Interview with Prof. Pamela Weathers

Professor Pamela Weathers PhD, Dept. of Biology and Biotechnology, Worcester Polytechnic Institute, Worcester MA 01609 USA

Prof. Pamela Weathers is an internationally recognized expert on Artemisia annua and artemisinin, having worked with the plant and its phytochemicals including the antimalarial drug, artemisinin, for >25 years.

Which methods have been used so far to cure malaria infections? Which were the most effective? Which role did Artemisinin and Artemisia tea infusions play?

There have been a variety of methods used against malaria including a plethora of pure compounds, e.g. quinine, chloroquine, and most recently artemisinin combination therapies (ACTs) that incorporate derivatives of artemisinin, e.g. artesunate, artemether, dihydroartemisnin, with another antimalarial drug, e.g. lumefantrine, etc. Artemisinin is produced naturally in the plant Artemisia annua and is still mainly extracted and purified from large crops of plants grown in large plantations around the globe. These purified compounds have been used for about the last 150 yrs. Artemisia tea infusions have been used much longer, >2,000 yrs in Southeast Asia to treat fever as documented in the Chinese Materia Medica (Hsu 2006; Liao 2009; Willcox 2009; Wright et al. 2010). Although there was confusion about which species of Artemisia was used over those centuries, A. annua is now recognized as the most reliably consistent Artemisia species that also produces artemisinin. There is now even archeological evidence that A. annua was used therapeutically probably to treat malaria fever during the 7th-15th centuries in Rome where skeletal remains contained artemisinin (Gismondi et al. 2020). Artemisia afra, originating in southern Africa, also has antimalarial properties, and also has an indigenous history of use against malaria (Du toit and van der Kooy 2019; Liu et al. 2009).

How effective are Artemisia tea infusions for the treatment or prevention of Malaria?

Although there is a long history of successful use of Artemisia tea infusions to treat/cure a malaria infection, prophylaxis (prevention) is less clear. There are reports of successful prevention among Africans where the disease is common (Ogwang et al. 2011, 2012). However, European travelers who have never had malaria but used the plant to prevent getting the disease during travels throughout Africa returned with malaria (Lagarce et al. 2016). A recent study (Gruessner and Weathers 2021) looked into this confusing set of results and it seems that if a human has already had malaria, they were successful with using the tea to prevent future bouts. However, those who have never had malaria were unable to ward off the disease. The results of that study indicated that the blood serum of the malaria-naïve people were missing something that interacted with the tea infusions to kill the parasite. In contrast, the serum of those who had already had the disease had something in their serum that enabled the tea to kill the parasite. More work is required to understand better what in the tea and in the patients’ blood facilitate a preventative response. In other words, how does the tea and serum work in tandem to achieve prevention?

Are there any risks associated with using tea infusions as a method for malaria treatment or prevention?

As a therapeutic: A. annua is a generally recognized as safe (GRAS) medicinal plant (Duke 2001). To my knowledge there have no reported adverse effects of using a tea infusion for treating malaria. Patients respond very well to treatment with far fewer adverse effects than from the standard ACTs. WHO (WHO 2019) has challenged that using A. annua is a monotherapy, which is not well supported. For example, recent studies have shown that A. afra teas that have no artemisinin also kill trophozoites (a common malaria blood stage) and gametocytes (the stage that transmits the parasite back to the mosquito) (Snider and Weathers 2020). Artemisinin is important also against the ring stage of the parasite. Although killing of the ring stage correlated best to artemisinin content, the plant was equally effective against ring stage parasites in vitro compared to high concentrations of dihydroartemisinin and the comparative ACT (CoArtem™) (Gruessner and Weathers 2021). Together these and results of others (Suberu et al. 2013 and see Gruessner et al. 2019 review) indicate there is more in A. annua than just artemisinin that is antimalarial.

WHO (2019) also cautioned against use of Artemisia to treat malaria because they claim it is a monotherapy. A. annua is not a monotherapy. WHO claims without evidence that using A. annua will spur the rise of artemisinin resistance. Resistance most readily emerges when a single drug is used, a monotherapy, hence the development and use of ACTs, which are a combination of drugs. Consumption of Artemisia teas or direct consumption of encapsulated dried A. annua leaves involves ingestion of a plethora of molecules, many of which have antimalarial activity with artemisinin being the most potent  (see recent review by Gruessner et al. 2019).  Thus, the plant acts as a plant-based combination-therapy. Indeed, we published a study using mice infected with malaria to show that using the same concentrations of artemisinin, infected mice treated with the plant were far more resilient against the development of artemisinin resistance than were infected mice treated with equal amounts of pure artemisinin (Elfawal et al. 2015). The plant functioned as a natural ACT. Furthermore, the same study showed that mice infected with artemisinin-resistant parasites were successfully treated with A. annua thereby “curing” them of malaria while those treated with artemisinin remained infected.

Another challenge by WHO against using A. annua to treat malaria is that not enough artemisinin is bioavailable from the plant or tea to exceed the threshold concentration of artemisinin (9 µg/L; Alin and Bjorkman 1994) needed to kill the parasite. Again, both rodent (Weathers et al. 2011, 2014; Desrosiers et al. 2020) and some human studies (Rath et al 2003; Nair et al 2021) counter that claim. Properly prepared tea releases >95% of the artemisinin from the plant leaves into the hot water of a tea infusion (van der Kooy and Verpoorte 2011; Weathers and Towler 2012). The natural plant chemicals, e.g. essential oils, help facilitate more than a 40-fold increase in the artemisinin released into the blood of mice compared to equal amounts of pure artemisinin (Desrosiers and Weathers 2016, 2018; Weathers et al. 2011, 2014). In addition, many of the plant’s phytochemicals inhibit two liver P450s, 2B6 and 3A4, that metabolize artemisinin to therapeutically inactive products (Desrosiers et al. 2020). In humans there is also high bioavailability with resulting serum levels of artemisinin accounting for about a third of the artemisinin in the leaves that were orally consumed (Nair et al 2021). For example, 2 hr post consumption of 1 g of encapsulated leaves, there was about 2.3 mg artemisinin/L serum (Nair et al. 2021 see supplemental data). To further compare, Räth et al. (2004) measured about 27 µg artemisinin/L at 30 min post consumption of a tea infusion of 1 g of leaves. In both cases, the amount of serum artemisinin delivered from either leaf consumption or a tea infusion greatly exceeded the minimum threshold amount of artemisinin, 9 µg/L, required to kill the parasites.

WHO (2019) also challenged the consistency of A. annua plant material. However, studies showed that use of rooted clonal cuttings provides artemisinin and total flavonoid consistency, i.e. 12.76±2.28 mg/g DW and 4.63±0.9 mg/g DW, respectively, in A. annua crops grown annually in a diversity of conditions for at least 7 yrs (Gruessner et al. 2019). The dried leaf content of artemisinin and total flavonoids also remains stable for at least 4 yrs if kept dry and stored out of direct sun (Gruessner et al. 2019; Simonnet et al. 2010).

Alin MH, Bjorkman A (1994) Concentration and time dependency of artemisinin efficacy against Plasmodium falciparum in vitro. Am J Trop Med Hyg 50:771–776

Desrosiers M, Weathers PJ 2016 Effect of leaf digestion and artemisinin solubility for use in oral consumption of dried Artemisia annua leaves to treat malaria. J Ethnopharmacology 190:313–318

Desrosiers MR, Weathers PJ 2018 Artemisinin permeability via Caco-2 cells increases after simulated digestion of Artemisia annua leaves. J Ethnopharmacology 210:254-259

Desrosiers, M.R., Mittelman, A., Weathers, P.J. 2020 Dried Leaf Artemisia annua Improves Bioavailability of Artemisinin via Cytochrome P450 Inhibition and Enhances Artemisinin Efficacy Downstream. Biomolecules 10, 254

Duke, J. A. (2001). Handbook of phytochemical constituent GRAS herbs and other economic plants. CRC press.

Du Toit A, Van der Kooy F. 2019 Artemisia afra, a controversial herbal remedy or a treasure trove of new drugs?. Journal of Ethnopharmacology. Nov 15;244:112127.

Elfawal MA, Towler MJ, Reich NG, Weathers PJ, Rich SM. 2015 Dried whole plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin. PNAS USA 112:821-6

Gismondi A, Baldoni M, Gnes M, Scorrano G, D’Agostino A, Di Marco G, et al. (2020) A multidisciplinary approach for investigating dietary and medicinal habits of the Medieval population of Santa Severa (7th-15th centuries, Rome, Italy). PLoS ONE 15(1): e0227433

Gruessner, B.M., Cornet-Vernet, L., Desrosiers, M.R., Lutgen P., Towler, M.J., Weathers P.J. It is not just artemisinin: Artemisia sp. for treating diseases including malaria and schistosomiasis. Phytochem Rev (2019) 18:1509-1527

Gruessner BM, Weathers PJ (2021) In vitro analyses of Artemisia extracts on Plasmodium falciparum suggest a complex antimalarial effect. PLoS ONE 16(3): e0240874.

Hsu E. (2006). Reflections on the ‘discovery’ of the antimalarial qinghao. British journal of clinical pharmacology, 61(6), 666–670.

Lagarce L, Lerolle N, Asfar P, Le Govic Y, Lainé-Cessac P, de Gentile L. A non-pharmaceutical form of Artemisia annua is not effective in preventing Plasmodium falciparum malaria. Journal of Travel Medicine. 2016;23(5, taw049).

Liao F. (2009). Discovery of Artemisinin (Qinghaosu). Molecules, 14(12), 5362–5366.

Liu NQ, Van der Kooy F, Verpoorte R. Artemisia afra: a potential flagship for African medicinal plants? South African Journal of Botany. 2009 Apr 1;75(2):185-95.

Nair, M. S., Huang, Y., Fidock, D. A., Polyak, S. J., Wagoner, J., Towler, M. J., & Weathers, P. J. (2021). Artemisia annua L. extracts inhibit the in vitro replication of SARS-CoV-2 and two of its variants. Journal of ethnopharmacology, 274, 114016. Advance online publication.

Ogwang P, Ogwal J, Kasasa S, Ejobi F, Kabasa D, Obua C. Use of Artemisia annua L. infusion for malaria prevention: mode of action and benefits in a Ugandan community. Br J Pharm Res. 2011;1:124e32.

Ogwang PE, Ogwal JO, Kasasa S, Olila D, Ejobi F, Kabasa D, et al. Artemisia Annua L. Infusion Consumed Once a Week  Reduces Risk of Multiple Episodes of Malaria: A Randomised Trial in a Ugandan Community. Tropical Journal of Pharmaceutical Research. 2012;11(3):445-53.

Räth, K., Taxis, K., Walz, G., Gleiter, C. H., Li, S. M., & Heide, L. (2004). Pharmacokinetic study of artemisinin after oral intake of a traditional preparation of Artemisia annua L. (annual wormwood). The American journal of tropical medicine and hygiene, 70(2), 128–132

Simonnet, X., Quennoz, M., Carlen, C., Lopez, O., Kowalyzyn, D., Ciccia, G. and Desmarchelier, C. (2010). Performance of Artemisia annua L. Cultivars in Different Locations in Argentina. Acta Hortic. 860, 187-192

Snider D., Weathers, P. 2020 In vitro reduction of Plasmodium falciparum gametocytes: Artemisia spp. tea infusions vs. artemisinin. J Ethnopharmacology. 268: 113638

Suberu JO, Gorka AP, Jacobs L, Roepe PD, Sullivan N, Barker GC, Lapkin AA (2013) Anti-plasmodial polyvalent inter-actions in Artemisia annua L. aqueous extract—possible synergistic and resistance mechanisms. PLoS ONE 8:e80790

van der Kooy, F., & Verpoorte, R. (2011). The content of artemisinin in the Artemisia annua tea infusion. Planta medica, 77(15), 1754–1756.

Weathers PJ, Towler MJ 2012 The flavonoids casticin and artemetin are poorly extracted and are unstable in Artemisia annua tea infusion. Planta Medica 78: 1024–1026.

Weathers PJ, Arsenault PR, Covello P, McMickle A, Reed D, Teoh KH, 2011 Artemisinin production in Artemisia annua – studies in planta and results of a novel delivery method for treating malaria and other neglected diseases. Phytochemistry Reviews, 10:173–183.

Weathers PJ, Elfawal MA, Towler, MJ, Acquaah-Mensah G, Rich SM 2014 Pharmacokinetics of artemisinin delivered by oral consumption of Artemisia annua dried leaves (pACT) in healthy vs. Plasmodium chabaudi-infected mice. J Ethnopharmacology 153: 732-736

WHO 2019 The use of non-pharmaceutical forms of Artemisia.

Willcox M. (2009). Artemisia species: From traditional medicines to modern antimalarials–and back again. Journal of alternative and complementary medicine (New York, N.Y.), 15(2), 101–109.

Wright, C. W., Linley, P. A., Brun, R., Wittlin, S., & Hsu, E. (2010). Ancient Chinese methods are remarkably effective for the preparation of artemisinin-rich extracts of Qing Hao with potent antimalarial activity. Molecules (Basel, Switzerland), 15(2), 804–812.

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