Natural products: Call for hard evidence

Abstract

Wild plants, algae, fungi etc. are an essential part of people's diet all over the world (Bacchetta et al., 2016). According to the Food and Agriculture Organization of the United Nations more than 100 million people in the European Union, or about 20% of the world's population, consume wild plants as part of their diet and/or for medicinal purposes (Bacchetta et al., 2016). A further >65 million (14% of the world's population) occasionally collect some form of wild plants (Bacchetta et al., 2016). In the context of human evolution, wild plants are of particular importance as they are at the dynamic interface between food and pharmacology. Plants are not just a simple food but can also be a type of dietary supplement with hypothesized cardiopreventive and chemopreventive properties (Lu et al., in press; Visioli, 2022). Among the proposed mechanisms of action of plants as dietary supplements, anti-inflammatory, hepatoprotective and neuroprotective effects are of major importance and are being actively investigated, although the intracellular signalling pathways responsible for these effects remain to be fully elucidated (Forman et al., 2014). Moreover, some plants contain potentially antibacterial products that could theoretically be used in the current and urgent search for new antibiotics to overcome resistance (Bacchetta et al., 2016; Wernli et al., 2023). Indeed, the bioactive components of plants (hereafter referred to as natural products) are being actively researched by pharmacologists worldwide.

In addition to pharmaceutical preparations, health food stores in many countries offer products made from or enriched with natural products (Visioli, 2022). Examples include coffee based on Cichorium intybus, syrup made from Taraxacum spp. and pasta, to which the powder of Urtica spp. has been added to take advantage of the alleged health benefits of natural products (Bacchetta et al., 2016). However, the true nature and extent of the pharmacological activities of natural products are still largely unexplored (with some notable exceptions, e.g. atropine, digoxin, paclitaxel, quinine, quinidine, morphine and capsaicin, among others). Furthermore, the actual impact of regular consumption of these molecules on the prevention of chronic diseases is currently unclear. Scientists have shown that wild vegetables often contain high concentrations of minerals and phytochemicals, such as (poly)phenols, terpenoids or polysaccharides, and high levels of some vitamins, for example A and C. In fact, a plant-based diet is associated with a higher life expectancy (Fadnes et al., in press; Willett et al., 2019). One of the proposed mechanisms of action is that various plants produce biologically active secondary metabolites, many of which are phenolic in nature and thought to be involved in plant defence mechanisms. From an ethnopharmacological perspective, people have used plants in a ‘clinical’ framework for millennia (Bacchetta et al., 2016). Today, many active compounds are extracted from plants and formulated and marketed as ‘nutraceuticals’ or ‘functional foods’, often with ambiguous legislation and a ‘natural’ halo effect (Visioli, 2022).

Nevertheless, there are little data on the efficacy and safety of natural products in pharmaceutical food preparations, as only a very limited number of plant species have been thoroughly investigated. Large arrays of molecules are poorly characterized (Tome-Carneiro & Visioli, 2016). Similarly, there are few surveys on natural products for veterinary medicine, which is an ever-growing market (Stoev, 2024). The metabolic pathways of natural products can also produce toxic compounds that need to be detected to protect human and animal health. Complex extracts may also contain high levels of toxins that might accumulate in the environment in a fashion similar to that of synthetic pharmacological preparations (U.S. Environmental Protection Agency, 2024). Most importantly, the vast majority of natural products have been studied in in vitro models using human cells (often at supra-physiological concentrations) and have indeed been shown to possess potentially beneficial activities that have yet to be demonstrated in vivo, particularly in humans (Tome-Carneiro & Visioli, 2016). Indeed, an often-overlooked aspect of natural products pharmacology is that their bioavailability is seldom investigated. Very often, the molecules responsible for the biological effects are the in vivo metabolites of, for example, (poly)phenols (Favari et al., 2024; Visioli et al., 2011), whose formation exhibits high inter-individual variability (Favari et al., 2024) and that are quite difficult to synthesize, and then studied in vitro to elucidate their targets and mechanisms of action.

Given the potential of natural products for various aspects of human well-being, it is important to involve a variety of stakeholders and disciplines in the investigation of health-related properties. For this reason, IUPHAR has initiated a project aimed at establishing a science-based registry of natural products and their pharmacological activities, with a view to providing a better understanding of their potential influences on human health.

There is a need for a joint effort. A successful research activity should take up the challenge of establishing scientific collaboration between different disciplines, and between scientists and society in order to promote discussion on knowledge, practices and values, and generate results that are relevant to pharmacology and society in general.

From a pharmacological perspective, it is important to evaluate the effects of selected natural products on important determinants of health, such as immune response and inflammation (among others, as noted above). This activity should ideally be extended to the evaluation of the pharmagenomic effects of selected natural products in humans. The broad spectrum of bioactivities that characterize natural products (those that are well characterized molecularly and much less characterized in crude preparation, such as teas) should be thoroughly tested to improve human health, ideally following the protocols of allopathic medicine.

Finally, appropriate dissemination and communication activities are essential to raise consumer awareness of natural products and their use, in order to optimize their consumption as healthy and also, as a mandatory part of future politics and environmentally friendly ‘medicines’. These activities should also gain the support of stakeholders and policymakers to expand efforts for the cultivation, commercialization and, in turn, valorization of plants with high phytochemical content in a virtuous cycle. We believe the time is right to produce and disseminate hard evidence on the pharmacological actions of natural products and we ask stakeholders to contribute to IUPHAR's effort.

FV wrote the article.

The author declares no conflicts of interest.