Taste shaped the use of botanical drugs

Reviewer #1 (Public Review):

Summary:
The authors explored correlations between taste features of botanical drugs used in ancient times and therapeutic uses, finding some potentially interesting associations between intensity and complexity of flavors and therapeutic potential, plus some more specific associations described in the discussion sections. I believe the results could be of potential benefit to the drug discovery community, especially for those scientists working in the field of natural products.

Strengths:
Owing to its eclectic and somehow heterodox nature, I believe the article might be of interest to a general audience. In fact, I have enjoyed reading it and my curiosity was raised by the extensive discussion.

The idea of revisiting a classical vademecum with new scientific perspectives is quite stimulating.

The authors have undertaken a significant amount of work, collecting 700 botanical drugs and exploring their taste and association with known uses via eleven trained panelists.

Weaknesses:
I have some methodological concerns. Was subjective bias within the panel of participants explored or minimized in any manner? Were the panelists exposed to the drugs blindly and on several occasions to assess the robustness of their perceptions? Judging from the total number of taste assessments recorded and from Supplementary Material, it seems that not every panelist tasted every drug. Why? It may be a good idea to explore the similarity in the assessments of the same botanical drug by different volunteers. If a given descriptor was reported by a single volunteer, was it used anyway for the statistical analysis or filtered out?

The idea of "versatility" is repeatedly used in the manuscript, but the authors do not clearly define what they call "versatile".

The introduction should be expanded. There are plenty of studies and articles out there exploring the evolution of bitter taste receptors, and associating it with a hypothetical evolutionary advantage since bitter plants are more likely to be poisonous. Since plant secondary metabolites are one of the most important sources of therapeutic drugs and one of their main functions is to protect plants from environmental dangers (e.g., animals), this evolutionary interplay should be at least briefly discussed in the introductory section. Since the authors visit some classical authors, Parecelsus' famous quote "All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison" may be relevant here. Also note that some authors have explored the relationship between taste receptors and pharmacological targets (e.g., Bioorg Med Chem Lett. 2012 Jun 15;22(12):4072-4).

Reviewer #2 (Public Review):

Summary:
This is an unusual, but interesting approach to link the "taste" of plants and plant extracts to their therapeutic use in ancient Graeco-Roman culture. The authors used a panel of 11 trained tasters to test ~700 different medicinal plants and describe them in terms of 22 "taste" descriptors. They correlated these descriptors with the plant's medical use as reported in the De Materia Medica (DMM 1st Century, CE). Correcting for some of the plants' evolutionary phylogenetic relationships, the authors found that taste descriptors along with intensity measures were correlated with the "versatility" and/or specific therapeutic use of the medicine. For example, simple but intense tastes were correlated with the versatility of a medicine. Specific intense tastes were linked to versatility while others were not; intense bitter, starchy, musky, sweet, cooling, and soapy were associated with versatility, but sour and woody were negatively associated. Also, some specific tastes could be associated with specific uses - both positive and negative associations. Some of these findings make sense immediately, but others are somewhat surprising, and the authors propose some links between taste and medicinal use (both historical and modern use) in the discussion. The authors state that this study allows for a re-evaluation of pre-scientific knowledge, pointing toward a central role of taste in medicine.

Strengths:
The real strength of this study is the novelty of this approach - using modern-day tasters to evaluate ancient medicinal plants to understand the potential relationships between taste and therapeutic use, lending some support to the idea that the "taste" of a medicine is linked to its effectiveness as a treatment.

Weaknesses:
While I find this study very interesting and potentially insightful into the development and classification of certain botanical drugs for specific medicinal use, I would encourage the authors to revise the manuscript and the accompanying figures significantly to improve the reader's understanding of the methods, analyses, and findings. A more thorough discussion of the limitations of this particular study and this general type of approach would also be very important to include.

The metric of versatility seems somewhat arbitrary. It is not well explained why versatility is important and/or its relationship with taste complexity or intensity. Similarly, the rationale for examining the relationships between individual therapeutic uses and taste intensity/complexity is not well explained, and given that a similar high intensity/low complexity relationship is common for most of the therapeutic uses, it restates the same concepts that were covered by the initial versatility comparison. There are multiple issues with the figures - the use of icons is in many cases counterproductive and other representations are not clear or cause confusion (especially Figure 3). The phylogenetic information about the botanicals is missing. Also missing is any reference/discussion about how that analysis was able to disambiguate the confounding effects of shared uses and tastes of drugs from closely related species.