From prehistoric times man has looked to wild and domestic animals for sources of herbal remedies. Both folklore and living examples provide accounts of how medicinal plants were obtained by observing the behaviour of animals. Animals too learn about the details of self-medication by watching each other. To date, perhaps the most striking scientific studies of animal self-medication have been made on the African great apes. The great ape diet is often rich in plants containing secondary compounds of non-nutritional, sometimes toxic, value that suggest medicinal benefit from their ingestion. Chimpanzees (Pan troglodytes), bonobos (Pan paniscus) and gorillas (Gorilla gorilla) are known to swallow whole and defecate intact leaves. The habit has been shown to be a physical means of purging intestinal parasites. Chimpanzees and man co-existing in sub-Saharan Africa are also known to ingest the bitter Vernonia amygdalina for the control of intestinal nematode infections. In light of the growing resistance of parasites and pathogens to synthetic drugs, the study of animal self-medication and ethno-medicine offers a novel line of investigation to provide ecologically-sound methods for the treatment of parasites using plant-based medicines in populations and their livestock living in the tropics. Eating can be dangerous. While food contains nutrients and calories that animals need to produce heat and energy, it may also contain harmful parasites, bacteria, or chemicals. To guide food selection, the senses of taste and smell have evolved to alert us to the bitter taste of poisons and the sour taste and off-putting smell of spoiled foods. These sensory systems help people and animals to eat defensively, and they provide the brake that helps them avoid ingesting foods that are harmful. But choices about which foods to eat are motivated by more than avoiding the bad; they are also motivated by seeking the good.The first benefit everyone notices from trying herbal bitters is improved digestion. You feel it right away– the tongue awakens, your brow furrows, and in a few minutes a familiar rumble begins in the belly. Bitters make themselves known. It is the obvious secret of what the French call « apéritifs et digestifs » ; Cynar, Campari, Amer Pico, Fernet-Branca, Underberg, Fée verte, Suze. But the injection of digestive prowess that follows a bitter taste stimulus is just the tip of the iceberg. Most medicinal plants have a bitter taste. Bitter tastants also are bronchodilators, improve glucose utilisation, insulin secretion and other beneficial functions
MK McMullen, JM Whitehouse, A Towell. Bitter tastants alter gastric-phase postprandial haemodynamics, J Ethnopharmacology, May 5, 2014.
C D Dotson, Lan Zhang, SD Munger. Bitter taste receptors influence glucose homeostasis, PlosONE, 2008, 3, 12, e3974
This is of course something most good herbalists already understand, since it is a well-known tenet of traditional Chinese medicine. But it is always interesting to note when modern research uncovers some of the mechanisms behind this age-old wisdom. For example, that bitters help increase circulating levels of IgG and IgM
Clarize M. de Korne, Luuk T. Lageschaar Regulation of Plasmodium sporozoite motility by formulation components. Malaria Journal May 2019
Bitter taste receptors not only on the tongue, but in the entire body.
Some antimalarial drugs, like quinine, are so bitter that their consumption had to be inforced by disciplinary action. Mostly infants and young children reject bitter tastants.
Until recently it was a general belief that bitter drugs triggers a cephalic signal like in Pavlovs dog who starts the salivation and digestion process when he hears a bell. But it is well known now, that in addition to being located in the mouth, on taste buds of the tongue, bitter receptors also are found in the gut.
Kimberly Palatini, Mickey Wilson, Diverse Classes of Bitter Phytochemicals Modulate Carbohydrate Metabolism and Immune Responses through Gastrointestinal Bitter Taste Receptors. April 2015. The FASEB Journal vol. 29 no. 1 Supplement 405.5
Bitter taste receptors (specifically of the T2R subfamily) are found almost everywhere in the body, and research is developing a new understanding about their importance in a range of functions: digestion and liver function, to be sure, but also immunity, blood sugar balance, mood, and most recently, cardiovascular function. Taken as a whole, the effects that come from stimulating bitter T2R receptors conspire to moderate and balance many physiologic processes, generally improving their efficiency and making us more resilient in the face of challenge.
Reszka E, Nowakowska-Swirta E, Kupczyk Expression of Bitter Taste Receptors in the Human Skin In Vitro. J Clinic Res Bioeth (2015) 6: 218. doi:10.4172/2155-9627.1000218
It is now accepted that a chemosensory machinery exists in the gastrointestinal tract. Changes in the luminal contents of the gastrointestinal tract modulate gastrointestinal functions, including absorption of nutrients, food intake, and protection against harmful substances. Mucosal enteroendocrine cells act as primary chemoreceptors by releasing signaling molecules in response to changes in the luminal environment, which in turn activate nerve terminals.
This underlies the traditional indications for digestive bitters: dyspepsia, indigestion and reflux, gas and bloating.
Meyerhof W, Batram C, Kuhn C, The molecular receptive ranges of human TAS2R bitter taste receptors. Chem Senses. 2010 Feb;35(2):157-70.
Sternini, Catia. Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing. American Journal of Physiology-Gastrointestinal and Liver Physiology 292.2 (2007): G457-G461.
If the cephalic hypothesis were correct, or the only possible explanation, it would be wise to stop mixing the Artemisia herbal tea with nutrients able to hide its bitterness. Sugar coating of bitter medicines was introduced by Big Pharma to enhance compliance so that patients can complete doses. Some people argue that sugar coating provides energy for malaria parasites.
This also implies that in vitro trials which do not consider the in vivo metabolisms triggered by bitter molecules may sometimes be useless in assays with herbal extracts. Most investigations into the antimalarial activity of African plants are centered on finding an indigenous equivalent to artemisinin, the compound from which current frontline antimalarial drugs are synthesized. As a consequence, the standard practice in ethnopharmacological research is to use in vitro assays to identify compounds that inhibit parasites at nanomolar concentrations. This approach fails to take into consideration the high probability of acquisition of resistance to parasiticidal compounds since parasite populations are placed under direct selection for genetic changes that confer a survival advantage.
The history of bitter Artemisia plants
Artemisia is thought to be the plant translated as "wormwood" in English language versions of the Bible (apsinthos in the Greek text). Wormwood is mentioned seven times in the Jewish Bible, always with the implication of bitterness. It is mentioned once in the New Testament. Wormwood is the "name of the star" in the Book of Revelation 8:11 (kai to onoma tou asteros legetai ho Apsinthos) that John of Patmos envisions as cast by the angel and falling into the waters, making them undrinkably bitter. Further references in the Bible show wormwood was a common herb known for its bitter taste. (Deuteronomy 29:17, Proverbs 5:4, Jeremiah 9:15, 25:15, Lamentations 3:15,19, Amos 5:7).
SinceGreco-Roman times bitter tastants have been used in Europe for various diseases. In Africa the consumption of bitter medicinal plants is higher in areas with endemic parasitic infections.
J Mennella, A Spector. The bitter taste of medicines. Clin Ther 2013 35, 1225-124
Since Artemisia annua has been used against malaria since centuries in Europe (Italy, France, Serbia…) and Artemisia afra in many African countries, the use of these plants is legal according to WHO/EDM/TRM/2000.1 (Traditional use refers to documentary evidence that a substance has been used over three or more generations of recorded use for a specific health related or medicinal purpose. In this case WHO maintains its position that there is no requirement for pre-clinical toxicity testing.Pre-clinical toxicity testing is only required for new medicinal herbal products which contain herbs of no traditional history of use).
Genetic variation in bitter taste perception
It was previously known that people vary in their ability to taste bitter substances.The perception of bitter taste is thought to be innate .Bitter taste perception is a variable trait influenced by genetic variation in the T2R bitter taste receptor gene family. Caucasians may be more likely to dislike grapefruit than East Asians. Women, infants, pregnant women (first trimester) are more sensitive. East Asians dislike cauliflower, radish, coffee, black tea.
Christine Rose Asik. Genetic variation in bitter taste perception, food preference and dietary intake. Tesis. Graduate Department of Nutritional Sciences. University of Toronto. 2010
W Meyerhof, M Behrens. Human bitter taste perception. Chem Senses, 2005, 30, i14-i15
AN Pronin, Hong Xu, Specific alleles of bitter receptor genes influence human sensitivity to bitterness. Current Biology, 2007, 17, 1403-1408
Another frequent genetic trait which plays a role in malaria is G6PD (Glucose-6-phosphate dehydrogenase deficiency). In a small trial G6PD deficient subjects showed greater taste sensitivity to the bitter quinine sulfate than do de G6PD normal subjects. They also may find Artemisia herbal tea too bitter.
Greene LS, McMahon L, DiIorio J. Co-evolution of glucose-6-phosphate dehydrogenase deficiency and quinine taste sensitivity. Ann Hum Biol. 1993 Sep-Oct;20(5):497-500.
Which molecules are bitter ?
Polyphenols are not known to significantly contribute to bitterness. If they did, it would be a disaster for many wines.
F Brossaud, V Cheynier. Bitterness and astringency of grape and wine polyphenols. Australian Journal of Grape and Wine Research
The proanthocyanidin (condensed tannins) content does not contribute to the bitter taste of juices or wines. Black currant extracts from the most bitter cultivars have the lowest contents of proanthocyanidins regardless of the processing method. This finding indicates the existence of other bitter compounds in black currants. But proanthocyanidins contribute to astringency of wines. Often there is confusion between bitterness and astringency, the latter mainly related to tannins.
Laaksonen OA, Salminen JP, Proanthocyanidins and Their Contribution to Sensory Attributes of Black Currant Juices. J Agric Food Chem. 2015 Jun 10;63(22):5373-80.
Nor do polyunsaturated fatty acids as present in Artemisia plants contribute to the bitter taste. They even mask the bitterness.
Kayako Ogi, Haruyuki Yamashita, Long-Chain Fatty Acids Elicit a Bitterness-Masking Effect on Quinine and Other Nitrogenous Bitter Substances by Formation of Insoluble Binary Complexes. J. Agric. Food Chem. 2015, 63, 8493−8500
Scopoletin, a coumarin, present in several Artemisia plants has a bitter taste or rather a bitter smell. Data on this topic are scarce, but scopoletin probably is not a main contributor to bitter taste. Artemisia vulgaris ans Artemisia dracunculus are bitter and they do not contain scopoletin.
We found no scientific paper that claims that artemisinin contributes to the bitterness of Artemisia infusions. Artemisia afra herbal tea is bitter despite the absence of artemisinin in this plant. The bitternes of Artemisia absinthium is due to absinthin, but also to thujone a molecule present in other Artemisia varieties like Artemisia afra or Artemisia herba alba. The only bitter molecule present in sizeable amounts in all Artemisia species are saponins. Based on scarce data in the literature the content of saponins in Artemisia plants is around 1%. Most of the semi-quantitative data on the presence of saponins in plants and in Artemisins are based on the so called froth test.
In fact saponins protect plants from phytopathogenic microorganisms, phytophagous mammalian and insects. Saponins are found in many vegetables and plants and are also present in some marine organisms.
Most medicinal plants are rich in saponins, which to some extent are responsible for their bitterness, and probably for their therapeutic properties.
The potential role of bitter saponins
Saponins are widely distributed plant natural products with vast structural and functional diversity. They are typically composed of a hydrophobic aglycone, which is extensively decorated with functional groups prior to the addition of hydrophilic sugar moieties, to result in surface-active amphipathic compounds
Saponins are widely used as adjuvants in vaccines.
Govind Ragupathi, Jeffrey R Gardner. Natural and synthetic saponin adjuvant QS-21 for vaccines against cancer. Expert Rev Vaccines. 2011 Apr; 10(4): 463–470.
H Florian et al., Synergistic action of saponins and monoterpenes in HeLa cells and in erythrocytes, Int J Phytotherapy, Oct 2011.
It needs to be mentioned here that Aluminium hydroxide is used as adjuvant too. And Artemisia annua leaves are rich in Aluminium.
Ebiamadon Andi Brisibe, Fraideh Brisibe , Jorge F.S. Ferreira, Nutritional characterisation and antioxidant capacity of different tissues of Artemisia annua L. Food Chemistry, 2009. 115, 1240-1246
Immature gametocytes home in the spleen. In vitro studies have shown that a number of saponins activate B-cells and T-cells in the spleen. Activation of macrophages or monocytes can result in phagocytosis of these gametocytes
Chavali SR, Francis T, Campbell JB. An in vitro study of immunomodulatory effects of some saponins. Int J Immunopharmacol. 1987;9(6):675-83.
Sponaas AM, Freitas do Rosario AP,Migrating monocytes recruited to the spleen play an important role in control of blood stage malaria. Blood. 2009 Dec 24;114(27):5522-31
Concerning mature stage V gametocytes, a study from the Tulane University in Louisiana is an eye opener and may help to explain why Artemisia herbal tea significantly inhibes transmission of gametocytes to mosquitoes, and why ACTs don’t. Live gametocytes resist phagocytosis. But gametocytes, killed or damaged are readily phagocytized. Saponins have haemolytic properties and are often used in in vitro studies for the lysis of infected red blood cells in order to liberate merozoites and gametocytes for the assays. In sharp contrast to live intact gametocytes, the authors observed that saponin-liberated gametocytes were readily taken up by phagocytosis. In the case of the saponin released gametocytes, it was extremily difficult to identify parasite structures. They had been severily damaged by the lysis.
Geetha P. Bansal, Corey S. Weinstein, and Nirbhay Kumar. Insight into phagocytosis of mature sexual (gametocyte) stages of Plasmodium falciparum using a human monocyte cell line. Acta Trop. 2016 May; 157: 96–101.
Saponins increase the pemeability of the small intestinal mucosal cells, facilitating the uptake of materials to which the gut normally would be impermeable, such as drugs.
Chapman L, Johns T, Mahunnah RL. Saponin-like in vitrocharacteristics of extracts from selected non-nutrient wild plant food additives used by Masaai in meat and milk based soups. Ecol Food Nutr 1997;3
Madgula VL, Ali Z, Smillie Alkaloids and saponins as cytochrome P450 inhibitors from blue cohosh (Caulophyllum thalictroides) in an in vitro assay. Planta Med. 2009 Mar;75(4):329-32. doi: 10.1055/s-0028-1112207.
Hellum BH, Nilsen OG. In vitro inhibition of CYP3A4 metabolism and P-glycoprotein-mediated transport by trade herbal products. Basic Clin Pharmacol Toxicol. 2008 May;102(5):466-75.
Saponins also inhibit cytochromes. Blue cohosh, Caulophyllum thalictroides is a popular herb, roots and rhizomes of which have been extensively used for women's health. It contains the saponins, caulosides which 100 microM inhibit CYP3A4 by 40%. Inhibition of CYP 3A4 leads to an improved bioavailability of drugs. On some 20 samples provided by IFBV-BELHERB Luxembourg the university VUB of Brussels found that many Artemisia plants are strong inhibitors, stronger than ketoconazol or grapefruit juice.
Lazaridi Kristina. Invloed van de chemische samenstelling van Artemisia annua op CYP3A4-activiteit en antioxidant vermogen. Masterproef voorgelegd tot het verkrijgen van de graad van Apotheker. Academiejaar 2013-2014, Vrije Universiteit Brussel.
Carica papaya has also been extensively used as antimalarial, mainly the extracts of the leaves which are very bitter and contain a lot of saponins.
Maestrini M, Tava A, In Vitro Anthelmintic Activity of Saponins Derived from Medicago spp. Plants against Donkey Gastrointestinal Nematodes. Vet Sci. 2019 Mar 29;6(2).
I.E. Liener , in Encyclpedia of Food Sciences and Nutrition, 2003
Herbivores, saponins and bitter tastants
In livestock feeds, saponins often reduce plant palatability and function as anti-feedants. We learned this when we offered to a few cows freshly cut Artemisia annua from our plantations. After a first interest, they showed disgust and disappointment. Bitter taste receptors TAS2R in the nasal respiratory epithelium may have discouraged them, even before they swallowed the plant.
The corollary is obvious : plants produce toxic substances as a defense stratgy from herbivores.All this goes back to a study which we run with the University of Liège-Gembloux in 2011. It was found that saponins significantly reduce the production of ammonia in the rumen of cattle. Inversily they increase the concentration of amino acids in the gut. The mucosal permeability will be higher, favouring the hydrolysis of proteins, Methane emississions will be low. The general effect in cattle feed is beneficial.
But they modify gut microbes and protozoa. Overfeeding with saponin rich plants may lead to intestinal lesions and liver damage.
Benoit V., Constant C., De Fays M., Deleixhe G., Millet C., Sana G Etude des possibilités de développement de la culture d'Artemisia annua L. dans les zones tropicales de basse altitude d’Afrique subsaharienne. Gembloux Agro-Bio Tech (ULg). Projet interdisciplinaire. 23/12/2011
Hess, H.D., Kreuzer, M., Diaz, T.E., Lascano, C.E., Carulla, J.E., Soliva, C.R., Machmuller, A., 2003. Saponin rich tropical fruits affect fermentation and methanogenesis in faunated and defaunated rumen fluid.Animal Feed Science and Technology,109:79–94