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Plants are rich in a variety of compounds. Many are secondary metabolites and include aromatic substances, most of which are phenols or their oxygen-substituted derivatives such as tannins (Hartmann 2007; Jenke-Kodama, Müller, and Dittmann 2008). Many of these compounds have antioxidant properties (see Chapter 2 on antioxidants in herbs and spices). Ethnobotanicals are important for pharmacological research and drug development, not only when plant constituents are used directly as therapeutic agents, but also as starting materials for the synthesis of drugs or as models for pharmacologically active compounds (Li and Vederas 2009). About 200 years ago, the first pharmacologically active pure compound, morphine, was produced from opium extracted from seeds pods of the poppy Papaver somniferum . This discovery showed that drugs from plants can be purified and administered in precise dosages regardless of the source or age of the material (Rousseaux and Schachter 2003; Hartmann 2007). This approach was enhanced by the discovery of penicillin (Li and Vederas 2009). With this continued trend, products from plants and natural sources (such as fungi and marine microorganisms) or analogs inspired by them have contributed greatly to the commercial drug preparations today. Examples include antibiotics (e.g., penicillin, erythromycin); the cardiac stimulant digoxin from foxglove ( Digitalis purpurea ); salicylic acid, a precursor of aspirin, derived from willow bark ( Salix spp .); reserpine, an antipsychotic and antihypertensive drug from Rauwolfia spp .; and antimalarials such as quinine from Cinchona bark and lipid-lowering agents (e.g., lovastatin) from a fungus (Rishton 2008; Schmidt et al. 2008; Li and Vederas 2009). Also, more than 60% of cancer therapeutics on the market or in testing are based on natural products. Of 177 drugs approved worldwide for treatment of cancer, more than 70% are based on natural products or mimetics, many of which are improved with combinatorial chemistry. Cancer therapeutics from plants include paclitaxel, isolated from the Pacific yew tree; camptothecin, derived from the Chinese “happy tree” Camptotheca acuminata and used to prepare irinotecan and topotecan; and combretastatin, derived from the South African bush willow (Brower 2008). It is also estimated that about 25% of the drugs prescribed worldwide are derived from plants, and 121 such active compounds are in use (Sahoo et al. 2010). Between 2005 and 2007, 13 drugs derived from natural products were approved in the United States. More than 100 natural product-based drugs are in clinical studies (Li and Vederas 2009), and of the total 252 drugs in the World Health Organization’s (WHO) essential medicine list, 11% are exclusively of plant origin (Sahoo et al. 2010).

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• 1.1. HERBAL MEDICINE: A GROWING FIELD WITH A LONG TRADITION
• 1.2. HERBAL MEDICINE AND THE AGING POPULATION
• 1.3. HERBAL MEDICINES: CHALLENGES AND REGULATIONS
• 1.4. RESEARCH NEEDS
• 1.5. CONCLUSIONS
• ACKNOWLEDGMENTS
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• Barnes P. M, Bloom B, Nahin R. Complementary and alternative medicine use among adults and children: United States, 2007. CDC National Health Statistics Report # 12. 2008. www.cdc.gov/nchs/data/nhsr/nhsr012.pdf . www.cdc.gov/nchs/data/nhsr/nhsr012.pdf access date: 5 Nov. - PubMed
• Beckman K. B, Ames B. N. The free radical theory of ageing matures. Physiol Rev. 1998;78:47–81. - PubMed
• Benzie I. F. F, Wachtel-Galor S. Biomarkers in long-term vegetarian diets. Adv Clin Chem. 2009;47:170–208. - PubMed
• Benzie I. F, Wachtel-Galor S. Vegetarian diets and public health: Biomarker and redox connections. Antioxid Redox Signal. 2010;13(10):1575–91. - PubMed

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Herbal Medicine: A Comprehensive Review

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Traditional herbal medicine: overview of research indexed in the scopus database

• Original Article
• Published: 28 October 2022
• Volume 23 , pages 1173–1183, ( 2023 )

Cite this article

• Hassan Hussein Musa 1 , 2 ,
• Taha Hussein Musa 2 , 3 ,
• Olayinka Oderinde   ORCID: orcid.org/0000-0002-2050-0948 4 ,
• Idris Hussein Musa 5 ,
• Omonike Olatokunbo Shonekan 6 ,
• Tosin Yinka Akintunde 7 &
• Abimbola Kofoworola Onasanya 8  

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Traditional herbal medicine has been playing an essential role in primary health care globally. The aim of this work is to present an overview of traditional herbal medicine research productivity over the past years. The data was accessed from the Scopus database ( www.scopus.com ), while VOSviewer.Var1.6.6, Bibliometrix, and R studio were used for further analysis of the obtained data. The results showed that researches on traditional herbal medicine increased annually after 1990, followed by a corresponding increase in global citations during the period, with a total of 22,071 authors contributing to all the publications. Yiling Wang of Shanghai Institute of Drug Control, Shanghai, China was the most productive author (TNP = 303), while Journal of “Evidence-based Complementary and Alternative Medicine”, and “Journal of Ethnopharmacology” were the top ranked journals, respectively. Also, China, Japan, and India were found to be the top Corresponding Author's Countries for researches on traditional herbal medicine, as Beijing University of Chinese Medicine, China Academy of Chinese Medical Sciences and China Medical University were top affiliations. Moreover, National Natural Science Foundation of China, National Key Research and Development Program of China, Ministry of Science and Technology of the People's Republic of China, and Ministry of Science and Technology, Taiwan were top funding agencies, with more than 100 documents. The bibliometric research study has revealed an annual increasing trend in traditional herbal medicine, while also revealing that the topmost ranked authors and funding agencies were from Asia especially China.

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Introduction

Traditional herbal medicine (or alternative herbal medicine) has played an essential role as a source of primary health care for many, globally (Maroyi and Cheikhyoussef 2015 ), as it has maintained the health of majorly Africans and Asians for thousands of years with a unique medical system built based on empirical- and accumulated knowledge. It has been reported that ~ 70–80% of Africa’s emerging urban and rural population rely on traditional herbal medicine for health intervention (Hostettmann et al. 2000 ; Lee et al. 2019 ), and even at the moment, billions of people around the world are taking traditional herbal medicine daily in form of food, drugs or supplements (Aydin et al. 2016 ). Traditional herbal medicine have been reported to have been used to cure or prevent many diseases and ailments including gastroesophageal reflux disease (Dai et al. 2020 ), prevents postoperative recurrence of small hepatocellular carcinoma (Zhai et al. 2018 ), adjuvant for chemo- and radiotherapy for cancer (Qi et al. 2010 ), adjunctive therapy for nasopharyngeal cancer (Kim et al. 2015 ), resectable gastric cancer (Lee et al. 2018 ), treatment of viral infections, stress and anxiety as well as improve mental health during Covid-19 pandemic (Shahrajabian et al. 2021 ; Yu et al. 2020 ), just to mention a few. Therefore, sustainable management towards traditional herbal medicine, the reactions, and challenges in the monitoring and safety of plant resources are essential sources of new drugs development which are used in treating several diseases ranging from general body pain to complicated diseases in humans (Kutalek and Prinz 2005 ; Maroyi and Cheikhyoussef 2015 ).

Bibliometric analysis has been used in many fields including Covid-19 and mental health (Akintunde et al. 2021 ), gum arabic (Musa et al. 2021a ), neem (Onasanya et al. 2022 ) and in diseases such as sickle cell anemia (Musa et al. 2021b ), anticancer research using herbal medicine (Basu et al. 2017 ), herbal medicine for pain (Wang and Meng 2021 ), medical treatment of cardiovascular diseases (Huang et al. 2016 ), and natural products against cancer (Du and Tang 2014 ). The findings from these studies have helped researchers to explore new directions for future research while also playing a fundamental role in decision making regarding policy, in addition to identifying new perspectives on potential collaborations in these fields (Basu et al. 2017 ; Du and Tang 2014 ; Huang et al. 2016 ; Musa et al. 2021a , 2021b ; Wang and Meng 2021 ). However, there is yet any bibliometric analysis reportedly conducted to enhance the understanding of research hotspots, frontiers, and trends in the traditional herbal medicine indexed in the Scopus, as this will initaiate a focus on future researches and identify gaps, hence assist to explore current patterns and trends in literatures (Dol et al. 2021 ). Furthermore, using bibliometric analysis will enable researchers have a good grasp of the basic characteristics of the publications done over the years with empirical evidence on traditional medicine.

Therefore, in order to identify and further promote the growth and development of traditional herbal medicine, we used Bibliometric analysis to analyse all the published literatures therein. This technique can draw the primary bibliometric landscapes of the development of topics, highlighting the most active authors, influential countries or regions, topmost research interests in the fields and the hot topics covered over the past years, in addition to the international and national collaboration networks among authors, countries or regions. Hence, this paper aims to establish via analysis, the research productivity on the traditional herbal medicines indexed in the Scopus database, while assessing the research gaps by reviewing the published literatures.

Materials and methods

Sources of data.

A bibliographic data acquisition was carried out using the Scopus database ( https://www.scopus.com/ ) updated to March 2, 2022. Scopus is a world leading scientific database widely known for its extensive database of abstracts and citations which offers researchers the most comprehensive literature (covering all fields of natural sciences, medicine, social sciences and life sciences) retrieval.

Search strategy

We developed our search by examining related publications on traditional herbal medicine using the following query with the corresponding search approach based on:

TITLE ("traditional herbal medicine") OR TITLE ("Herbal medicine") OR TITLE ("herbal drug") OR TITLE ("Traditional Chinese medicine") OR TITLE ("Chinese medicine") OR TITLE ("Persian medicine") OR TITLE ("traditional Iranian medicine") OR TITLE ("Ayurveda") AND (EXCLUDE (PUBYEAR, 2022) OR EXCLUDE (PUBYEAR, english AND limit-to AND doctype)) AND (LIMIT TO (DOCTYPE, "ar")) AND (LIMIT-TO (LANGUAGE, "English")).

To ensure the high quality and academic nature of the literatures, only full research articles published in English were included. Initially, the search query returned 10,163 documents and the authors thereafter screened the titles of these articles for relevance. The total extracted docuemtns were harvested after retrieval and saved as Bib format, CSV format, and RIS format for further analysis using the bibliometric tool to run the frequency and generating, visualizing, and analyzing the maps. Two authors (THM and HHM) used bibliometric techniques to set a protocol to retrieve and collect reliable and relevant publications on traditional herbal medicine, as shown in Fig.  1 . More also, the research category and organisations which enhanced the research productivity over the years were manually retrieved, while the quality of publication was assessed by calculating author’s or journal’s H-index (Fassin and Rousseau 2019 ; Garfield et al. 2006 ). The Journals’ impact factor (IF) for the year 2020 was also considered for visualising analysis results by using two bibliometric visualization tools (Garfield et al. 2006 ).

The inclusion and exclusion process on traditional herbal medicine related-publications

Data analysis analysis

Bibliometric data were presented using descriptive mapping analysis via VOSviewer, while Var1.6.6 was used for developing, constructing and viewing the bibliometric maps analysis by the unit of co-occurrence analysis, co-citation and bibliographic coupling to examine the length (L) or total length strength (TLS) occurrences or reports between authors, keywords in the titles, abstracts, organizations and countries within the distributed clusters (van Eck and Waltman 2010 ). Also, bibliometrix and a R package were used to perform the comprehensive bibliometric science mapping analysis (Dervis 2019 ).

Basic characteristics of global publication analysis

In total, 10,163 articles met the criteria of articles published during year 1909 to 2021. It was observed that there was an annual increase in the number of publications after the year 1990 (Fig.  2 ). Of the 10,163 publications, an average of 15.09 citations per documents were found in 2552 Journals, which involved 22,071 authors with 2.34 Collaboration Index (CI) (Table 1 ).

Year-wise distribution of number of publications, 1905–2021

Analysis of 10 top highly-cited documents

The recognition of a document on traditional herbal medicine can be reflected by the number of times it is cited, as presented in Table 2 , on the descriptive analysis of the top 10 articles that have been published on the domain per citation during the years of investigation. An article titled “TCMSP: a database of systems pharmacology for drug discovery from herbal medicines” which was published in the Journal of Cheminformatics by Ru JL et al. (Ru et al. 2014 ) received the top-ranked cited article with 1346 citations and 149.5556 Total Citations Per Year. This was followed by the article “Some traditional herbal medicines, some mycotoxins, naphthalene and styrene, published with World Health Organization International Agency for Research On Cancer (WHO–IARC 2002 ) which received 774 citations and 36.8571 Total Citations Per Year (Table 2 ).

Journal analysis and quality of the publication

A total of 2552 journals were involved in the publication of traditional herbal medicine researches indexed in the Scopus database. The analysis revealed that the Journal of “Evidence-based Complementary and Alternative Medicine” was the topmost productive journal (h_index = 32, TNP = 401), followed by Journal of Ethnopharmacology (h_index = 57, TNP = 359) and then Chinese Journal of Integrative Medicine (h_index = 18, TNP = 253) as presented in Table 3 .

Evaluation of scientific research by geographical area

In the evaluation of the scientific output based on geographical area, it was found that ninety-four (94) Corresponding Author's Countries contributed to the traditional herbal medicine-based published works, out of which only the top 10 most productive countries were listed in Table 4 . People’s Republic of China was revealed to be the most productive (TNP = 4585), followed by the Japan (TNP = 730), India (TNP = 485), USA (TNP = 479) and Korea (TNP = 339), respectively. Meanwhile, the highly cited countries revealed that China is the topmost with reported 67,287 citations at an average citation of 14.675, followed by Japan with 14,372 citations at an average of 19.688 citations and then United States of America with 13,011 at an average of 27.163 citations, while Germany (3163 citations at an average of 27.991 citations) and Iran (1848 citations at an average of 9.625 citations) are coming from the rear back, on traditional herbal medicine-based researches published during the study period.

Authors productivity and co-authorship analysis

On the authors’ productivity, a total of 22,071 authors have been revealed to have contributed to traditional herbal medicine publications within the study period. The analysis of the top 10 authors shows that Yiling Wang from Shanghai Institute of Drug Control, Shanghai, China has the highest contribution with 303 published articles and an H_index of 39, followed by Zhang Y of Yunan University of Chinese Medicine College with 228 published documents and an H_index of 27, among other reported authors, as given in Table 5 .

Top subject areas and funding sponsors for research on traditional herbal medicine

In order to analyse the key subject areas in relation to traditional herbal medicine, most of published articles were indexed in field of Medicine (6005; 38.0%), Pharmacology, Toxicology and Pharmaceutics (2607; 16.5%), Biochemistry, Genetics and Molecular Biology (1885; 11.9%), Chemistry (1341; 8.5%), Agricultural and Biological Sciences (552; 3.5%), Nursing (343; 2.2%), Immunology and Microbiology (337; 2.1%), Chemical Engineering (320; 2.0%), Environmental Science (277; 1.8%), Health Professions (273; 1.7%), amongst other subject areas (Fig.  3 ). Moreover, majority of research fundings emanated form National Natural Science Foundation of China, National Key Research and Development Program of China, and Ministry of Science and Technology of the People's Republic of China. Furthermore, Beijing University of Chinese Medicine, China Academy of Chinese Medical Sciences, China Medical University, and Shanghai University of Traditional Chinese Medicine were amongst the top listed affiliations (Table 6 ).

Subject area on traditional herbal medicine

Co-occurrence analysis

The network visualization of co-occurrence indicates the frequency number of a keyword that appeared to determine the hot topics, while the color of each point on the map represents the density of the term over the past years, and the color represents the cluster. Also, the lines between the items represent the links. All Keywords (the minimum number of occurrences of keyword with over 300) were selected, as only 81 Keywords met the threshold and were included in the network analyses, which show different occurrences of the topic as organized into three (3) clusters with links and total link strength given between the keywords (L = 3118, TLS = 521,963), as shown in (Fig.  4 A).

A Co-occurrence of Keyword Plus analysis ( A ). B Co-author networks analysis among organizations C Co-author networks analysis among countries

Co-author networks analysis among authors, organizations, and countries or regions

Based on a threshold of 10, the minimum number of documents for an author was selected, yielding a total of 47 organizations (Fig.  4 B), which were thereafter organized into 5 distinct groups/clusters with links and total links strength (L = 77, TLS = 346), while countries were organized into 7 clusters with links and total links strength (L = 420, TLS = 2285), as shown in Fig.  4 C.

Bibliometrics has played a significant role in influencing policymaking as well as presenting a better understanding of scientific fields (Akintunde et al. 2021 ; Onasanya et al. 2022 ). The data for this study were retrieved from Scopus because the database provides different h_index ratings for authors who will need them to track citations and determine the impact of their publications (Musa et al. 2021c ). The total number of traditional herbal medicine related-publications has been increasing annually since the year 1990, as traditional herbal medicine has gained attractive attention due to easy accessibility, affordability, safety, promising efficacy, and being environmentally bening (Musa et al. 2021d ; Shahrajabian et al. 2019 ). Their essential roles in public health have led many people of different nationalities to rely on traditional herbal medicince (Soleymani and Shahrajabian 2018 ), as many herbs and plants included in several traditional systems have promising bioactive compounds for modern drug therapy (Shahrajabian et al. 2020 ) (Fig.  5 ).

Prisma flow diagram of the inclusion and exclusion process of the on traditional herbal medicine related-publications

The recognition of a document on traditional herbal medicine can be reflected by the number of times it is cited as presented in Scopus and other databases. “TCMSP: a database of systems pharmacology for drug discovery from herbal medicines” (Ru et al. 2014 ) and “Some Traditional Herbal Medicines, Some Mycotoxins, Naphthalene and Styrene” (WHO–IARC 2002 ) were reported to have being the most influential documents, with the highest number of total citations, as the research of J. Ru and coworkers (Ru et al. 2014 ) focussed on drug discovery from herbal medicines.

The analysis of journals based on h_index, total citations, number of documents, and Journal impact factors for the year 2021, revealed that Evidence-Based Complementary and Alternative Medicine, Journal of Ethnopharmacology and Chinese Journal of Integrative Medicine were the topmost ranked journals, based on their total number of publications, total citations and h_index, as these journals are more concentrated in traditional herbal medicines.

Also, the total number of traditional herbal medicine-focused publications generated 94 countries, with China, Japan, India and the USA being the topmost ranked countries in that order. This is in addition to the top 10 most productive authors coming only from China. This is of no coincidence as China is a reservoir of various high-valued medicinal plants, which have been used in the cosmetics, nutraceutical and pharmaceutical industries (Sun and Shahrajabian 2020 ). Increasing the research productivity in China is an indicator of the previous published reports that highlighted that herbal medicine is an essential part of traditional medicine which is part of Chinese culture. Moreso, traditional herbal medicine has been in practise in China for thousands of years (Fabricant and Farnsworth 2001 ). Due to the importance of traditional chinese herbal medicine in Chinese culture, Beijing University of Chinese Medicine and the Chinese Academy of Chinese Medical Sciences were the highest ranked in Organizations-enhanced traditional herbal medicine researches, as the top ten affiliations based on traditional herbal medicines were mainly Chinese domiciled, while the other developing countries are still lagging in conventional herbal medicine research productivity, although most developing countries depend on conventional herbal medicine to treat many diseases (Sen and Chakraborty 2017 ). The lagging in traditional herbal medicine-based researches in most developing countries could be attributed to fewer funding agencies that support scientific researches with grants. The results further revealed that the top ranking authors were Yiling Wang, Zhang Y, Yan-Da Li and Jong-Jing Wang, while Beijing University of Chinese Medicine, Chinese Academy of Chinese Medical Science, China Medical University and Shanghai University of Traditional Chinese Medicine, all based in China, were top ranking organizations. Furthermore, the cooperation networks facilitated by the creation of a database for storing a large portion of the data and their transformation into valuable information , has effectively contributed to the progress of the traditional medicine information system (Noraziah et al. 2011 ). Noteworthy, China’s Comprehensive Herbal Medicine Information System for Cancer has served as an appropriate information resource for traditional medicine researchers (Fang et al. 2005 ), while Web-based Decision Support System for Prescription in Herbal Medicine could play a significant role in controlling the quality of the herbal drugs prescriptions. Also, developed for consulting with the patients in the e-health system, e-health Record System in Australia has successfully assisted traditional medicine practitioners in the treatment management (Bjering et al. 2011 ). Although, there are some limitations as we have only included documents published in English language, while only one database, Scopus was used even though other databases such as Web of Sciences (WoS), Embase, PubMed, and Google scholar have also contributed extensively in the coverage of traditional herbal medicine researches.

Conclusions

The current study is the first bibliometric analysis of traditional herbal medicine scientific researches and publications. The study has shown an increasing publishing trend in recent years, in addition to identifying the global patterns of research, which serves as a tool in supporting the decisions and policies in traditional medicine. However, there is a need to increase research activities and international collaborations, particularly in developing countries as the present world system has been pushing for green and natural products rather than the synthetic ones.

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Acknowledgements

The authors acknowledge the support of the Biomedical Research Institute, Darfur College, Nyala, Sudan, while also appreciating the research innovation of The Organization of African Academic Doctors (OAAD), Nairobi, Kenya for enhancing research collaboration and innovations in Africa.

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Hassan Hussein Musa

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Hassan Hussein Musa & Taha Hussein Musa

Key Laboratory of Environmental Medicine Engineering, Department of Epidemiology and Health Statistics, School of Public Health, Ministry of Education, Southeast University, Nanjing, 210009, China

Taha Hussein Musa

Department of Chemical Sciences (Chemistry Unit), Faculty of Natural and Applied Sciences, Lead City University, Ibadan, Nigeria

Olayinka Oderinde

School of Medicine, Darfur University College, Nyala, Sudan

Idris Hussein Musa

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Lagos, Lagos, Nigeria

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Department of Sociology, School of Public Administration, Hohai University, Nanjing, China

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Musa, H.H., Musa, T.H., Oderinde, O. et al. Traditional herbal medicine: overview of research indexed in the scopus database. ADV TRADIT MED (ADTM) 23 , 1173–1183 (2023). https://doi.org/10.1007/s13596-022-00670-2

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SYSTEMATIC REVIEW article

Current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments.

• 1 Institute of Pharmaceutical Biology, Goethe University, Frankfurt, Germany
• 2 Institute of General Practice, Goethe University, Frankfurt, Germany
• 3 Department of Urology and Pediatric Urology, University Medical Center Mainz, Mainz, Germany
• 4 Department of Family Medicine, Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands
• 5 Department of Public Health and Primary Care, Academic Centre of General Practice, KU Leuven, Leuven, Belgium

Herbal medicines are becoming increasingly popular among patients because they are well tolerated and do not exert severe side effects. Nevertheless, they receive little consideration in therapeutic settings. The present article reviews the current state of research on the clinical benefits of herbal medicines on five indication groups, psychosomatic disorders, gynecological complaints, gastrointestinal disorders, urinary and upper respiratory tract infections. The study search was based on the database PubMed and concentrated on herbal medicines legally approved in Europe. After applying defined inclusion and exclusion criteria, 141 articles were selected: 59 for psychosomatic disorders (100% randomized controlled trials; RCTs), 20 for gynecological complaints (56% RCTs), 19 for gastrointestinal disorders (68% RCTs), 16 for urinary tract infections (UTI, 63% RCTs) and 24 for upper respiratory tract infections (URTI) (79% RCTs). For the majority of the studies, therapeutic benefits were evaluated by patient reported outcome measures (PROs). For psychosomatic disorders, gynecological complaints and URTI more than 80% of the study outcomes were positive, whereas the clinical benefit of herbal medicines for the treatment of UTI and gastrointestinal disorders was lower with 55%. The critical appraisal of the articles shows that there is a lack of high-quality studies and, with regard to gastrointestinal disorders, the clinical benefits of herbal medicines as a stand-alone form of therapy are unclear. According to the current state of knowledge, scientific evidence has still to be improved to allow integration of herbal medicines into guidelines and standard treatment regimens for the indications reviewed here. In addition to clinical data, real world data and outcome measures can add significant value to pave the way for herbal medicines into future therapeutic applications.

1 Introduction

Plant derived drugs have been used since humans have started treating physical and mental illnesses. They are part of Traditional Medicine in different cultures all over the world ( Yuan et al., 2016 ). Since then, medicine and treatment procedures have evolved and while in Traditional Medicine a holistic approach of life focusing on health and its maintenance was common philosophy, present Modern Medicine has a clear emphasis on unravelling the changes leading to disease and eradiating it ( Fries, 2019 ). Traditional medicine has a rigorous algorithm of identifying the root of the disease, which is based on traditional concepts, which, unfortunately, are considered obsolete nowadays, despite their practical longevity (e.g., acupuncture, ayurveda). The problem is that this traditional medical epistemology is not fully understood and science has limited tools to “translate” it into modern terms.

With the success of synthetic drugs along with the design of targeted therapies interfering specifically with the respective disease-related signaling pathways, herbal medicines have been eliminated from modern rational treatment strategies. The most important obstacles for the use in novel therapy strategies is that markers to measure clinical efficacy of herbal medicine have not been developed so far. Markers of efficacy of herbal drugs could also be useful to distinguish between patients who could benefit from a therapy with herbal medicines from those who will not. First preclinical studies already indicate that those markers or “signatures” (e.g., mRNA, miRNA) could be found in the future ( Bachmeier et al., 2007 ; Bachmeier et al., 2008 ; Bachmeier et al., 2009 ; Bachmeier et al., 2010 ; Killian et al., 2012 ; Kronski et al., 2014 ).

In the last years, more and more patients report on the perceived efficacy of herbal drugs and praise the absence of undesired side effects and the good tolerability.

The following section provides insights into the standard therapies of selected ailments for which herbal medicines may be a rational alternative.

1.1 Indications suitable for treatment with herbal medicines

Herbal medicines are in particular suitable for the treatment of non-life-threatening conditions for which knowledge from traditional use is available pointing to their clinical benefits in treating the respective ailment ( Wachtel-Galor and Benzie, 2011 ). This applies especially to psychosomatic disorders, gynecological complaints, and upper respiratory tract infections. However also for other diseases like gastrointestinal diseases, urinary tract infections herbal medicines have been clinically applied and—as we will show in this review—with some success.

Standard Care of psychosomatic disorders comprises the application of synthetic psychotropic drugs and psychotherapy ( Laux, 2021 ). Psychotropic drugs are used not only for the treatment of depressive disorders and anxiety, but also for sleep disorders, excitation and chronic pain ( Gründer and Benkert, 2012 ). However undesired adverse events having negative impact on quality of life can occur like, e.g., weight gain, sexual dysfunction, sedation, headache and tremor ( Grunze et al., 2017 ). In addition their use, in particular benzodiazepines, can lead to addiction and drug abuse ( Soyka and Mann, 2018 ) and interactions with other medication has to be taken into consideration especially in older multimorbid patients ( Burkhardt and Wehling, 2010 ). About 23% of all over 70-year-old people have psychosomatic disorders with about 40% requiring therapy ( Haupt and Vollmar, 2008 ). In this context herbal medicines represent an interesting alternative to avoid the above-mentioned problems with standard synthetic drugs. However, they do not belong to standard therapy-options and therefore are underrepresented in therapy-guidelines ( Bittel et al., 2022 ). Nevertheless they play an important role in self-medication of patients ( Stange, 2014 ) probably due to their favorable ratio between benefit and side-effects.

Gynecological complaints include, e.g., menopausal and premenstrual symptoms. According to the German medical guideline for post- and perimenopause, vasomotor symptoms of the peri- and post-menopause such as hot flushes and sweating should be treated with hormone therapy for menopause (hormone replacement therapy; HRT), if not contraindicated ( AWMF, 2020 ). The side effects of HRT include edema, joint pain, psychological symptoms or even thrombosis and breast cancer ( Maclennan et al., 2004 ). Herbal medicines, on the other hand, are characterized by a low risk of adverse events which increases patients’ adherence and in consequence prevents therapy discontinuations ( AWMF, 2020 ). Premenstrual syndrome (PMS) is characterized by recurring physical and psychological symptoms in the days before menstruation. There are currently no medical guidelines in German-speaking countries for the treatment of PMS. Systematic reviews on hormonal treatments (oral contraceptives, progesterone and estrogen) ( Ford et al., 2006 ; Lopez et al., 2007 ; Naheed et al., 2013 ; Kwan and Onwude, 2015 ) and acupuncture/acupressure ( Armour et al., 2018 ) point to ambiguous evidence. Treatment with serotonin reuptake inhibitors was shown to be effective but was associated with frequent side effects, e.g., nausea and asthenia ( Marjoribanks et al., 2013 ).

Gastrointestinal diseases include several conditions like irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), liver disease (hepatitis), and functional dyspepsia (FD).

Beside dietary changes, stress management and psychotherapy, severe cases of IBS and IBD require additional medication to reduce inflammation or to slow down the intestinal irritations. However patients often complain about the side effects of medical treatment like, e.g., dizziness or weight gain (particularly caused by steroids), or undesired fatigue, headache, and/or tiredness associated with the intake of methotrexate ( Feagan et al., 1995 ). Common types of hepatitis are viral hepatitis B and C. Antiviral therapy represents the treatment of choice to fight the virus caused disease. However, poor tolerability and significant adverse effects that include, for example, headaches, dizziness, depression, and irritability often lead to treatment discontinuation, further decreasing response rates ( Cornberg et al., 2002 ). FD is a common gastrointestinal disorder treated by proton pump inhibitors (PPI) or H2 receptor antagonist, and/or treatment with tricyclic antidepressants or prokinetic agents. As in all cases, adverse side effects may occur ranging from dizziness to the development of diabetes mellitus type 2 ( Yuan et al., 2021 ).

Urinary tract infections (UTI) with estimated 150 million cases worldwide each year reflect the most common outpatient infections ( Zavala-Cerna et al., 2020 ). Women are more susceptible than men with a lifetime incidence of 50%–60%. Application of antibiotics represents the standard treatment regimen to overcome the infection. However, serious side effects, predominantly exerted on the digestive system, may outweigh the benefits of this drug class. Most importantly, routine use of antibiotics bears the risk to trigger the selection of resistant strains. Hence, avoiding antibiotic treatment of UTI has gained high priority among the urologic community ( Jung et al., 2023 ). Lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) requires a medical therapy which aims to reduce the BPH-related complications. A range of synthetic drugs is available to treat this condition. However, these have a range of side effects, including postural hypotension, dizziness, asthenia, abnormal ejaculation, intraoperative floppy iris syndrome (α1-blocker), or decreased libido, gynecomastia, and erectile dysfunction (5α-reductase inhibitors) ( Cheng et al., 2020 ). Due to this, patients often discontinue treatment.

The most common acute upper respiratory infections include bronchitis, rhinosinusitis and common cold. Common cold or acute viral rhinosinusitis is triggered by a viral infection/inflammation of the nose and by definition has a duration up to 10 days. According to Jaume and co-workers ( Jaume et al., 2020 ) the recommended therapy (mainly symptomatic) contains of paracetamol, NSAIDs, second-generation antihistamines to reduce symptoms the first 2 days; nasal decongestants with small effect in nasal congestion in adults; combination of analgesics and nasal decongestants; ipratropium bromide for reducing rhinorrhea; probiotics; zinc when administered the first 24 h after the onset of symptoms; nasal saline irrigations; and some herbal medicines. About 5% of adults have an episode of acute bronchitis each year. An estimated 90% of these seek medical advice for the same ( Saust et al., 2018 ). Acute bronchitis is caused by infection of the large airways commonly due to viruses and is usually self-limiting. Bacterial infection is uncommon. Still, often antibiotics are prescribed, despite lacking effectiveness ( Tanner and Karen Roddis, 2018 ). Most medical guidelines advice a “wait-and-see” policy, the use of antihistamines and cough medicines is discouraged.

1.2 Objectives

In the last decade we experienced a renaissance of herbal medicines with a rising demand especially for the treatment of the before-mentioned indications. This implicates that there is an urgent need for a scientific progress towards a rational phytotherapy, which will combine the benefits of “Modern Medicine” with the “Traditional Knowledge” on the therapeutic benefits of herbal medicines.

In order to create a basis of knowledge to build upon novel interdisciplinary research ideas towards the establishment of herbal medicines into rational therapeutic strategies, we extracted information from clinical studies. Thereby we aimed to get an overview on.

- which herbal medicines have been studied so far for which ailment

- which outcomes have been studied

- what quality level (level of evidence) the published studies have

Answering these questions, we create a comprehensive critical picture of the current knowledge on clinical efficacy and benefits as well as on failures and possible adverse events. Based on the results of these studies we give recommendations for practitioners and patients.

2.1 Search strategy and selection of scientific reports

Information on the therapeutic use of herbal medicines in different ailments was collected from scientifically published articles by conducting a search in the database PubMed for each of the five indication groups according to the following inclusion and exclusion criteria.

2.1.1 Inclusion criteria

1. Herbal Medicine

2. Disorders/complaints (see section “Indications Suitable for Treatment with Herbal Medicines”). Depending on the ailment, the term “herbal medicine” was combined with a, b, c, d, or e respectively:

a.Psychosomatic symptoms (depressive disorder, sleeping disorders/insomnia, anxiety, cognitive impairment)

b.Gynecological complaints (climactic symptoms, menstrual symptoms, premenstrual syndrome)

c.Gastrointestinal disorders/dyspepsia

d.Urinary tract infections

e.Upper respiratory tract infections

3. Clinical Trial

Exclusion criteria

a. Reports in languages other than German or English language

b. No full-text available

c. Study protocols

d. Traditional medicine (e.g., Traditional Chinese Medicine, Ayurveda, etc. ),

e. Aroma therapy

f. Dietary supplements

g. Self-made extracts and preparations

h. Adjuvant treatment with herbal medicine

i. Herbal medicines without market access in the EU

j. In vivo / in vitro studies (pre-clinical studies)

k. Homeopathy

l. Acupuncture/acupressure

m. Children and youth (under the age of 18 years)

n. Healthy volunteers

o. Primary preventive interventions (incl. Pre-post-operative complaints)

p. Predominant comorbidities

q. Case studies/case reports

r. Televised, internet-based or web-based trials

Reasons for exclusion criteria:

a, b: Authors should be able to read and understand the full text; c: clinical results should have been obtained from a study; d, e, f, g, h, i: selected in order to filter all available information on legally approved (in Europe in particular in Germany) herbal medicines or the respective standardized extract (HMPC Monographs of the European Medical Agency - EMA) only; j: preclinical evidence should be excluded; k, l: alternative naturopathic therapy forms should be excluded; m: children should be excluded due to different drug metabolism; n, o: healthy volunteers should be excluded in order to obtain information on clinical therapeutic benefits; p: predominant comorbidities should be excluded because they can affect the efficacy of the herbal drug in particular when co-administered with other drugs; q; clinical benefits from single cases are difficult to generalize; r: excluded for methodological reasons, e.g., data interpretation.

2.2 Data extraction and quality assessment of scientific reports

To get an overview on the characteristics of all included articles, a table was created for each indication group containing information on the publication, the study design, the population and treatment duration, the indication and the primary outcome, the herbal medicine and comparison treatment (comparator) as well as the results. Furthermore, we performed a quality assessment of the collected reports according to the following scoring method.

• 1 point for an observational study or a pre-post observational comparison

• 2 points for a clinical trial

• 3 points for a randomized controlled trial plus 1 additional point for blinding

Thereby, a score between 1 and 4 was obtained indicating the quality for all scientific reports; respectively publications with the highest level of evidence (RCT + blinded) had a scoring value of four points (see Figures 1 – 5 ).

FIGURE 1 . Numbers of studies and outcomes.

3.1 Psychosomatic disorders

A search for publications with the terms “psychosomatic disorder” and “herbal medicine” yielded only 64 results. Therefore, the search was extended with more specific terms (see inclusion criteria) yielding in 4.440 hits for depressive disorder, 1.907 hits for sleeping disorders, 2.380 hits for anxiety and 1.374 hits for cognitive impairment including Alzheimer’s disease. After eliminating all publications according to the exclusion criteria 59 publications remained. Among those, 39 studies were related to depressive disorders, 4 to sleeping disorders, 6 to anxiety and 10 to cognitive impairment and Alzheimer’s disease (neurological disorders). Most of them were double blind randomized controlled trials (quality group 4). For the treatment of depressive disorders predominantly Hypericum perforatum L (St. John’s Wort; SJW) was used and only few studies examined the clinical benefits of Rhodiola rosea L (Rosewood). Valeriana officinalis L (Valerian Root) and Humulus lupulus L (Hops) extracts were preferred for the treatment of sleeping disorders, while for anxietyextracts of Lavandula angustifolia (Lavender) were studied. Extracts of Ginkgo biloba L (Maidenhair Tree) were used in clinical studies with patients having neurological disorders (cognitive impairment and Alzheimer’s disease). Supplementary Table S1 provides an overview of the studies, their characteristics and results (see also Figure 1 ).

3.1.1 Depressive disorders

The use of herbal medicines in depressive disorders is well examined and in particular the clinical benefits of SJW are well supported by clinical studies of high quality. All 37 selected studies on the use of SJW in depressive disorders ranging from mild to severe forms have been double-blind randomized controlled trials (quality group 4). Study duration was predominantly between 4 and 8 weeks and only few studies examined the effects for longer time periods of up to 6 months. The majority of the studies reported positive therapeutic effects concerning Hamilton depression rating scale (HAMD) as primary outcome parameter and only 5 of them ( Shelton et al., 2001 ; Davidson et al., 2002 ; Bjerkenstedt et al., 2005 ; Moreno et al., 2006 ; Rapaport et al., 2011 ) did not demonstrate superiority as compared to placebo or pre-post.

In six studies (published predominantly before the year 2000) comparing SJW with tricyclic anti-depressive drugs the clinical benefits of the herbal drug in respect to placebo or in pre-post comparison was at least equal to the synthetic drug no matter if it was imipramine ( Vorbach et al., 1994 ; Vorbach et al., 1997 ; Philipp et al., 1999 ; Woelk, 2000 ), maprotiline ( Harrer et al., 1994 ) or amitriptyline ( Wheatley, 1997 ). However, with regards to tolerability, SJW was clearly superior to any of the tricyclic antidepressants.

The more recent studies compared the efficacy of SJW with the selective serotonin reuptake inhibitors (SSRI) paroxetine, sertraline, citalopram and fluoxetine. In most of the 18 studies the therapeutic benefits of SJW were at least equal to those of the SSRIs ( Harrer et al., 1999 ; Berger et al., 2000 ; Brenner et al., 2000 ; Friede et al., 2001 ; van Gurp et al., 2002 ; Bjerkenstedt et al., 2005 ; Gastpar et al., 2005 ; Szegedi et al., 2005 ; Anghelescu et al., 2006 ; Gastpar et al., 2006 ; Sarris et al., 2012 ). In two studies SJW was even superior to fluoxetine ( Fava et al., 2005 ) or paroxetine ( Seifritz et al., 2016 ) in reducing depressive symptoms. In one study the responders of a previous study were included in a further RCT testing the efficacy of SJW against citalopram. Here the numbers of patients with relapse was lower in the SJW group as compared to citalopram ( Singer et al., 2011 ). The results of one study indicated that SJW was less efficacious than both fluoxetine and placebo, however in this study the group on SJW had the lowest remission rates ( Moreno et al., 2006 ). In two studies no statistical differences in HAMD scores between SJW, placebo and citalopram ( Rapaport et al., 2011 ) or sertraline ( Davidson et al., 2002 ) could be found with adverse effects in the SJW and the SSRI groups.

In most of the above-mentioned studies, comparing the efficacy of SJW to standard therapy, a placebo group was included. However, in 13 studies SJW was tested exclusively against placebo whereby two of these studies examined the efficacy of different dosages of SJW extract ( Laakmann et al., 1998 ; Kasper et al., 2006 ). In these studies, the higher concentrations had the better clinical benefits. In a continuation study of the effect of SJW in long term treatment a higher dosage (1,200 mg/d) was not superior to the lower one (600 mg/d) ( Kasper et al., 2007 ). Interestingly the higher dosages were still well tolerated although mild adverse events related to gastrointestinal disorders were observed in a small portion of the patients ( Kasper et al., 2006 ). In only one of our selected studies SJW was not effective in comparison to placebo for the treatment of major depression but safe and well tolerated ( Shelton et al., 2001 ). In all other studies SJW was superior to placebo no matter if given in low ( Laakmann et al., 1998 ; Lecrubier et al., 2002 ; Randlov et al., 2006 ), medium ( Kasper et al., 2006 ; Kasper et al., 2007 ; Mannel et al., 2010 ) or in high ( Hansgen et al., 1994 ; Harrer et al., 1994 ; Sommer and Harrer, 1994 ; Kalb et al., 2001 ; Uebelhack et al., 2004 ; Kasper et al., 2006 ; Kasper et al., 2007 ; Kasper et al., 2008 ) dosages.

For the efficacy of Rhodiola rosea in treatment of depressive disorders only few studies were performed so far. Therefore, a clear conclusion cannot be drawn, especially as the outcomes are not homogenous. While one study investigating the efficacy of R. rosea against placebo and the SSRI sertraline reported on a statistically not-significant inferiority of the herbal medicine ( Mao et al., 2015 ) another study demonstrated clinical benefits concerning the symptoms of depression, insomnia, emotional instability and somatization against placebo. In this study two dosages of R. rosea were tested and the higher dose (680 mg/d) showed even positive effects on self-esteem ( Darbinyan et al., 2007 ).

3.1.2 Sleeping disorder

Interestingly the search for qualitatively high clinical studies (according to our inclusion and exclusion criteria) revealed only few studies. The majority of them investigated the efficacy of valerian alone ( Donath et al., 2000 ) or in combination with hops ( Koetter et al., 2007 ) compared to placebo ( Donath et al., 2000 ; Koetter et al., 2007 ) or to oxazepam ( Dorn, 2000 ; Ziegler et al., 2002 ). All studies reported clinical benefits, however while the one research group reported that valerian alone was efficacious against insomnia ( Donath et al., 2000 ) the other group reported on clinical benefits only in combination with hops ( Koetter et al., 2007 ). Both study designs were placebo-controlled. In comparison to oxazepam valerian was not inferior and both therapy options improved sleep quality (SF-B) in a similar fashion ( Dorn, 2000 ; Ziegler et al., 2002 ).

3.1.3 Anxiety

Herbal Medicines with lavender extracts were clinically studied for the treatment of anxiety. Between 2010 and 2019 six qualitatively high studies performed in Germany, Austria and Switzerland reported on the beneficial effects of lavender against symptoms of anxiety with improvements on the Hamilton anxiety rating (HAMA) scale as primary outcome ( Kasper et al., 2010 ; Woelk and Schlafke, 2010 ; Kasper et al., 2014 ; Kasper et al., 2015 ; Kasper et al., 2016 ; Seifritz et al., 2019 ) and all studies used the same extract (WS1265). Four of the 6 studies were performed by the same group, however the study design differed. In these studies the efficacy of lavender was either compared to placebo ( Anghelescu et al., 2006 ; Kasper et al., 2010 ; Kasper et al., 2016 ; Seifritz et al., 2016 ) and/or to paroxetine ( Kasper et al., 2014 ) and lorazepam ( Woelk and Schlafke, 2010 ). Overall, the lavender preparation was regarded as efficacious and safe.

3.1.4 Neurological disorders (cognitive impairment and Alzheimer)

We selected 10 studies investigating the efficacy of ginkgo biloba extract in the treatment of cognitive impairment and Alzheimer’s Disease (AD) with 8 of them testing against placebo ( Le Bars et al., 1997 ; Le Bars et al., 2002 ; Le Bars, 2003 ; van Dongen et al., 2003 ; Schneider et al., 2005 ; Napryeyenko et al., 2007 ; Gavrilova et al., 2014 ; Gschwind et al., 2017 ), one against rivastigmine ( Nasab et al., 2012 ) and one against donepezil ( Mazza et al., 2006 ). In three of the studies two different ginkgo extracts did not show superiority over placebo regarding the primary outcome. In detail 5 of the studies showed that extracts of ginkgo biloba lead to a decrease in NPI composite score ( Gavrilova et al., 2014 ) improved significantly ADAS-Gog and GERRI ( Le Bars et al., 1997 ; Le Bars et al., 2002 ; Le Bars, 2003 ), or the SKT test battery ( Napryeyenko et al., 2007 ) as outcome parameters. In three studies ginkgo extracts did not show superiority over placebo regarding the primary outcome parameters ADAS-cog ( Schneider et al., 2005 ), gait analyses ( Gschwind et al., 2017 ) or SKT test-battery ( van Dongen et al., 2003 ), whereby in one of these studies the primary outcome parameter ADAS-cog also declined in the placebo group rendering the results of the study inconclusive ( Schneider et al., 2005 ). With respect to the AD conventional medication rivastigmine, ginkgo biloba extract was inferior regarding the primary outcome parameters MMSE and SKT test-battery ( Nasab et al., 2012 ). Finally one study in which gingko biloba was more efficacious than placebo and equal to the second generation cholinesterase inhibitor donepezil ( Mazza et al., 2006 ) was heavily criticized by two other groups ( Corrao et al., 2007 ; Korczyn, 2007 ), making it difficult to estimate if the use of ginkgo containing herbal medicines are justified for the treatment of mild to moderate AD.

3.2 Gynecological complaints

Of 383 search hits, 20 articles met the inclusion criteria. Eleven studies were related to menopausal symptoms and nine to PMS. Most were double-blind randomized controlled trials or observational studies ( Figure 2 ). The studies on menopausal symptoms reported mainly positive results and the results concerning PMS were exclusively positive ( Figure 2 ). The tested phytopharmaceuticals contained Cimicifuga racemosa (L.) (Black cohosh) (10 studies) and Salvia officinalis (Sage) (1 study) for the treatment of menopausal symptoms and Vitex agnus-castus L (VAC, Chaste tree) (8 studies) and SJW (1 study) for PMS. Supplementary Table S2 provides an overview of the study characteristics and results.

FIGURE 2 . Numbers of studies and outcomes.

3.2.1 Menopausal symptoms

In studies examining the clinical benefits of black cohosh for the treatment of menopausal symptoms, sample sizes ranged from n = 62 to n = 6,141. Treatment duration was between 12 weeks and 9 months. The herbal drug dosages ranged from 20 to 127.3 mg.

In comparison to HRT, the benefit-risk-balance points to significant non-inferiority and superiority of black cohosh ( Bai et al., 2007 ). In three other studies menopausal complaints improved overall, but differences between black cohosh and HRT were not significant ( Wuttke et al., 2003 ; Nappi et al., 2005 ; Friederichsen et al., 2020 ). The combination of black cohosh with SJW significantly reduced menopausal complaints and was superior to transdermal estradiol ( Briese et al., 2007 ). Independent of a high or low dose, menopausal complaints decreased significantly ( Liske et al., 2002 ; Drewe et al., 2013 ). Adverse events rates were lower in the low dose group ( Drewe et al., 2013 ) or similar to the high dose group ( Liske et al., 2002 ). Menopausal symptoms decreased significantly more for black cohosh compared to placebo ( Osmers et al., 2005 ). In another study with 62 participants, the difference between the symptom scores just approached significance ( Wuttke et al., 2003 ). Interestingly, this also applies to the comparison of conjugated estrogens and placebo. Adverse events rates did not differ significantly between black cohosh and placebo ( Wuttke et al., 2003 ; Osmers et al., 2005 ). Significant and clinically relevant reductions in menopausal symptoms ( Vermes et al., 2005 ) or higher quality of life ( Julia Molla et al., 2009 ) were observed after treatment with black cohosh compared to therapy start. Sage taken for 8 weeks significantly decreased the number of menopausal hot flushes from week to week ( Bommer et al., 2011 ). Observed treatment-related adverse events were mild and occurred in only one person. However, no comparison was made to another treatment or placebo.

3.2.2 Premenstrual syndrome

Eight studies dealt with the treatment of PMS with VAC. The sample sizes ranged from n = 43 to n = 1,634. Treatment duration was three cycles; Berger et al. (2000) added three subsequent cycles without treatment. The administered dosages ranged from 1.6 to 20 mg extract.

Results of studies comparing VAC with pyridoxine or placebo were similar. PMS symptom reduction was significantly more pronounced for VAC compared to pyridoxine ( Lauritzen et al., 1997 ) or placebo ( Schellenberg, 2001 ; Bachert et al., 2009 ; Barrett et al., 2010 ; Schellenberg et al., 2012 ). Rates of adverse events were similar between groups in each study ( Loch et al., 2000 ; Schellenberg, 2001 ; Barrett et al., 2010 ; Schellenberg et al., 2012 ). Schellenberg et al. (2012) compared a VAC reference dose to a lower and higher dose; the results were in favor for the reference dose compared to the low dose. No significant differences between the high and reference dose emerged. The number of participants with adverse events was slightly elevated for the high dose. In single-arm studies, symptoms of PMS significantly decreased after three cycles of VAC treatment ( Berger et al., 2000 ; Loch et al., 2000 ; Momoeda et al., 2014 ). Only mild PMS-like adverse events were observed. Berger et al. demonstrated a gradual symptom return after therapy completion ( Berger et al., 2000 ). PMS symptoms were significantly higher compared to the end of the treatment, but still 20% lower than at baseline.

A clinical study testing the efficacy of SJW in treating mild PMS ( Canning et al., 2010 ) demonstrated significant improvements in physical (e.g., food craving) and behavioral (e.g., confusion) symptoms compared to placebo. The effect on mood (e.g., irritability) and pain (e.g., cramps) was not significant.

3.3 Gastrointestinal disorders

A search for publications with the search terms “gastrointestinal disorder” and “herbal medicine” yielded a total of 19 results after applying the exclusion criteria. Of these, eight studies were related to hepatic disorders, three publications dealt with IBD, two studies focused on IBS, and six studies had been done on FD. Most of them were done in a double-blinded randomized controlled manner ( n = 12) ( Figure 3 ). Silybum marianum (L.) Gaertn (Silymarin, milk thistle) was used in patients suffering from a hepatic disease. Patients with IBD were treated with Artemisia absinthium L (wormwood) or Potentilla erecta (tormentil). The standardized extract STW 5 containing Iberis amara (bitter candytuft), Glycyrrhiza glabra L (Liquorice), Carum carvi L (caraway), Mentha × piperita (peppermint), Melissa officinalis L (lemon balm) , Matricaria chamomilla (chamomile) , Angelica archangelica (wild celery), Chelidonium majus (greater celandine) and milk thistle has been applied in IBS and FD. The same has been done with the standardized extract STW 5-II which in contrast to STW 5 is free of wild celery, greater celandine, and milk thistle. SJW has been used to treat patients suffering from IBS. A combination of the standardized extracts WS 1340 (peppermint oil) and WS 1520 (caraway oil) was used for patients with FD. Supplementary Table S3 and Figure 3 provide an overview of the study characteristics and results.

FIGURE 3 . Numbers of studies and outcomes.

3.3.1 Hepatic disease

Trials on steatohepatitis, cirrhosis and different kinds of hepatitis ( n = 18) included patient cohorts ranging from 14 to 200 participants, all of them aged >18 years. Patients were treated with silymarin orally or intravenously ( Pares et al., 1998 ; Tanamly et al., 2004 ; Ferenci et al., 2008 ; Hawke et al., 2010 ; Fried et al., 2012 ; Adeyemo et al., 2013 ; Fathalah et al., 2017 ; Tanwar et al., 2017 ) with dosages ranging from 280 to 2,100 mg/day or 5–20 mg/kg/day, respectively. Six studies compared the HM group to a placebo group ( Pares et al., 1998 ; Tanamly et al., 2004 ; Hawke et al., 2010 ; Fried et al., 2012 ; Adeyemo et al., 2013 ; Tanwar et al., 2017 ). Silymarin did not reduce virus titers and/or serum alanine transaminase (ALT) in patients with Hepatitis C and non-alcoholic Steatohepatitis C, compared to placebo ( Adeyemo et al., 2013 ). The same observation has been made by others ( Hawke et al., 2010 ). Furthermore, the integration of silymarin into a PEGylated (Peg)-interferon based regimen did not improve the outcome of HCV patients in terms of HCV RNA suppression and Enhanced Liver Fibrosis score performance ( Tanamly et al., 2004 ). There was also no effect of silymarin on HCV patients who were previously unsuccessfully treated with interferon (multicenter, double-blind, placebo-controlled trial) ( Fried et al., 2012 ). Although HCV-patients reported to “feel better” after 12 months of silymarin therapy in a further study, symptoms and quality of life (QOL) scores did not differ between the silymarin and the placebo group ( Tanamly et al., 2004 ). Treatment with silymarin was also well tolerated over a period of 2 years. However, the course of liver cirrhosis in this patient cohort has not been improved ( Pares et al., 1998 ). Contrasting these results, dose escalating studies on HCV cirrhotic patients revealed positive effects of silymarin or silibinin (also milk thistle), in a way that high-dosed silymarin (1,050 mg/day) improved QOL and biochemical parameters of chronic HCV-decompensated cirrhotic patients with no serious adverse events ( Ferenci et al., 2008 ; Fathalah et al., 2017 ) compared to low-dosed silymarin (420 mg/day). Notably, silibinin exerted a dose-dependent antiviral effect on Peg-interferon/ribavirin non-responders ( Ferenci et al., 2008 ; Fathalah et al., 2017 ).

3.3.2 Inflammatory bowel disease (IBD)

Between 2007 and 2009, three clinical trials on CD or IBD have been conducted, two in Germany (quality groups 1 and 2) and one in the United States (quality group 4) ( Huber et al., 2007 ; Omer et al., 2007 ; Krebs et al., 2010 ). Patients were treated with wormwood or tormentil for 3–10 weeks. A total of 30 patients were treated with wormwood or placebo ( Omer et al., 2007 ; Krebs et al., 2010 ). In this context, wormwood decreased tumor necrosis factor alpha levels and the CD activity index score, whilst scores for IBD questionnaire and Hamilton depression scale have been improved, compared to the controls ( Omer et al., 2007 ; Krebs et al., 2010 ). Daily intake of tormentil reduced clinical activity index scores in all patients, however, during the wash out phase scores increased again. Tormentil has been proven to be safe for ulcerative colitis patients in dosages up to 3,000 mg/day ( Huber et al., 2007 ).

3.3.3 Irritable bowel syndrome (IBS)

Symptoms of IBS were treated with STW 5 and STW 5-II or SJW (both studies were quality group 4) ( Madisch et al., 2004b ; Saito et al., 2010 ). The clinical trial carried out by Madisch et al. compared the effects of the treatment group with those of bitter candytuft mono-extract and placebo. STW 5 and STW 5-II (60 drops/day over 4 weeks) significantly reduced the total abdominal pain and the IBS score compared to placebo and bitter candytuft mono-extract ( Madisch et al., 2004b ). The study carried out by Saito and others investigated the clinical efficacy of SJW pointing to a lower effect as compared to placebo ( Saito et al., 2010 ).

3.3.4 Functional dyspepsia (FD)

Six studies on patients suffering from FD were performed, including treatment with either a WS 1520/WS 1340 combination ( n = 3) ( Madisch et al., 1999 ; Rich et al., 2017 ; Storr and Stracke, 2022 ) or with STW 5 ( von Arnim et al., 2007 ) and/or STW 5-II ( n = 3) ( Rösch et al., 2002 ; Madisch et al., 2004a ). WS 1340/WS 1520 was documented to be a “valuable” ( Storr and Stracke, 2022 ) or an “effective” therapeutic regimen ( Rich et al., 2017 ), as it relieved pain and improved disease-specific QOL, compared to placebo. The primary outcome of WS 1340/WS 1520 was also proven to be comparable to the prokinetic agent cisapride ( Madisch et al., 1999 ).

It is to be noted that the use of cisapride has meanwhile be restricted by the EMA due to the risk of potentially life-threatening cardiac arrhythmia [ https://www.ema.europa.eu/en/medicines/human/referrals/cisapride ].

Similar results have been presented in the STW 5 and STW 5-II trials. The gastrointestinal symptom score was significantly lowered when compared to the placebo group ( Madisch et al., 2004a ; von Arnim et al., 2007 ), with a therapeutic response comparable to cisapride ( Rösch et al., 2002 ).

3.4 Urinary tract infection (UTI) and lower urinary tract symptoms (LUTS)

Initial search on herbal drugs in urologic clinical trials pointed to 263 manuscripts published between 1983 and 2022. Narrowing the search to “herbal medicine” (HM) 18 relevant publications were identified. One publication was nearly identical to another one and, therefore, has not been taken care of in this chapter, one article only reviewed former trials (16 publications remaining). All of them were related to lower urinary tract infection (UTI), or acute uncomplicated cystitis, respectively. Four different HM have been applied, either compared to placebo or guideline-based treatment ( n = 12).

3.4.1 Urinary tract infections (UTI)

Several studies investigated the standardized herbal extract BNO 1045 which contains Centaurium erythraea Rafin, herba (Centaury); Levisticum officinale Koch, radix (Lovage); and Rosmarinus officinalis L., folium (Rosemary). In two studies, the clinical benefits of BNO 1045 in preventing UTI in high-risk women undergoing urodynamic studies (UDS) ( Miotla et al., 2018 ) or urogynecological surgeries ( Wawrysiuk et al., 2022 ) was evaluated. High-risk women were defined as: age over 70, elevated postvoid residual urine>100 mL, recurrent UTI, pelvic organ prolapse (POP) ≥II in POP-Q scale, and neurogenic bladder. No statistical differences in UTI incidence were found between patients receiving antibiotics or BNO 1045. No superiority of antibiotics over BNO 1045 has been confirmed as well in a subsequent prospective study on postoperative UTI after midurethral sling surgery (MUS) ( Rechberger et al., 2020 ). In another study, an herbal mixture based on D-mannose, Arctostaphylos uva-ursi, Betula pendula, and Berberis aristata was compared to BNO 1045 in reducing symptoms of UTI after MUS ( Rechberger et al., 2022 ). The rationale was based on the EAU 2022 guidelines which recommended D-mannose as prophylaxis of UTI. In this context, BNO 1045 was proven to be similar effective, compared to the herbal mixture. The use of BNO 1045 has been documented here to be a potential and valuable alternative to antibiotics for UTI prevention. All four trials have been carried out in the same institution involving the same main investigators which were (partially) associated with the manufacturer of BNO 1045.

A randomized, double-blind, multicenter Phase III clinical trials compared the efficacy and of BNO 1045 to antibiotics concerning symptoms and recurrence rates in women with uncomplicated UTI. Based on the endpoints “UTI-recurrence” and “additional antibiotics use”, BNO 1045 was proven to be non-inferior to antibiotic treatment ( Wagenlehner et al., 2018 ). In a retrospective cohort study, data from outpatients in Germany with at least one diagnosis of acute cystitis or UTI and a prescription of either BNO 1045 or standard antibiotics were analyzed ( Holler et al., 2021 ). Compared to antibiotics, BNO 1045 was associated with significantly fewer recurrence rates of UTI and with reduced additional antibiotic prescription. BNO 1045 was propagated to be an effective and safe symptomatic treatment option for acute cystitis or UTI.

In an open-labeled, randomized, controlled trail the effect of BNO 1045 to prevent recurrences of cystitis in younger women was evaluated ( Sabadash and Shulyak, 2017 ). All patients received an antibacterial therapy, the test group was additionally treated with BNO 1045. The integration of BNO 1045 prevented bacteriuria and recurrent cystitis episodes more frequently (primary outcome), compared to the control group without BNO 1045. This may indicate superiority of the combination therapy. However, interpretation of the results of the study is limited due to the lack of blinding on both sides - patients and physicians. A further study without any involvement of the manufacturer (no conflicts of interest noted) included younger women with acute uncomplicated cystitis. All patients received the same therapy, the nonsteroidal anti-inflammatory drug ketoprofen in combination with BNO 1045 ( Kulchavenya, 2018 ). Quite interestingly, although the majority of the patients responded well to the therapy, the investigators also observed patients who only slightly responded, or did not respond to treatment at all. The authors concluded that uncomplicated cystitis might be cured by BNO 1045 instead of antibiotics which may be required only in minor cases. Still, the data seems to be over-interpreted, since patients were treated with both ketoprofen and BNO 1045 which does not allow to conclude to one drug alone.

Aside from BNO 1045, further herbal medicines have been investigated in clinical studies. Tablets with a standardized herbal extract containing Armoraciae rusticanae radix (Horseradish root) (80 mg) and Tropaeoli majoris herba (Nasturtium) (200 mg) have been applied to patients suffering from chronically recurrent UTI symptoms, with the result that recurrent UTI symptoms were less, compared to the placebo group ( Albrecht et al., 2007 ). However, a subsequent trial failed to demonstrate non-inferiority of this extract to antibiotics due to a poor recruitment rate ( Stange et al., 2017 ). Actually, no respective clinical trials with sufficient statistical power are underway.

3.4.2 Lower urinary tract symptoms LUTS

Clinical studies have also been conducted with an herbal medicine containing the standardized extracts WS 1473 Sabal serrulata Schult.f (Sabal fruit) (160 mg) and WS1031 Urtica dioica L (Urtica root) (120 mg). All studies were related to the treatment of lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH). The study protocols (placebo-controlled, double-blind, multicentric) were similar in all trials with the International Prostate Symptom Score (I-PSS), quality of life index, uroflow and sonographic parameters as the outcome measures for treatment efficacy. In one study ( Lopatkin et al., 2005 ) patients were randomized to either the herbal medicine (WS 1473 and WS1031) (treatment group) or placebo (control group) while in another study patients received either WS 1473 and 1031 or the α1-adrenoceptor antagonist tamsulosin ( Engelmann et al., 2011 ). A further study was based on the previous mentioned study ( Lopatkin et al., 2005 ), whereby all patients were offered participation in a further 48-week follow-up with WS 1473/1031 ( Lopatkin et al., 2007 ). Independent on the study design, it was concluded that WS 1473/1031 is superior to the placebo, and not inferior to tamsulosin in the treatment of LUTS. In a later re-evaluation of the data sets, WS 1473/1031 was shown to significantly improve nocturnal voiding frequency compared to placebo, with similar effects compared to tamsulosin or the 5α-reductase inhibitor finasteride ( Oelke et al., 2014 ). No further studies have been enrolled since then. However, a database search in 2022 including 3,000 private practices in Germany revealed a significant association between WS 1473/1031 prescription and reduced incidence of urinary incontinence and urinary retention compared to tamsulosin and tamsulosin/dutasteride (5α-reductase blocker), as well as reduced incidence of erectile dysfunction compared to dutasteride ( Madersbacher et al., 2023 ). In all four studies the manufacturer of the extract was involved.

One observational study was investigating the effectiveness of a standardized herbal extract containing a combination of Cucurbita pepo L (Marrow), Rhus aromatica bark (Fragrant sumac), and hops, in women with overactive bladder ( Gauruder-Burmester et al., 2019 ). Of the 113 patients included, nearly the half (61 patients) used concomitant medications (e.g., antihypertensive, levothyroxine, lipid/cholesterol lowering agents, low dose ASS, NSAIDS) within the frame of a routine clinical setting. Considering the noninterventional character of this study, the herbal combination was demonstrated to improve overactive bladder symptoms and quality of life. A controlled study has not yet been initiated.

3.5 Upper respiratory tract infections (URTI)

The search on herbal medicines for the indication Upper Respiratory Infections revealed 24 publications.

The most common indications studied for the effectiveness of herbal medications were sinusitis, viral acute Rhisosinusitis (ARS) and common cold (N = 13), bronchitis (N = 8), and less frequently on acute cough (N = 2) and Acute lower and upper tract respiratory infections (N = 1) and chronic rhinosinusitis (N = 1). Most of them (N = 18) were double-blind randomized placebo-controlled trials, there were also randomized controlled trials that compared herbal medication to other herbal medication (N = 2) or to antibiotics (N = 1). Other study designs involved prospective cohorts (N = 3) and one retrospective cohort.

3.5.1 Sinusitis/common cold and chronic rhinosinusitis

Studies on treatment of acute sinusitis and acute rhinosinusitis used a follow-up period between 7 and 14 days, with the (adapted) Sinusitis Severity Score (SSS) (N = 2), the Major Symptom Score (MSS) (N = 4), the Total Symptom Score (N = 1) and facial pain relief (N = 1) as primary endpoints. All studies reported significantly improvement of the intervention group over the placebo or control group.

The treatment of acute sinusitis and acute rhinosinusitis with Eps 7630 (standardized root extract of Pelargonium sidoides DC (Pelargonium) was studied in two double blind randomised placebo controlled trials ( Bachert et al., 2009 ; Dejaco et al., 2019 ) and in one prospective ( Perić et al., 2020 ), randomized, open-label, non-inferiority study comparing study medication to Amoxicillin All three studies reported a significant superiority resp. Non-inferiority for Eps 7630. The use of the standardized herbal extract BNO 1016 ( Primulae flos (Primrose), Gentiana lutea Ruiz and Pav. Ex G.Don (Yellow gentian), Rumicis herba (Sorrel), Sambuci flos (Elderflower) and verbenae herba (Vervain) was tested in two randomised placebo controlled trials ( Jund et al., 2015 ), one of which was blinded ( Jund et al., 2015 ). Both studies showed stronger impact on the symptom score for BNO 1016 compared to placebo. One more study tested BNO 1016 in a multicenter, prospective, open-label study comparing its effect to intranasal fluticasone furoate, with patients in both groups showing improvement ( Passali et al., 2015 ). ELOM-080 (standardized herbal drug preparation containing specially destilled oils from Eucalyptus (Eucalypt) and Citrus ×sinensis (Sweet orange) and Myrtus (Myrtle) and Citrus limon (L.) Osbeck (Lemon oil)) was evaluated once in a double blind randomised placebo controlled trial ( Federspil et al., 1997 ) and once in a prospective, non-interventional parallel-group trial where the control group received BNO 1016 ( Gottschlich et al., 2018 ). In both studies BNO 1016 showed superior results.

The use of extracts containing Echinacea for the treatment of common cold was positively tested in two studies, reporting on total number of facial tissues used in three to 7 days after intervention start ( Naser et al., 2005 ) and on the Total Daily Symptom Scores (TDSS) after 7 days ( Goel et al., 2004 ). No statistically significant differences were observed between treatment groups for the total symptom score (SS) after 14 days. In two other studies testing capsules/pills containing Echinacea angustifolia root and Echinacea purpurea root and E. purpurea herb there was no statistically significant difference between the intervention and placebo group concerning severity and duration of self-reported symptoms ( Barrett et al., 2002 ) or global severity ( Barrett et al., 2010 ).

In a double blind randomised placebo controlled trial BNO 1016 was tested for the treatment of chronic rhinosinusitis. The results reveal that the herbal drug was not superior over placebo regarding the Major Symptom Score (MSS) in week 8 and week 12 ( Palm et al., 2017 ).

3.5.2 Bronchitis

For bronchitis, nine studies were included, of which six were double-blind randomized placebo-controlled trials, testing EPs 7630 (N = 5) ( Matthys et al., 2003 ; Chuchalin et al., 2005 ; Matthys and Heger, 2007 ; Matthys et al., 2010 ; Kähler et al., 2019 ) or ELOM-080 (N = 1) ( Gillissen et al., 2013 ). The prospective observational studies included a standardized syrup of Hedera helix L (Ivy leaves) (N = 1) ( Fazio et al., 2009 ), pills with ethanolic Ivy-leaves dry extracts (N = 1) ( Hecker et al., 2002 ) and EPs 7630 (N = 1) ( Matthys and Heger, 2007 ).

Using a follow-up period of 7 days to 4 weeks, all but one (double-blinded placebo controlled trial) ( Matthys et al., 2003 ) reported positive effects of the study medication on either Bronchitis Severity Scores, change of symptoms and coughing frequency.

3.5.3 Acute cough

The treatment of acute cough with EA-575 (standardized extract from H. helix L.) was tested against placebo in one double blind randomized placebo controlled trial and reported a significantly better improvement of cough severity (CS) assessed by Visual Analogue Scale (VAS) in the intervention group after 1 week as compared to placebo ( Schaefer et al., 2016 ).

3.5.4 Acute lower and upper tract respiratory infections

We included one retrospective cohort study comparing people with acute lower and upper tract respiratory infections who were prescribed a phytopharmaceutical to those who were not prescribed such drugs. They found that extract EPs 7630 (description see 3.5.1) (odds ratio (OR) 0.49 [95% CI: 0.43–0.57]) and thyme extract (OR 0.62 [0.49–0.76]) compared to no phytopharmaceutical prescription exhibited the strongest decrease in antibiotics prescriptions among patients treated by general practitioners ( Martin et al., 2020 ).

4 Discussion

The aim of this review is to depict the current evidence for the therapeutic efficacy of herbal medicines. Therefore, we conducted a literature search with defined inclusion and exclusion criteria in particular to select information from clinical studies with high levels of evidence and legally approved (in Europe) herbal medicines. Certainly, life-threatening disease are not suitable for the treatment with herbal medicines. This is the reason why we limited our perspective on psychosomatic disorders, gynecological complaints, gastrointestinal disorders and common infectious diseases of the urinary and the upper respiratory tract. Additionally, we concentrated on clinical trials with adult patients. It is to be emphasized that respective studies using herbal drugs have also been done in children with psychosomatic diseases ( Verlaet et al., 2017 ; Schloss et al., 2021 ), IBS ( Menon et al., 2023 ), gastrointestinal disorders ( Michael et al., 2022 ), UTIs ( Ching, 2022 ), and URIs ( Mancak Karakus et al., 2023 ) to mention only some examples.

The use of herbal medicines in the treatment of psychosomatic disorders is widespread and accordingly a high number of clinical studies was available for our analysis. In our literature search, the term “psychosomatic disorders” has been chosen. This term has not been clearly defined but is related to diseases which involve both physical and psychological illness. In other words, the respective symptoms are caused by mental processes and not directly by a physical disorder. The hits we got are based on this “terminology”. In contrast, the term “mental illnesses” which also includes psychological or behavioral manifestations is strictly defined as “health conditions with changes in emotion, thinking or behavior” ( Stein et al., 2021 ). However, even this definition is problematic, since there are concerns about specific conditions, the discrimination between independent biological entities or value-laden social constructs, and the defined indicators of dysfunction ( Stein et al., 2021 ). Independent on these concerns, we did not apply this search term. Therefore, we cannot exclude that (very few) articles have not been discovered with our search strategy.

For the treatment of depressive disorders, St. John’s wort is well-established and the studies we selected were predominantly positive regarding improvement of symptoms. Concurrently, SJW is well tolerated and in the majority of the studies at least equal to conventional medication like tricyclic anti-depressants and selective serotonin reuptake inhibitors, which exhibit in part notable adverse events impacting patients’ quality of life of ( Voican et al., 2014 ; Jakobsen et al., 2017 ).

In contrast evidence for insomnia and anxiety was thinner. It would be worthwhile to study the use of herbal drugs as alternative medication for the treatment of sleeping disorders, as for elderly people or long term use conventional hypnotics are not always the best option ( Wortelboer et al., 2002 ; Cheng et al., 2020 ). All the studies we included were using valerian root extract alone or in combination with Humulus lupulus extract and showed positive effects on sleep without notable side effects. The few studies we selected for anxiety demonstrated efficacy of lavender extract (Lavandula angustifolia) and also here we had a homogenous picture of good efficacy along with good tolerability.

Several years ago, consistent beneficial effects of Ginkgo biloba for patients with cerebral insufficiency were proven in a systematic review ( Kleijnen and Knipschild, 1992 ). However, the methodologic quality of many trials was considered to be poor. Moreover, the studies entailed a heterogeneous collection of target health problems, ranging from overt dementia to noncognitive manifestations of brain dysfunction, such as vertigo and tinnitus. More recently, the results of several new Ginkgo biloba trials have been published, most of them focusing on dementia, and showing positive effects. Probably the most talked about is the trial of the North American EGb Study Group, which was published in the JAMA in 1997 and showed a modest improvement of the cognitive performance and the social functioning of the demented patients involved ( Le Bars et al., 1997 ), which is well in line with the studies we have collected.

In addition, menopausal symptoms and premenstrual syndrome are suitable for treatment with herbal medicines. In the here collected studies, no overall negative effects were observed and adverse events did not occur more frequently than in the comparison groups. A consistent picture emerged when comparing herbal treatment with synthetic drugs or placebo: while herbal drugs and treatment with, e.g., HRT or pyridoxine showed equal efficacy, herbal treatment was in general superior to placebo administration, except for one study.

Effective treatment of menopausal symptoms with black cohosh is supported with multiple study designs. Regardless of the study quality, there are no contradictory results.

The evidence for the treatment of PMS with VAC initially appears similar to that of black cohosh for menopausal symptoms. However, the sample sizes have been insufficient and there was a complete lack of comparisons of VAC with other therapies. Also of interest are the hints on the importance of the dose and continuous administration. A higher dosage did not have a higher efficacy compared to the standard dosage, but slightly more participants experienced adverse events ( Momoeda et al., 2014 ). This suggests a preference for the standard dosage of VAC. Continuous use of VAC is recommended, as it has been shown that symptoms increase significantly, even if they are still lower than before therapy ( Bachert et al., 2009 ).

However, further research is needed for both gynecological indications. Only one study each on sage for menopausal symptoms and SJW for premenstrual symptoms was found ( Lauritzen et al., 1997 ; Lauritzen et al., 1997 ; Adeyemo et al., 2013 ). The trend-setting results point to positive effects which have to be confirmed.

For gastrointestinal disorders herbal drugs were, at least partially, shown to be similar efficacious as the standard treatment. Selected, non-toxic plant derived natural compounds may, therefore, replace synthesized drugs which are associated with undesired negative side effects and the therapeutic potential of the compounds may depend on both the plant extract and the type of disease to be treated. Indeed, SJW was not efficacious in treating IBS, whereas WS 1340/WS 1520 and STW 5 and STW 5-II showed efficacy in both IBS and FD. Considering the broad spectrum of gastrointestinal complaints, therapy of severe liver disease may require more effort than treatment of moderate dyspepsia and, hence, herbal medicine may not replace standard therapy.

As no standard therapy has so far been established for FD ( Madisch et al., 2018 ) and IBS ( Lacy et al., 2021 ) the design of clinical studies is difficult, making it impossible to compare the phytodrug group with a “reference” cohort, and to finally assess the value of the phytodrugs.

Particular attention should be given to STW 5 containing greater celandine which has been related to liver and biliary tract disorders ( Zielińska et al., 2018 ). Therefore, careful preclinical examination of potential toxic properties of a compound of question is necessary before starting clinical trials.

Overall, most of the studies were well designed (multicenter, double-blind, placebo-controlled trials) with large cohorts. Considering the low side effects and often significant improvements, it might be useful to conduct further studies to either gain more detailed information about herbal medicine or to transfer the knowledge to diseases with a similar cluster of symptoms, so that distinct ailments might particularly benefit from herbal medicine ( Chey et al., 2015 ).

With respect to urinary tract infections (UTI), herbal medicines have been proven to be similar effective as antibiotics. Undoubtedly, the data encourages further research on herbal medicines as alternatives to antibiotics in acute lower uncomplicated UTI ( Wagenlehner et al., 2018 ). The use of herbal medicines has also been considered to be a good and safe alternative to perioperative antibiotic prophylaxis ( Miotla et al., 2018 ). However, whether herbal medicines may reduce or even replace antibiotics in future guideline-based regimen requires more prospective studies conducted on large groups of participants ( Wawrysiuk et al., 2022 ).

It is important to note in this context that one study discriminated between HM responders and non-responders ( Kulchavenya, 2018 ). This phenomenon is highly important, since it indicates that the application of HM in general might be restricted to a subset of patients. Unfortunately, no ongoing trials have been enrolled in this matter, and none of the publications cited here discussed the problem of acquired or innate resistance, at least from a theoretical point of view.

LUTS caused by BPH was treated differently than UTI, since the complications of BPH, namely, urinary incontinence, polyuria, urinary retention, and erectile dysfunction, have to be targeted. The clinical trials published so far point to the benefit of herbal medicines in reducing BPH symptoms. However, it is not clear yet whether the integration of herbal medicines may allow to reduce or even to avoid the use of standard medical therapeutics in this case.

Overall, several clinical studies conducted in the last years document a beneficial role of herbal medicines in the treatment of UTI and LUTS.

Upper Respiratory Infections (URIs) are a frequent cause of troublesome symptoms, that might be appropriately treated with herbal medicine. Most studies included in this paper evaluated herbal medicines for the treatment of acute bronchitis or common cold and acute sinusitis or rhinosinusitis.

The majority of the studies we included for the treatment of acute bronchitis tested P. sidoides against placebo and reported a statistically significant decrease of bronchitis symptoms and/severity. This is in line with the results of a systematic review and meta-analysis ( Agbabiaka et al., 2008 ), although a more recent systematic review judged that the evidence was of low quality ( Timmer et al., 2013 ). Evidence for other herbal medicines in the treatment of acute bronchitis was scarce.

For the treatment of common cold we found some indications of effectiveness of P. sidoides , Eucalyptus, sweet orange, myrtle and lemon oil (ELOM-080) and for Gentianae radix, Primulae flos, Sambuci flos, Rumicis herba and verbenae herba (BNO 1016). A recent systematic review with network meta-analysis, showed very little solid evidence of herbal medicine versus placebo for common cold, with only P. sidoides and Andrographis paniculata showing a reliable decrease of symptoms. Better results were found for herbal medicine versus placebo concerning health related quality of life (HRQoL) (in particular Spicae aetheroleum ) and for symptoms (Cineole and P. sidoides ) ( Hoang et al., 2023 ). A further systematic review reported on the efficacy of P. sidoides (liquid and tablet preparation) for the treatment of acute bronchitis, showing a positive results with, however, low evidence quality ( Timmer et al., 2013 ).

Although herbal medicines are considered to be safe in principle, this might not always be the case. Some herbal compounds are suspected to be carcinogenic and/or hepatotoxic. Herbal products have also been shown to inhibit and/or induce drug-metabolizing enzymes ( Moreira et al., 2014 ). This has to be taken into account, since herbal medicines are often used in combination with conventional drugs. In this context, preparations with SJW may reduce the efficacy of chemotherapy and of anticoagulants but enhance the one of certain consciousness-lowering agents (e.g., sedative medicines, antidepressants) ( Nicolussi et al., 2020 ; Scholz et al., 2021 ). Due to potential liver toxicity of chelidonium majus, preparations containing more than 2.5 mg daily dose of whole chelidonium alkaloids had to be withdrawn, and for all preparations with lower daily doses, their instruction leaflet must include warnings on liver toxicity ( Rosien, 2019 ). Therefore, the drug’s safety must always be carefully investigated and guaranteed by the producers and the regulatory authorities.

The analysis of the outcomes in the selected disorders reflects that herbal medicines are most efficacious for the treatment of URTI ( Figure 5 ), followed by gynecological complaints ( Figure 2 ) and psychosomatic disorders ( Figure 1 ). For the treatment of urological diseases ( Figure 4 ) in particular UTI and LUTS, we could select only 16 studies according to our strict inclusion/exclusion criteria and therefore more studies of high quality have to be performed to gain a better insight into the efficacy of herbal drugs for these ailments. Gastrointestinal diseases hold a special position as only the added value of the phytodrugs to the conventional therapy was tested. In addition, the number of studies we selected was small ( Figure 3 ), making it difficult to judge the efficacy of herbal drugs for this indication.

FIGURE 4 . Numbers of studies and outcomes.

FIGURE 5 . Numbers of studies and outcomes.

This report on the current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments has some limitations.

1. The literature search had to be restricted to Pubmed, because other relevant databases like e.g., EMBASE or CINAHL have not been accessible to the authors.

2. Further limitations are the small cohorts in some of the studies

3. Or that the results/outcomes of some studies have been re-analyzed from previous studies.

4. A general obstacle of data interpretation is that for some indications, in particular for gastrointestinal diseases, herbal medicines are predominantly co-administered with standard therapy, which makes it difficult to estimate the clinical benefit of the phytodrug alone.

5 Perspective

Our literature research gives insights into applied herbal medicines for selected indications, the study outcomes and their quality. Based on our results, we (the authors) provide an overview for patients and healthcare practitioners which extracts can be recommended for the treatment if which disorder/complaint ( Supplementary Table S1 ).

In this context we recommend in particular H. perforatum L. for depressive disorder, V. agnus castus L. for menstrual complaints, Cimicifica racemose (L.) for menopausal symptoms, a combination of I. amara L., M. chamomilla L., Mentha × piperita L., C. carvi L., G. glabra L. and M. officinalis L., for functional dyspepsia, a combination of C. erythraea , Levisticum officinale W.D.J.Koch and Rosmarinus officinalis L. for uncomlicated urinary tract infections, P. sidoides DC. for bronchitis and sinusitis and finally H. helix for cough ( Supplementary Table S1 ). These recommendations are based on studies with the highest levels of evidence (RCTs).

However, evidence for efficacy of herbal medicines is still not satisfying in order to integrate them in conventional medicine guidelines and standard treatment regimen, which is the reason why statutory health insurances do not reimburse the costs. In fact, herbal medicines are highly popular and accepted among patients, since their application is safe since they do not exert severe side-effects. Especially when conventional medical therapies fail due to undesired side effects having a negative impact on the quality of life, patients are willing to purchase herbal medicines at their own expense. Often doctors do not know about the self-medication activities of their patients and in consequence cannot monitor the treatment with herbal medicines and possible interactions with other drugs.

The discrepancy between available results from clinical research and the use of herbal medicines under everyday conditions shows that we need to perform more interdisciplinary research studies in the future in order to collect scientific sound evidence on their benefits. Clinical research can provide information on the efficacy of phytodrugs and the importance of genetic dispositions and metabolism as well as possible interactions with other medicines. For effectiveness under everyday conditions (from bedside to practice), methods of health services research are necessary. With the help of these, the outcomes of herbal medicines can be recorded from different perspectives, in particular those of the patients (patient-reported outcomes (PROs)). For longitudinal observations, analyses of health insurance and sales volume data are also relevant, using prescriptions and the over-the-counter sales to get a picture on the needs of the patients and the acceptance of phytotherapy by healthcare practitioners. In order to pave the way for the integration of herbal medicines into therapy guidelines and regimens, findings from clinical studies should be carefully evaluated for their transferability to everyday healthcare within the scope of health services research. This way could lead to novel rational efficacious therapy strategies with less side-effects and better compliance of the patients.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material , further inquiries can be directed to the corresponding author.

Author contributions

SS: Investigation, Formal analysis, Writing–Original Draft. JR: Investigation, Formal analysis, Writing–Original Draft, Visualization. MA: Methodology, Investigation, Formal analysis, Writing–Original Draft. RB: Investigation, Formal analysis, Writing–Original Draft. BB: Conceptualization, Methodology, Investigation, Formal analysis, Writing–Original Draft, Supervision. All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2023.1234701/full#supplementary-material

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Keywords: herbal medicine, clinical benefits, psychosomatic disorders, gynecological complaints, gastrointestinal disorders, urinary tract infections, upper respiratory tract infections

Citation: Salm S, Rutz J, van den Akker M, Blaheta RA and Bachmeier BE (2023) Current state of research on the clinical benefits of herbal medicines for non-life-threatening ailments. Front. Pharmacol. 14:1234701. doi: 10.3389/fphar.2023.1234701

Received: 05 June 2023; Accepted: 08 September 2023; Published: 28 September 2023.

Reviewed by:

Copyright © 2023 Salm, Rutz, van den Akker, Blaheta and Bachmeier. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Beatrice E. Bachmeier, [email protected]

† These authors have contributed equally to this work and share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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The multifunctional role of herbal products in the management of diabetes and obesity: a comprehensive review.

1. Introduction

2. pathogenesis of obesity, 3. obesity and diabetes, 3.1. obesity: current concerns and treatments, 3.2. diabetes: current concerns and treatments, 4. relationship between diabetes and obesity, genetic factors linking obesity and diabetes, 5. phytogenic compounds, 5.1. possible therapeutic compounds for obesity, 5.1.1. compounds suppress food intake, panax quinquefolius (american ginseng), panax ginseng (asian ginseng), hoodia gordonii (hoodia), vaccinium spp. (blueberry), 5.1.2. compounds stimulate energy expenditure, nelumbo nucifera (indian lotus), capsicum annuum (chili pepper), 5.1.3. compounds regulate lipid metabolism, camellia sinensis (green tea), vaccinium angustifolium (wild blueberry), cinnamomum spp. (cinnamon), 5.1.4. possible therapeutic compounds that regulate carbohydrate metabolism, camellia sinensis (teas), glycine max merr (soybean), 5.2. possible therapeutic compounds for diabetes, 5.2.1. possible therapeutic compounds that regulate insulin resistance, glycyrrhiza glabra (liquorice), trigonella foenum-graecum (fenugreek), gymnema   sylvestre, 5.2.2. possible therapeutic compounds regulate β-cell function, ervatamia microphylla (kerr), anoectochilus roxburghii (jewel orchid), nymphaea   stellata, 5.2.3. compounds with multiple antidiabetic activities, capsicum frutescens (solanaceae), momordica charantia (cucurbitaceae), vitis vinifera (grape vine), 5.3. possible therapeutic compounds for both obesity and diabetes, 6. different therapeutic targets of diabetes, treating with herbal products, 6.1. inhibition of dpp-4, 6.2. inhibition of protein tyrosine phosphatase 1b (ptp1b), 6.3. inhibition of α-glycosidase, 6.4. activation of nrf2, 6.5. modification of pancreatic beta cells, 6.6. inhibition of aldose reductase enzyme, 6.7. regulation of autophagy, 7. different therapeutic targets of obesity, treating with herbal products, 7.1. inhibition of aryl hydrocarbon receptors, 7.2. inhibition of adipogenesis by methylxanthine, 7.3. recover the disruption of melanocortin 4 receptor (mc4r) protein, 7.4. increase the secretion of adiponectin, 8. conclusions and future prospects, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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Rahman, M.M.; Islam, M.R.; Shohag, S.; Hossain, M.E.; Rahaman, M.S.; Islam, F.; Ahmed, M.; Mitra, S.; Khandaker, M.U.; Idris, A.M.; et al. The Multifunctional Role of Herbal Products in the Management of Diabetes and Obesity: A Comprehensive Review. Molecules 2022 , 27 , 1713. https://doi.org/10.3390/molecules27051713

Rahman MM, Islam MR, Shohag S, Hossain ME, Rahaman MS, Islam F, Ahmed M, Mitra S, Khandaker MU, Idris AM, et al. The Multifunctional Role of Herbal Products in the Management of Diabetes and Obesity: A Comprehensive Review. Molecules . 2022; 27(5):1713. https://doi.org/10.3390/molecules27051713

Rahman, Md. Mominur, Md. Rezaul Islam, Sheikh Shohag, Md. Emon Hossain, Md. Saidur Rahaman, Fahadul Islam, Muniruddin Ahmed, Saikat Mitra, Mayeen Uddin Khandaker, Abubakr M. Idris, and et al. 2022. "The Multifunctional Role of Herbal Products in the Management of Diabetes and Obesity: A Comprehensive Review" Molecules 27, no. 5: 1713. https://doi.org/10.3390/molecules27051713

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• Review Article
• Published: 28 January 2021

Natural products in drug discovery: advances and opportunities

• Atanas G. Atanasov   ORCID: orcid.org/0000-0003-2545-0967 1 , 2 , 3 , 4 ,
• Sergey B. Zotchev 2 ,
• Verena M. Dirsch   ORCID: orcid.org/0000-0002-9261-5293 2 ,
• the International Natural Product Sciences Taskforce &
• Claudiu T. Supuran   ORCID: orcid.org/0000-0003-4262-0323 5  

Nature Reviews Drug Discovery volume  20 ,  pages 200–216 ( 2021 ) Cite this article

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Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments — including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances — are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.

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Introduction.

Historically, natural products (NPs) have played a key role in drug discovery, especially for cancer and infectious diseases 1 , 2 , but also in other therapeutic areas, including cardiovascular diseases (for example, statins) and multiple sclerosis (for example, fingolimod) 3 , 4 , 5 .

NPs offer special features in comparison with conventional synthetic molecules, which confer both advantages and challenges for the drug discovery process. NPs are characterized by enormous scaffold diversity and structural complexity. They typically have a higher molecular mass, a larger number of sp 3 carbon atoms and oxygen atoms but fewer nitrogen and halogen atoms, higher numbers of H-bond acceptors and donors, lower calculated octanol–water partition coefficients (cLogP values, indicating higher hydrophilicity) and greater molecular rigidity compared with synthetic compound libraries 1 , 6 , 7 , 8 , 9 . These differences can be advantageous; for example, the higher rigidity of NPs can be valuable in drug discovery tackling protein–protein interactions 10 . Indeed, NPs are a major source of oral drugs ‘beyond Lipinski’s rule of five ’ 11 . The increasing significance of drugs not conforming to this rule is illustrated by the increase in molecular mass of approved oral drugs over the past 20 years 12 . NPs are structurally ‘optimized’ by evolution to serve particular biological functions 1 , including the regulation of endogenous defence mechanisms and the interaction (often competition) with other organisms, which explains their high relevance for infectious diseases and cancer. Furthermore, their use in traditional medicine may provide insights regarding efficacy and safety. Overall, the NP pool is enriched with ‘bioactive’ compounds covering a wider area of chemical space compared with typical synthetic small-molecule libraries 13 .

Despite these advantages and multiple successful drug discovery examples, several drawbacks of NPs have led pharmaceutical companies to reduce NP-based drug discovery programmes. NP screens typically involve a library of extracts from natural sources (Fig.  1 ), which may not be compatible with traditional target-based assays 14 . Identifying the bioactive compounds of interest can be challenging, and dereplication tools have to be applied to avoid rediscovery of known compounds. Accessing sufficient biological material to isolate and characterize a bioactive NP may also be challenging 15 . Furthermore, gaining intellectual property (IP) rights for (unmodified) NPs exhibiting relevant bioactivities can be a hurdle, since naturally occurring compounds in their original form may not always be patented (legal frameworks vary between countries and are evolving) 16 , although simple derivatives can be patent-protected (Box  1 ). An additional layer of complexity relates to the regulations defining the need for benefit sharing with countries of origin of the biological material, framed in the United Nations 1992 Convention on Biological Diversity and the Nagoya Protocol, which entered into force in 2014 (ref. 17 ), as well as recent developments concerning benefit sharing linked to use of marine genetic resources 18 .

Steps in the process are shown in purple boxes, with associated key limitations shown in red boxes and advances that are helping to address these limitations in modern natural product (NP)-based drug discovery shown in green boxes. The process begins with extraction of NPs from organisms such as bacteria. The choice of extraction method determines which compound classes will be present in the extract (for example, the use of more polar solvents will result in a higher abundance of polar compounds in the crude extract). To maximize the diversity of the extracted NPs, the biological material can be subjected to extraction with several solvents of different polarity. Following the identification of a crude extract with promising pharmacological activity, the next step is its (often multiple) consecutive bioactivity-guided fractionation until the pure bioactive compounds are isolated. A key limitation for the potential of this approach to identify novel NPs is that many potential source organisms cannot be cultured or stop producing relevant NPs when taken out of their natural habitat. These limitations are being addressed through development of new methods for culturing, for in situ analysis, for NP synthesis induction and for heterologous expression of biosynthetic genes. At the crude extract step, challenges include the presence in the extracts of NPs that are already known, NPs that do not have drug-like properties or insufficient amounts of NPs for characterization. These challenges can be addressed through the development of methods for dereplication, extraction and pre-fractionation of extracts. Finally, at the last stage, when bioactive compounds are identified by phenotypic assays, significant time and effort are typically needed to identify the affected molecular targets. This challenge can be addressed by the development of methods for accelerated elucidation of molecular modes of action, such as the nematic protein organization technique (NPOT), drug affinity responsive target stability (DARTS), stable isotope labelling with amino acids in cell culture and pulse proteolysis (SILAC-PP), the cellular thermal shift assay (CETSA) and an extension known as thermal proteome profiling (TPP), stability of proteins from rates of oxidation (SPROX), the similarity ensemble approach (SEA) and bioinformatics-based analysis of connectivity (connectivity map, CMAP) 23 , 189 , 190 , 191 , 192 .

Although the complexity of NP structures can be advantageous, the generation of structural analogues to explore structure–activity relationships and to optimize NP leads can be challenging, particularly if synthetic routes are difficult. Also, NP-based drug leads are often identified by phenotypic assays , and deconvolution of their molecular mechanisms of action can be time-consuming 19 . Fortunately, there have been substantial advances 20 both in the development of screening assays (for example, harnessing the potential of induced pluripotent stem cells and gene editing technologies) and in strategies to identify the modes of action of active compounds (reviewed previously 21 , 22 , 23 ).

Here, we discuss recent technological and scientific advances that may help to overcome challenges in NP-based drug discovery, with an emphasis on three areas: analytical techniques, genome mining and engineering, and cultivation systems. In the concluding section, we highlight promising future directions for NP drug discovery.

Box 1 Natural products that activate the KEAP1/NRF2 pathway

An example of a pathway affected by diverse natural products (NPs) is the KEAP1/NRF2 pathway. This pathway regulates the expression of networks of genes encoding proteins with versatile cytoprotective functions and has essential roles in the maintenance of redox and protein homeostasis, mitochondrial biogenesis and the resolution of inflammation 196 , 197 , 198 , 199 .

Activation of this pathway can protect against damage by most types of oxidants and pro-inflammatory agents, and it restores redox and protein homeostasis 200 . The pathway has therefore attracted attention for the development of drugs for the prevention and treatment of complex diseases, including neurological conditions such as relapsing–remitting multiple sclerosis 201 and autism spectrum disorder 202 .

Dimethyl fumarate (DMF), the methyl ester of the NP fumarate (a tricarboxylic acid (TCA) cycle intermediate that is found in both animals and plants), is one of the earliest discovered inducers of the KEAP1/NRF2 pathway 203 , 204 . The origins of the development of DMF as a drug date back to the use in traditional medicine of the plant Fumaria officinalis . Initially, fumaric acid derivatives were used for the treatment of psoriasis as it was thought that psoriasis is caused by a metabolic deficiency in the TCA cycle that could be compensated for by repletion of fumarate 205 . Despite this erroneous assumption, DMF is effective in treating psoriasis, both topically and orally, and is the active principle of Fumaderm, which has been used clinically for several decades in the treatment of plaque psoriasis in Germany. More recently, a DMF formulation developed by Biogen has been tested in other immunological disorders, with successful phase III trials in multiple sclerosis 206 , 207 leading to its approval by the FDA and EMA in 2013.

The isothiocyanate sulforaphane, isolated from broccoli ( Brassica oleracea ) 208 , is among the most potent naturally occurring inducers of the KEAP1/NRF2 pathway 209 and has protective effects in animal models of Parkinson 210 , Huntington 211 and Alzheimer 212 diseases, traumatic brain injury 213 , spinal cord contusion injury 214 , stroke 215 , depression 216 and multiple sclerosis 217 . Sulforaphane-rich broccoli extract preparations are being developed as preventive interventions in areas of the world with unavoidable exposure to environmental pollutants, such as China; the initial results of a randomized clinical trial showed rapid and sustained, statistically significant increases in the levels of excretion of the glutathione-derived conjugates of benzene and acrolein 218 , and a follow-up trial (NCT02656420) also demonstrated dose–response-dependent benzene detoxification 219 . In a placebo-controlled, double-blind, randomized clinical trial in young individuals (age 13–27 years) with autism spectrum disorder, sulforaphane reversed many of the clinical abnormalities 202 ; these encouraging findings led to a recently completed clinical trial in children (age 3–12 years) (NCT02561481; results of the trial are not yet publicly available). An α-cyclodextrin complex of sulforaphane known as SFX-01 (developed by Evgen Pharma) is being clinically studied for its potential to reverse resistance to endocrine therapies in patients with ER + HER2 - metastatic breast cancer (phase II trial completed 220 ) and in patients with subarachnoid haemorrhage (phase II trial NCT02614742 recently completed; results not yet publicly available). Currently, a clinical trial of SFX-01 in patients hospitalized with COVID-19 is in its final stages of preparation.

Finally, the pentacyclic triterpenoids bardoxolone methyl (also known as RTA 402) and omaveloxolone (RTA 408), which are semi-synthetic derivatives of the NP oleanolic acid, are the most potent (active at nanomolar concentrations) activators of the KEAP1/NRF2 pathway known to date 221 . These compounds have shown protective effects in numerous animal models of chronic disease 222 , and are currently in clinical trials for a wide range of indications, such as chronic kidney disease in type 2 diabetes, pulmonary arterial hypertension, melanoma, radiation dermatitis, ocular inflammation and Friedreich’s ataxia 200 . Most recently, bardoxolone methyl has entered a clinical trial in patients hospitalized with confirmed COVID-19 (NCT04494646).

Application of analytical techniques

Classical NP-based drug research starts with biological screening of ‘crude’ extracts to identify a bioactive ‘hit’ extract, which is further fractionated to isolate the active NPs. Bioactivity-guided isolation is a laborious process with a number of limitations, but various strategies and technologies can be used to address some of them (Fig.  2 ). For example, to create libraries that are compatible with high-throughput screening, crude extracts can be pre-fractionated into sub-fractions that are more suitable for automated liquid handling systems. In addition, fractionation methods can be adjusted so that sub-fractions preferentially contain compounds with drug-like properties (typically moderate hydrophilicity). Such approaches can increase the number of hits compared with using crude extracts, as well as enabling more efficient follow-up of promising hits 24 .

a | An illustrative example of the application of liquid chromatography–high-resolution mass spectrometry (LC–HRMS) metabolomics in the screening of natural product (NP) extracts is the work of Kurita et al. 58 , in which 234 bacterial extracts were subjected to image-based phenotypic bioactivity screening and LC–HRMS metabolomics. Clustering of the resulting data allowed prioritization of promising extracts for further analysis, resulting in the discovery of the new NPs, quinocinnolinomycins A–D. b | Another illustrative example of LC–HRMS screening of NP extracts is the work of Clevenger et al. 85 , who obtained novel NP extracts through heterologous expression of fungal artificial chromosomes (FACs) containing uncharacterized biosynthetic gene clusters (BGCs) from diverse fungal species in Aspergillus nidulans . Analysis of the LC–HRMS metabolomics data with a FAC-Score algorithm directed the simultaneous discovery of 15 new NPs and the characterization of their BGCs.

Metabolomics was developed as an approach to simultaneously analyse multiple metabolites in biological samples. Enabled by technological developments in chromatography and spectrometry, metabolomics was historically applied first in other research fields, such as biomedical and agricultural sciences 2 . Advances in the analytical instrumentation used in NP research 25 , 26 , coupled with computational approaches that can generate plausible NP analogue structures and their respective simulated spectra 27 , have also enabled application of ‘omics’ approaches such as metabolomics in NP-based drug discovery. Metabolomics can provide accurate information on the metabolite composition in NP extracts, thus helping to prioritize NPs for isolation, to accelerate dereplication 28 , 29 and to annotate unknown analogues and new NP scaffolds. Moreover, metabolomics can detect differences between metabolite compositions in various physiological states of producing organisms and enable the generation of hypotheses to explain them, and can also provide extensive metabolite profiles to underpin phenotypic characterization at the molecular level 30 . Both options are very useful in understanding the molecular mechanisms of action of NPs.

For metabolite profiling, NP extracts are analysed by NMR spectroscopy or high-resolution mass spectrometry (HRMS), or respective combined methods involving upstream liquid chromatography (LC) 31 , 32 , such as LC–HRMS, which can separate numerous isomers present in NP extracts 33 . Moreover, such combined methods might integrate HRMS and NMR, allowing the simultaneous use of the advantages of both techiques 34 , 35 . NMR analysis of NP extracts is simple and reproducible, and provides direct quantitative information and detailed structural information, although it has relatively low sensitivity, meaning that it generally enables profiling only of major constituents 33 . The applications of NMR in NP research are versatile 36 and the technique is used both directly for metabolomics of unfractionated NP extracts and for structural characterization of compounds and fractions obtained with appropriate separation methods, most often LC. HRMS is the gold standard for qualitative and quantitative metabolite profiling 33 and is most commonly applied in combination with LC. HRMS can also be used in the direct infusion mode (called DIMS) 37 , whereby samples are directly profiled by MS without a chromatography step, or in MS imaging (MSI) 38 , which enables determination of the spatial distribution of NPs within living organisms. HRMS enables routine acquisition of accurate molecular mass information, which together with appropriate heuristic filtering can provide unambiguous assignment of molecular formulae for hundreds to thousands of metabolites within a single extract over a dynamic range that may exceed five orders of magnitude 31 , 39 . However, challenges remain in data mining and in the unambiguous identification of the metabolites using various workflows relying on open web-based tools 40 .

Dereplication of secondary metabolites in bioactive extracts includes the determination of molecular mass and formula and cross-searching in the literature or structural NP databases with taxonomic information, which greatly assists the identification process. Such metadata, which are difficult to query in the literature, are often compiled in proprietary databases, such as the Dictionary of Natural Products , which encompasses all NP structures reported with links to their biological sources (see Related links). However, a comprehensive experimental tandem mass spectrometry (MS/MS) database of all NPs reported to date does not exist, and a search for experimental spectra across various platforms is hindered by the lack of standardized collision energy conditions for fragmentation in LC–MS/MS 25 .

In this respect, the Global Natural Products Social (GNPS) molecular networking platform developed in the Dorrestein laboratory is an important addition to the toolbox 41 . Molecular networking organizes thousands of sets of MS/MS data recorded from a given set of extracts and visualizes the relationship of the analytes as clusters of structurally related molecules. This improves the efficiency of dereplication by enabling annotation of isomers and analogues of a given metabolite in a cluster 42 . The recorded experimental spectra can be searched against putative structures and their corresponding predicted MS/MS spectra generated by tools such as competitive fragmentation modelling (CFM-ID) 43 . Based on such approaches, vast databases of theoretical NP spectra have been created and applied in dereplication 44 . The GNPS molecular networking approach has limitations, however, such as better applicability to some classes of NPs than others and the uncertainty of structural assignment among possible predicted candidates. Efforts to address such issues are ongoing 45 , 46 , 47 , including overlaying molecular networks of large NP extract libraries with taxonomic information to improve the confidence of annotation 48 . Overall, molecular networking mainly allows better prioritization of the isolation of unknown compounds by strengthening the dereplication process and elucidating relationships between NP analogues, and rigorous structure elucidation for NPs of interest should not be neglected.

Another useful platform for metabolite identification is METLIN 49 , which includes a high-resolution MS/MS database with a fragment similarity search function that is useful for identification of unknown compounds. Other databases and in silico tools such as Compound Structure Identification (CSI): FingerID and Input Output Kernel Regression (IOKR) can be used to search available fragment ion spectra, as well as to generate predicted spectra of fragment ions not present in current databases 50 . A novel computational platform for predicting the structural identity of metabolites derived from any identified compound has also been recently reported 51 , which should increase the searchable chemical space of NPs.

To accelerate the identification of bioactive NPs in extracts, metabolomics data can be matched to the biological activities of these extracts 52 . Various chemometric methods such as multivariate data analysis can correlate the measured activity with signals in the NMR and MS spectra, enabling the active compounds to be traced in complex mixtures with no need for further bioassays 53 , 54 , 55 . Furthermore, several analytical modules involving different bioassays and detection technologies can be linked to allow simultaneous bioactivity evaluation and identification of compounds present in small amounts (analytical scale) in complex compound mixtures 34 , 35 .

Metabolomics data can be integrated with data obtained by other omics techniques such as transcriptomics and proteomics and/or with imaging-based screens. For example, Acharya et al. used this approach to characterize NP-mediated interactions between a Micromonospora species and a Rhodococcus species 56 . In another interesting example, Kurita et al. developed a compound activity mapping platform for the prediction of identities and mechanisms of action of constituents from complex NP extract libraries by integrating cytological profiling 57 with untargeted metabolomics data from a library of extracts 58 , and identified quinocinnolinomycins as a new family of NPs causing endoplasmic reticulum stress 58 (Fig.  2a ).

Analytical advances that enable the profiling of responses to bioactive molecules at the single-cell level can also accelerate NP-based drug discovery. Irish, Bachmann, Earl and colleagues developed a high-throughput platform for metabolomic profiling of bioactivity by integrating phospho-specific flow cytometry, single-cell chemical biology and cellular barcoding with metabolomic arrays (characterized chromatographic microtitre arrays originating from biological extracts) 59 . Using this platform, the authors studied the single-cell responses of bone marrow biopsy samples from patients with acute myeloid leukaemia following exposure to microbial metabolomic arrays obtained from extracts of biosynthetically prolific bacteria, which enabled the identification of new bioactive polyketides 59 .

Finally, advances in analytical technologies continue to support the rigorous structure determination of NPs of interest. The progressive development of higher-field NMR instruments and probe technology 60 , 61 has enabled NP structure determination from very small quantities (below 10 µg) 62 , 63 , which is important, as the available quantities of NPs are often limited. In addition, microcrystal electron diffraction (MicroED) has recently emerged as a cryo-electron microscopy-based technique for unambiguous structure determination of small molecules 64 and is already finding important applications in NP research 65 . The increased resolution and sensitivity of analytical equipment can also help address problems associated with ‘residual complexity’ of isolated NPs; that is when biologically potent but unidentified impurities in an isolated NP sample (which could include structurally related metabolites or conformers) lead to an incorrect assignment of structure and/or activity 66 , 67 . To avoid futile downstream development efforts, Pauli and colleagues recommended that lead NPs should undergo advanced purity analysis at an early stage using quantitative NMR and LC–MS 67 .

Genome mining and engineering

Advances in knowledge on biosynthetic pathways for NPs and in developing tools for analysing and manipulating genomes are further key drivers for modern NP-based drug discovery. Two key characteristics enable the identification of biosynthetic genes in the genomes of the producing organisms. First, these genes are clustered in the genomes of bacteria and filamentous fungi. Second, many NPs are based on polyketide or peptide cores, and their biosynthetic pathways involve enzymes — polyketide synthases (PKSs) and nonribosomal peptide synthetases (NRPSs), respectively — that are encoded by large genes with highly conserved modules 68 .

‘Genome mining’ is based on searches for genes that are likely to govern biosynthesis of scaffold structures, and can be used to identify NP biosynthetic gene clusters 69 , 70 , 71 . Prioritization of gene clusters for further work is facilitated by advances in biosynthetic knowledge and predictive bioinformatics tools, which can provide hints about whether the metabolic products of the clusters have chemical scaffolds that are new or known, thereby supporting dereplication 72 , 73 . Such predictive tools for gene cluster analysis can be applied in combination with spectroscopic techniques to accelerate the identification of NPs 65 and determine the stereochemistry of metabolic products 66 . Furthermore, to extend genome mining from a single genome to entire genera, microbiomes or strain collections, computational tools have been developed, such as BiG-SCAPE, which enables sequence similarity analysis of biosynthetic gene clusters, and CORASON, which uses a phylogenomic approach to elucidate evolutionary relationships between gene clusters 74 .

Phylogenetic studies of known groups of talented secondary metabolite producers can also empower discovery of novel NPs. Recently, a study comparing secondary metabolite profiles and phylogenetic data in myxobacteria demonstrated a correlation between the taxonomic distance and the production of distinct secondary metabolite families 75 . In filamentous fungi, it was likewise shown that secondary metabolite profiles are closely correlated with their phylogeny 76 . These organisms are rich in secondary metabolites, as demonstrated by LC–MS studies of their extracts under laboratory conditions 77 . Concurrent genomic and phylogenomic analyses implied that even the genomes of well-studied organism groups harbour many gene clusters for secondary metabolite biosynthesis with as yet unknown functions 78 . The phylogeny of biosynthetic gene clusters, together with analysis of the absence of known resistance determinants, was recently used to prioritize members of the glycopeptide antibiotic family that could have novel activities. This led to the identification of the known antibiotic complestatin and the newly discovered corbomycin as compounds that act through a previously uncharacterized mechanism involving inhibition of peptidoglycan remodelling 79 .

Many microorganisms cannot be cultured, or tools for their genetic manipulation are not sufficiently developed, which makes it more challenging to access their NP-producing potential. However, biosynthetic gene clusters for NPs can be cloned and heterologously expressed in organisms that are well-characterized and easier to culture and to genetically manipulate (such as Streptomyces coelicolor , Escherichia coli and Saccharomyces cerevisiae ) 80 . The aim is to achieve higher production titres in the heterologous hosts than in wild-type strains, improving the availability of lead compounds 80 , 81 , 82 . Vectors that can carry large DNA inserts are needed for the cloning of complete NP biosynthetic gene clusters. Cosmids (which can have inserts of 30–40 kb), fosmids (which can harbour 40–50 kb) and bacterial artificial chromosomes (BACs; which can have inserts of 100 kb to >300 kb) have been developed 83 . For fungal gene clusters, self-replicating fungal artificial chromosomes (FACs) have been developed, which can have inserts of >100 kb (ref. 84 ). FACs in combination with metabolomic scoring were used to develop a scalable platform, FAC-MS, allowing the characterization of fungal biosynthetic gene clusters and their respective NPs at unprecedented scale 85 . The application of FAC-MS for the screening of 56 biosynthetic gene clusters from different fungal species yielded the discovery of 15 new metabolites, including a new macrolactone, valactamide A 85 (Fig.  2b ).

Even in culturable microorganisms, many biosynthetic gene clusters may not be expressed under conventional culture conditions, and these silent clusters could represent a large untapped source of NPs with drug-like properties 86 . Several approaches can be pursued to identify such NPs. One approach is sequencing, bioinformatic analysis and heterologous expression of silent biosynthetic gene clusters, which has already led to the discovery of several new NP scaffolds from cultivable strains 87 . Direct cloning and heterologous expression was also used to discover the new antibiotic taromycin A, which was identified upon the transfer of a silent 67 kb NRPS biosynthetic gene cluster from Saccharomonospora sp. CNQ-490 into S. coelicolor 88 . To transfer a biosynthetic gene cluster of such size, a platform based on transformation-associated recombination (TAR) cloning was developed. This platform enables direct cloning and manipulation of large biosynthetic gene clusters in S. cerevisiae , maintenance and manipulation of the vector in E. coli , and heterologous expression of the cloned gene clusters in Actinobacteria (such as S. coelicolor ) following chromosomal integration 88 , and is an alternative to BACs for heterologous expression of large biosynthetic gene clusters.

Heterologous expression has limitations, such as the need to clone and manipulate very large genome regions occupied by biosynthetic gene clusters and the difficulty of identifying a suitable host that provides all conditions necessary for the production of the corresponding NPs. These limitations can be circumvented by activating biosynthetic gene clusters directly in the native microorganism through targeted genetic manipulations, generally involving the insertion of activating regulatory elements or deletion of inhibitory elements such as repressors or their binding sites. For example, a derepression strategy of deleting gbnR , a gene for a transcriptional repressor in Streptomyces venezuelae ATCC 10712 was used by Sidda et al. in the discovery of gaburedins, a family of γ-aminobutyrate-derived ureas 89 . An example of the activator-based strategy is the constitutive expression of the samR0484 gene in Streptomyces ambofaciens ATCC 23877, which led to the discovery of stambomycins A–D, 51-membered cytotoxic glycosylated macrolides 72 . Alternatively, silent biosynthetic gene clusters can be activated using repressor decoys 90 , which have the same DNA nucleotide sequence as the binding sites for the repressors that prevent the expression of the clusters. When these decoys are introduced into the bacteria, they sequester the respective repressors, and the ‘endogenous’ binding sites in the genome remain unoccupied, leading to derepression of the previously silent biosynthetic genes and production of the corresponding NPs. This approach has been applied to activate eight silent biosynthetic gene clusters in multiple streptomycetes and led to the characterization of a novel NP, oxazolepoxidomycin A 90 . The repressor decoy strategy is simpler, easier and faster to perform than the deletion of genes encoding regulatory factors. However, it has the same limitation as other approaches that rely on the introduction of recombinant DNA molecules into cells: it is necessary to develop protocols for efficient introduction of DNA into the targeted host strain, and the decoy must be maintained on a high-copy plasmid to ensure efficient repressor sequestration.

Another approach focused on exchange of regulatory elements is based on the CRISPR–Cas9 technology. The promise of this technique is exemplified in a recent work by Zhang et al., which demonstrated that CRISPR–Cas9-mediated targeted promoter introduction can efficiently activate diverse biosynthetic gene clusters in multiple Streptomyces species, leading to the production of unique metabolites, including a novel polyketide in Streptomyces viridochromogenes 91 . The CRISPR–Cas9 technology was also used to knock out genes encoding two well-known and frequently rediscovered antibiotics in several actinomycete strains, which led to the production of different rare and previously unknown variants of antibiotics that were otherwise obscured, including amicetin, thiolactomycin, phenanthroviridin and 5-chloro-3-formylindole 92 .

Approaches that rely on sequencing, bioinformatics and heterologous expression can also enable the identification of novel NPs from bacterial strains that have not yet been cultivated (Fig.  3a ). For example, Hover et al. searched the metagenomes of 2,000 soil samples for biosynthetic gene clusters for lipopeptides with calcium-binding motifs. This led to the discovery of malacidins, members of the calcium-dependent antibiotic family, via heterologous expression of a 72 kb biosynthetic gene cluster from a desert soil sample in a Streptomyces albus host strain 93 (Fig.  3b ). However, in comparison with some of the other above-discussed strategies 72 , 89 , 90 , this metagenome-based discovery approach is more suited to finding new members of known NP classes rather than discovery of entirely new classes. In another study, Chu et al. developed a human microbiome-based approach that identified nonribosomal linear heptapeptides called humimycins as novel antibiotics active against methicillin-resistant Staphylococcus aureus (MRSA) 94 (Fig.  3c ). The structure of the NPs was predicted via bioinformatics analysis of gene clusters found in human commensal bacteria, followed by their chemical synthesis. A major strength of this innovative approach is that it is entirely independent of microbial cultivation and heterologous gene expression. Nevertheless, there are limitations related to the accuracy of computational chemical structure predictions and the feasibility of total chemical synthesis if structures are complex.

a | Genome mining-based approaches to explore the biosynthetic capacity of microorganisms rely on DNA extraction, sequencing and bioinformatics analysis. The vast majority of microbes from different environments and microbiota communities have not been cultured, and their capacity to produce natural products (NPs) was largely inaccessible until recently. In the case of unculturable microorganisms, the bioinformatics analysis step can be followed by either targeted heterologous expression of biosynthetic gene clusters (BGCs) prioritized as being likely to yield relevant new NPs or direct chemical synthesis of ‘synthetic–bioinformatic’ NP-like compounds. b , c | These two approaches are exemplified by the recent discoveries of malacidins (panel b ) and humimycins (panel c ), respectively 93 , 94 . A major strength of the ‘synthetic–bioinformatic’ approach is that it is entirely independent of microbial culture and gene expression. Its limitations are the accuracy of computational chemical structure predictions and the feasibility of total chemical synthesis. NRPS, nonribosomal peptide synthetase.

The genomes of plants or animals can also be mined for novel NPs. For example, mining of 116 plant genomes enabled by identification of a precursor gene for the biosynthesis of lyciumins, a class of branched cyclic ribosomal peptides with hypotensive action produced by Lycium barbarum (popularly known as goji), identified diverse novel lyciumin chemotypes in seven other plants, including crops such as soybean, beet, quinoa and eggplant 95 . Genome mining in the animal kingdom is exemplified by the work of Dutertre et al., which used an integrated transcriptomics and proteomics approach to discover thousands of novel venom peptides from Conus marmoreus snails 96 . Proteomics analysis revealed that the vast majority of the conopeptide diversity was derived from a set of ~100 genes through variable peptide processing 96 .

Some bioactive compounds initially isolated from marine organisms might be products of symbionts, and genome mining can facilitate the characterization of such NPs. For example, it has been shown that bioactive compounds from the sponge Theonella swinhoei are produced by bacterial symbionts 97 , and characterization of the symbiont ‘ Candidatus Entotheonella serta’ using single-cell genomics led to the discovery of gene clusters for misakinolide and theonellamide biosynthesis 98 . Another example of a marine NP produced by a bacterial symbiont is ET-743 (trabectedin), originally isolated from the tunicate Ecteinascidia turbinate . A meta-omics approach developed by Rath et al. revealed that the producer of this clinically used anticancer agent is the bacterial symbiont ‘ Candidatus Endoecteinascidia frumentensis’ 99 .

Similarly, plant microbiomes also represent a large reservoir for the identification of novel bioactive NPs (such as the antitumour agents maytansine, paclitaxel and camptothecin, which were initially isolated from plants and later shown to be produced by microbial endophytes) 100 that can be tapped by genome mining approaches. An illustrative example is a recent work by Helfrich et al. that identified hundreds of novel biosynthetic gene clusters by genome mining of 224 bacterial strains isolated from Arabidopsis thaliana leaves 101 . A combination of bioactivity screening and imaging mass spectrometry was used to select a single species for further genomic analysis and led to the isolation of a NP with an unprecedented structure, the trans -acyltransferase PKS-derived antibiotic macrobrevin 101 .

Targeted genetic engineering of NP biosynthetic gene clusters can be of high value if the producing organism is difficult to cultivate or the yield of a NP is too low to allow comprehensive NP characterization. Rational genetic engineering and heterologous expression contributed to increase the production of vioprolides, a depsipeptide class of anticancer and antifungal NPs in the myxobacterium Cystobacter violaceus Cb vi35, by several orders of magnitude. In addition, non-natural vioprolide analogues were generated by this approach 102 . Similarly, promoter engineering and heterologous expression of biosynthetic gene clusters was reported to result in a 7-fold increase in the production of the cytotoxic NP disorazol 103 , and a 328-fold increase in the production of spinosad, an insecticidal macrolide produced by the bacterium Saccharopolyspora spinosa 104 .

Besides increasing NP yields, targeted gene manipulation can also be used to alter biosynthetic pathways in a predictable manner to produce new NP analogues with improved pharmacological properties, such as higher specific activity, lower toxicity and better pharmacokinetics. Such biosynthetic engineering approaches depend on a solid understanding of the biosynthetic pathway leading to a specific NP, access to the genes specifying this pathway and the ability to manipulate them in either the original or a heterologous host. Recent advances in biosynthetic engineering have enabled faster and more efficient production of NP analogues, including the development of methods for accelerated engineering and recombination of modules of PKS gene clusters 105 , NRPSs 106 , 107 and NRPS–PKS assembly lines 108 , as well as elucidation of mechanisms for polyketide chain release that are contributing to NP structural diversification 109 , 110 . Examples of biosynthetic engineering applied to several important NPs include the generation of analogues of the immunosuppressant rapamycin 111 , the antitumour agents mithramycin 112 and bleomycin 113 , and the antifungal agent nystatin 114 .

It should be noted that biosynthetic engineering has limitations regarding the parts of the NP molecule that can be targeted for modifications, and the chemical groups that can be introduced or removed. Considering the complexity of many NPs, however, total synthesis may be prohibitively costly, and a combined approach of biosynthetic engineering and chemical modification can provide a viable alternative for identifying improved drug candidates. For example, biosynthetic engineering may create a ‘handle’ for addition of a beneficial chemical group by synthetic chemistry, as demonstrated for the biosynthetically engineered analogues of nystatin mentioned above; further synthetic chemistry modifications resulted in compounds with improved in vivo pharmacotherapeutic characteristics compared with amphotericin B 115 , 116 .

Advances in microbial culturing systems

The complex regulation of NP biosynthesis in response to the environment means that the conditions under which producing organisms are cultivated can have a major impact on the chance of identifying novel NPs 87 . Several strategies have been developed to improve the likelihood of identifying novel NPs compared with monoculture under standard laboratory conditions and to make ‘uncultured’ microorganisms grow in a simulated natural environment 117 (Fig.  4 ).

New strategies for isolating previously uncultured microorganisms can enable access to new natural products (NPs) produced by them. a | To recapitulate the effect of complex signals coming from the native environment, microorganisms can be cultivated directly in the environment from which they were isolated. This concept is used with the iChip platform, in which diluted environmental samples are seeded in multiple small chambers separated from the native environment with a semipermeable membrane. The potential of this approach is illustrated by the recent discovery of teixobactin, a new antibiotic with activity against Gram-positive bacteria 134 , 135 . b | Another important recent development involves obtaining information from environmental samples using omics techniques such as metagenomics to identify and partially characterize microorganisms present in a specific environment before culturing. An approach relying on such preliminary information was recently used to engineer the capture of antibodies based on genetic information, which resulted in the successful cultivation of previously uncultured bacteria from the human mouth 145 . This reverse genomics workflow was validated by the isolation and cultivation of three species of Saccharibacteria (TM7) along with their interacting Actinobacteria hosts, as well as SR1 bacteria that are members of a candidate phylum with no previously cultured representatives.

One well-established approach to promote the identification of novel NPs is the modulation of culture conditions such as temperature, pH and nutrient sources. This strategy may lead to activation of silent gene clusters, thereby promoting production of different NPs. The term ‘One Strain Many Compounds’ (OSMAC) was coined for this approach about 20 years ago 118 , but the concept has a longer history 119 , with its use being routine in industrial microbiology since the 1960s 120 .

While OSMAC is still widely used for the identification of new bioactive compounds 121 , 122 , this approach has limited capacity to mimic the complexities of natural habitats. It is difficult to predict the combination of cues (which might also involve metabolites secreted by other members of the microbial community) to which the microorganism has evolved to respond by switching metabolic programmes. To account for such kinds of interactions, co-culturing using ‘helper’ strains can be applied 123 . This can enable the production and identification of new NPs, as illustrated by recent studies in which particular fungi were co-cultured with Streptomcyes species 124 , 125 .

Study of the molecular mechanisms underlying the ability of helper strains to increase the cultivability of previously uncultured microbes can lead to the identification of specific growth factors, allowing expansion of the number of species that can be successfully cultured. This strategy was used by D’Onofrio et al. for the identification of new acyl-desferrioxamine siderophores (iron-chelating compounds) as growth factors produced by helper strains promoting the growth of previously uncultured isolates from marine sediment biofilm 117 , 126 . The siderophore-assisted growth is based on the property of these compounds to provide iron for microbes unable to autonomously produce siderophores themselves, and the application of this approach led to the isolation of previously uncultivated microorganisms 126 . The development of strategies to cultivate microbial symbionts that produce NPs only upon interaction with their hosts can promote access to new NPs. Microbial symbionts interacting with insects or other organisms are a highly promising reservoir for the discovery of novel bioactive NPs produced in a unique ecological context 127 , 128 , 129 , 130 . To stimulate NP production, culturing strategies can be developed that better mimic the native environment of microbial symbionts of insects, including the use of media containing either lyophilized dead insects 131 or l -proline, a major constituent of insect haemolymph 132 .

Strategies to mimic the natural environment even more closely by harnessing in situ incubation in the environment from which the microorganism is sampled have been developed, dating back to more than 20 years ago with the biotech companies OneCell and Diversa. They developed platforms that allowed the growth of some previously uncultivated microbes from various environments based on diluting out and suspension in a single drop of medium 120 , 133 . More recently, such strategies have been highlighted by the development and application of a platform dubbed the iChip, in which diluted soil samples are seeded in multiple small chambers separated from the environment with a semipermeable membrane 134 . After seeding, the iChip is placed back into the soil from which the sample was taken for an in situ incubation period, allowing the cultured microorganisms to be exposed to influences from their native environment. The power of this culturing approach was demonstrated by the discovery of a new antibiotic, teixobactin, produced by a previously uncultured soil bacterium 135 , 136 (Fig.  4a ). This platform may be of great significance for NP drug discovery, given that it has been estimated that only 1% of soil organisms have so far been successfully cultured using traditional culturing techniques 137 .

The omics strategies discussed in previous sections can complement efforts to explore NPs produced upon microbial interactions. The application of such a strategy is illustrated in the work of Derewacz et al., who analysed the metabolome of a genome-sequenced Nocardiopsis bacterium upon co-culture with bacteria of the genera Escherichia , Bacillus , Tsukamurella and Rhodococcus 138 . Around 14% of the metabolomic features found in co-cultures were undetectable in monocultures, with many of those being unique to specific co-culture genera, and the previously unreported polyketides ciromicin A and B, which possess an unusual pyrrolidinol substructure and displayed moderate and selective cytotoxicity, were identified 138 . Other examples include a ‘culturomics’ approach that combines multiple culture conditions with MS profiling and 16S rRNA-based taxonomy to identify prokaryotic species from the human gut 139 , and an ultrahigh-throughput screening platform based on microfluidic droplet single-cell encapsulation and cultivation followed by next-generation sequencing and LC–MS, which allows investigation of pairwise interactions between target microorganisms 140 . The latter approach enabled identification of a slow-growing oral microbiota species that inhibits the growth of S. aureus 140 .

Historically early-adopted microbial culturing approaches led to a bias reflected in the predominant discovery of NPs from microorganisms that are easy to cultivate (such as streptomycetes and some common filamentous fungi). As a result, a vast number of NPs from such ‘easy to culture’ microbes have already been characterized, and conventional screening efforts tend to yield disappointing returns associated with frequent rediscovery of known NPs and their closely related congeners. Therefore, culturing strategies aimed at previously unexplored (or under-investigated) microbial groups, with the potential to produce NPs with entirely new scaffolds and bioactivities (such as Burkholderia , Clostridium and Xenorhabdus ) are of high interest 141 , 142 . Closthioamide, the first secondary metabolite from a strictly anaerobic bacterium, was discovered from Clostridium cellulolyticum by this approach 143 . Targeted isolation of such species is important, and a genome-guided approach to achieve this goal has recently been demonstrated for Burkholderia strains in environmental samples 144 . Another highly innovative approach to the isolation and cultivation of previously uncultured bacteria was recently reported by Cross et al. 145 , who used genomic information to engineer antibodies predicted to target selected microorganisms and to specifically capture these microorganisms from complex communities and to isolate them in pure cultures. This approach was validated by isolation and cultivation of previously uncultured bacteria from the human oral cavity 145 (Fig.  4b ), and it could be applicable to a wide range of target organisms if suitable cultivation conditions can be identified for the isolated cells.

Despite these advances in culturing strategies, artificial conditions still do not fully represent the complex environment of natural habitats. To circumvent this problem, microbial and NP diversity can also be accessed via extraction of organisms and/or their NPs in situ. To directly gain compounds produced in the natural marine environment (which may be missed otherwise), resin capture technology can be used to capture compounds on inert sorbent supports ready to be desorbed, analysed and tested for biological activity 146 . Sustainable approaches for in situ extraction with green solvents, such as glycerol or natural deep eutectic and ionic solvents (NADES), could be used directly during field work 147 , 148 . To improve dereplication, analytical equipment miniaturization is also facilitating in situ analysis; examples include the introduction of devices for physicochemical data analysis, such as micro-MS and portable near infrared spectroscopy 149 , 150 .

Outlook for NPs in drug discovery

The technological advances discussed above have the potential to reinvigorate NP-based drug discovery in both established and emerging areas. NPs have long been the key source of new drugs against infectious diseases, especially antibiotics (reviewed elsewhere 151 , 152 ). Selected NPs with antimicrobial properties discovered by leveraging advances discussed in the sections above, including strategies to exploit the human microbiome for novel NPs 94 , 153 are highlighted in Figs  3 , 4 . Along with the search for new NPs with antimicrobial activities, researchers are continuing to develop and optimize already known NP classes, making use of advances in biosynthetic engineering 154 , total synthesis 155 or semi-synthetic strategies 156 , 157 . In addition, antivirulence strategies could represent an alternative approach to fighting infections 158 , for which NPs targeting bacterial quorum sensing could be of interest 159 .

NPs also have a successful history as cancer therapeutics, which has been well covered in other reviews 160 , 161 , 162 , 163 . An important new opportunity in this field is the capacity of some NPs to trigger a selective yet potent host immune reaction against cancer cells, particularly given the intense interest at present in strategies that could improve response rates to immune checkpoint inhibitors by turning ‘cold’ tumours ‘hot’ 164 . For example, NPs such as cardiac glycosides 165 can increase the immunogenicity of stressed and dying cancer cells by triggering immunogenic cell death, characterized by the release of damage-associated molecular patterns (DAMPs), which could open new avenues for drug discovery or repurposing 166 , 167 , 168 .

Botanical therapies containing complex mixtures of NPs have long attracted interest owing to the potential for synergistic therapeutic effects of components within the mixture 169 , 170 . However, the variability of the NP composition in the starting plant material owing to factors such as environmental variations in the location at which the plants were collected is a major challenge for the development of botanical drugs 1 . With the advances in technology for their characterization, such as metabolomics discussed above, as well as development of regulatory guidance for complex mixtures of NPs ( see Related links ), it is becoming more feasible to develop such mixtures as therapeutics, rather than to identify and purify a single active ingredient 171 .

Since gut microbiota are considered to play a major role in health and disease 172 , 173 , 174 , and NPs are known to affect the gut microbiome composition 175 , 176 , 177 , 178 , this area is an emerging opportunity for NP-based drug discovery. However, drug discovery efforts in this area are still in their infancy, with many open questions remaining 179 . A future direction may be the characterization of single microbiota-derived species for particular therapeutic applications, and the advances in culturing strategies, genome mining and analytics discussed above will be of great importance in this respect.

Many advances discussed above are supported by computational tools including databases (such as genomic, chemical or spectral analysis data; see ref. 180 for a recent review on NP databases) and tools that enable the analysis of genetic information, the prediction of chemical structures and pharmacological activities 181 , the integration of data sets with diverse information (such as tools for multi-omics analysis) 182 and machine learning applications 183 .

Although this Review focuses on technologies that enable the discovery of novel NPs, it is important to acknowledge that unmodified NPs may possess suboptimal efficacy or absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. So, for development of NP hits into leads and ultimately into successful drugs, chemical modification may be required. In addition, bringing a compound into clinical development requires a sustainable and economically viable supply of sufficient quantities of the compound. Total chemical synthesis, semi-synthesis using a NP as a starting point for analogue generation and biosynthetic engineering modifying biosynthetic pathways of the producing organism will be of great importance in this context (Fig.  5 ). Recent advances in chemical synthesis and biosynthetic engineering technologies are strongly empowering NP-based drug discovery and development by enabling property optimization of complex NP scaffolds that were previously regarded as inaccessible. This allows the enrichment of screening libraries with NPs, NP hybrids, NP analogues and NP-inspired molecules, as well as superior structure functionalization approaches (including late-stage functionalization) for optimization of NP leads 94 , 105 , 106 , 107 , 108 , 184 , 185 , 186 , 187 , 188 .

Unmodified natural products (NPs) often possess suboptimal properties, and superior analogues need to be obtained in order to yield valuable new drugs. a | NP analogues can be accessed through the development of total chemical synthesis followed by chemical derivatization, through semisynthesis using a NP as a starting point for the introduction of chemical modifications, and through biosynthetic engineering using manipulations of biosynthetic pathways of the producing organism to generate NP analogues. b , c | Tetracyclines are an example of NP-derived antibiotics that have already yielded several generations of successfully marketed semisynthetic and synthetic derivatives. The first generation of tetracyclines (such as chlortetracycline and tetracycline) were unmodified NPs, while the two subsequent generations of analogues with optimized properties were semisynthetic (second-generation, doxycycline, minocycline; third-generation, tigecycline) and the most recently developed fourth-generation analogues (eravacycline) are entirely synthetic, accessed via total synthesis 193 , 194 . More recent examples of property optimization of other classes of NPs through total chemical synthesis followed by chemical derivatization or through semisynthesis are illustrated by studies focused on analogues of chrysomycin A (panel b ) 195 and arylomycins (panel c ) 157 , respectively. d | The biosynthetic engineering approach has also shown potential; for example, in the generation of analogues of rapamycin 111 , bleomycin 113 (panel d ) and nystatin 114 . 6′-deoxy-BLM A2, 6′-deoxy-bleomycin A2; BLM A2, bleomycin A2.

Finally, although NP-based drug discovery offers a unique niche for diverse forms of academia–industry collaboration, a key challenge is that scientific and technological expertise is often scattered over many academic institutions and companies. Focused efforts are needed to support translational NP research in academia, which has become more difficult in recent years given the decline in the number of large companies actively engaged in NP research. A conventional solution to improve academia–industry interaction is to focus the relevant expertise under one umbrella and in close spatial proximity. For example, the Phytovalley Tirol, centred in Innsbruck, Austria, brings together several research institutions and companies (among others, the Austrian Drug Screening Institute (ADSI), the Michael Popp Research Institute for New Phyto-Entities, Bionorica Research and Biocrates Life Sciences AG) with the aim of accelerating NP-based drug discovery. Another solution could be virtual consortia, such as the International Natural Product Sciences Taskforce ( INPST ) that we have recently established (see Related links), which provides a platform for integration of expertise, technology and materials from the participating academic and industrial entities.

In conclusion, NPs remain a promising pool for the discovery of scaffolds with high structural diversity and various bioactivities that can be directly developed or used as starting points for optimization into novel drugs. While drug development overall continues to be challenged by high attrition rates, there are additional hurdles for NPs due to issues such as accessibility, sustainable supply and IP constraints. However, we believe that the scientific and technological advances discussed in this Review provide a strong basis for NP-based drug discovery to continue making major contributions to human health and longevity.

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Acknowledgements

This paper is affectionately dedicated in memory of Dr Mariola Macías (1984–2020) M.D., Ph.D. in Immunology, Emergency Physician at Hospital Punta Europa, Algeciras (Cadiz), Spain and active member of a research team working against SARS-CoV-2. An excellent professional and a better person. Her humanity, kindness, special and unmistakable smile, generosity, dedication and professionalism will never be forgotten. The authors are grateful to P. Kirkpatrick for his editorial contribution, which resulted in a greatly improved manuscript. A.G.A. acknowledges support from the Austrian Science Fund (FWF) project P25971-B23 (‘Improved cholesterol efflux by natural products’). R.B. acknowledges support by a grant from the Austrian Science Fund (FWF) P27505. V.B. acknowledges support by a grant from the Austrian Science Fund (FWF) P27682-B30. N.B. is recipient of an Australian Research Council DECRA Fellowship. A.C. and E.I. thank the Ministerio de Ciencia, Innovación y Universidades, Spain (Project AGL2017-89417-R) for support. M. Diederich is supported by the National Research Foundation (NRF) (grant number 019R1A2C1009231), by a grant from the MEST of Korea for Tumour Microenvironment Global Core Research Center (GCRC) (grant number NRF-2011-0030001), by the Creative-Pioneering Researchers Program through Seoul National University (Funding number: 370C-20160062), by the Brain Korea 21 (BK21) PLUS programme, by the ‘Recherche Cancer et Sang’ foundation, by the ‘Recherches Scientifiques Luxembourg’ association, by the ‘Een Häerz fir kriibskrank Kanner’ association, by the Action LIONS ‘Vaincre le Cancer’ association and by Télévie Luxembourg. The research work of A.T.D.-K. is funded by Cancer Research UK (C20953/A18644), the Biotechnology and Biological Sciences Research Council (BB/L01923X/1), Reata Pharmaceuticals, and Tenovus Scotland (T17/T14). B.L.F. acknowledges BMBF (TUNGER 036/FUCOFOOD) and AIF (AGEsense) for supporting his research. M.I.G. acknowledges financial support from the European Union’s Horizon 2020 research and innovation programme, project PlantaSYST (SGA No 739582 under FPA No. 664620) and the BG05M2OP001-1.003-001-C01 project, financed by the European Regional Development Fund through the ‘Science and Education for Smart Growth’ Operational Programme. K.M.G. is supported by the UK Medical Research Council (MC_UU_12011/4), the National Institute for Health Research (NIHR Senior Investigator (NF-SI-0515-10042) and the NIHR Southampton Biomedical Research Centre), the European Union (Erasmus+ Capacity-Building ENeA SEA Project and Seventh Framework Programme (FP7/2007-2013), projects EarlyNutrition and ODIN (grant agreements 289346 and 613977), the US National Institute On Ageing of the National Institutes of Health (award no. U24AG047867) and the UK ESRC and BBSRC (award no. ES/M00919X/1). Research in the laboratory of C.W.G. is supported by the Austrian Science Fund (FWF) through project P32109 and a NATVANTAGE grant 2019 by the Wilhelm Doerenkamp-Stiftung. A.K. acknowledges support by national funds through FCT-Foundation for Science and Technology of Portugal within the scope of UIDB/04423/2020 and UIDP/04423/2020. A.L. acknowledges HKBU SDF16-0603-P02 for supporting this research. F.A.M. acknowledges the support by Ministerio de Economia y Competitividad, Spain (project AGL2017-88083-R). A.M. acknowledges the support by a grant of the Romanian Ministry of Research and Innovation, CNCS – UEFISCDI, project number PN-III-P1-1.1-PD-2016-1900 – ‘PhytoSal’, within PNCDI III. G.P. acknowledges the support by NIH G12-MD007591, Kleberg Foundation and NIH R01-AG066749. M.R. acknowledges support by the Swiss National Science Foundation (Schweizerischer Nationalfonds, SNF), and by the Horizon 2020 programme of the European Union. J.M.R. acknowledges the support from the Austrian Science Fund (FWF: P24587), the Natvantage grant 2018 and the University of Vienna, Austria. G.L.R. acknowledges the group of Cellular and Molecular Nutrition (BJ-Lab) at the Institute of Food Sciences, National Research Council, Avellino, Italy. A.S.S. acknowledges the support by UIDB/00211/2020 with funding from FCT/MCTES through national funds. D.S. acknowledges the support by FWF S10711. D.S. is an Ingeborg Hochmair Professor at the University of Innsbruck. K.S.W. is supported by the National Centre for Research and Development (4/POLTUR-1/2016) and the National Science Centre (2017/27/B/NZ4/00917) and Medical University of Lublin, Poland. E.S.S. thanks Universidad Central de Chile, through Dirección de Investigación y Postgrado, for supporting this research. H. Stuppner acknowledges support by the Austrian Research Promotion Agency (FFG), the Austrian Science Fund (FWF) and the Horizon 2020 programme of the European Union (RISE, 691158). A.S. was granted by Instituto de Salud Carlos III, CIBEROBN (CB12/03/30038) and EU-COST Action (CA16112). M.W. acknowledges the support by DFG, BMBF, EU, CSC, DAAD, AvH and Land Baden Württemberg. J.L.W. is grateful to the Swiss National Science Foundation (SNF) for supporting its natural product metabolomics projects (grants nos. 310030E-164289, 31003A_163424 and 316030_164095). S.B.Z. acknowledges the support by University of Vienna, Vienna, Austria. M.H. acknowledges an EPSRC CASE Award (with Pukka Herbs Ltd, UK as industrial partner). I.B.-N. acknowledges the support of Competitivity Operational Program, 2014–2020, entitled ‘Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance’ — CANTEMIR, No. 35/01.09.2016, MySMIS 103375; project PNCDI III 2015-2020 entitled ‘Increasing the performance of scientific research and technology transfer in translational medicine through the formation of a new generation of young researchers’ — ECHITAS, no. 29PFE/18.10.2018. This work was also funded by the Italian Ministry for University and Research (MIUR), grant PRIN: rot. 2017XYBP2R (to C.T.S).

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Marc Diederich

Jacqui Wood Cancer Centre, Division of Cellular Medicine, School of Medicine, University of Dundee, Dundee, UK

Albena T. Dinkova-Kostova

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College of Life Sciences, Northwest University, Xi’an, China

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Laboratory of Metabolomics, The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Plovdiv, Bulgaria

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Mark J. S. Miller

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Rolf Müller

German Centre for Infection Research (DZIF), Partner Site Hannover, Braunschweig, Germany

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Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy

Ferdinando Nicoletti

Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USA

George Perry

Department of Drug Science, University of Catania, Catania, Italy

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Dipartimento di Farmacia, University of Salerno, Fisciano, Italy

Luca Rastrelli

Energy Metabolism Laboratory, Institute of Translational Medicine, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, Switzerland

Michael Ristow

Institute of Food Sciences, National Research Council, Avellino, Italy

Gian Luigi Russo

National Institute for Agricultural and Veterinary Research (INIAV), Vila do Conde, Portugal

Ana Sanches Silva

Center for Study in Animal Science (CECA), ICETA, University of Porto, Porto, Portugal

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Paracelsus Medical University Salzburg, Salzburg, Austria

Daniela Schuster

Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria

The NatPro Centre, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland

Helen Sheridan

Independent Laboratory of Natural Products Chemistry, Medical University of Lublin, Lublin, Poland

Krystyna Skalicka-Woźniak

Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimioupolis Zografou, Athens, Greece

Leandros Skaltsounis

Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Santiago de Compostela, Spain

Eduardo Sobarzo-Sánchez

Instituto de Investigación y Postgrado en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago, Chile

Janssen Pharmaceuticals Research & Development, San Diego, CA, USA

David S. Bredt

Institute of Pharmacy/Pharmacognosy, Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innsbruck, Austria

Hermann Stuppner

Research Group on Community Nutrition and Oxidative Stress, and Health Research Institute of the Balearic Islands (IdISBa), Department of Fundamental Biology and Health Sciences, University of Balearic Islands, Palma de Mallorca, Spain

Antoni Sureda

CIBEROBN (Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, Madrid, Spain

Institute of Molecular Biology ‘Roumen Tsanev’, Department of Biochemical Pharmacology and Drug Design, Bulgarian Academy of Sciences, Sofia, Bulgaria

Nikolay T. Tzvetkov

Pharmaceutical Institute, University of Bonn, Bonn, Germany

Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Italian National Council of Research, Bari, Italy

Rosa Anna Vacca

Inflammation Research Center, San Diego, CA, USA

Bharat B. Aggarwal

Department of Clinical Sciences, Università Politecnica delle Marche, Ancona, Italy

Maurizio Battino & Francesca Giampieri

International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang, China

Maurizio Battino, Jianbo Xiao & Maria Daglia

Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

Francesca Giampieri

College of Food Science and Technology, Northwest University, Xi’an, Shaanxi, China

Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany

Michael Wink

School of Pharmaceutical Sciences, University of Geneva, CMU, Geneva, Switzerland

Jean-Luc Wolfender

Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, CMU, Geneva, Switzerland

Nutrition and Bromatology Group, Department of Analytical Chemistry and Food Science, Faculty of Food Science and Technology, University of Vigo — Ourense Campus, Ourense, Spain

Jianbo Xiao

Oral and Maxillofacial Radiology, Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China

Andy Wai Kan Yeung

Team Bio-PeroxIL, ‘Biochemistry of the Peroxisome, Inflammation and LipidMetabolism’ (EA7270)/University Bourgogne Franche-Comté/Inserm, Dijon, France

Gérard Lizard

Bionorica SE, Neumarkt/Oberpfalz, Germany

Michael A. Popp

Research Group ‘Pharmacognosy and Phytotherapy’, UCL School of Pharmacy, London, UK

Michael Heinrich

‘Graduate Institute of Integrated Medicine, College of Chinese Medicine’, and ‘Chinese Medicine Research Center’, China Medical University, Taichung, Taiwan

Research Center for Functional Genomics, Biomedicine and Translational Medicine, Institute of Doctoral Studies, ‘Iuliu Hatieganu’ University of Medicine and Pharmacy, Cluj-Napoca, Romania

Ioana Berindan-Neagoe

Department of Experimental Pathology, ‘Prof. Dr. Ion Chiricuta’, The Oncology Institute, Cluj-Napoca, Romania

Helmholtz-Center for Infection Research, Department of Microbial Drugs, Braunschweig, Germany

Marc Stadler

Department of Pharmacy, University of Naples Federico II, Naples, Italy

Maria Daglia

Natural Products Laboratory, Institute of Biology, Leiden University, Leiden, Netherlands

Robert Verpoorte

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the International Natural Product Sciences Taskforce

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Correspondence to Atanas G. Atanasov or Claudiu T. Supuran .

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Competing interests.

A.G.A. is executive administrator of the International Natural Product Sciences Taskforce (INPST) and Digital Health and Patient Safety Platform (DHPSP). M. Banach has served on the speakers’ bureau of Abbott/Mylan, Abbott Vascular, Actavis, Akcea, Amgen, Biofarm, KRKA, MSD, Novo-Nordisk, Novartis, Sanofi-Aventis, Servier and Valeant, has served as a consultant to Abbott Vascular, Akcea, Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Lilly, MSD, Novartis, Polfarmex, Resverlogix, Sanofi-Aventis, and has received grants from Amgen, Mylan, Sanofi and Valeant. R.B. collaborates with Bayer Consumer Health and Dr Willmar Schwabe GmbH & Co. KG, and is scientific advisory committee member of PuraPharm International (HK) Limited and ISURA. G.K.B. is a board member of Bionorica SE. M. Daglia has received consultancy honoraria from Pfizer Italia and Mylan for training courses for chemists, and is a member of the INPST board of directors. A.T.D.-K. is a member of the Scientific and Medical Advisory Board of Evgen Pharma plc. I.E.O. is Dean of Faculty of Pharmacy, Gazi University, Ankara, Turkey, member of the Traditional Chinese Medicine Experts Group in European Pharmacopeia, and principal member of Turkish Academy of Sciences (TUBA). B.L.F. is a member of the INPST Board of Directors and has received research funding from Dr Willmar Schwabe GmbH & Co. KG. K.M.G. has received reimbursement for speaking at conferences sponsored by companies selling nutritional products and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec and Danone. C.W.G. is chairman of the scientific advisory board of Cyxone AB, SE. M.H.’s research group has received charitable donations from Dr Willmar Schwabe GmbH & Co. KG and recently completed a research project sponsored by Pukka Herbs, UK. A.L. is a member of the board of directors of Kaisa Health. M.J.S.M. is president of Kaiviti Consulting and consults for Gnosis by LeSaffre. F.N. is cofounder and shareholder of OncoNox and Aura Biopharm. G.P. is on the board of Neurotez and Neurotrope. M.R. serves as an adviser for the Nestlé Institute of Health Sciences. G.L.R. is a member of the board of directors of INPST. N.T.T. is Founder and CEO of NTZ Lab Ltd and advisory board member of INPST. M.W. collaborates with Finzelberg GmbH and Schwabe GmbH. J.L.W. collaborates with Nestlé and Firmenich. M.A.P. is CEO and owner of Bionorica SE. J.H. is an employee of and holds shares in UCB Pharma Ltd. M.M. is Founder and Chairman of Sami–Sabinsa Group of Companies. D.S.B. is an employee of Janssen R&D. M. Bodkin is an employee of Evotec (UK) Ltd.

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Tetravalent carbon atoms forming single covalent bonds with other atoms within the molecular structure. A higher fraction of sp 3 carbons within molecules is a descriptor that indicates more complex 3D structures.

This guideline for the likelihood of a compound having oral bioavailability is based on several characteristics containing the number 5. It predicts that a molecule is likely to have poor absorption or permeation if it has more than one of the following characteristics: there are >5 H-bond donors and >10 H-bond acceptors; the molecular weight is >500; or the partition coefficient LogP is >5. Notably, natural products were identified as common exceptions at the time of publication in 1997.

Pharmacological screening of natural product extracts yields hits potentially containing multiple natural products that need to be considered for further study to identify the bioactive compounds. Dereplication is the process of recognizing and excluding from further study such hit mixtures that contain already known bioactive compounds.

Assays that rely on the ability of tested compounds to exert desired phenotypic changes in cells, isolated tissues, organs or animals. They offer a complementary strategy to target-based assays for identifying new potential drugs.

The use of genomic data to reveal evolutionary relationships. In the context of natural product drug discovery, the use of phylogenomics is based on the assumption that organisms that have closer evolutionary relationships are more likely to produce similar natural products.

The distance of compared taxa on a constructed phylogenetic tree (also known as an evolutionary tree). Closer distance of compared taxa indicates a closer evolutionary relationship.

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Atanasov, A.G., Zotchev, S.B., Dirsch, V.M. et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 20 , 200–216 (2021). https://doi.org/10.1038/s41573-020-00114-z

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• Open access
• Published: 05 October 2020

Quality control of the traditional herbs and herbal products: a review

• Amruta Balekundri 1 &
• Vinodhkumar Mannur 1  

Future Journal of Pharmaceutical Sciences volume  6 , Article number:  67 ( 2020 ) Cite this article

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Herbal medicinal material and product need is increasing, and with this increase in the need, it is very much an essential requirement to maintain the quality of them.

The quality of the herbals is altered by various physical, chemical, and geographical aspects which contribute to the quality of these materials. Apart from that, adulteration is also an increasing concern when it comes to herbal material quality. Various chemical and phytochemical test, analytical techniques, and hyphenated analytical techniques are used for determining the quality aspects of the herbal materials in the herbal pharmaceuticals.

These techniques can be used as quality control tool in assessing the quality of herbal materials and herbal pharmaceuticals.

Quality is of prime concern to human beings in all aspects of life. When it comes to the quality of the pharmaceuticals which are consumed by humans, it is of utmost important as they are used for the wellbeing of the human kind. There are stringent guidelines and regulation for the quality control of the synthetically synthesized chemical pharmaceuticals. They have to undergo various series tests and quality control checks before being marketed and consumed by the patients and consumers. Due to this stringency in the regulations, the quality of the synthetically manufactured pharmaceuticals is maintained up to the mark which assures both safety and efficacy of the pharmaceutical products.

Herbal medicinal products are the ones which are obtained from the plant resources for the treatment and wellbeing of mankind. It is very much essential that even the quality of the herbal medicines is being controlled as that of the chemically synthesized medicines. But unfortunately the regulation norms for the herbals are not as strict when compared to the synthetic drugs. This is leading to a decrease in the quality standards of the herbal products by intentional and sometimes unintentional adulteration, spurious drugs, substitution of drugs, and many other ways which are prone to decreasing the quality of the herbal materials which are marketed and consumed for the healthy survival. But instead of this, it is leading to hazardous effects on the health of the consumers. So it is very much required to control the quality standards of the herbal drugs and products for the betterment of the mankind.

Standardization and the phytochemicals investigation are carried out; apart from these, there are various quality control tools which are used to assure the quality aspects of the herbals. Both qualitative and quantitative measures are required for the quality assurance of them. Different techniques like UV (ultraviolet) and IR (infrared) are mostly used for the qualitative aspects whereas HP-TLC (high-performance thin-layer chromatography), HP-LC (high-pressure/performance liquid chromatography), SFC (supercritical fluid chromatography), thermal analysis, ICP-MS (inductively coupled plasma-mass spectroscopy), LC-MS (liquid chromatography-mass spectroscopy), and GC-MS (gas chromatography-mass spectroscopy) are used for the quantitative estimation of the herbal products for quality control assessment.

As there is a growing demand for herbal pharmaceuticals, there is a need to assure their quality. Almost about 80% of the population is depending on the herbs for the treatment, cure, and prevention. So the different tools and techniques must be implied to verify and insure the required quality to be incorporated into the herbal material and products. There must be guidelines and/or norms framed for carrying out the quality control testing of the herbs which are almost or equally strict as that of the synthetic pharmaceuticals. This will help to maintain the quality standards of the herbal pharmaceutical which is the challenging task and need of the hour in the pharmaceutical research and quality assurance.

Standardization of medicinal herbs and products

The phytochemical constituents present in herbal formulations vary with the variation in the climate, composition, and components of the soil and the region where grown; all these parameters contribute as the obstruction in the process of standardization. The gradual increase in the adulteration and also substitution of herbal drugs are due to the rise in deforestation area. This adulteration and substitution harms the safety and efficacy of the drug.

Adulteration, substitution, and lack of skilled personnel are the main reasons for unavailability of genuine herbal drugs. By use of advanced quality control technique and suitable standards, there is need to assure the quality of the medicinal herbal products. Identification, quality, and purity of herbs and herbal product confirmation are done by the means of standardization. Preliminary identification, physical properties, chemical properties, and biological properties together contribute to the purity of herbs. This purity defines the freshness as well as the quality of the herbal products.

Quality control of herbals is of greater importance for preservation of quality of the natural herbs and products. When the quality control aspect has identification of substance, adulterants, and substitutes; purity of material; and assay of active chemical constituent of greater importance of the particular herb, then they are called as pharmacopeial aspects of quality control. The process where the qualitative and quantitative values of herbs are measured against the prescribed or set standards and parameters is standardization.

Based on the different important evaluation parameters like organoleptic properties, ash values, moisture content, microbial contamination, and chromatographic and spectroscopic evaluations, the WHO for the standardization of herbal drugs with current and future trends has set guidelines for standardization methods and procedures [ 1 , 2 , 3 ].

Modern analytical techniques for the analysis of the herbal drugs are very much essential for global acceptance of Ayurveda and traditional herbs. Scientific basics of quality of the traditional herbs and ayurvedic products can be gained by complete and accurate pharmacognostical assessment. For the authentication and standardization the organoleptic tests, physicochemical studies and pharmacognostical scheme are at most needed [ 4 ]. For the prevention of the genuine herbal materials getting adulterated, the data reported from microscopic and macroscopic studies can serve as an added advantage for identification of adulterants and authentication of genuine herbs. Moreover for confirmation of parameters for the standardization and the identification of the secondary metabolites (alkaloids, tannins, glycosides, saponins, and flavonoids) will act as a useful tool [ 5 , 6 , 7 ].

In accordance with the process for formulation of standard setting of herbal drugs in the pharmacopeia and other standard texts, the microscopic investigation(qualitative and quantitative), macroscopic (shape and markings), identifications (adulterants and genuine drug), physicochemical parameters (moisture content, acid insoluble ash, water soluble ash), pharmacognostical scheme, and other parameters reported for the first time can play a role of significant tool for authentication of herbs in future studies [ 8 , 9 , 10 ].

Thermal analysis for the characterization of herbs and herbal products

In verification of quality, purity and integrity of the herbals special techniques and strategies are applied due to the complex nature of the components of the herbals. Thermal stability of the samples, determination of the mass and enthalpy variation, high sensitivity, reproducibility and rapid response to the variation of results are the qualities of the thermal techniques like thermo gravimetric analysis (TGA) and differential thermal analysis (DTA) [ 11 ].

For the characterization of herbal extract and herbal drug products, thermal analysis can be used as an effective tool. Control of raw material quality, determination of purity, determination of thermal stability, compatibility of stability of substances, qualitative and quantitative drug analysis are important applications of the thermal methods. The reaction order ( n ), activation energy (Ea), frequency factor ( A ), and degradation constant are the different parameters used in the characterization of the herbal extracts which can be evaluated and studied with the thermal techniques (like TGA and DTA). Further, the absolute water content, crystal water content, and thermal degradation can also be assessed by these thermal techniques [ 12 , 13 ].

In thermal analysis, time and temperature functions are used as defining parameters. The temperature ranges from 25 to 1000 °C are used in the thermal analytical procedures. Mass Signals are obtained during the heating processes of the analysis which reveal about the mass loss (mass lost in the thermal degradation process) in different defining steps (endothermic and exothermic) [ 14 ].

Determination of the variation in both iso-thermal and non-iso-thermal conditions contribute for the stability of aspects of the substances under the thermal analysis.

Interaction between the components of the drugs is studied by the interaction between the excipients and the active pharmaceutical ingredients (API) as the compatibility criteria by the means of TG, DTG (differential thermo gravimetric analysis), and differential scanning calorimetry (DSC) thermal analytical techniques. For the thermal behavior of polymers, TG and DSC are used as an evaluating tool for polymer and drug compatibility as pre-formulation study of the new formulations to be established [ 15 ].

The drugs are to be disposed after the thermal degradation is taken place, so prior to this disposal process, studies are conducted where in the behavioral patterns of the drug after and during the degradation process are studies so that the level of toxicity nature of the drugs and drug product can be analyzed which can help in accessing the process to be selected for disposing of such degraded drugs and drug product as the preventive measure to reduce the potential hazard caused by the disposed degraded substances to the environment.

Arrhenius equation is of utmost importance for calculations to be carried out from the data collected from thermal analysis,

Ln K = ln A − Ea/RT [OR] k ( T ) = A.e −Ea/RT

where A = frequency factor,

K = rate constant,

Ea = activation energy, and

R = gas constant (8.314Jk −1 mol −1 )

When the value of the temperature component increases in the equation, the value of the exponential part reduces and in turn there is an increase in the value of k .

The minimum energy required for the thermal process is called activation energy. As the particle size of the sample plant material decreases there is increase in the surface area and instability of sample, so this increase in the surface area leads to the lowering of the activation energy for the thermal process. So as the particle size decreases the value of activation energy also decreases (Table 1 ) [ 12 ].

HP-TLC analytical technique for the herbal botanical formulation quality control

To establish the pharmacopeial standards of various herbal ayurvedic, Siddha as well as other medicinal herb formulations by the means of HPTLC fingerprinting profile as a major quality control aspect. By this, HPTLC means phytochemical components of the formulations can be disclosed and efficacy, safety, and quality can be assured [ 19 , 20 ].

The efficiency and safety of the final herbal medicine is based on the quality and the profile of the components of the formulations. Difficulty or barriers in the way of quality control testing of the herbal formulations are due to the complexity and variation in the chemical components of herbal-based formulations or compositions. Modern analytical techniques like HPTLC are used to bypass the problems which are covering the way of quality control aspects of herbal formulations [ 21 , 22 , 23 ].

With the growing advances in science, HPTLC is becoming one of the prime options for the quality control of the herbal plants. HPTLC technique is used simultaneously in comparison with both reference and samples and can work as quality control tool apart from identification. Based on the recommendation of monographs, various tests are carried out for the identification and quality control of the herbal plants and formulations. Peak profiles and their intensities are obtained from the HPTLC fingerprint images which give both qualitative and quantitative results in comparison with reference standards. Marker compound identification, percentage of purity, and minimum content information is also obtained by this technique of HPTLC [ 24 , 25 , 26 , 27 ].

For preliminary analysis for identification of adulteration and substitutes, pharmacognostic and phytochemical test and physicochemical properties act as the quantitative tests. For quantitative estimation of the phyto-constituents, HP-TLC technique is widely used due to the accuracy and simplicity of the technique. When samples are collected which differ in the area where they are grown and the climatic conditions, they are evaluated for different properties and phytochemical components. Apart from chromatograms and fingerprints digital images, visual detection is also possible even when the amount of samples and standards are prepared in microliter concentration. Simultaneous application of samples and standards on the same HP-TLC plate is possible and due to this property, it becomes easier during the comparative studies of herbal drugs and formulations [ 28 , 29 , 30 , 31 ].

HP-LC analytical technique for analysis of botanical formulations for the quality control

In the discovery domain, the identification (quantitative and qualitative) of active compounds from the herbal extract is the most difficult and challenging task. In modern discovery, the processes like isolation with preparative bio-activity do not match the pace as they are slow and tedious, whereas modern systems prefer for easy, accurate, and fast processes to be utilized. Traditional techniques, which use multiple isolations, can lead to decrease or completely vanishing of the activity of the active compound. So to overcome the drawbacks, profiling of compounds with HPLC analytical technique is done in modern discovery to identify the multiple compounds accurately due to versatility of the analytical technique [ 32 , 33 , 34 ].

For the quality assurance, herbs and traditional medicinal products obtained from the extract of plants can be estimated for the chemical components with HPLC technique. In the identification of chemical phyto-constituents in herbal medicine products, the standardization technique with the marker profile is of greater benefit as the quantifications of the multiple constituents from the herbal medicinal formulations have issues related to safety and efficacy of the active essentials.

Separation of the components from traditional poly-herbal medicinal formulations HPLC serves as one of the convincing analytical technique as it has being gaining importance for qualification, quantification, and authentication aspects in the quality control of herbs.

Further harvesting season, drying techniques, plant origin, presence of heavy metals, and microbial contents are the major reasons which vary the quality of the herbs and come in the way of quality control of herbs [ 35 , 36 , 37 ].

In the estimation of presence of active chemical and biological markers in the complex traditional herbal products, HPLC can be used as a beneficial tool for standardization with both quantitative and qualitative estimation. For the analysis of the thermo-liable substance present in the traditional herbal formulations, one of the prime options of analysis is HPLC technique with advancement of isocratic and gradient elution. Analysis of poly-component medicinal herbal products is also possible as well as effective with RP-HPLC (reverse phase-high-performance liquid chromatography). The technique of HPLC and RP-HPLC serves high reproducibility and ease of automation in the identification of multiple constituents of botanical preparations.

The liquid-liquid partitioning, solid-extraction, preparative liquid chromatography, and thin-layer chromatographic fractionation are the sampling techniques used to reduce the complexity of the matrix effect. Due to the complexity of the matrix the co-elution of the peaks of the multi-components of the herbal marker compound takes place during the HPLC analysis process of that particular compound under analysis [ 38 ].

Supercritical fluid chromatography (SFC) as a tool for quality control of herbs

The growing hazardous effect of the synthetic chemicals and organic solvents on the environment has developed need for the focus towards the green chemistry principles with increase in number of methods and processes which comply with the same. To acquire the principle analytes from the compounds even when different matrices are being used, supercritical fluid chromatography technique is used as an alternative for conventional organic solvent methods (like HPLC) [ 39 ].

In supercritical fluid chromatography method, compressed carbon dioxide (CO 2 ) with small part of organic solvents (like methanol) are together used as the mobile phase, where major part is of carbon dioxide and minor is organic solvent; due to this ratio, the supercritical fluid chromatography (SFC) method is named as an alternative chromatography.

SFC method is an eco-friendly method as it utilizes very less quantity of organic solvents and the low viscosity of mobile phase as the pressure drop is less when compared with liquid chromatographic techniques [ 40 ]. The organic solvents being used are to be stored properly with proper precautions as they are highly flammable in nature and hence utmost care must be taken for prevention of dangerous accidents causing fire and explosions. The high purchase price and disposal of organic also adds up to the disadvantage of the organic solvents [ 41 ].

Lipid, flavonoid, phenolic, alkaloids, saponins, carbohydrates, and analysis of wide variety of analytes can be carried out with the SFC technique. The fat-soluble vitamin analysis is gaining more importance.

Fast analysis in comparison with HPLC and GC technique SFC analysis uses significant shorter period of time and low amount of solvents and is eco-friendly which are the most important characteristics of the SFC technique. A broad multi-residue method can be carried out with the SFC technique as it analyses both polar and non-polar compounds with very high sensitivity. In the analytical SFC method, development has rapid equilibrium of volume as well as enhanced hydrophobic component (molecule) elutions. As water is absent in the system, this serves as an advantage for the SFC technique for the residues from ionization point.

SFC is also been noted as an unconventional method of sample preparation. It also finds application in large scale industries due to selective techniques and environment-friendly method. The integrity and quality of the analytical material is maintained prior to analysis due to absence of oxygen (no oxidation process), absence of light (no photolysis), and low temperature (no temperature dependent degradation) in the working environment of the SFC technique which also adds up to the advantages [ 42 , 43 ].

ICP-MS (inductively coupled plasma-mass spectroscopy)

Elemental composition present in medicinal plants play crucial role in the biological system of living organisms the medicinal herbs can serve as an essential part in providing trace elements to humans in their diet. Medicinal plants during the process of cultivation get easily contaminated and therefore there must be well-defined limits of elemental composition decided for medicinal plants. The ability of element accumulation of plant and the geochemical nature of the soil are responsible for the level of presence of the elements in the medicinal plants. These medicinal plants are the connecting link between the living beings and trace elements. Natural origin of the medicinal herbals cannot assure the quality and safety as the quality dilutions take place due to industrialization, fertilizer, agricultural pesticides, pollutants, storage, and marketing process.

Ionic and non-ionic are the two forms in which the trace elements are available in plants. And these ionic and non-ionic forms are responsible for toxicity and level of bioavailability in living organisms. Chromium (Cr), copper (Cu), cobalt (Co), ferrous (Fe), and zinc (Zn) are the metals which when consumed in excess amounts lead to toxicity, whereas cadmium (Cd), lead (Pb), and mercury (Hg) are toxic elements even when consumed in low concentrations [ 44 ].

The elemental content associated with active chemical compound of the medicinal plant adds up both benefits and hazardous effects to the herbal product. The concentration of elemental content differs with the different geographical variation, and its most influencing factors are rainfall, type of soil and its pH, and temperature. So the environmental geographical condition in which the medicinal herbs are grown plays a crucial role and is to be taken in consideration. ICP-MS (inductively coupled plasma-mass spectroscopy) and PIXE (partial induced X-ray emission) are the methods being used for analytical and chemo-metric studies on herbs. These methods are useful to gain information about the relation between the medicinal plant elemental content and their effect on particular disease treatment [ 45 ].

For quality and safety of the herbal products, heavy metal testing is of the crucial concern. Elemental specificity, multi-isotope detection, high sensitivity, dynamic range, and possibility of extremely low detection limit are the advances provided by the ICP-MS analytical technique used for trace and ultra-trace element concentration detections [ 46 ].

Medicinal plants that undergo the elemental content analysis can be used as an alternative over the synthetically fortified drugs when we get a clear picture of the elemental composition of the medicinal herbs; hence, this medicinal herb can be used to overcome the trace metal deficiencies as well as no side effect of the chemically metal fortified synthetic products [ 47 ].

Disorders related to brain, digestive, kidney, liver, pancreas, reproductive system, and central nervous systems are caused when the elemental components go on accumulating in the living human body. Further, this can lead to various cancer cells developing if the exposure is high and repetitive. So it is very much required to analyze the limit of elemental content and composition in the medicinal herbal products [ 48 ].

LC-MS for the quality control of botanical herbs

When HPLC method is used individually without other method in combination, it has certain drawbacks in the raw material extract in complex matrix analysis where prior treatment for the API concentration and purification is needed for the process to be simplified and give better results. This drawback is overcome by using the mass spectroscopy (MS)-coupled HPLC technique that is LC-MS (liquid chromatography-mass spectroscopy), in which the technique highly improves the sensitivity of detection. For the method simplification of LC-MS-ion trap mass spectroscopy (Ion trap LC-MS), quadrapole time of flight high-resolution mass spectroscopy (Q-TOF HRMS) and triple-quadrapole mass spectroscopy (TQ LC-MS) are the different technique which can be coupled with the HPLC analytical method [ 49 ].

Structure characterization, molecular mass, information of fragmentation, retention time, and broad range of detection and high separation of analytical compounds are the abilities of the LC-MS technique. Raw plant material extract and marketed product identification, quantification, and quality control of the herbs can be carried out with LC-MS combined technique [ 50 ].

Complete documentation of the data necessary for the online qualitative analysis of the herbal extract can be acquired by performing LC fingerprinting process. The hyphenated LC-MS technique is employed where the structure elucidation of chemical components of the herbal extract is not possible individually with the HPLC analytical method. Identification of chromatographic peaks and the comparison study online is possible by use of the LC-MS technique.

Further, the detection of the adulterants in the extracts and botanical products and phytochemical analysis of the herbs has become easier due to the advantageous LC-MS technique which is applied for the process. The separation process as well as the identification process of the various compounds which are structurally similar can be identified; this serves as one of the most superior qualitative tool among the various tools for the analysis of different herbs and the adulterants. With the advances of the LC-MS technique, the screening and characterization of the adulterants (unknown and known) which are novel analog can also be detected and identified by applying this technique in the quality control of the materials [ 51 ].

For the analysis of the complex traditional herbals with high resolution, efficiency and sensitivity which is used to gain accurate mass information are all present in the powerful tool for analysis which is UHPLC-Q-TOF/MS (ultra-high-performance liquid chromatogram coupled with electrospray ionization tandem quadrapole-time of flight/mass spectroscopy). For the potential analysis of components of the chemical markers, the multivariate statistical analysis which are basically dependent on the available chemical information which makes the identification of the components much simpler. This UHPLC is one of the advance types in the LC-MS analytical technique [ 52 ].

GC-MS (gas chromatography-mass spectroscopy) in the quality control analysis of herbs

GC-MS (gas chromatography-mass spectroscopy) is the analytical technique which is the combination of GC (gas chromatography) which separates the different components of the mixtures of the chemical compounds whereas the MS (mass spectroscopy) which analyses the components which are being separated by the GC. In case of the herbal product analysis, the extract can be analyzed for the principle component by the GC-MS technique. GC-MS can also be used in the pharmaceutical industries, cosmetic products, food industry, and environmental and forensic application for the analysis of the components of the compound basically the active pharmaceutical ingredients.

The most important analysis which is carried out by GC-MS is the analysis of the thermo-stable volatile compounds and the volatile derivatives. Qualitative and quantitative analysis of the volatile oil determination is carried out by the GC-MS technique; it is also possible to determine the multiple components of the compound and drug metabolites. LC-MS is comparatively more sensitive than the GC-MS but LC-MS cannot analyze the thermally stable volatile components whereas it is only able to analyze the thermally unstable non-volatile compounds.

Identification of components (qualitative), separation of components, and quantification of different compounds are both volatile and non-volatile in a single analysis. It is possible to carry out the simultaneous analysis of different compounds [ 53 , 54 , 55 ].

In the field of the forensic science the GC-MS technique pre-treatment process is being used which is extremely simple when compared to the conventional pre-treatment process that is less complex in nature; this process is called as headspace solid-phase microextraction (HS-SPME) and together with GC-MS it is said to be HS-SPME-GC/MS. Different detection techniques are used in coupling with the GC-MS techniques that are electron capture detection (ECD) and electron ionization (EI) with single quadrapole MS and/or triple quadrapole MS (MS-MS) [ 56 , 57 ].

Matrix-matched calibration standards are used in the gas chromatography to compensate for the matrix effect in this technique and this is one of the simple most and cheap technique. The GC-MS/MS technique performance is affected by the extract purity which is under analysis and is injected to the system, as the biochemical range of the herbs is wide in range and the nature of the herb is also complicated.

The GC-MS technique is not suitable for the thermo-liable compounds. In case of the non-volatile components, they must be derivatized and then the analysis must be carried out [ 58 , 59 ].

Comparison of HPLC, HP-TLC, and GC

The comparison of chromatographic techniques is shown in Table 2 .

In the case of the herbal products which are part of traditional medicine system, the novel formulations developed are required to be standardized for safety, efficacy, and potency. It is required that the various techniques are used for the quality control examination of the herbs, which can be regulated to gain the required quality products by setting proper norms. And this in turn will provide the safer use and effective treatment and required potency of the products which will benefit mankind and society by providing means of wellbeing.

Availability of data and materials

All data and materials are available upon request.

Abbreviations

Frequency factor

Active pharmaceutical ingredient

Differential scanning calorimetry

Differential thermal analysis

Differential thermo gravimetric analysis

Activation energy

Electron capture detection

Gas chromatography-mass spectroscopy

High-pressure/performance liquid chromatography

High-performance thin-layer chromatography

Headspace solid-phase micro extraction

Inductively coupled plasma-mass spectroscopy

Rate constant

Liquid chromatography-mass spectroscopy

Partial induced X-ray emission

Quadrapole-time of flight high-resolution mass spectroscopy

Gas constant (8.314 Jk −1 mol −1 )

Reverse phase-high-performance liquid chromatography

Supercritical fluid chromatography

Thermal analysis

Thermo gravimetric analysis

Triple-quadrapole mass spectroscopy

Ultra-high-performance liquid chromatogram coupled with electrospray ionization tandem quadrapole-time of flight/mass spectroscopy

Ultraviolet

World Health Organization

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Herbal medicines: a cross-sectional study to evaluate the prevalence and predictors of use among Jordanian adults

• Faris El-Dahiyat   ORCID: orcid.org/0000-0002-5264-8699 1 ,
• Mohamed Rashrash 2 ,
• Sawsan Abuhamdah 3 , 4 ,
• Rana Abu Farha 5 &
• Zaheer-Ud-Din Babar 6  

Journal of Pharmaceutical Policy and Practice volume  13 , Article number:  2 ( 2020 ) Cite this article

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Introduction

Understanding why adults resort to herbal medicine can help in planning interventions aimed at increasing awareness regarding herbal use. This study sought to investigate the prevalence and to determine factors for predicting the use of herbal medicine among Jordanian adults.

A cross-sectional study was conducted involving 378 older adults who were randomly selected from two different areas of Jordan. A questionnaire was used to gather data and validation criteria for validity and reliability of the content were tested by content and face validity in a panel of experts.

From a total of 500 invited participants, 378 completed the questionnaire. The prevalence of the use of of herbal products in this study was high at 80.2%. Herbal medicines use was not associated with any demographic factors other than age ( p  < 0.05). Moreover, the only associated health-related characteristic was the patient’s disease state including, notably, hypertension ( p  < 0.05). Reasons for not using herbal medicines as reported by nonusers included mainly a lack of belief in their efficacy (52.2%). Another two important reasons were that the individuals believed themselves to healthy and have no need for their use (31.3%) and the unavailability of enough information about the herbal medicines (29.7%). Finally, the most common side effects as reported by patients in this study were nausea and vomiting (9.3%), and, to a lesser extent, skin rash (2.1%).

There is a high rate of use of herbal medicines in Jordan, especially among hypertensive patients. Therefore, there is a need to establish effective herbal medicine policies and health education programs to discuss the benefits and risks of herbal medicine use, with the aim of maximizing patient-desired therapeutic outcomes.

Herbal medicines are substances one can eat or drink and may be vitamins, minerals, or herbs or parts of these substances. They can be defined as ‘plants or plant parts used for their scent, flavour, or therapeutic properties’ [ 1 ]. Herbal medicines are distinct from drugs wherein they are exempted from needing to meet premarketing safety and efficacy standards required for conventional drugs to adhere to [ 2 ]. The use of herbal medicines has increased remarkably throughout the world, with many people now using these products for the treatment of many health problems in health care practice across different countries [ 3 ].

People report using herbal medicine to meet a variety of health care needs, including disease prevention and to cure chronic illnesses such as dyslipidemia, hypertension, diabetes, cancer, and inflammatory bowel diseases [ 4 , 5 ].

The usage of herbal medicines in the world varies depending on location and the prevalence has increased recently. In the Arab world, similar rates have been found. About 80% of the population in Arab societies relies on herbal medicines for the prevention and treatment of illness [ 6 ]. For instance, in Egypt, 37% of the population reported using herbal medicines [ 7 ], while, in Saudi Arabia, a higher proportion of the population (73%) have used herbal medicines [ 8 ]. In Jordan, herbal medicine has maintained popularity as a result of historical, cultural, and psychosocial factors [ 9 ]. The most common reasons for using traditional herbal medicine are that it is inexpensive, more closely corresponds with the patient’s beliefs, avoids concerns about the adverse effects of chemical (synthetic) medicines, satisfies a need for more personalised health care, and allows for a greater public approach to health information [ 10 ].

It is hypothesised that as the use of herbal medicine increases among Jordanian adult populations so too do the occurrence of adverse effects and herbal drug interactions. Knowledge of the predictors of herbal use may help health care providers to identify patients at high risk who would be candidates for receiving additional guidance on the safe use of herbal medicines [ 11 ]. Such could further provide pathways for facilitating positive social changes by developing stricter governmental policies to ensure consumer safety and promote high-quality products and by driving the development of public awareness interventions about herbal use and related health risks.

The present study aimed to examine the prevalence and to identify factors predicting the use of herbal medicine among adults in Jordan. Understanding why adults resort to herbal medicine can help with planning interventions to increase awareness about herbal use. Such could also shed light on the importance of setting frameworks to regulate the entry into, distribution, and use of herbal medicine in the Jordanian market.

Study design, subjects, and setting

This was a cross-sectional study that was carried out in Jordan. Data collection period was from 10 March to 19 April 2017. During the study period, 500 Jordanian individuals were invited to participate in this study and to fill out an anonymous questionnaire designed to evaluate the nature of their herbal medicine use and to identify factors predicting their use of herbal medicine. Participants were Universities students and their family members. Universities staff and their family. The students were approached while participating in different classes. The study objectives were explained to them and they were informed that the study was to assess the knowledge and beliefs about the use of herbal medicine in Jordan.

Questionnaire deployment and data collection

Data collection was carried out using self-administered questionnaires that were developed by the researchers based on questions extracted from previous studies [ 12 , 13 ].

Content validity and face validity of the items questionnaire was evaluated in a panel of experts. Qualitative face validity was evaluated by asking the opinion of experts including a sample of the target group and 5 faculty members, assessed the questionnaire for appropriateness, complexity, attractiveness and relevance for the items. The items were edited and reworded based on their statements. Content validity was also evaluated by qualitative and quantitative methods. In the qualitative phase, we invited two expert panel to evaluate and discuss the essentiality of the questionnaire items, its wording and scaling, and its relevance. In quantitative method, content validity ratio (CVR) and content validity index (CVI) were tested for each item. If CVR was greater than the criterion of the Lawshe’s table [ 14 ] for each item, the item was weighed as essential; if not, it was omitted. According to the Lawshe table [ 14 ], an acceptable CVR value for 5 experts is 0.99.

The questionnaire was divided into four sections. The first section dealt with respondents’ acquisition, recommendations, and trust of currently available information on herbal medicines. The second part inquired about respondents’ attitudes towards herbal medicines The third part requested the health-related characteristics of study participants. The final section characterised the respondents’ demographics. The methods for response were organised differently, including using single-answer, multiple-answer (participants were allowed to choose more than one answer), and four-point Likert scale (i.e., 1 = strongly disagree, 2 = disagree, 3 = agree, and 4 = strongly agree) schemes.

Ethical considerations

This study was conducted following the guidelines outlined in the World Medical Association’s Declaration of Helsinki [ 15 ]. Ethical approval for conducting this study was obtained from the Institutional Review Board Committee at Applied Science Private University.

The participation of members of the Jordanian public was strictly voluntary. Informed consent of the participants was obtained prior to study inclusion and no personal data of the participants are reported. The anonymity of respondents was preserved in the study, as the names of participants were not included.

Sample-size calculation and sampling technique

A sample size calculation was performed using the following formula:

Where P is the anticipated prevalence of students’ knowledge, d is the desired precision, and z is the appropriate value from the normal distribution for the desired confidence.

Using a 95% confidence level (CI), 10% precision level, and 50% anticipated prevalence of inappropriate knowledge, a minimum sample size of 96 people was considered as accurately representative for the purpose of this study. In this study, we tried to approach 500 subjects to increase the generalizability of the study. A convenience sampling technique was employed to approach students based on their accessibility and proximity to the researcher.

Statistical analysis

All data were entered and analysed using SPSS© version 22 (IBM Corp., Armonk, NY, USA). Categorical variables were expressed as frequencies and percentages, while continuous variables were presented as means ± standard deviations (SDs). The chi-squared test was used to evaluate demographic and health-related characteristics associated with herbal medicines.

Multiple logistic regression analysis was used to identify attitude-related factors that best predicted the use of herbal medicines in the study population, using odds ratio (OR) values as a measure of association. A p -value of less than 0.05 was considered to be statistically significant.

The first draft of the questionnaire was formed through a grounded theory study and extensive literature review. The questionnaire was divided into four sections. The first section dealt with respondents’ acquisition, recommendations, and trust of currently available information on herbal medicines. The second part inquired about respondents’ attitudes towards herbal medicines. The third part requested the health-related characteristics of study participants. The final section characterised the respondents’ demographics.

In qualitative face validity, by consideration of the expert panel, four items were deleted due to content overlap. One item was also omitted due to complexity. In qualitative content validity, we changed two items according to the experts’ recommendations. In the quantitative stage, CVR of all the items was between 0.99, except for 4-items that had a CVR < 0.62 and therefore were deleted.

The CVI for each item scale was the proportion of experts who rated an item as 3 or 4 on a 4-point scale [ 16 ]. Clarity, simplicity, and relevancy of each item were scored in a four-point Likert scale (from 1: not relevant, not simple, and not clear to 4: very relevant, very simple, and very clear). Items with scores less than 0.7 were omitted. CVI of other items were between 0.8–1.

Construct validity of this questionnaire was evaluated by 378 respondents with mean age of 26.7 ± 5.60 years. Detailed demographic data of the study participants are as shown in Table  1 . A total of 378 respondents responded to the questionnaire and the majority of them reported using herbal medicine (80.8%). The main reason for the nonparticipation of the remaining students ( n  = 122) was a lack of interest in the subject of the study. About two-thirds of respondents were female (69.6%). The majority had either bachelor or college degrees of education (62.9%) and had an annual income of less than 1000 (68.3%).

Table  2 shows responses pertaining to health-related characteristics and the use of herbal medicines. More than three-quarters of the study sample admitted using herbal medicines. The majority of participants rated their health as either excellent or very good (71.4%) but no significant association between the provided health rating and the usage of herbal medicines was observed. About 80% of the study population did not report the presence of any chronic disease, and there was no association between the presence of chronic illness and the use of herbal medicine found. The most prevalent chronic diseases among the study subjects were hypertension followed by diabetes (9.5 and 5.6%, respectively), and there was a statistically significant association between the type of chronic illness and the admitted use of herbal medicines. More than half of the respondents were somewhat unfamiliar with herbal medicines (52.6%). Among those who used herbs, about one-third were using them only during certain seasons, and approximately half of them reported used herbal remedies followed by vitamins and minerals, respectively (48.9 and 21.7%). The main reasons for using the products were to treat disease and maintain health (44.8%). Approximately 22% of consumers experienced side effects from using herbal medicines including, most commonly, vomiting and nausea (9.3%).

Table  3 indicates that the majority of consumers obtained herbal medicines from herbalists followed by from a pharmacy (37.8 and 23.0%, respectively). Herbal medicine use was mainly recommended by family and friends (39.7%) followed by pharmacists (17.7%) and mass media (12.4%). Pharmacists and medical doctors were the individuals most trusted to provide accurate information on herbal medicines (24.6 and 23.3%, correspondingly).

Reported attitudes towards herbal medicines, as presented in Table  4 , revealed that the majority of respondents agreed with six statements and disagreed with two statements. The reported disagreements were with the statements if a herbal medicines is for sale to the public, I am confident that it is safe and herbal medicines are better for me than conventional medicines. The strongest agreement was with the statement herbal medicines can maintain and promote health followed by that the respondents desired to know more about the safety and efficacy of herbal medicines and about the possibility of the use of herbal medicines to treat illnesses (83.3, 79.6, and 77.8%, respectively).

Multivariate logistic regression analysis outcomes comparing who agreed and disagreed about certain statements regarding herbal medicine use are shown in Table  5 . The highest odds were found among people who agreed about the use of herbs to maintain health (OR: 3.9, 95% CI: 0.12–0.57), while the least significant odds were found among those who agreed with the statement a lot of the health claims made by the manufacturers of herbal medicines are unproven (OR: 0.515, 95% CI: 1.05–3.60). Other significant predictors were herbal medicines can be used to treat illness and if a herbal medicineis for sale to the public , I am confident that it is safe ( p  < 0.05).

The nonusers’ reasons for not using herbal medicines are shown in Table  6 . The highest percentage explained that they feel they are healthy and have no need for herbal medicines or they do not have enough information about herbal medicines. There was a significant association between the nonuse of herbal medicines and the mentioned reasons ( p  < 0.05).

The prevalence of herbal use in this study (80.2%) was the highest when compared with findings presented in other studies from Middle Eastern areas [ 5 , 17 , 18 ] and the United States [ 19 ]. The majority of previous studies reported a higher rate of use of herbal medicines among hypertensive patients [ 20 , 21 , 22 ]. In this study, the use of herbal medicines was not associated with any of the recorded demographic factors but age. Moreover, the only associated health-related characteristic was the patient’s disease state, including specifically hypertension. On the contrary, other studies showed an association with some demographic variables such as educational level or marital status as reported by Ibrahim et al. [ 17 ]. Another survey in Turkey showed a significant association with almost all demographic variables considered [ 21 ].

Our study’s findings were consistent with those of other studies, which reported a degree of independence between sociodemographic factors and the use of herbal medicines [ 23 ]. Any discrepancy might be attributed to different perspectives and definitions of herbal medicines among different populations due to variations in the recognition and valuation of herbal medicines as well as attitudes towards herbal medicines among different cultures.

An assortment of herbal medicines is known to be applicable in managing high blood pressure, which is supported by the findings of this study and other studies conducted in developing countries [ 21 , 24 ]. The low cost and acceptability of traditional herbal medicines in different cultures made users confident with adopting these products for both therapeutic and prevention reasons. Moreover, the use of herbal medicines has a historical context and is well-accepted in Islamic culture, further strengthening users’ acceptance of these products.

Reasons for not using herbal medicines are different as reported by nonusers, and no significant single reason for non usage was stated. However, the highest percentage of nonusers reported they did not believe in the efficacy of herbal medicines. Other important reasons were that the individuals felt healthy and had no need for its use and there was unavailability of adequate information about the herbal medicines. These findings might prompt manufacturers of these herbal products to disseminate more information and perform more outreach and education regarding their products.

The highest adopted products were herbal remedies, as about of half of our sample used these products, followed to a lesser extent by vitamins and minerals, and the total percentage represents less than one-quarter of our population. Our results indicated that older patients were the most frequent users of herbs, vitamins, and minerals. This can be explained by the fact that the older population has more ailments and health issues as compared with their younger counterparts and hence are likely looking for additional health and wellness support.

The reasons for the use of herbs as reported by the study population were mainly to treat diseases and to maintain health followed by preventing illness, which are logical findings in relation to the use of such herbal products. The use of herbal medicines was recommended by family and friends to the greatest extent and secondly by pharmacists, while physician recommendations were the most infrequent recommendations received. Consistently, other studies found nearly the same pattern where seekers do not ask medical advice and instead depend upon friends and family members for guidance [ 25 , 26 ].

The most common side effects as reported by patients in this study were nausea and vomiting and, to a lesser extent, skin rash, which is inconsistent with the findings of other studies that found other multiple side effects including mainly skin rash as the primary unwanted effect of traditional therapy [ 25 , 27 ]. Side effects and drug interactions are common among users of these herbal products, as they are users of other medications such as antihypertensive drugs; hence, health care professionals should be vigilant and educate patients regarding these issues. In addition, the lack of accurate or regulated dosing of these products is another major concern. All of these aspects represent potential sources of debate among health professionals about the risk–benefit ratio and effectiveness of these products.

Limitations

Study participant recruitment was done inside universities, so most of the study sample was from specific age groups spanning students’ ages. Another limitation was the convenience sampling method used in this study. Our findings may not be extrapolated to the broader population of Jordan or to those of other countries.

We found that the use of herbal medicines is common among the study population, including specifically hypertensive patients, in Jordan, and the same is true among other Middle East populations. Demographic characteristics are not significantly related to the use of herbal medicines. The only determinant of the use of these products is the presence of elevated blood pressure. Nausea and vomiting were the most common side effects reported by consumers of herbal medicines. It is worth knowing that herbal products are not risk-free and the risk of drug interactions is not currently well-studied, so further research in this area is warranted and health care professionals should suggest caution to patients where appropriate.

Availability of data and materials

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors are extremely grateful to the survey participants who took the time to participate in the study. Without their participation and feedback, this study would not have been possible.

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Rana Abu Farha

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FD conceptualized the project with ZB. FD performed data collection, entry and analysis. MR contributed to data analysis and interpretation. FD, SA, MR, RA and ZUD contributed to manuscript development, The final version was approved by all authors.

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El-Dahiyat, F., Rashrash, M., Abuhamdah, S. et al. Herbal medicines: a cross-sectional study to evaluate the prevalence and predictors of use among Jordanian adults. J of Pharm Policy and Pract 13 , 2 (2020). https://doi.org/10.1186/s40545-019-0200-3

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Plant-derived natural products for drug discovery: current approaches and prospects

Noohi nasim.

1 Centre for Biotechnology, Siksha ‘O’ Anusandhan (Deemed to be University), Bhubaneswar, Odisha 751003 India

Inavolu Sriram Sandeep

Sujata mohanty.

2 Department of Biotechnology, Rama Devi Women’s University, Vidya Vihar, Bhubaneswar, Odisha 751022 India

Nature has abundant source of drugs that need to be identified/purified for use as essential biologics, either individually or in combination in the modern medical field. These drugs are divided into small bio-molecules, plant-made biologics, and a recently introduced third category known as phytopharmaceutical drugs. The development of phytopharmaceutical medicines is based on the ethnopharmacological approach, which relies on the traditional medicine system. The concept of ‘one-disease one-target drug’ is becoming less popular, and the use of plant extracts, fractions, and molecules is the new paradigm that holds promising scope to formulate appropriate drugs. This led to discovering a new concept known as polypharmacology, where natural products from varying sources can engage with multiple human physiology targets. This article summarizes different approaches for phytopharmaceutical drug development and discusses the progress in systems biology and computational tools for identifying drug targets. We review the existing drug delivery methods to facilitate the efficient delivery of drugs to the targets. In addition, we describe different analytical techniques for the authentication and fingerprinting of plant materials. Finally, we highlight the role of biopharming in developing plant-based biologics.

Introduction

Plants are a source of a wide range of natural products that possess various therapeutic properties and are continuously explored to develop novel drugs [ 78 ]. For ages, traditional medicines have depended on these natural products to treat many diseases. Today, most of the pharmaceutical medications are processed from these natural products. Natural products are made up of many bioactive compounds. These bioactive compounds impart biological activity against several disease-causing agents. To date, numerous secondary metabolites with diverse structures and pharmacological properties have been identified from plants [ 31 , 78 ]. Knowledge adhered by the traditional medicine system has paved the way for the ongoing exploration of medicinal plants for manufacturing pharmaceutical products [ 59 ]. More than 85–90% of the world’s population depends on the traditional medicine system for combating various diseases [ 93 ].

The isolation of morphine, the first natural and pure plant-derived compound, from Papaver somniferum in 1803 marked the beginning of the era of drug discovery [ 44 ]. About 70,000 herbal plants have been used for medicinal applications, mainly in Asian medicines. About 20% of the available plants are used for medicinal purposes in India. These medicinal plants are the storehouse of unlimited ethnobotanical compounds, which are being utilized today for various drug delivery programs (Table ​ (Table1). 1 ). The advancement in genomics, proteomics, transcriptomics and metabolomics has enhanced the contribution of natural products in drug discovery. Metabolomic studies are progressively employed to identify novel drugs and drug targets, interpret drug action mechanisms and maintain records of developed drugs and their therapeutic effects.

Important natural products derived from plant sources

Types of plant-based molecules

Conceptually, plants can be utilized in many ways to extract their therapeutic potential. The most implied usage is in the form of homemade remedies such as herbal teas. Plant extracts in crude form or standardized fractions are used in various pharmaceutical products such as powders, tinctures, pills, etc. Several bioactive compounds have also been extracted from plants and are directly used as drugs.

Small molecules

Plants produce various signalling molecules (auxin, abscisic acid, cytokinin, gibberellic acid, salicylic acid, ethylene, jasmonate and brassinosteroid) and secondary metabolites (alkaloids, terpenoids and phenylpropanoids) which play a crucial role in various developmental and defence processes. These molecules play a vital role in regulating the plants' life cycle and are often referred to as small molecules. These small molecules are released in the state of stress to protect the plant from pathogens, cold, or UV light. Because of their small size (< 500 Da) and diverse mechanism of action, they have dominated the traditional system of medicine and remain the primary component of an ever-expanding therapeutic toolbox [ 104 ].

Plant-made biologics

Biotechnological advancement has enabled the use of plants to produce therapeutic proteins for manufacturing medicines and biotech drugs for treating fatal diseases such as cancer, diabetes, HIV, cystic fibrosis, heart disease, and Alzheimer's disease. These plant-made biologics (PMBs) or plant-made pharmaceuticals (PMPs) provide an efficient, safer, and cost-effective platform to produce therapeutic proteins compared to traditional tools based on animal cell cultures and microbial fermentation, which are dependent on expensive facilities. Further, there is a minimum chance of animal or human pathogen infection in plants, making them a competent platform and one of the fastest-growing classes of pharmaceutical products. PMBs have also facilitated the patient’s access to medicines. Many life-saving drugs can be manufactured through these plant-produced proteins [ 12 ]. The first approved PMB Elelyso (taliglucerase alfa) is a carrot made enzyme engineered in carrot cells and used to treat Gaucher´s disease [ 27 ]. Vaccines for the influenza virus are under clinical trials [ 71 ], whereas plant-derived lectins are in the pipeline to produce novel anti-cancer biologics [ 20 ]. Under the current global pandemic caused by COVID-19, there is an urgent need to adapt low-budget technologies for manufacturing PMBs against COVID-19. In this context, a promising biopharmaceutical candidate is anticipated, and vaccines based on Virus-like particles (VLPs) have been announced [ 74 ].

Phytopharmaceutical drugs

Phytopharmaceutical drug (PPD) is a new class of herbal drugs that are prepared according to the guidelines issued by AYUSH (Department of Ayurveda, Unani, Siddha, and Homeopathy) and CDSCO (Central Drugs Standards Control Organization), in India. These drugs are prepared from herbal plants having a long history of being used as traditional medicines, but proper documentation is not available. PPD is defined as a standardized and purified fraction of a medicinal plant extract consisting of a minimum of four bio-active phytoconstituents and is used to cure and prevent diseases [ 9 ]. Usually, the herbal drug manufacturing process lacks proper control and regulation. Hence, guidelines have been incorporated for the analytical analysis and standardization of these herbal drugs for their safe consumption. PPDs are enriched extracts composed of phytomolecules, flavonoids, carotenoids, polyphenols, lycopene, anthocyanidins, omega-3 fatty acids, phytoestrogens, and glucosinolates having distinct pharmacological properties against many human health problems such as allergy, inflammation, diabetes, and many more [ 66 ].

Need for production of plant-based drugs

Natural products have always attracted the pharmaceutical industry, with interest in plant-derived drugs and alternative therapies for many reasons. Though synthetic medicines provide quick relief, many adverse effects accompany them. Synthetic medicine is costly due to its manufacturing process and may be inaccessible to a large section of the world’s population. On the other hand, traditional medicines are by and large harmless, more effective with minimum side effects, and easily metabolized and absorbed in the body. Due to the cultural and social belief of the people, they are widely accepted, affordable and easily accessible to the people. Increased scientific studies and clinical trials by researchers and pharmaceutical companies have provided evidence-based medicines [ 93 ]. Furthermore, the purification and standardization of a single compound is more convenient, thereby facilitating its use in the modern drug delivery system.

Challenges in production of phytopharmaceutical drugs

Despite several advantages, there exist a few challenges associated with the production of PPD. Plant-derived products sometimes lack quality and are ineffective due to India's poor regulation of natural products. As a result, there is a decline in trade and reluctance in prescribing PPDs. Other hurdles include (i) low yield of the plant material used, (ii) solubility level of plant extracts in water and other solvents, (iii) presence of cytotoxic components in the extract, (iv) limited bio-availability of the sample, (v) inappropriate use of available phytomedicines leading to toxic accidents, (vi) error in botanical identification of plants and their use, (vii) unauthorized usage of popular remedies, (viii) domestic accidents due to consumption of decorative plants having cardiotonic components, (ix) haemorrhagic accidents and hypertensive accidents due to coumarin derivatives present in some plants, (x) presence of oestrogenic components in plants, (xi) use of plants causing allergic reactions due to pollens or volatile components [ 66 ].

Approaches for phytopharmaceutical drug development

Many approaches have been developed for drug development depending on the aim and desired end-product used as a herbal medicine or a part of different formulations.

Ethnopharmacology

The most important and decisive step for any pharmacological study is selecting the plant. Usually, plants with a history of being used in traditional medicines by different ethnic groups are preferred and such type of approach is known as ethnobotany or ethnopharmacology [ 81 ] (Fig.  1 A). Various extraction methods and herbal formulae used by the ethnic groups form the base of this approach. Herbal formulations provide concise information regarding the medicinal properties possessed by the herbal formula. Details on how the drug is consumed and the amount used are also acknowledged. However, proper screening of the herbal drug is needed as different ethnic groups have varied health concepts and healthcare systems. Hence, the symptoms should be properly interpreted before using any herbal formulation therapeutically. Ethnopharmacological approach coupled with random high throughput screening has also been employed and is known as the biorational approach. The long history of therapeutic uses increases the hit rate of bioactivity for a new drug candidate. It thus simplifies drug selection, making it the most effective search engine for identifying drugs from nature [ 93 ].

Schematic representation of herbal drug discovery showing how different approaches are applied based on desired product A Workflow of procedures involved in Ethnopharmacology (EP) and reverse pharmacology (RP) for development of plant-based drugs B Phytochemical evaluation of prepared extracts by high throughput screening (HTS) and fragment-based drug discovery (FBDD) for identification of lead molecules and their subsequent utilization in drug development C Integration of polypharmacology (PP) and network pharmacology (NP) approaches for modern drug discovery. C1-C12 in pink color represents different drug compounds and P1-P12 in blue are different protein targets

Biologically active constituents which possess pharmaceutical properties are isolated from the plant extracts during the drug development process. The whole plant extract is more active than an individual compound in some cases. Plant extracts consist of several structurally diverse chemical components that may be present in low or high concentrations and are responsible for the herbal extract’s overall quality. Bioactivity-guided fractionation of these extracts is needed to isolate and identify bioactive compounds. Bioactive standardized extracts are essential when the pharmacological effect is due to the synergistic effect of many compounds and is not governed by a single component. For instance, the “standardized extract” of Gingko contains ginkgolides A, B, C, and M that can inhibit platelet aggregation factor (PAF)-induced platelet aggregation [ 3 ]. On the other hand, bioactive standardized saponin fractions of Panax ginseng  were found to be more active than isolated compounds [ 94 ]. Several bioactive standardized molecules have also been reported [ 19 , 65 ].

Reverse pharmacology

Conventional drug development has opened new paths for drug discovery, but sometimes it can be inefficient and expensive. A trans-disciplinary approach has recently emerged, which is cost-effective with reduced time and toxicity levels compared to the conventional method. This new approach is called reverse pharmacology (RP) (Fig.  1 A) [ 69 ]. RP is based on the experimental validation of the documented findings leading to identifying effective drugs. It includes the documentation of the clinical studies done for herbal formulations used in folk medicine. This is followed by studies on drug dose, drug tolerance, and in vitro and in vivo analysis of the formulation for drug target activity. The last phase includes the clinical and experimentation studies at different levels of biological organization. This leads to the proper identification and validation of RP study in correlation with the safety and efficacy of the herbal drug. Therefore, RP has replaced the common route of “laboratory-to-clinic” with the “clinic-to-laboratories” pathway [ 82 ]. RP is the bridge between modern technologies and traditional medicines and has improved their collaboration. RP approach is based on targeted screening of the potential compounds with functional activity and can further be used for drug discovery. RP based drug discovery starts and ends with humans, thereby assuring their safety and efficacy [ 5 ].

High throughput screening

For decades pharmaceutical screening of natural products has been carried out for identifying potential drugs. However, high throughput screening (HTS) is the latest approach applied widely for drug delivery programs. HTS incorporates high-quality components and assays used to explore the biological activity of many samples (Fig.  1 B). Various bioactive natural compounds and their derivatives have been identified with anti-cancer, anti-diabetic, and anti-inflammatory activities, whereas over a hundred natural compounds are under clinical screening. However, there is an increased interest in the possibility of assaying these natural compounds from traditionally used medicines. With the advancement of analytical tools and fractionation techniques for identifying, isolating, and purifying natural products, screening of these natural compounds is now in accordance with the HTS [ 49 ].

Fragment-based drug discovery

The fragment-based drug discovery (FBDD) approach is a new concept used as an alternative to HTS in the pharmaceutical industry. This approach is based on the structure-based drug design and uses X-ray crystallography or NMR spectroscopy to identify potent drug molecules (Fig.  1 B). FBDD can reduce attrition and can locate leads for the biological targets which were previously intractable. It can identify very small molecules (fragments) with low-molecular-weight (∼150 Da), which bind to macromolecules or drug leads. To extend FBDD to more laboratories, new and improved computational tools and biophysical methods are being developed and new fragment libraries are being designed [ 21 ].

Polypharmacology

In the past few years, drug research has witnessed several significant transformations. Of late, many drugs are withdrawn from the market after a few days of release. Thus, developing novel drug discovery methods has become a great challenge [ 68 ]. Several bioactive molecules (alkaloids, phyllanthins, piperidines, bacosides, curcumin) from medicinal plants have successfully treated many human diseases. Moreover, complex diseases such as cancer, heart diseases, multiple sclerosis, and diabetes require a multi-targeted approach. Hence, a new technique known as polypharmacology has emerged, which is based on a multi-target approach (Fig.  1 C). This approach involves designing drugs that can modulate multiple targets compared to the traditional concept of one gene, one drug, one disease [ 23 ]. The advances in omics technologies and bioinformatics further enabled the identification of key targets in these diseases.

The multitarget drug approaches offer several advantages in comparison to existing combinational therapies. Single molecule acting on several targets offers greater efficacy and reduces toxicity than drug combinations. In addition, there are chances of adverse synergistic effects in combined drugs which pose challenges during testing. However, the regulatory issues which delay clinical trials, are minimum with single compounds [ 4 ]. Besides, natural products are also known to have higher polypharmacological profiles than synthetic molecules [ 23 ]. Different studies have employed the polypharmacology approach for understanding the mechanisms involved in Traditional Chinese Medicines (TCM) [ 99 ]. Fang et al. [ 23 ] illustrated the polypharmacological profile of five natural compounds (curcumin, epigallocatechin gallate, quercetin, resveratrol, berberine) and presented different methods for studying drug-target interactions. Similarly, a machine learning-based virtual screening approach was utilized to identify the polypharmacological profile of a natural product galantamine [ 36 ]. Construction of databases and development of new bioinformatics tools will accelerate and improve polypharmacology-based studies [ 90 , 92 , 98 , 103 ]. More recently, Polypharm-DB has been developed to identify drug candidates for COVID19 [ 42 ]. Thus, polypharmacology offers an excellent solution for drug repurposing in the future.

Network pharmacology

With the advancement in system biology, the concept of ‘one-disease one-target drug’ is becoming less popular and comprehends difficulties in treating complex diseases. Hence, new concepts of multiple targets, i.e., polypharmacology and network pharmacology, are gaining impetus (Fig.  1 C). The concept of network pharmacology is based on systems biology, network analysis, redundancy, connectivity, and pleiotropy [ 50 ]. It offers ways to improve drugs' clinical efficacy by monitoring the side effects and toxicity level by studying the drug’s kinetic and biological profile [ 39 ]. According to network biology theory, bioactive compounds that can act on two or more targets are more efficient than those working on single targets [ 39 ]. Hence, network pharmacology is the next paradigm in drug discovery because of its cost-effective structure and efficiency in explaining the principles of network theory and systems biology. Many case studies for traditional medicines are based on this network pharmacology approach [ 16 , 91 , 96 ]. The network pharmacology approach is also applied for studying different biological systems, diseases, drugs, and “compound-proteins/genes-disease” pathways based on network biology [ 102 ].

Phytopharmaceutical drug delivery systems

Herbal drugs have gained popularity because they are less toxic and possess better therapeutic properties. But due to the unstable acidic pH and solubility issues, the drug concentration in the blood plasma can decrease, leading to reduced healing effects. Though the plant metabolites such as flavonoids, glycosides, etc., possess therapeutic properties, their polar nature and large molecular size restrict their absorption through the lipid rich biological membranes reducing their bioavailability. The introduction of a novel drug delivery system for plants has minimized the drug loss and degradation in the target tissues. It has narrowed down the side effects with enhanced therapeutic efficacy and improved drug bioavailability [ 20 ].

Available approaches for efficient drug delivery include nanoparticles, bioadhesive microspheres, chitosan-based hydrogels, pulsatile drug delivery system, self-emulsifying drug delivery systems, liposomes, phytosomes etc. (Fig.  2 ).

Different herbal drug delivery systems

Nanoparticles

Nanotechnology has emerged as an efficient system in resolving the issues related to herbal drugs’ stability, solubility, and bioavailability [ 7 ]. The system employs surface-engineered nanoparticles to increase the therapeutic efficiency of phytochemicals in targeting specific body sites. Nanoparticles derived from plant viruses (tobacco mosaic virus) are effectively used as drug carriers in immunotherapeutic and chemotherapeutic stimulation of tumour-associated immune cells [ 20 ]. The introduction of Nanoparticles in the drug delivery system has eased phytochemical transportation beyond the biological membranes with their precise target delivery with minimum degradation. Different nano formulated phytochemicals include hypericin, curcumin, silymarin, etc. [ 75 ].

Bioadhesive microspheres

Bioadhesive microspheres (BMs) are unique drug delivery systems that provide intimate contact of the drug with the biological membrane. It comprises micro-particles and microcapsules which are in the range of 1–1000 μm in diameter. BMs are tailored by combining microspheres with bio-adhesive properties. This coupling enhances the bioavailability and target specificity of the drug at the absorption site. Different polymers used to customize the BMs influence their surface properties, bioadhesion force, drug release pattern, and clearance. These polymers include biodegradable, non-biodegradable, insoluble, and soluble polymers. BMs have been produced for eye tissues, mucosal tissues, oral and respiratory tissues, gastrointestinal and urinary tract. They are used to control the release of the drug and targeted drug delivery to specific sites in the body [ 88 ].

Chitosan-based hydrogels

Hydrogels are swelled cross-linked networks of polymers that can absorb large amount of water [ 48 ]. The characteristic features of hydrogel include swelling potential, mechanical strength similar to host tissues and biodegradability. Hydrogels are made up of either natural or synthetic polymers. Biopolymers like chitosan have been mainly used for hydrogel preparation as they can structurally modify themselves. Chitosan has hydrophilic nature and possesses biocompatibility and biodegradability properties. Hydrogels can carry small drug molecules, reduce their side effects, and enhance their concentration at the site of action. Chitosan-based hydrogels are mainly used for the controlled delivery of therapeutic components. The mucoadhesive characteristics of chitosan facilitate tissue binding capacity for specific drug delivery [ 70 ].

Pulsatile drug delivery system

Controlled drug delivery systems deliver the drugs at a constant rate and continuous release. However, some conditions require intermittent drug delivery, i.e., a time lag. Such delivery is achieved by the pulsatile drug delivery system (PDDS). PDDS closely imitates the body’s mechanism of releasing insulin in a controlled way as and when needed. PDDS can effectively deliver the drug in the optimum amount at the right place and time. This system has been successfully used for hypercholesterolemia, asthma, hypertension, arthritis, and peptic ulcer cardiovascular diseases. For pulsatile delivery, time-dependent systems and pH-dependent systems, etc., are used, which have polymers sensitive to temperature, pH change and light [ 40 ]. PDDS offers many advantages over conventional drug delivery systems including the persistent amount of drug at the site of action, reduced drug dose, preventing fluctuations, controlling side effects, and improving patient compliance. Thus, this pulsatile drug delivery with coordinated biological rhythms and therapeutic needs provides minimum harm and maximum health benefit to the patient [ 14 ].

Self-emulsifying drug delivery systems

The self-emulsifying drug delivery approach is very promising for herbal drug formulations with poor water solubility and lipophilic plant actives [ 13 ]. A self-emulsifying drug delivery system (SEDDS) is a thermodynamically stable solution composed of drug, oil, surfactant and cosurfactant. When the solution is mixed with water and gently stirred, it immediately forms oil-in-water micro/nano emulsion. These emulsions range from a few nanometres to several microns. ‘‘Self-micro emulsifying drug delivery systems’’ (SMEDDS) form oil droplets in the range of 100–250 nm, whereas ‘‘Self-nano emulsifying drug delivery systems’’ (SNEDDS) range 5100 nm [ 43 ]. SEDDS has been effectively used to enhance the bioavailability of poorly absorbed plant metabolites such as patchouli alcohol [ 101 ], mangiferin [ 97 ]. SEDDS is preferred over other drug delivery methods because of its simple and easy nature, and it also can be stored in liquid and solid forms. Hence, SEDDS can be efficiently used to improve herbal drugs’ bioavailability and solubility.

Liposomes are non-toxic, biodegradable drug delivery vehicles that can accommodate hydrophobic and hydrophilic materials. They are spherical, with one or multiple concentric membranes and a solvent for their free diffusion. They are made up of polar lipids and are used to alter the pharmacokinetics profile of drugs. Liposomes can accelerate the drug solubility, stability, bioavailability, intracellular uptake and biodistribution. They can improve and maintain the drugs’ therapeutic features and their level for a long duration and thus are used as a drug delivery system. Liposomes have been used as drug carriers for proteins, small drug molecules, viruses, nucleotides, and other biologically active compounds [ 76 ]. Recently, a herbal drug loaded in nano liposomal vesicles has been used to deliver plant-derived bioactive molecules with anti-cancer properties [ 32 ].

Bioactive compounds mostly have less bioavailability due to their oral intake. Lipid-rich biomembranes pose a hindrance in the crossing of water-soluble phytoconstituents. Thus, herbal extracts that are insoluble in lipids can be dissolved in phospholipids in a specific ratio and converted into lipid-compatible molecular complexes with therapeutic properties. This technology is based on the phospholipid complex procedure which involves a chemical reaction between polyphenolic plant actives and phospholipids containing phosphatidylcholine known as phytosome. The technique also produces cellular vesicles, which protect these water-soluble phytocomponents (flavonoids, terpenoids, phenolics) from getting destroyed by the gut microflora and gastric secretions. This procedure enhances the therapeutic index of the plants’ active compounds [ 7 ]. It ensures better quality and efficient target delivery of active plant components. This technology has provided better chemical linkage of the drug and accelerated its penetration through the skin in reduced doses. Thus, the phytophospholipid complex technique has provided an advanced and systemic absorption of herbal extracts. Hence, these phytophospholipid complexes are promising candidates for better drug dosage therapy with anti-inflammatory, cardiovascular, anticancer, and hepatoprotective applications [ 2 ].

Authentication of plant-derived molecules

Herbal drugs have been widely accepted globally and are in high demand because of their claimed health benefits. This has led to their massive adulteration for which many authentication tools have been developed to evaluate their quality and authenticity. Herbal formulations consist of many bioactive compounds in minimal concentration, which may significantly affect the overall quality of the phytomedicine [ 31 ]. Herbal drugs being mixtures of various components, need certain qualitative and quantitative analysis. For the quality of an herbal drug, standardization is the prerequisite. The drug quality is affected by multiple factors such as inter or intraspecies variation, environmental factors, season, time and methods of harvesting, geographical location of the herb, plant part used, storage and processing practices, etc. [ 22 , 73 ].

In recent times, chromatographic fingerprinting is one of the most important and powerful techniques used to evaluate the quality of herbal drugs [ 41 ]. In 1991, chromatographic fingerprinting was accepted by WHO as a technique for the identification and consistency evaluation of the herbal drugs. American Food and Drug Administration (FDA), European Medicine Evaluation Agency (EMEA) and Chinese State Food and Drug Administration (SFDA) also accepted the chromatographic fingerprint of traditional medicines as standards and chromatographic fingerprinting technology as an alternative method for the quality check of herbal drugs [ 34 , 85 ].

The criterion for assessing the individual herbal material is the common pattern obtained from the chromatographic fingerprinting from various samples of the same species. To ensure the safety and efficacy of an herbal drug, a chemical fingerprint (CF) is developed which represents a unique profile of the phytochemical composition of the sample [ 52 ]. This chemical fingerprint has specific features. The first feature is the intactness of the CF having a specific profile for identification which is constituted by all the detectable components of the sample. Second, two levels of significance should be present, i.e., ‘elementary’ quality control which includes the identification and quantification of the herbal medicine, and the other is ‘intensive’ quality control which serves the in-depth studies of the CF with chemometrics, information theory and other sophisticated technologies. Thus, a CF of a product can be accepted economically and technologically for its official and industrial specifications [ 52 ]. Other identification methods include DNA barcoding which uses short DNA sequences from the sample plant genome for species identification [ 58 ]. The acceptance of a herbal drug is based on the principles of safety, consistency and efficacy [ 35 ]. Thus, chemical fingerprinting should be the top priority as it is the fundamental level for the quality check of herbal drugs.

Several chromatographic fingerprinting techniques have been developed for the quality check and authenticity of herbal medicine. In general, fingerprints can be developed by various spectroscopic and chromatographic techniques. Spectroscopic fingerprints can be developed by using Raman or Nuclear Magnetic Resonance (NMR) spectroscopy or Infrared (IR) spectroscopy [ 30 ]. Mass spectrometric (MS) fingerprints also can be developed. Chromatographic fingerprints can be obtained using Thin-layer chromatography (TLC) [ 77 ], High-performance thin-layer chromatography (HPTLC) [ 18 ], High performance liquid chromatography (HPLC) [ 17 ], Ultra-high performance liquid chromatography (UHPLC) [ 105 ], Capillary electrophoresis (CE) [ 29 ], Gas chromatography (GC) [ 64 ], Gas chromatography-mass spectrometry (GC–MS) [ 61 ], Two-dimensional gas chromatography-time-of-flight mass spectrometry (GCxGC-TOFMS) [ 63 ].

HPLC is analytical equipment widely used for checking the authenticity of herbal products. HPLC coupled with multivariate analysis is used for differentiating two closely related herbs [ 31 ]. HPTLC is an easily operated tool with low cost and high sample throughput. It can analyze many samples parallelly and give accurate results. It is widely used for detecting adulterants in herbal samples [ 18 ]. UPLC is an advanced liquid chromatographic technique requiring less solvent as a mobile phase and completes the analysis in minimal time. It is also more efficient in separating and resolving analyte mixtures. It is broadly used for pharmaceutical and biomedical analysis of various samples [ 60 ]. GC is a dynamic analytical technique well known for detecting and quantifying volatile components. The stability, improved visualization, efficient separation and sensitivity for detection by Flame ionization detector (FID) or Mass spectrometry (MS), makes this instrument a robust tool for the study of essential oils and herbal formulations [ 61 ]. GCMS is one of the most widely accepted tools for identifying and qualitatively evaluating herbal drugs' volatile components. It has been used widely by many workers to analyze various phytoconstituents because of its high efficiency, reproducibility, sensitive detection, simplicity and stability [ 61 ], GC × GC-TOFMS is the most efficient separation tool for analyzing complex mixtures due to its high resolution and high peak capacity. Using two columns with varying separation methodology makes this technique more advantageous by increasing resolution, sensitivity, and identification of more unknown compounds [ 63 ]. This technique can be used to detect minor components, develop comprehensive fingerprints and detect unknown volatile constituents of the herbal drug.

Plant biopharming

Over the past decade, plant biotechnology has advanced exponentially and utilizing plants as an alternative for producing recombinant biomolecules is the latest breakthrough in science. Transgenic and transient systems have been developed vigorously to produce high yields of recombinant molecules like enzymes, hormones, antibodies, vaccines and enhanced protein expression [ 74 ]. Plants commonly used as bioreactors include tobacco, tomato, rice, potato, and corn. Tobacco plants are most extensively used as a transgenic platform to produce pharmaceutical products [ 25 ]. To date, many transgenic plants have been raised for the production of plant-based vaccines such as viral vaccines, bacterial vaccines, immunocontraceptive vaccines, etc. [ 46 ].

Biopharming or molecular pharming could be a safer system for pharmaceutical production than yeast, bacteria or cultured mammalian cells because the produced recombinant biomolecules are free from human pathogens, DNA sequences and endotoxins [ 87 ]. The plant system has also erased the post-translational modifications that occur when using bacteria [ 83 ]. Though biopharming is a better system, the structural authenticity of the plant-derived human proteins is very important because it affects their behavior in vivo [ 8 ]. Plant-derived human proteins have carbohydrate groups but lack the terminal galactose and sialic acid. A minor change in the glycan structure can alter recombinant proteins' activity and distribution and make them immunogenic when delivered to humans. Hence confirming a recombinant protein's authenticity is paramount in biopharming [ 87 ].

Transfer and expression of genes in plants can be achieved by agroinfiltration, viral transfection, transient expression, nuclear transformation etc. [ 62 ]. Plant viral vectors have also been engineered to produce pharmaceuticals. These viruses do not cause infection to humans or animals and can produce large amounts of heterologous proteins in the plants [ 33 ]. The engineered plant virus expresses the desired protein during viral replication in the plant cells. The method is advantageous in producing a high amount of recombinant protein expression. The recombinant protein is then purified before vaccine development [ 46 ]. Many plant virus expression systems have been used such as cucumber mosaic virus (CMV), tobacco mosaic virus (TMV), cowpea mosaic virus (CPMV) etc. [ 28 ]. Plants are a source of numerous bioactive molecules that possess several pharmaceutical properties such as anti-viral, anti-bacterial, anti-fungal, etc. Many of these compounds might be present in low amounts in the plant. Thus, biotechnology has provided a gateway for the rescue of these components through advanced technologies and their potential utilization in the development of plant-based biologics.

Over the years, the biotechnology industry has overcome key challenges such as small-molecule resistance, identifying new phytochemicals with a new mode of action and finding new druggable targets. Natural products are the base of novel therapeutic compounds and pose minimum adverse effects. Though the process of drug discovery is slow and time-consuming, recent advances in the plant-based biomanufacturing system, the production and commercialization of herbal drugs and plant-made biologics have gained impetus. The advantages offered by the biopharming platform have provided scope for the development of plant-made cancer biologic which is the need of the hour. Many other medical conditions can be cured if the traditional and modern medical systems work synchronously through integrated approaches. Almost 80–90% of the world’s biodiversity is under-explored and can be a potential source of novel natural compounds and drug leads that can be efficiently used against emerging infectious diseases. Advanced plant production systems being low-cost systems with high safety and scalability also provide scope to produce plant biologics for controlling pandemic outbreaks. The current pandemic which occurred due to the outbreak of COVID-19 has affected the whole world and there is an urgent need to develop a cure. Presently, a number of vaccines have been approved for clinical trials, many are in the pipeline, and some are already being tested on the patients. At this stage, plant-based biologics hold great potential in providing an efficient system to develop anti-viral vaccines against SARS-CoV-2 for fighting the detrimental effects caused by this pandemic.

Acknowledgements

Author acknowledge the facilities and support provided by the Siksha ‘O’ Anusandhan Deemed University and Rama Devi Women's University, Bhubaneswar.

Author contribution

NN conceived the idea, performed literature search and prepared the first draft, IS helped in literature search, writing and review of the draft and SM provided overall supervision and reviewed of the manuscript.

Corresponding Editor: Umesh C. Lavania; Reviewers: Ram J Singh, Anita Mukherjee.

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