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Published in final edited form as: Glob Health Econ Sustain. 2025 Feb 5;3(3):1–17. doi: 10.36922/ghes.4927

Medicinal plants as more sustainable therapeutic solutions: Artemisia annua and Artemisia afra as case studies

Pamela J Weathers 1,*
PMCID: PMC13485337  NIHMSID: NIHMS2194893  PMID: 42614870

Abstract

Humans have used botanicals as traditional medicines for millennia, yet Western biomedicine has shunned many of these as undefined and often unreliable. While not all botanicals have a strong scientific basis or can be directly used as therapeutics, two, Artemisia annua and A. afra, are quite well-established for their safety and efficacy within ethnopharmacological and scientific literature. A. annua, being better studied, is especially effective against many diseases. It is inexpensive, has consistent phytochemical content within a cultivar grown in its local region, evades the evolution of parasite drug resistance, and can be reliably produced on both large and small scale. Well-defined botanical drugs offer major benefits for more sustainable global healthcare. This review highlights these two plant species are offered as examples of how broader implementation of botanical drugs can decrease costs, promote environmental sustainability, and deliver economic benefits—especially to rural communities—by empowering them to manage their healthcare needs more sustainably. Comparisons are made between the agricultural and production costs of an extracted natural product vs. Artemisia as a traditional botanical medicine. The review also examines the impact of climate on these two crops and provides a brief comparison of the carbon footprints of traditionally produced botanical drugs versus their commercially produced counterparts. A specific, successful example of sustainable production of A. annua is also described. Overall, there are many well-established reasons to advocate for broader approval of botanical drugs to strengthen global healthcare systems.

Keywords: Rural Artemisia production, Dried leaf Artemisia, Artemisinin, Malaria, Artemisinin bioavailability, Artemisinin drug resistance, Artemisia phytochemical consistency

1. Introduction

About 80% of the global population relies on traditional medicines, with medicinal plants constituting a significant component of this usage (Organization, 2002; WHO, 2013). As highlighted in the case described here, they also can offer a more sustainable and cost-effective approach to treating many diseases. Artemisia annua L. and Artemisia afra Jacq. ex Willd. are two widely used medicinal plants (Figure 1). A. annua, in particular, is grown commercially on large plantations across equatorial Africa, China, India, and Southeastern Asia and is mainly used for the extraction of its potent antimalarial compound, artemisinin (ART). The ART content of A. annua varies widely from 0.2–1.6% (weight/weight; w/w) and is usually disproportionate to artemisinic acid (AA), ranging from 0–0.4% (w/w); another important component is dihydroartemisinic acid (DHAA), which ranges from 0.01–1.6 % (w/w) (Larson et al., 2013). A. afra, which does not produce ART, is not grown as extensively or commercially as A. annua. It is native to southern Africa and is increasingly being grown locally. Extracted ART (eART), AA, and DHAA are semi-synthesized and derivatized to form artesunate (AS), dihydroartemisinin (DHA), or artemether (AM). These are then combined with an antimalarial drug, e.g. lumefantrine, mefloquine, amodiaquine, to treat malaria patients using a commercially available ART-based combination therapy (ACT). The cost of ACTs is still significantly subsidized by the West with the aim of reducing the global malaria burden (Goodman et al., 2024; White, 2008). Several clinical studies showed that the traditional use of A. annua was effective against malaria (Daddy et al., 2017; Munyangi et al., 2019; Räth et al., 2004; Zime-Diawara et al., 2015).

Figure 1.

Figure 1.

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Artemisia annua, A. afra, artemisinin, and its derivatives used in the formulations of ART-based combination therapy (ACT).

Beyond malaria, ART and A. annua have also shown great efficacy against many other infectious diseases including those caused by viruses (Devaraj & Roelofson, 2015; Efferth, 2018; Lubbe et al., 2012; Nair et al., 2021; Romero et al., 2005; Zhou et al., 2021), bacteria (Daddy et al., 2021; Efferth, 2009; Kellogg et al., 2024; Kiani et al., 2023; Kim & Neiva, 2015; Martini et al., 2020; Zheng et al., 2019), and especially parasites, including schistosomiasis, leishmania, trypanosomiasis, and Lyme disease (Ashraf et al., 2022; Berrizbeitia de Morgado et al., 2017; Daddy et al., 2017; Derda et al., 2016; Efferth, 2009; Elfawal et al., 2012; Elfawal et al., 2015; Feng et al., 2019; Feng et al., 2015; Feng et al., 2014; Ferreira et al., 2011; Ghaffarifar et al., 2015; Islamuddin et al., 2012; Kane et al., 2019; Mesa et al., 2017; Mishina et al., 2007; Naß & Efferth, 2018; Taljaard et al., 2022). Four of these diseases are exemplified in Table 1. Of particular recent interest is A. afra, a closely related Artemisia species that lacks ART, but demonstrates efficacy against many of the same diseases, thereby suggesting the broad therapeutic potential of the non-ART phytochemicals it contained (Gruessner et al., 2019; Kane et al., 2019; Snider & Weathers, 2021; Taljaard et al., 2022; Weathers, 2023).

Table 1.

Exemplar cases of some global diseases susceptible to artemisinin (ART) and Artemisia annua.

Disease Cases (×106) Deaths (×103) Vector Main causative agent
Malaria 2491 ~6001 mosquito Plasmodium falciparum, P. vivax, P. ovale
Tuberculosis 7.52 ~1,3002 human Mycobacterium tuberculosis
Schistosomiasis (bilharzia) 2403 ~11.73 freshwater snails Schistosoma guineensis, S. intercalatum, S. mansoni, S. japonicum, S. mekongi
Leishmaniasis 0.7–14 ~20–305 sandfly Leishmania major, L. infantum, L. tropica, L. donovani
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A. annua also demonstrates efficacy against an emerging list of chronic ailments, such as fibrosis (Dolivo et al., 2021; Larson et al., 2018; Larson et al., 2019; Weathers, Towler, et al., 2024), a pathology common to many diseases susceptible to ART/Artemisia treatment (Mutsaers et al., 2023; Nardo et al., 2021; Sewanan et al., 2023; Singh et al., 2023), osteoarthritis (Hunt et al., 2016; Stebbings et al., 2016), and general inflammation (de Faveri Favero et al., 2024; Desrosiers et al., 2020). Recently, even A. afra showed potent antifibrotic effects (Weathers, Towler, et al., 2024). Along with the many in vitro and some human studies, the efficacy of A. afra suggests that phytochemicals other than ART in both species are therapeutically efficacious (Ashraf et al., 2022; Daddy et al., 2021; Gruessner et al., 2019; Kane et al., 2019; Kellogg et al., 2024; Kiani et al., 2023; Martini et al., 2020; Ntutela et al., 2009; Snider & Weathers, 2021). Key results are further described in four additional important areas: botanical crop consistency, safety, bioavailability of the compound, and resilience against evolution of ART drug resistance.

2. Key features of Artemisia as a botanical drug

2.1. Phytochemical consistency

It is critical for a medicinal plant to be cultivated with a consistent phytochemical content to provide a reliable therapeutic outcome. A. annua grown from seed resulting from cross-pollination results in significant variation in phytochemical content. Cultivars must be selected to grow within the photoperiod of the target geographical region. Many cultivars have already been optimized for regional environmental climates, supported by efficacy studies and human clinical trials: SAM (Elfawal et al., 2012; Elfawal et al., 2015; Weathers, Elfawal, et al., 2014), Artemis (Räth et al., 2004); Anamed A3 (Daddy et al., 2017), LUX and BUR (Munyangi et al., 2019). To minimize phytochemical diversity these cultivars should be grown via two methods. Clonal-rooted cuttings, even from hybrid stock (Wetzstein et al., 2018), will provide consistent ART and total flavonoid content (Gruessner et al., 2019; Weathers & Towler, 2014). Another option is to self-pollinate a high-producing cultivar suitable to the local region and use it to generate a homozygous seed that will provide consistent phytochemical content (Alejos-Gonzalez et al., 2011; Ma et al., 2015).

2.2. Safe to consume

A. annua is safe for oral consumption as evidenced by more than 2,000 years of documented traditional use in the Chinese Materia Medica (Hsu, 2006; Tu, 2016). Using a powdered water extract of A. annua, Han et al. (2020) conducted a clinical trial that showed significant liver recovery compared to placebo in patients with liver disease, who were treated twice daily for 56 days. There were no observed adverse effects. In human studies using tea infusions for up to seven days to treat malaria, there were also no major adverse effects (Munyangi et al., 2019; Räth et al., 2004; Zime-Diawara et al., 2015). Similarly, no adverse effects were reported when A. annua extract (Arthrem®) were taken twice daily for three (Stebbings et al., 2016) or six months (Hunt et al., 2016), while the reduction in arthritis was evident as determined by the WOMAC® assessment. While no toxicity of water extracts of A. annua was reported, nor toxicity of grapeseed oil, Arthrem® is a supercritical CO2 extraction of A. annua in grapeseed oil and there were reports in a few users of suspected liver toxicity of the product (Savage et al., 2019). Although an oil extract could potentially deliver a toxic dose of ART, this seems unlikely given that its median lethal dose (LD50) is more than 5 g/kg in rat; consumption of such a high dose seems improbable, if not impossible. Such results, however, caution against ad hoc mixing of plant extracts without extensive testing for potential unintended consequences. Nevertheless, A. annua has a long history of safe use.

Although for centuries A. afra was used indigenously in southern Africa, this species has been less studied. Kane et al. (2019), however, conducted an acute lethal dose study in mice and showed that extracts delivered orally had an LD50 over 2,500 mg/kg of body weight. There was also no difference in two key liver enzymes, alanine transaminase (ALT) and aspartate transaminase (AST), compared to controls. These results indicate that A. afra does not cause liver toxicity.

2.3. Greater bioavailability of ART

As a pure drug, ART is not particularly bioavailable (Titulaer et al., 1990). ART is a relatively nonpolar prodrug that has a solubility (LogS) of -3.42 and a total polar surface area (TPSA) of 53.99 Å2 (Parveen, 2021). In vivo, ART is metabolized in the liver to a number of therapeutically inactive metabolites and into its more polar active form, DHA (LogS = -4.10; TPSA = 46.15 Å2) (Parveen, 2021). Consumed with its plant constituents, the drug is more bioavailable—up to 40-fold greater as determined in mouse studies (Weathers et al., 2011), and consistent with other human and rodent studies (Desrosiers et al., 2020; Räth et al., 2004; Weathers, Elfawal, et al., 2014), showing that ART was delivered into the serum well above the 9 μg/L minimum antimalarial threshold required to kill, e.g., malaria parasites (Alin & Bjorkman, 1994). There are a number of reasons explaining this enhanced bioavailability. When digested, A. annua increases the solubility of ART four-fold (Desrosiers & Weathers, 2016), improves ART transport across the intestinal barrier (Desrosiers & Weathers, 2018), and, once in the liver, inhibits the main cytochrome P450s, 2B6 and 3A4 (Desrosiers et al., 2020; Kane et al., 2022), which metabolize ART. This results in a greater distribution of ART to organs including, the brain, heart, lungs, muscle, and liver, compared to pure ART (pART) (Desrosiers et al., 2020).

2.4. No ART drug resistance

With over 2,000 years of use, consumption of a more complex botanical drug like Artemisia also obviates the emergence of single-molecule drug resistance. Using two murine malaria models, Elfawal et al. (2015) tested pART and A. annua at equal ART concentrations to generate ART-resistant Plasmodium parasites. While resistance was readily developed using pART, no resistance emerged using A. annua. WHO and research (Ataba et al., 2022) claim that the use of A. annua modalities to treat malaria could increase ART-drug resistance in the parasite, but there is no evidence to date to substantiate this claim. Indeed, evidence to the contrary was provided by Elfawal et al. (2015), who showed that ART-induced drug resistance was successfully treated with A. annua, but not with pART, even at higher doses than those from the consumed plant material. Furthermore, Daddy et al. (2017) also used A. annua dried leaf tablets to successfully treat 18 patients who had severe malaria and were not responding either to ACT or intravenous AS. Two of the pediatric patients were successfully revived from coma after treatment. These human results correlate well with the rodent studies of Elfawal et al., showing that A. annua could treat malaria that is not responsive to the standard drugs.

3. Comparisons between Artemisia and eART production: Current and emerging prospects

Use of these plants through more traditional means, or with a simple Western biomedical approach such as encapsulated powdered dried leaves or emulsions, is much more sustainable than the extraction and purification of the active molecules, or the chemical synthesis of such molecules. The plant in its entirety also requires no solvents other than water, so there are no excess energy consumption and capital costs associated with processing operations. The use of locally-guided, protocol-driven agriculture has a significant impact on many women, who represent about 40% of the agricultural labor force in low- and middle-income countries (Palacios-Lopez et al., 2017). Additionally, local jobs are created when based on locally grown crops. If well-established protocols are followed for all production, preparation, and delivery stages of these medicinal plants, then therapeutic results are quite reliable. Development of well-controlled use of these two medicinal plants results in the empowerment of people especially in low- and middle-income countries and impacts the United Nation’s (UN) sustainability goals (No. 1, 3, 5, 8, 11, and 12) that focus on reduced poverty, good health and wellbeing, gender equality, decent work and economic growth, responsible consumption and production, and sustainable cities and communities. Failure to recognize and encourage the responsible development of these two important medicinal crops is a necropolitical choice made by Western biomedicine and regulating bodies, e.g. the WHO (Staub, 2023). The following is a comparative discussion on the inclusion of these plants as a more sustainable part of therapeutic protocols for treating many diseases that afflict and kill millions annually, with cases and deaths from four examples presented in Table 1.

3.1. Production of Artemisia versus eART

While A. afra is not globally commercially produced yet, there are thousands of acres of global A. annua plantations mainly for the extraction of ART for ACTs. The global A. annua extract market size was valued at US$ 75 million in 2023, growing at a compound annual growth rate of 19.8%, and is projected to reach US$ 225.3 million by 2030.1 Traditional use of both pART and eART first involves growing the plant and in 2010 Ellman (Ellman, 2010) estimated the costs of agricultural production of the plant, many steps of which are common to both traditional use of A. annua and eART production. These estimates are shown in Table 2; while similar for commercial and smallholder growers, the estimates were nevertheless 40% lower for the smallholder grower, mainly due to lower costs of plants, fertilizer, irrigation, and harvesting.

Table 2.

Estimated agricultural costs to grow A. annua in 2010 (Ellman, 2010; verified costs with East African Botanicals Ltd)

Task Commercial grower
(US$/ha)		 Smallholder grower
(US$/ha)
Land preparation 75.00 75.00
Seed or seedlings1 180.00 10.00
Nursery1 0.00 30.00
Transplant & infilling 35.00 35.00
Fertilizer 60.00 40.00
Weeding 40.00 40.00
Irrigation 80.00 20.00
Pest & disease control 10.00 10.00
Cutting & stooking 40.00 35.00
Threshing & cleaning 20.00 15.00
Storage & transport 30.00 30.00
Total 570.00 340.00
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1

Commercial grower purchased seedlings from a nursery; smallholder germinated seeds on site.

For eART, additional costs are incurred by extraction and purification of ART and other artemisinic compounds from the plant, a process that involves many steps, commonly known as unit operations (unit ops). While exact production steps and costs are often proprietary secrets, de Vries et al. (de Vries et al., 1999) described the general process in 1999. It is briefly described with cost estimates in 1998 shown in Table 3. After the leaves are threshed from plants, they are then milled and homogenized to yield a relatively uniform material for extraction. Extraction is via an organic solvent with various heating steps included to yield eART, which is then analyzed for purity. eART is then derivatized via a semi-synthetic process to yield AS, DHA, or AM, which are required to formulate commercial ACTs for malaria treatment. Derivatization is necessary to enhance the bioavailability of ART. Other plant phytochemicals like AA and DHAA can also be recovered and converted via a semi-synthetic production of additional ART from the plant biomass, thereby improving overall recovery. In addition to the two major heating steps that require energy input, the process also generated some hazardous solvent waste. Alternatively, the traditional tea infusion method directly uses the dried leaves of the A. annua plant to deliver pART, decreasing the production cost by 29% compared to eART (Table 3).

Table 3.

Estimated cost of production of extracted artemisinin (eART) vs. pure artemisinin (pART) (de Vries et al., 1999)

Unit operations (unit ops) eART
(US$)1 		pART-AN
(US$)		 Reduction
pART vs. eART (%)
from 500 kg dry leaves yielding ~1 kg ART 143.91 143.91 0.0
Extraction solvents 20.63 0.00 100.0
Chemicals2 1.73 0.00 100.0
Energy3 12.95 1.30 90.0
Labor4 11.99 2.40 80.0
Assays 0.96 0.96 0.0
Interest4 11.03 2.21 80.0
Depreciation4 11.03 2.21 80.0
Maintenance4 2.40 0.48 80.0
Total 216.63 153.46 29.2
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1

Based on 1998 values as reported in de Vries et al. (1999)

2

No chemicals are needed; those for assays are incorporated into the assays line.

3

Significantly fewer unit ops for pART as the production required no heat.

4

Reflects fewer unit ops for pART as described in the text.

Abbreviations: eART: Extracted artemisinin; pART: Pure artemisinin.

A more Western biomedical adaptation of the tea infusion is encapsulation or tableting of powdered dried A. annua leaves, which involves milling, homogenization, ART assay, and either compression into tablets or encapsulation (Daddy et al., 2017; Weathers & Towler, 2014). Costs of these production approaches for both eART and pART were estimated in 1998 by de Vries et al. (Tables 2, 3). Although these costs did not account for dealing with the hazardous waste generated, it was noted that after hexane distillation, the hexane solvent was recovered and reused (de Vries et al., 1999). More recently, Goel et al. (2018) reported that plants grown on the Indo-Gangetic plains of India could yield ten 500 mg compressed A. annua leaf tablets at a cost of approximately US$ 0.17 in 2018, suggesting this option as an affordable and efficacious approach for treating malaria and other diseases afflicting Southeast Asians.

3.2. Towards a greener eART process

Some improvements in eART extraction and purification have been developed, but their implementation is not clear. Nevertheless, newer technologies like supercritical CO2 (scCO2) extraction offer the potential to reduce overall costs with a reduction in energy and hazardous waste (de Vries et al., 1999). In a 2006 review (Lapkin et al., 2006), various extraction technologies were compared and assessed for their ART recovery efficiency and cost. Although deemed a “green” solvent, ethanol was less efficient than hexane extraction, but scCO2, ionic liquids (IL), and hydrofluorocarbon (HFC) offered promising improvements for extraction. IF and HFC, however, have high capital costs with potentially harmful greenhouse gas emissions and higher energy costs. While slightly less efficient, scCO2 was cited as a mature off-the-shelf processing technology, having already been developed for applications such as decaffeinating coffee (Lapkin et al., 2006). Interestingly, Babacan et al. (2022) recently showed that using ethanol as the extraction solvent was as efficient as hexane and six other solvents at extracting ART when coupled with 1.5% (w/v) of powdered charcoal. Charcoal optimized chlorophyll removal and facilitated the desorption of ART, and, after drying, yielded a white crystalline powder consisting of ART, suggesting that a more sustainable production process may be possible. Efforts are afoot to use more environmentally friendly solvents for ART extraction. For example, Cao et al. (2017) used deep eutectic solvents, e.g., N81Cl-NBA, that can be reused several times and are thus notably “greener” for extracting ART. Interestingly, Triemer et al. (2018) exploited the presence of chlorophyll in a toluene crude extract of A. annua that along with trifluoracetic acid (TFA) in an LED photobioreactor converted dihydroartemisinic acid (DHAA, quite labile and often lost in the extraction process) to ART at lower than typical unit op temperatures. The resulting ART still requires final purification, but using powdered charcoal as suggested by Babacan et al. (2022) could yield an even “greener” process. Unfortunately, the environmental cost of charcoal production (Chidumayo & Gumbo, 2013) was not considered. There are also efforts aimed at minimizing other wastes and to also add value to the process, such as using discarded A. annua stems—very woody and thick—as a source for the production of high-quality cellulose derivatives (Risite et al., 2022).

3.3. ART produced thorugh synthetic biology approach: Boon or bust?

A major scientific breakthrough in synthetic biology ART (sbART) production was achieved by Paddon et al. (2014), who engineered both yeast and E. coli to produce a late precursor of ART, ultimately enabling yeast production of 25 g/L AA that could be extracted and semi-synthetically converted into ART. The process was scaled up and commercial production of WHO-approved ART was initiated by Sanofi in 2013. Despite a stellar technical achievement, the microbial production of ART was met with a huge socioeconomic backlash resulting in the closure of the Sanofi production facilities in the West. African growers realized that they would be put out of business with this production scheme, so they planted huge amounts of A. annua for eART. That significantly reduced the price of ART such that the sbART was no longer cost-effective for Sanofi (Peplow, 2013, 2016). In 2009 (News, 2009) over 4,000 small stakeholder farmers were growing A. annua, potentially representing more than 4,000 families whose livelihoods depended on the cultivation of A. annua. Indeed, ethical concerns regarding sbART were raised, particularly due to its impact on farmer livelihoods. Additionally, the cost of sbART was consistently higher than that of eART, and sbART represented a shift of wealth from the global South to the global North (Dalziell & Rogers, 2022). Considering the massive financial input (>US$ 50 million from the Gates Foundation and collaborating institutions) into producing sbART in significant quantities, the anticipated long-term impact on malaria has not been realized. Indeed, ART resistance is now spreading throughout Africa and there is urgency in addressing this pending disaster (Dhorda et al., 2024; Ishengoma et al., 2024). There also is no reason why the use of sbART, extraction and production of eART/AA, and traditional A. annua (pART) approaches cannot co-exist (Brisibe & Chukwurah, 2013).

3.4. The whole plant is the most sustainable solution: Efficacy and production options

Unfortunately, the production of eART focuses solely on ART, missing the synergistic potential of the plant in its entirety. Only powdered, encapsulated dried leaves of the plant offer the full therapeutic potential of its phytochemicals, along with the crucial benefit of pART resilience against the evolution of ART drug resistance. The key concerns for using any drug are threefold: efficacy, consistency, and safety. As already noted in Section 1.0, pART from A. annua is highly efficacious when produced and used in a consistent form. Furthermore, when A. annua is grown in the same locale, it yields phytochemically consistent crops with consistent ART and total flavonoid content (Gruessner et al., 2019). Traditional medicines are the norm, especially in low- and middle-income countries, and controlled use of traditional tea is successful and expanding as later described in Section 4.0. Another option with minimal capital input is the encapsulation or tableting of powdered dried leaves of A. annua. These options are described in the next section.

3.5. A semi-Western biomedical approach for using intact Artemisia for therapeutics

While there is a broad effort afoot to standardize the production and the use of A. annua as a traditional tea infusion (as described in Section 4.0), there is a semi-Western biomedical alternative: formation of compressed dried leaf tablets or encapsulation of powdered dried leaves with a small-scale processing operation envisioned as shown in Figure 2. Briefly, an insulated freight container, used in other localized production systems (Diaz, 2023), is equipped with a dry leaf stripper to remove major stems; the remaining small stems and leaves are ground into a powder, which is then either compressed into tablets without the need for excipients (N’Guessan et al., 2019; Weathers & Towler, 2014) or compacted into 00 capsules. Tablets or capsules are then de-dusted and packaged into blister, bottle, or plastic bags to contain sufficient quantity for a full course of malaria treatment (exact dosage yet to be determined). Paper bags are not recommended for long-term storage because in high-humidity environments the plant material will likely degrade.

Figure 2.

Figure 2.

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Use of a freight container for the production of either tablets or capsules of powdered dried leaf A. annua or A. afra. This layout shows a small tablet production system. By replacing the tablet press with a 00 capsule filler and the blister packing machine with a plastic bag filling machine, the production system can accommodate capsules instead of tablets. QC is inexpensively accomplished using TLC fingerprinting. Abbreviations: QC: Quality control; HVAC: heating ventilation air conditioning; TLC: Thin-layer chromatography.

4. NGO efforts and successes at providing ART via A. annua traditional tea infusions

There are well-established and expanding grassroots efforts to provide a standardized traditional Artemisia medicine. While there are a number of different nongovernmental organizations (NGOs), such as ANAMED and Fight the Fever (FTF) (Staub, 2023), who have been supporting the use of A. annua tea infusions, efforts by La Maison de l’Artemisia (LMA) have been particularly successful with 9 million people treated at approximately 95% efficacy (Dr. Lucile Cornet-Vernet, personal communication, Sept. 6, 2024). As of July 2024, LMA has 130 Houses of Artemisia in 28 countries.2 LMA Paris is gradually obtaining approval for the use of A. annua and A. afra in LMAs within each country, but there is often reticence to approving the use of a tea infusion as a recognized therapeutic option. Indeed, there have been both local and international efforts to impede such efforts (Weathers, Desrosiers, et al., 2024).

4.1. The approach of LMA

Begun in 2014, LMA has since standardized the production and use of A. annua tea infusion for treating malaria. Medicinal tea is consistent with African culture (Mahomoodally, 2013), but differences in the cultivation (Ferreira et al., 2018; Thu et al., 2011) and preparation of the plant (Hsu, 2013) can alter its efficacy. Thus, consistency is imperative. According to WHO Director-General, Dr Margaret Chan:

“…traditional medicines, of proven quality, safety, and efficacy, contribute to the goal of ensuring that all people have access to care. For many millions of people, herbal medicines, traditional treatments, and traditional practitioners are the main source of health care, and sometimes the only source of care. This is care that is close to homes, accessible, and affordable. It is also culturally acceptable and trusted by large numbers of people. The affordability of most traditional medicines makes them all the more attractive at a time of soaring healthcare costs and nearly universal austerity. Traditional medicine also stands out as a way of coping with the relentless rise of chronic non-communicable diseases.”

(WHO, 2013)

To treat RDT-diagnosed malaria or bilharzia (schistosomiasis), the tea is made using 5 g dried leaves per liter of boiling water and infused for 15 minutes before filtering the leaves. Adults drink 1 L per day, divided into 3 aliquots, and repeated for 7 days. Children of five years or younger drink half the dose for 7 days. The tea is prepared fresh each day. LMA has a treatment page with an infographic showing how to use dried leaves or even fresh leaves, measured as one and four handfuls of leaves, respectively.3

As stated on the LMA website, the LMAs are “multidisciplinary centers of expertise, responsible for overseeing the rational distribution of Artemisia in malaria-endemic countries according to an ethical charter (ecologically, economically and socially responsible)”.4 Within each country, the LMAs are organized into National Artemisia House, which aims to influence and impact national malaria control policy, to lobby national authorities to recognize Artemisia as an effective local therapy against malaria, to apply within each country for Marketing Authorization (MA) for Artemisia, to organize the local small stakeholders within that country into an efficient and competitive value chain, and last to stabilize the national prices of Artemisia herbal tea and coordinate the purchase of official packaging (Figure 3). LMA also has worked with agronomists and plant biologists to select cultivars of A. annua that grow well in the equatorial photoperiod where malaria is prevalent. Thus, LMA organizes all the supply chains related to cultivation and distribution, according to social principles of economic solidarity. LMA also organizes science-based agronomic and medical training. LMA also educates vulnerable populations, such as those in remote areas and malaria-endemic areas, about health issues and ways to obtain local treatment. LMA lobbies at both the local and national levels to inform policymakers of its efforts and successes. These efforts of LMA involve all stakeholders through an inclusive community approach, integrated with the scientific community.

Figure 3.

Figure 3.

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Workers from La Maison d’Artemisia in Bangui, Central African Republic, holding packets of A. annua tea and the packaging details designed to prevent counterfeiting of LMA Artemisia products (courtesy of Lucile Cornet-Vernet of LMA, Paris).

LMAs operate according to a three-leg social business model with a social mission “to fight against malaria and ensure access is provided to the most vulnerable”. Meshing with this is their environmental mission to promote local, sustainable, and responsible production of Artemisia plant material for tea infusions and other related products including soaps and creams. Through these efforts, they have successfully acheived the third leg of their business model, fulfilling its economic mission to create jobs and encourage financial autonomy. Thus, the LMA model is self-sustaining and, in contrast to Western-subsidized ACT, does not depend on continued Western support. An example of a recently established LMA in Bangui, Central African Republic, was provided in an interview with Lucie Peters, who worked for the parent LMA in Paris that funded the start-up of the Bangui LMA.

“We have created a quality Artemisia sector in Bangui (cultivation, processing, marketing). Everyone involved in this value chain is now paid. Two farmers now produce Artemisia: one produces Artemisia annua and the other Artemisia afra. Two others are in the process of setting up their fields and testing Artemisia cultivation. Visits and follow-up are organized with them. The quality of the packaging has been improved: exact grammage, integration of all the stems, presentation of the packets, introduction of batch numbering for which the producers have been trained, introduced in July 2023. The Artemisia House France has contributed to the construction of the processing workshop and the purchase of protective equipment (gloves, masks, aprons, etc.). At the same time, we’ve carried out a number of public awareness campaigns, reaching around 7,000 people. Today, it’s common to hear people call us “Mr. or Mrs. Artemisia” in the street and to meet people who know about the plant. We have organised 10 training sessions, mainly in Bangui, and obtained recognition and support from national institutions. At the same time, we are developing scientific research into the plant, in particular with the Pasteur Institute in Bangui. And we have entered into a number of partnerships.5”

4.2. Treating children as well as pregnant and lactating women

Malaria especially afflicts and kills children younger than 5 years old.6 Treating children with oral medications is challenging; however, mixing with milk or other palatable foods could enhance oral delivery (Bonati et al., 2011; Onimus et al., 2013; Weathers, Jordan, et al., 2014). Suppositories made from powdered A. annua have also been developed using excipients such as shea butter, enhanced with 4% colloidal silica; however, it is not clear whether they have undergone clinical testing (Nague et al., 2022). While suppositories seem reasonable for very young children who cannot ingest an oral therapeutic, diarrhea may preclude administration. If shown to be efficacious, it would be possible to add suppository formation into the general process design illustrated in Figure 2. Although it has been poorly studied, there is some preliminary evidence suggesting that lactating mothers may transfer ART to their infants (Jansen et al., 2006). Far less is known about the effects of Artemisia on pregnant women, however, anecdotal reports suggest that some pregnant women in Africa drink tea infusion of A. annua if they contract malaria during pregnancy. Interestingly, the pharmacokinetics of DHA are not significantly different for pregnant and nonpregnant women (Rijken et al., 2011).

5. Other concerns

5.1. Quality control

Quality control (QC) of both incoming plant material and the end product can be easily and inexpensively achieved using two different thin layer chromatography (TLC) assays for predetermined validation of phytochemical consistency, including the display of general terpenoids, ART, and flavonoid (Figure 4). This simple analytical procedure is also important to maintain vigilance against counterfeit Artemisia herbal tea. HPTLC (Khan et al., 2015) and TLC provide a visual phytochemical “fingerprint” of each plant extract; these methods yield consistent results across multiple crops of the same cultivar grown in the same location (Gruessner et al., 2019) and should be compared to certified reference material. While other methods such as HPLC-UV are more capital-intensive and may thus be out of range for small operations like LMA. QC analysis should be performed for each batch of received and processed material. Indeed, if multiple crops arrive simultaneously and are validated to be within the phytochemical range of what has been determined to be acceptable for therapeutically active A. annua (or A. afra), then they can be combined, mixed, powdered, and used in bulk for tablet or capsule formation.

Figure 4.

Figure 4.

Open in a new tab

TLC of Artemisia annua. Vanillin staining for increasing concentrations of A. annua extracts (A) and pure ART (B). (C) p-anisaldehyde staining for increasing concentrations of A. annua extracts. Total flavonoids separation and viewing under visible light (D) and with DPBA staining under UV light (E). Abbreviations: ART: Artemisinin; DBPA: 2-aminoethyl diphenylborinate; TLC: Thin-layer chromatography; UV: Ultraviolet.

There are many different TLC mobile phases for phytochemical fingerprinting. For the TLCs shown in Figure 4, the method is briefly described as follows: 25 mg of dried leaves or leaf powder are extracted in 4 mL methylene chloride. Plastic-backed silica gel 60 F254 plates are used as the stationary phase. For terpenoid and ART separation, the mobile phase is a 5:11:4 mixture of methylene chloride, hexane, and acetone. For flavonoid separation, the mobile phase is a 10:5:4:1 mixture of hexane, acetone, ethyl acetate, and formic acid. To visualize the terpenes, vanillin (6 g vanillin in 100 mL ethanol and 1 mL sulfuric acid) will yield dark purple-blue spots and the ART Rf is approximately 0.5 after heating at 100°C for 10 minutes, then viewed under visible light. Alternatively, p-anisaldehyde spray (Weathers, Towler, et al., 2024) will stain terpenes blue-purple and ART dark pink (Figure 4C). Flavonoids can be visualized using 0.5% (weight/volume, w/v) 2-aminoethyl diphenylborinate (DPBA) in methanol and viewing under UV light.

The advantages and disadvantages of incorporating either or both Artemisia species into any of the aforementioned modes of delivery for approved therapeutic regimens are summarized in Table 4.

Table 4.

Advantages and disadvantages of using Artemisia leaves for therapeutics.

Mode Advantages Disadvantages
Tea infusion

  • Low capital costs

  • Well-established by LMA

  • Efficacious for malaria treatment (according to LMA)

  • Practical for rural areas

  • Creates local jobs

  • Needs large-scale clinical trial to validate for malaria

  • Needs clinical trials to validate for other diseases

  • The reticence of regulatory agencies to approve

  • Not practical for urban areas

  • Potential for inconsistent dosing
Powdered dried leaf capsules

  • Easy to manufacture

  • Consistent dosing

  • More practical for urban areas

  • Creates local jobs

  • Easier regulatory approval as a botanical drug

  • A preliminary trial suggested efficacy for malaria (Onimus et al., 2013)

  • Option as a suppository for less than five years old patients

  • Higher capital costs compared to tea infusion

  • Needs large-scale clinical trial to validate

  • Needs clinical trials to validate for other diseases

  • More akin to a Western drug rather than a traditional medicine, thereby potentially less acceptance by some cultures.
Powdered dried leaf tablets

  • Easy to manufacture

  • Consistent dosing

  • More practical for urban areas

  • Creates local jobs

  • Easier regulatory approval as a botanical drug

  • A small trial reported efficacy for malaria (Daddy et al., 2017)

  • Higher capital costs compared to tea infusion

  • Needs large-scale clinical trial to validate malaria

  • Needs clinical trials to validate for other diseases

  • More akin to a Western drug rather than a traditional medicine, thereby potentially less acceptance by some cultures.
Open in a new tab

Abbreviation: LMA: La Maison d’Artemisia.

5.2. Fake Artemisia

The ACT antimalarial drugs suffer from counterfeiting {Feeney, 2024 #143} and unfortunately counterfeit Artemisia tea leaves are now also appearing as reported in a Benin study where three commercially available samples were analyzed using TLC (Ganfon et al., 2019). Only two contained ART, the definitive marker for A. annua. While there is a plethora of possible analytical methods available to detect authenticity of an herbal product, most methods other than TLC are too expensive or complex for quick analysis (Liu et al., 2023). Although LMA warns its members to be aware of counterfeit Artemisia tea with key identifying features of packaging shown for identification (Figure 3), such readily copied images and packaging are readily, albeit illegally, copied, so analytical methods are essential. Unlike A. annua, there unfortunately seems to be no key marker compound to authenticate A. afra.

6. Sustainability considerations

6.1. Artemisia vs. ACT carbon footprint

As part of its sustainability effort, Carbone 4 compared the carbon emissions of ACTs with local production and traditional use of Artemisia as the therapeutic tea infusion promoted by LMA.7 ACT inputs included Artemisia leaf extraction, semi-synthesis of the molecule (e.g., AS, DHA, AM), excipient addition, packaging, and transportation for a carbon dioxide equivalent (CO2e) of 122 g CO2e/treatment. The LMA Artemisia tea approach inputs included the Artemisia leaves, packaging, and transportation for a carbon dioxide equivalent (CO2e) of 15 g CO2e/treatment. Carbone 4 estimated that shifting from 100% ACT to 100% Artemisia tea infusion could save 25 kt CO2e, equivalent to 100 million kilometers driven by automobiles.

6.2. Climate change effects on Artemisia: Temperature, water, CO2

Our changing climate will alter regional agricultural outputs with increased heat, drought, excessive rainfall, or cold temperatures. Modeling suggests that Artemisia cultivation, currently maximized in the midlatitudes will suffer similar consequences potentially shifting further towards the poles as the equatorial regions and lower latitudes further warm, affecting current cultivation areas (Ding et al., 2020; Wang et al., 2022). Plant growth and metabolism are impacted by photosynthesis, the control of which depends on the integration of temperature, light intensity, and CO2 levels. When Artemisia plants were grown at CO2 level of 400 ppm, increasing temperature from 30°C to 37°C decreased A. annua photosynthesis by 15%, but doubling the CO2 level to 800 ppm resulted in only about a 9% decrease in photosynthesis (Daussy & Staudt, 2020). While ART was not measured, arteannuin B, produced in a side branch of the ART biosynthetic pathway, decreased by 50% when CO2 was doubled from 400 to 800 ppm at 30°C, but by only 25% when both temperature and CO2 were elevated. Interestingly, plant dry mass increased with increasing CO2 levels. In another study, ART increased only slightly in A. annua plantlets when CO2 concentration was tripled from 500 to 1500 μmol mol−1 air (Supaibulwattana et al., 2011). Prolonged water stress (drought) has a negative effect on plant biomass productivity; however, if applied judiciously and approximately 36 hours prior to harvest, it can increase ART production in A. annua leaves by almost 30% (Marchese et al., 2010). Young A. annua requires regular watering to become established with deep roots but requires less attention to watering as they mature. As A. annua cultivation shifts in latitude, the photoperiod changes, and depending on the cultivar, flowering may be induced earlier; this can also lead to changes in biomass per hectare and alterations in phytochemical concentrations, such as ART (Marchese et al., 2023). Together, these studies show that to achieve consistent ART and other phytochemicals, climate change will affect how and where A. annua can be cultivated.

7. Conclusion

For millennia, humans have experimented with the natural world, especially plants, to discover mixtures and species that could aid in promoting health. While not all herbs and plants are necessarily safe to use directly, A. annua and A. afra are two excellent examples of plants with robust histories of traditional use for the treatment of various ailments. Both Artemisia species appear to be therapeutically effective when used as an oral complex mixture including plant extracts and the whole plant. Production and use costs are reduced with a smaller carbon footprint. This results in not only greater efficacy but also enhanced economic and environmental sustainability, all of which the NGO La Maison d’Artemisia appears to have achieved.

Are we to ignore all that valuable history and scientific rediscovery of these beneficial plants in favor of purifying molecules that are costly, environmentally burdensome, often less efficacious, promote income and gender inequality, and eventually contribute to drug resistance? We should encourage more research and approval of these medicinal plants for broader, more cost-effective therapeutic use, rather than cherry-pick certain options that lead to necropolitical decisions. Other plant species may also offer similar benefits for sustainable therapeutic use, and regulatory bodies should be more supportive of the reasonable development and approval of such medicinal plants for the global community.

Acknowledgments

Gratitude is extended to Prof. Sarah Strauss of the WPI Global School, Prof. Robert Krueger Social of Science and Policy Studies, Worcester Polytechnic Institute for critical review of the manuscript, and to Dr. Melissa Towler of Biology and Biotechnology also from WPI for editorial review and the TLC images.

Funding

Some of the data shared in this report were derived from studies funded to P.J. Weathers (Award No.: NIH-2R15AT008277-02) from the National Center for Complementary and Integrative Health, which partially funded the analysis of the plant material in this study. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Center for Complementary and Integrative Health or the National Institutes of Health.

Footnotes

4

https://maison-artemisia.org/en/home/ (accessed July 31, 2024)

Conflict of interest

The author declares no competing interests.

Further disclosure

The paper may be uploaded to or deposited in a preprint server at a later point.

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