.uk

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