In ancient times people used trial and error to identify medicinal plants as being effective. Later, diseases were believed to arise from imbalances in body fluids (or ‘humours’), and botanical drugs were thought to restore this balance through the power of their taste. Modern science rejects this theory but does recognise the importance of chemosensation – our sensitivity to chemicals through taste and smell. These senses evolved in humans to help us seek out nutrients and avoid toxins and may also have guided the ancient uses of botanical drugs.

There are many records of historical medicinal plant use and ailments, which makes it possible to explore possible relationships between therapeutic uses of botanical drugs and their chemosensory qualities. To investigate if therapeutic uses of botanical drugs could indeed be predicted by taste and flavour, Leonti, Baker et al. collected 700 botanical drugs identified in an ancient text, named De Materia Medica, which dates back to the 1^st century CE.

The researchers asked volunteer tasters to classify the botanical drugs using 22 taste descriptions, such as bitter, aromatic, burning/hot, and fresh/cooling. The volunteers were also asked to score the strength of these tastes. Leonti, Baker et al. then used statistical modelling to see if the participant’s taste descriptions could be used to predict the therapeutic uses of the drugs identified in the ancient text.

This revealed that of the 46 therapeutic indications described in the text, 45 showed significant associations with at least one taste quality. Botanical drugs with stronger and simpler tastes tended to be used for a wider range of therapeutic indications. This suggests that chemosensation influenced therapeutic expectations in ancient, prescientific medicine.

The study of Leonti, Baker et al. brings ancient medicine to life, offering valuable insights into the chemosensory aspects of medicinal plants and their potential applications in modern medicine. A next step would be to explore whether these insights could have relevance to modern science.

‘A bitter pill to swallow’ is just one of many common idioms referring to the taste of medicine, which from ancient to early modern times has relied mostly on botanical drugs (Touwaide, 2022). In ancient Greece and Rome, the expected effects of botanical drugs were explained by their taste (Jones, 1959; Einarson and Link, 1990; Jouanna, 2012) and according to the prevailing medical theory, disease resulted from a disequilibrium between bodily fluids or humours including phlegm, blood, yellow bile, and black bile; drugs affected the flow and balance of these humours (Jones, 1959; King, 2013). Theophrastus (300 BCE) attributed sweet the capacity to smoothen, astringent with the power to desiccate and solidify, pungent with the capacity to cut or to separate out the heat, salty with desiccating and irritating properties, and bitter with the capacity to melt and irritate (Einarson and Link, 1990). Other systems of medicine, such as Ayurveda and Traditional Chinese Medicine, continue to classify materia medica according to tastes and flavours (Dragos and Gilca, 2018; Shou-zhong, 1998), and indigenous societies use chemosensory qualities to select botanical drugs (Casagrande, 2000; Leonti et al., 2002; Shepard, 2004).

The perception of taste and flavour (a combination of taste, smell, and chemesthesis), here also referred to as chemosensation, has evolved to meet nutritional requirements and is particularly important in omnivores for seeking out nutrients and avoiding toxins (Rozin and Todd, 2016; Breslin, 2013; Glendinning, 2022). The rejection of bitter stimuli has generally been associated with the avoidance of toxins (Glendinning, 1994; Lindemann, 2001; Breslin, 2013) but to date no clear relationship between bitter compounds and toxicity at a nutritionally relevant dose could be established (Glendinning, 1994; Nissim et al., 2017). While bitter tasting metabolites occurring in fruits and vegetables have been linked with a lower risk for contracting cancer and cardiovascular diseases (Drewnowski and Gomez-Carneros, 2000), the avoidance of pharmacologically active compounds is probably the reason why many medicines, including botanical drugs, taste bitter (Johns, 1990; Mennella et al., 2013).

Botanical drugs are chemically complex and often used for a range of different health problems (Wagner et al., 2007). Chemical complexity determines pharmacological complexity, since different chemicals interact with different targets (Gertsch, 2011), and influence taste complexity and intensity (Spence and Wang, 2018; Breslin and Beauchamp, 1997; Green et al., 2010). Today, some associations between chemosensory qualities and therapeutic uses, such as bitter-tasting botanical drugs for stomach problems or astringent ones for diarrhoea, are still recognised in Western herbal medicine (Wagner et al., 2007). These observations establish a role for chemosensory qualities in medicine. Yet, taste and flavour are largely irrelevant to modern medicine, aside from the pharmaceutical industry looking for ways to mask bad tastes (Mennella et al., 2013).

Whether ancient systems of traditional medicine could be relevant to modern science is questionable. The theory of humours was the principal underlying the concept of Western medicine from ancient Graeco-Roman times until the Industrial Age, but as an entirely discredited theory it might be expected that associated practices also lack scientific basis.

However, we propose that taste and flavour perception of botanical drugs links humoral theory to modern medicine. We hypothesise that chemosensation and underlying physiological effects mediated by chemesthesis and taste receptor pharmacology co-explain the diversity of therapeutic uses of botanical drugs in ancient times. We further hypothesise that associations between perceived complexity and intensity of chemosensory qualities of botanical drugs and their versatility (number of categories of therapeutic use a botanical drug is recommended for) provide insights into the development of empirical pharmacological knowledge and therapeutic behaviour. If tastes and flavours, as determined by a modern-day tasting panel, do predict uses as recorded in ancient texts, this would be an unprecedented insight into how chemosensation in combination with physiological effects guided human behaviour in pre-historic times and conditioned therapeutic expectations and humoral theory in historic times. To test these hypotheses, we assessed the relationships between chemosensory qualities, their intensity, and complexity with therapeutic uses of botanical drugs described in Pedanios Dioscorides’ pharmacognostic compendium, De Materia Medica (DMM; Matthioli, 1970; Staub et al., 2016), the foremost pharmaceutical source of antiquity. DMM compiles knowledge on the sourcing, preparation, and therapeutic consensus of botanical drugs traded and used in the Eastern Mediterranean region of the Roman Empire during the first century CE (Riddle, 1985). We collected 700 botanical drugs described in DMM (Supplementary file 1) and used quality descriptors to represent chemosensation by a trained tasting panel scoring each botanical drug for presence and intensity of each quality (Figure 1; Supplementary files 2 and 3). We arranged the botanical drugs into therapeutic uses according to affected organs, therapeutic functions, diseases, and symptoms as indicated in DMM, and into broader and more inclusive categories of therapeutic use (Figure 1; Supplementary files 1 and 4). By applying phylogenetic generalised linear mixed models (PGLMMs) to our data and a plant phylogeny (Zanne et al., 2014; see Methods), we tested whether perceived taste and flavour qualities, as well as their overall intensity and complexity predict recorded therapeutic uses whilst simultaneously accounting for the confounding effects of the shared uses and chemosensory stimuli by drugs from closely related species.

Figure 1

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Unexpectedly, botanical drugs eliciting fewer but intense chemosensations were more versatile (Figure 2). People often associate complexity with intensity, and taste complexity is popularly interpreted with a higher complexity of ingredients (Spence and Wang, 2018). However, chemosensory perception is relative to exposed stimuli and simple tastes can be associated with complex chemistry when intense tastes mask weaker tastes, or when tastants are blended (Breslin and Beauchamp, 1997; Green et al., 2010). For example, starchy flavours or sweet tastes can be sensed when bitter and astringent antifeedant compounds are present below a certain threshold while salts enhance overall flavour by suppressing the perception of bitter tastants (Breslin and Beauchamp, 1997; Johns, 1990). On the other hand, combinations of different tastants or olfactory stimuli do not necessarily result in increased perceived complexity (Spence and Wang, 2018; Weiss et al., 2012). The relationship between intense chemosensation and versatility (Figure 2) is consistent with a perceived causal link between strong sensations and strong effects that is probably innate (Ganchrow et al., 1983; Glendinning, 1994). We also detected nuances in significance, and complete absence of significance across the relationships between individual therapeutic uses and complexity/intensity magnitudes for which we lack, however, more specific explanations (Figure 2—figure supplement 1).

Low therapeutic versatility of sour tasting drugs (12 negative associations) may best be understood by considering the uses that this taste was negatively associated with in our PGLMMs (Figure 3). For example, the significant association between sour and treatment of coughs (p_x = 0.038) and other respiratory problems (p_x = 0.042; Figure 3; Supplementary files 5 and 6) might be related to coughing triggered by acid signalling in the airways (Kollarik et al., 2007). Moreover, acidic solutions and tissue acidosis are associated with inflammation and nociception while acid reflux is a common cause of chronic cough probably triggered by an oesophageal-bronchial reflex (Irwin, 2006). The negative associations of sour but also salty drugs with pain management (p_x = 0.021 and 0.022, respectively; Figure 3; Supplementary files 5 and 6) are probably related to the avoidance of nociception known by personal experience to result from the contact between acidic or salty solutions and skin or mucous membrane lesions.

The therapeutic versatility of drugs perceived as sweet (13 positive associations) and starchy (12 positive associations) (Figure 3; Supplementary files 5 and 6) is influenced by the many staples and edible fruits that are also used for medicine (e.g. protein-rich Fabaceae seeds were often perceived as having starchy tastes). The daily use of food items, generally with a low toxicity, has allowed for a more detailed comprehension of their postprandial effects, which arguably has led to a diversification of uses. The 96 botanical drugs specifically mentioned also for food (though there are more than 150 edible drugs in our dataset; Supplementary file 1) show positive associations with starchy (p_x = 0.005), nutty (p_x = 0.002), and salty (p_x = 0.001) and negative associations with bitter (p_x = 0.007), woody (p_x = 0.001), and stinging (p_x = 0.033) chemosensory qualities.

Sweet sensations are known to induce analgesia (Kakeda et al., 2010) reflected here by a positive association of sweet-tasting drugs with the treatment of pain (p_x = 0.032). Both starchy (p_x = 0.001) and salty (p_x = 0.002) are associated with the treatment of diarrhoea and dysentery. Today, mixtures of glucose, starch, and electrolytes are used to treat secretolytic and inflammatory diarrhoea caused by bacterial enterotoxins (Thiagarajah et al., 2015; Binder et al., 2014). These oral rehydration solutions exploit sodium/glucose co-transport by sodium/glucose co-transporter 1 in the small intestine and sodium absorption through sodium-hydrogen antiporter 2 stimulated by short chain fatty acids synthesised from starch by bacteria in the colon (Thiagarajah et al., 2015; Binder et al., 2014). Drugs perceived as starchy are also positively associated with the treatment of topical ulcers (p_x = 0.001), skin infections (p_x = 0.025), other skin conditions (p_x = 0.035) and the topical treatment of venomous and non-venomous animal bites (p_x = 0.001) where plasters with lenitive properties might bring benefit. Moreover, fresh Fabaceae seeds contain protease inhibitors (Birk, 1996; Wink and Waterman, 2018) such as trypsin and chymotrypsin inhibitors, which have the potential to inhibit bacterial proteases and control bacterial virulence during cutaneous infections (Frees et al., 2013; Culp and Wright, 2017).

Bitter was the most frequently reported chemosensory quality and showed nine significant associations with therapeutic use – including the negative association with foods (Figure 3). Though many bitter compounds are toxic, not all bitter plant metabolites are (Glendinning, 1994; Drewnowski and Gomez-Carneros, 2000; e.g. iridoids, flavonoids, glucosinolates, bitter sugars). In part, this may be the outcome of an arms race between plant defence and herbivorous mammals’ bitter taste receptor sensitivities, resulting in the synthesis of metabolites capable of repelling herbivores and confounding the perception of potential nutrients by mimicking tastes of toxins. Here, poisons showed no association with bitter (perhaps because they were chosen so that they were unobtrusive and inconspicuous) but positive associations with aromatic (p_x = 0.041), sweet (p_x = 0.022), and soapy (p_x = 0.025) as well as a negative association with salty (p_x = 0.046) qualities (but see the discussion about humoral management).

Anti-inflammatory pharmacology of several bitter tasting compounds explains the positive associations with treatments of sciatica (p_x = <0.001; Figure 3). Bitter-tasting drugs to treat sciatica derive from several disparate lineages containing a range of different anti-inflammatory compound classes such as iridoids (Viljoen et al., 2012; Ajuga, Centaurium), sesquiterpene lactones (Coricello et al., 2020; Artemisia, Inula), triterpene saponines (Gepdiremen et al., 2006; Wang et al., 2014; Citrullus, Ecballium, Leontice), and cumarins (Kirsch et al., 2016; Opopanax, Ruta) (Supplementary files 1 and 2).

Generally, overarching explanations for versatility based on chemosensory perception are not feasible. However, we hypothesise that many of the associations we found (Figure 3; Supplementary files 5 and 6) are grounded in observed physiological effects mediated by chemesthesis and taste receptor pharmacology (Chandrashekar et al., 2006; Palmer and Servant, 2022). Cumulative evidence suggests that together with transient receptor potential channels (TRPs), extraoral taste receptors and ectopic olfactory receptors form a chemosensory network involved in homeostasis, disease response, and off-target drug effects (Foster et al., 2014; An and Liggett, 2018; Kang and Koo, 2012; Hauser et al., 2017; Clark et al., 2012). Bitter taste receptors, for instance, are located also in human airways where their activation mediates bronchodilation and the movement of motile cilia which leads to improved respiration and evacuation of mucus (Shah et al., 2009; Deshpande et al., 2010). Indeed, bitter showed positive associations with the treatment of breathing difficulties (p_x = 0.027) and other respiratory problems (p_x = 0.004). We find that drugs used to treat pain, including pain associated with breastfeeding (breast inflammation and lactation), are significantly more likely to have fresh and cooling qualities (p_x = 0.01 and 0.037, respectively). This is likely owing to interactions with TRP channels (McKemy et al., 2002; Behrendt et al., 2004; Proudfoot et al., 2006; Memon et al., 2019). Specifically, the TRPM8 channel mediates cold stimuli and is known to be activated by cooling essential oil constituents producing analgesic effects (McKemy et al., 2002; Behrendt et al., 2004; Proudfoot et al., 2006). Cooling menthol and eucalyptol have been shown to act as counterirritants inhibiting respiratory irritation caused by smoke constituents (Willis et al., 2011) explaining the positive association between drugs used to treat breathing difficulties with fresh and cooling flavours (p_x = 0.04). The strong positive association of burning and hot drugs with oral applications for treating musculoskeletal problems (p_x = 0.004) might be related to analgesic properties mediated by desensitising effects upon TRP channel interaction (Marwaha et al., 2016; Aroke et al., 2020). Burning and hot drugs are also positively associated with vascular problems (p_x = 0.042) including varices and haemorrhoids and can be explained with vasorelaxant effects transmitted by TRP channels on the endothelial cells (Montell, 2005; Pires and Earley, 2017). TRPV channels are also involved in kidney and urinary bladder functioning (Montell, 2005) and TRPV1-knockout mice urinate more frequently without voiding their bladder (Birder et al., 2002). Interactions with TRPV1 and other TRPV receptors might therefore explain the use of hot botanical drugs to treat other urinary problems including urinary retention, incontinence, kidney, and bladder problems (p_x = 0.047).

The concepts of humoral medicine may have derived from the observation that the appearance and consistency of bodily fluids during disease change and that they can be modified. The positive association of bitter taste with humoral management (p_x = 0.004) as well as with liver problems and jaundice (p_x = 0.002) is explained by uses intended to purge and resolve bitter bile and seems to include what we call choleretics and cholekinetics today, such as the roots of the great yellow gentian (Gentiana lutea) or the herb of the common vervain (Verbena officinalis). However, several of the plant drugs used for humoral management have strong emetic and purgative effects which are manifestations of their toxicity. Such remedies were abandoned along with humoral therapy and include drugs derived from squirting cucumber (Ecballium elaterium), castor bean (Ricinus communis), spurge (Euphorbia spp.), hellebore (Helleborus sp.), and white hellebore (Veratrum sp.). Astringent and woody qualities showed positive associations with the treatment of diarrhoea and dysentery (p_x = 0.029 and p_x = 0.019) where there is a need for controlling the flow of fluids and for drying them up. Similarly woody, often correlating with astringency (Scalbert et al., 1989), was also positively associated with the staunching of vaginal discharge (p_x = <0.001). Curiously, astringency showed positive associations with external applications for musculoskeletal conditions (p_x = 0.001) where drying internal bleeds and solidifying tissues and bones are needed. Negative associations of astringency emerged with conditions where the flux of humours, perspiration, and the evacuation of liquids and mucus are treatment strategies, such as in fever (p_x = 0.045), humoral management (p_x = 0.02), urinary calculus (p_x = 0.02), other urinary problems (retention, incontinence, kidney, and bladder problems, p_x = <0.001) and cough (p_x = 0.002). More obviously, the intake of salt aggravates fluid retention and oedema, and this is likely the reason why remedies for dropsy and oedema (diuretics) are negatively associated with salty tastes (p_x = 0.023).

While chemosensory qualities of botanical drugs and their physiological effects help to explain the persistence of humoral medicine until the 19th century, our study highlights the potential of chemosensory pharmacology in the development of herbal medicines. Botanical drugs with observed chemosensory profiles not aligned with those of their therapeutic use might represent drugs working beyond chemosensory pharmacology. Conversely, associations of chemosensory qualities with therapeutic uses of botanical drugs may certainly overlap with the presence of metabolites with specific therapy-relevant constituents acting beyond chemosensory pharmacology. This is, for instance, the case with opium (dried milk sap of Papaver somniferum) indicated for ‘cough’ and perceived as bitter (Figure 3; Supplementary files 1 and 2) but at the same time containing alkaloids with central cough suppressant properties (Dewick, 2001). Besides the associations discussed, other therapeutically relevant chemosensory receptor functions might be involved in the associations currently lacking explanations. While we are aware that the limitation of this study is the impossibility to address all associations found and the dependence on published pharmacological data for the explanatory part, our approach demonstrates the power of phylogenetic methods applied to human behaviour and assessment of plant properties. We show that chemosensory perception connects ancient therapeutic knowledge with modern science, even though aetiologies were fundamentally different in Graeco-Roman times. Our study offers a blueprint for macroscale re-evaluation of pre-scientific knowledge and points towards a central role for taste and flavour in medicine.

All data generated or analysed during this study are included in the manuscript and supporting files (Supplementary files 1–6).

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Author details

1. Marco Leonti

   Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing – original draft, Project administration, Writing – review and editing

   For correspondence

   mleonti@unica.it

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4726-9758

2. Joanna Baker

   School of Biological Sciences, University of Reading, Reading, United Kingdom

   Contribution

   Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   For correspondence

   j.l.a.baker@reading.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4904-6934

3. Peter Staub

   Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy

   Contribution

   Conceptualization, Data curation, Investigation, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4875-7064

4. Laura Casu

   Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy

   Contribution

   Resources, Data curation, Methodology, Project administration

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6480-8680

5. Julie Hawkins

   School of Biological Sciences, University of Reading, Reading, United Kingdom

   Contribution

   Supervision, Investigation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9048-8016

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