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The Federalist Papers

7 h total length

Discover the Genius of the Constitution

Thomas Jefferson described The Federalist Papers as “the best commentary on the principles of government, which ever was written.”

In this free ten-lecture course you will gain a deeper understanding of the purpose and structure of the American Founding by studying the arguments of America’s most influential Founders. Written between October 1787 and August 1788, The Federalist Papers  is a collection of newspaper essays written by James Madison, Alexander Hamilton, and John Jay in defense of the Constitution.

Taught by Hillsdale College’s politics faculty, this course explores the major themes of this classic work of American politics, such as the problem of majority faction, the importance of separation of powers, the nature of the three branches of government, and the argument concerning the Bill of Rights.

By enrolling in this course you will receive free access to the course lectures, readings, and quizzes to aid you in this examination of the greatest Constitution ever written.

We invite you to join us today in this urgent study of the Constitution and what has been lost by the modern assault on it.  

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Lessons in this course.

Introduction: Articles of Confederation and the Constitutional Convention

Written following the Constitutional Convention of 1787,  The Federalist Papers  is the foremost American contribution to political thought. Originally published as newspaper essays in New York, they were written by Alexander Hamilton, James Madison, and John Jay under the pen name Publius. The essays defended the merits of the Constitution as a necessary and good replacement for the Articles of Confederation, which had proven defective as a means of governance.

The Improved Science of Politics

Publius argued that the “science of politics . . . has received great improvement” in his own day. These improvements include separation of powers, legislative checks and balances, judges who serve a life term during good behavior, and what he called “the ENLARGEMENT of the ORBIT” of government. Contrary to the practice of previous republics, Publius argued that a republic had a much greater chance of achieving success if it is spread out over a large or extended territory, rather than a small or contracted one.

The Problem of Majority Faction

In  Federalist  10, Publius confronts one of the most important Anti-Federalist arguments against ratification: Republican government is impossible on a territory as large as the United States. In fact, such an undertaking had never been successful. In response, Publius proposes that the principal remedy for the political disease of faction—a disease “most incident to republican government”—is the large or extended sphere or territory.

Federalism and Republicanism

In the summer of 1787, the Framers labored to set up a political regime that would not only secure liberty and republicanism, but also bring energy and stability to the national government. Because of the failures of government under the Articles of Confederation, American political institutions were at risk. In order to secure these institutions, the Framers constructed a republican form of government that—among many other important features—instituted a new form of federalism.

Separation of Powers

In constituting a new government, the Framers knew that written rules—what Publius calls “parchment barriers”—would not be enough by themselves to protect liberty and prevent tyranny. Instead, Publius looks to the “interior structure” as the best means for keeping the branches properly and effectively separated. Separation of powers, the most important of the Constitution’s “auxiliary precautions,” works to prevent governmental tyranny, and by keeping each branch within its proper sphere of authority allows each branch to do its job well.

The Legislative: House and Senate

The Founders understood that the legislative branch is by nature the most powerful in a republican government. Experience of government under the Articles of Confederation, when state legislatures routinely encroached on executive and judicial powers, confirmed this. Thus, the Framers divided the legislative branch into two parts—the House and the Senate. In addition, they differentiated them as much as possible, consistent with the principles of republican government, with the goal of preventing tyranny and encouraging good government.

The Executive

Following their experience under the Articles of Confederation, and armed with the improved science of politics, the Framers instituted a unitary executive in the office of the president. Unlike the executive office in any previous republic, it was designed so as to ensure energy and responsibility in the executive, which are absolutely essential for good execution of the laws, and therefore for good government.

The Judiciary

In the Declaration of Independence, one charge leveled against King George III was that he had “made Judges dependent on his Will alone.” In framing a republican government, the Founders believed that an independent judiciary was indispensable. Publius argues that the term of life tenure during good behavior and a protected salary ensure this independence.

“The Constitution Is Itself . . . a Bill of Rights”

In  Federalist  84, Publius writes, “The truth is, after all the declamation we have heard, that the constitution is itself, in every rational sense, and to every useful purpose, A BILL OF RIGHTS.” In other words, the structure of the Constitution protects the rights of the people. In addition, the American people retain all powers not granted to the federal and state governments.

Conclusion: Constitutionalism Today

American government today is much different from the constitutional republic outlined in  The Federalist Papers —which relies on structure, representation, and limitations on the functions of the federal government. Administrative regulations and entitlements are two distinguishing features of modern government. These new features require a kind of government that is unlimited, disregards separation of powers, and violates the supreme law under which it claims to operate.

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The physics behind the most annoying thing that could ever happen to you: a paper cut, the physics behind a very annoying thing that could ever happen to you: a paper cut.

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Study combines data, molecular simulations to accelerate drug discovery

New research involving the uc college of medicine may lead to finding effective therapies faster.

Researchers from the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital have found a new method to increase both speed and success rates in drug discovery.

The study, published Aug. 30 in the journal Science Advances, offers renewed promise when it comes to discovering new drugs.

“The hope is we can speed up the timeline of drug discovery from years to months,” said Alex Thorman, PhD, co-first author and a postdoctoral fellow in the Department of Environmental and Public Health Sciences in the College of Medicine. 

Researchers combined two approaches for screening potential new drugs. First, they used a database from the Library of Integrated Network-based Cellular Signatures (LINCS) to screen tens of thousands of small molecules with potential therapeutic effects simultaneously. Then they combined the search with targeted docking simulations used to model the interaction between small molecules and their protein targets to find compounds of interest. That sped up the timing of the work from months to minutes — taking weeks of work required for initial screening down to an afternoon.

“Accuracy will only improve, hopefully offering new hope to many people who have diseases with no known cure, including those with cancer."

Alex Thorman, PhD Co-first author and postdoctoral fellow

Thorman said this faster screening method for compounds that could become drugs accelerates the drug research process. But it’s not only speed that is crucial. 

He added that this newer approach is more efficient at identifying potentially effective compounds.

“And the accuracy will only improve, hopefully offering new hope to many people who have diseases with no known cure, including those with cancer,” Thorman said.

It can also create more targeted treatment options in precision medicine, an innovative approach to tailoring disease prevention and treatment that takes into account differences in people's genes, environments and lifestyles. 

“An accelerated drug discovery process also could be a game changer in the ability to respond to public health crises, such as the COVID-19 pandemic,” said Thorman. “The timeline for developing effective drugs could be expedited.” 

Feature image at top: Collection of prescription drug bottles and pills. Photo/Provided.

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The University of Cincinnati is leading public urban universities into a new era of innovation and impact. Our faculty, staff and students are saving lives, changing outcomes and bending the future in our city's direction.  Next Lives Here.

Other co-first authors included Jim Reigle, PhD, a postdoctoral fellow at Cincinnati Children’s Hospital, and Somchai Chutipongtanate, PhD, an associate professor in the Department of Environmental and Public Health Sciences in the College of Medicine.

The corresponding authors of the study were Jarek Meller, PhD, a professor of biostatistics, health informatics and data sciences in the College of Medicine, and Andrew Herr, PhD, a professor of immunobiology in the Department of Pediatrics in the College of Medicine. 

Other co-investigators included Mario Medvedovic, PhD, professor and director of the Center for Biostatistics and Bioinformatics Services in the College of Medicine, and David Hildeman, PhD, professor of immunobiology in the College of Medicine. Both Herr and Hildeman have faculty research labs at Cincinnati Children’s Hospital. 

This research was funded in part by grants from the National Institutes of Health, a Department of Veterans Affairs merit award, a UC Cancer Center Pilot Project Award and a Cincinnati Children’s Hospital Innovation Fund award.

Those involved in the research are also co-inventors on three U.S. patents that are related to their work and have been filed by Cincinnati Children’s Hospital. 

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August 30, 2024

Researchers from the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital have found a new method to increase both speed and success rates in drug discovery. The study, published Aug. 30 in the journal Science Advances, offers renewed promise when it comes to discovering new drugs.

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Northeastern engineer is using AI and cloud computing to empower educational researchers

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NSF grant will help Ningfang Mi establish a comprehensive curriculum that incorporates AI, machine learning and cloud computing into educational research training programs.

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Northeastern University professor Ningfang Mi says she can help educational researchers unlock new insights into education policies, teaching strategies and student outcomes by utilizing AI and advanced cyberinfrastructure systems in the cloud.

The first time Mi experienced the educational analysis field, she says, she was surprised to learn that her colleagues in educational research didn’t know about advanced technologies and resources available to them to work with big data. There was a big gap between what educators and educational researchers needed and the tools they had access to or knew how to utilize, she says.

“There’s a very high potential we can help them improve their educational research and get more meaningful insights from their rich datasets,” Mi says.

For years, Mi, a professor of electrical and computer engineering, has been focusing her research on cloud computing — computing services such as servers, storage, databases and networking delivered over the internet to users who don’t have access or don’t want to maintain these IT resources themselves.

Typically, cloud computing, along with technologies like machine learning and artificial intelligence, Mi says, has been used mainly by computer science and engineering researchers, leaving fields like the social sciences behind.

“I want to encourage the development and usage of cyberinfrastructure in other domains and disciplines,” Mi says, “and particularly, in the educational domain.”

To boost adoption of advanced technologies in education, Mi has teamed up with computer science experts from different universities and an educational researcher. Their main goal is to prepare future workers in education analytics to use advanced cyberinfrastructure systems in the cloud. 

“This is not the classic computer-related research,” Mi says. “This is bringing together computer engineering and education research to provide training and resources.”

In the long term, the interdisciplinary team of experts aims to establish a comprehensive curriculum that incorporates AI, machine learning and cloud computing into educational research training programs. This will not only enhance the skills of current and future researchers, Mi says, but also ensure that education policies and practices are informed by the latest advancements in technology and data science.

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Mi and her collaborators have received a National Science Foundation grant for a four-year project titled “AI4EDU: Cloud Infrastructure-Enabled Training for AI in Educational Research and Assessment.” 

AI has become a focal point in educational policy discussions, Mi says, both on federal and state levels. Educational administrators and classroom teachers are being urged to adopt AI-driven tools and techniques, which can significantly enhance their ability to analyze large, complex datasets. 

The researchers believe this interest in AI within the education research community will continue to increase in the coming years, driven by data automatically generated by e-learning systems, online courses and tutoring systems. When combined with AI, this data can unlock new insights into education policies, teaching strategies and student outcomes.

The project will first develop a platform with innovative training modules and materials on the use of cloud computing resources for AI analytics that can be used by education researchers, school administrators, policymakers and even prekindergarten through Grade 12 teachers in North Carolina. Later, the experts plan to add to the platform sample projects with accompanying datasets for real-world hands-on training, data analysis and cloud management tools and a depository where the community can collect and share machine learning programs, datasets and code tailored for a variety of educational research tasks.  

“At the same time, our student researchers can extend their research from image and biomedical data processing with machine learning to educational research,” Mi says.

Some of the research questions that AI in education can help answer, Mi says, include the effects of education policies on teacher effectiveness, student academic achievement and psychological well-being; relationships between school policy, teacher quality, family resources and student academic achievement; and student developmental stages and the appropriate match between teaching strategies and learning styles.

The platform will be open-access, Mi says, meaning educational students and researchers from institutions with limited resources will still be able to benefit from its offerings. 

Mi and her collaborators are striving to make a lasting impact on education.

“This project can lead us to other kinds of multidisciplinary collaboration in the future,” Mi says.

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From left: Dr. Gregory Perreault, Dr. Mildred Perreault, Dr. Janelle Applequist, and Dr. Fan Yang.

Zimmerman School faculty present research papers during International Communication Association conference

• Michelle Holden, USF College of Arts and Sciences
• August 29, 2024

Accomplishments , Research

Four faculty members from the Zimmerman School of Advertising and Mass Communications recently presented research papers during the 74th Annual International Communication Association (ICA), which took place in June. The ICA aims to advance the scholarly study of human communication by encouraging and facilitating excellence in academic research worldwide.

Dr. Gregory Perreault , associate professor, presented a paper on joy in journalism.

“A lot of research in journalism studies is really sad: exploring audience hostility, difficult labor practices, and why journalists leave the field. But what I find to be more intriguing is why journalists stay. Noteworthy in all that scholarship is that they’re talking to still-working journalists,” he said. “My research team and I have a data set exploring particular pillars of joy—like generosity, humor, forgiveness—in the life experiences of journalists. Over the next year, we hope to look in particular at how journalists experience generosity (and offer it).”

Dr. Mildred Perreault , assistant professor, highlighted her work focusing on rural journalism and news and disaster communication ecology.

“It is important to share work at the international level so that you can learn more about other countries and also gain a broader understanding of our field. It also helps one to connect with new collaborators,” she explained. “International engagement, like presenting at ICA, is something that distinguishes USF scholars from other scholars at smaller universities, but also helps it align with peer AAU schools.”

She also shared that there were additional networking and engagement opportunities beyond paper presentations.

“I was also part of a group that examined efforts to engage underrepresented groups in academic scholarship about media and communication. That was a great opportunity to have deeper conversations about how to bring new voices into academic spaces.”

She adds that she received some great feedback after her paper was accepted, as well as during the conference, that she can edit for submission to a publication.

“Often the research process is lonely, but conferences make it much more engaging and collaborative. For example, with my work on rural journalism, I was able to participate in a panel discussion with several other scholars in this area. Since it is a niche area, it is a great opportunity to connect with media scholars all over the world who are studying something smaller communities,” she said.

Dr. Fan Yang , assistant professor, and Dr. Janelle Applequist , associate professor, presented their co-authored paper on a meta-analytic and scoping review of digital data-driven advertising.

“Presenting papers at this conference to a wider audience is crucial for several reasons. It provides an excellent opportunity to disseminate our findings and ideas, allowing us to collect constructive feedback from diverse perspectives and seek new collaborations that can enhance the quality and impact of my research. It also aligns with USF's strategic planning goals of engaging broader audiences and furthering internationalization efforts,” Yang explained.

“Presenting our work to a national/international audience contributes to USF's branding and fosters cross-cultural academic exchanges,” she added. “These presentations serve as a platform to showcase The Zimmerman School's cutting-edge research and innovative approaches in advertising and mass communication. This visibility not only enhances the school’s reputation, but also attracts potential students, faculty, and research partners, ultimately strengthening our position as a leader in the field.”

For Applequist, the experience of presenting research at these venues serves as a critical "first step" of her scholarly process. It provides an opportunity to receive and apply feedback from audience members before submitting a study for journal publication. 

“The diverse perspectives offered by colleagues from various fields, institutions, countries, and cultures foster a transdisciplinary approach that significantly enhances the quality and relevance of my (and my team's) work,” she said.

“Feedback provided by an audience member after Dr. Fan Yang and I presented our co-authored study resulted in great conversation regarding how the rigor of our methods (a meta-analytic and scoping review of digital data-driven advertising) could be adapted for more niche areas (e.g., direct-to-consumer advertising in the pharmaceutical industry). These types of studies would serve to inform the field of advertising while providing potential industry partners with critical information for enhancing their daily and annual operations.”

“As a proud member of the USF community, I am committed to publishing high-quality research that showcases our commitment to research excellence. I am very fortunate to be working alongside great colleagues and team members, focused next on grant-funded projects, including a collaboration with BayCare on social determinants of health, and a large-scale NIH-funded study where colleagues and I seek to enhance communication processes throughout clinical trials to address participant retention,” Applequist said.

Yang says she hopes to next deepen exploration of AI's impact on media consumption and human-machine communication.

“We plan to investigate the individual and social implications of AI-driven communicative technologies, as well as expand our studies on AI-powered social robots using cutting-edge tools available in our Media Research Center of The Zimmerman School. Our ultimate goal is to position The Zimmerman School at the forefront of AI research in media research, providing valuable insights for both academia and industry as we navigate the rapidly evolving landscape of AI-enhanced media ecosystems.”

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CAS Chronicles is the monthly newsletter for the University of South Florida's College of Arts and Sciences, your source for the latest news, research, and events at CAS.

• Artificial Intelligence

Exclusive: New Research Finds Stark Global Divide in Ownership of Powerful AI Chips

W hen we think of the “cloud,” we often imagine data floating invisibly in the ether. But the reality is far more tangible: the cloud is located in huge buildings called data centers, filled with powerful, energy-hungry computer chips. Those chips, particularly graphics processing units (GPUs), have become a critical piece of infrastructure for the world of AI, as they are required to build and run powerful chatbots like ChatGPT.

As the number of things you can do with AI grows, so does the geopolitical importance of high-end chips—and where they are located in the world. The U.S. and China are competing to amass stockpiles, with Washington enacting sanctions aimed at preventing Beijing from buying the most cutting-edge varieties. But despite the stakes, there is a surprising lack of public data on where exactly the world’s AI chips are located.

A new peer-reviewed paper , shared exclusively with TIME ahead of its publication, aims to fill that gap. “We set out to find: Where is AI?” says Vili Lehdonvirta, the lead author of the paper and a professor at Oxford University’s Internet Institute. Their findings were stark: GPUs are highly concentrated in only 30 countries in the world, with the U.S. and China far out ahead. Much of the world lies in what the authors call “Compute Deserts:” areas where there are no GPUs for hire at all.

The finding has significant implications not only for the next generation of geopolitical competition, but for AI governance—or, which governments have the power to regulate how AI is built and deployed. “If the actual infrastructure that runs the AI, or on which the AI is trained, is on your territory, then you can enforce compliance,” says Lehdonvirta, who is also a professor of technology policy at Aalto University. Countries without jurisdiction over AI infrastructure have fewer legislative choices, he argues, leaving them subjected to a world shaped by others. “This has implications for which countries shape AI development as well as norms around what is good, safe, and beneficial AI,” says Boxi Wu, one of the paper’s authors.

The paper maps the physical locations of “public cloud GPU compute”—essentially, GPU clusters that are accessible for hire via the cloud businesses of major tech companies. But the research has some big limitations: it doesn’t count GPUs that are held by governments, for example, or in the private hands of tech companies for their use alone. And it doesn’t factor in non-GPU varieties of chips that are increasingly being used to train and run advanced AI. Lastly, it doesn't count individual chips, but rather the number of compute “regions” (or groups of data centers containing those chips) that cloud businesses make available in each country.

Read More: How ‘Friendshoring’ Made Southeast Asia Pivotal to the AI Revolution

That’s not for want of trying. “GPU quantities and especially how they are distributed across [cloud] providers’ regions,” the paper notes, “are treated as highly confidential information.” Even with the paper’s limitations, its authors argue, the research is the closest up-to-date public estimate of where in the world the most advanced AI chips are located—and a good proxy for the elusive bigger picture.

The paper finds that the U.S. and China have by far the most public GPU clusters in the world. China leads the U.S. on the number of GPU-enabled regions overall, however the most advanced GPUs are highly concentrated in the United States. The U.S. has eight “regions” where H100 GPUs—the kind that are the subject of U.S. government sanctions on China—are available to hire. China has none. This does not mean that China has no H100s; it only means that cloud companies say they do not have any H100 GPUs located in China. There is a burgeoning black market in China for the restricted chips, the New York Times reported in August, citing intelligence officials and vendors who said that many millions of dollars worth of chips had been smuggled into China despite the sanctions.

The paper’s authors argue that the world can be divided into three categories: “Compute North,” where the most advanced chips are located; the “Compute South,” which has some older chips suited for running, but not training, AI systems; and “Compute Deserts,” where no chips are available for hire at all. The terms—which overlap to an extent with the fuzzy “Global North” and “Global South” concepts used by some development economists—are just an analogy intended to draw attention to the “global divisions” in AI compute, Lehdonvirta says. 

The risk of chips being so concentrated in rich economies, says Wu, is that countries in the global south may become reliant on AIs developed in the global north without having a say in how they work. 

It “mirrors existing patterns of global inequalities across the so-called Global North and South,” Wu says, and threatens to “entrench the economic, political and technological power of Compute North countries, with implications for Compute South countries’ agency in shaping AI research and development.”

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Research: How to Build Consensus Around a New Idea

• Devon Proudfoot
• Wayne Johnson

Strategies for overcoming the disagreements that can stymie innovation.

Previous research has found that new ideas are seen as risky and are often rejected. New research suggests that this rejection can be due to people’s lack of shared criteria or reference points when evaluating a potential innovation’s value. In a new paper, the authors find that the more novel the idea, the more people differ on their perception of its value. They also found that disagreement itself can make people view ideas as risky and make them less likely to support them, regardless of how novel the idea is. To help teams get on the same page when it comes to new ideas, they suggest gathering information about evaluator’s reference points and developing criteria that can lead to more focused discussions.

Picture yourself in a meeting where a new idea has just been pitched, representing a major departure from your company’s standard practices. The presenter is confident about moving forward, but their voice is quickly overtaken by a cacophony of opinions from firm opposition to enthusiastic support. How can you make sense of the noise? What weight do you give each of these opinions? And what does this disagreement say about the idea?

• DP Devon Proudfoot is an Associate Professor of Human Resource Studies at Cornell’s ILR School. She studies topics related to diversity and creativity at work.
• Wayne Johnson is a researcher at the Utah Eccles School of Business. He focuses on evaluations and decisions about new information, including persuasion regarding creative ideas and belief change.

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[SIGGRAPH Asia 2024, Journal Track] ToonCrafter: Generative Cartoon Interpolation

Doubiiu/ToonCrafter

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Tooncrafter: generative cartoon interpolation, 🔆 introduction.

⚠️ Please check our disclaimer first.

🤗 ToonCrafter can interpolate two cartoon images by leveraging the pre-trained image-to-video diffusion priors. Please check our project page and paper for more information.

1.1 Showcases (512x320)

1.2 Sparse sketch guidance

2. Applications

2.1 cartoon sketch interpolation (see project page for more details).

2.2 Reference-based Sketch Colorization

📝 Changelog

• Add sketch control and colorization function.
• [2024.05.29] : 🔥🔥 Release code and model weights.
• [2024.05.28] : Launch the project page and update the arXiv preprint.

Currently, our ToonCrafter can support generating videos of up to 16 frames with a resolution of 512x320. The inference time can be reduced by using fewer DDIM steps.

Install Environment via Anaconda (Recommended)

💫 inference, 1. command line.

Download pretrained ToonCrafter_512 and put the model.ckpt in checkpoints/tooncrafter_512_interp_v1/model.ckpt .

2. Local Gradio demo

Download the pretrained model and put it in the corresponding directory according to the previous guidelines.

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Calm down. Our framework opens up the era of generative cartoon interpolation, but due to the variaity of generative video prior, the success rate is not guaranteed.

⚠️ This is an open-source research exploration, instead of commercial products. It can't meet all your expectations.

This project strives to impact the domain of AI-driven video generation positively. Users are granted the freedom to create videos using this tool, but they are expected to comply with local laws and utilize it responsibly. The developers do not assume any responsibility for potential misuse by users.

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• Why don’t women use artificial intelligence?

Even when in the same jobs, men are much more likely to turn to the tech

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B e more productive . That is how Chat GPT , a generative-artificial-intelligence tool from Open AI , sells itself to workers . But despite industry hopes that the technology will boost productivity across the workforce, not everyone is on board. According to two recent studies, women use Chat GPT between 16 and 20 percentage points less than their male peers, even when they are employed in the same jobs or read the same subject.

The first study, published as a working paper in June, explores Chat GPT at work. Anders Humlum of the University of Chicago and Emilie Vestergaard of the University of Copenhagen surveyed 100,000 Danes across 11 professions in which the technology could save workers time, including journalism, software-developing and teaching. The researchers asked respondents how often they turned to Chat GPT and what might keep them from adopting it. By exploiting Denmark’s extensive, hooked-up record-keeping, they were able to connect the answers with personal information, including income, wealth and education level.

Across all professions, women were less likely to use Chat GPT than men who worked in the same industry (see chart 1). For example, only a third of female teachers used it for work, compared with half of male teachers. Among software developers, almost two-thirds of men used it while less than half of women did. The gap shrank only slightly, to 16 percentage points, when directly comparing people in the same firms working on similar tasks. As such, the study concludes that a lack of female confidence may be in part to blame: women who did not use AI were more likely than men to highlight that they needed training   to use the technology.

Another potential explanation for the gender imbalance comes from a survey of 486 students by Daniel Carvajal at Aalto University and Catalina Franco and Siri Isaksson at the Norwegian School of Economics ( NHH ). It also found a gender gap: female students enrolled in the NHH ’s only undergraduate programme were 18 percentage points less likely to use Chat GPT often. When the researchers separated students by admission grades, it became clear that the gap reflected the behaviour of mid- and high-performing women (see chart 2). Low performers were almost as likely as men to use the technology.

Why might this be? The researchers probed what was going on with some clever follow-up questions. They asked students whether they would use Chat GPT if their professor forbade it, and received a similar distribution of answers. However, in the context of explicit approval, everyone, including the better-performing women, reported that they would make use of the technology. In other words, the high-achieving women appeared to impose a ban on themselves. “It’s the ‘good girl’ thing,” reckons Ms Isaksson. “It’s this idea that ‘I have to go through this pain, I have to do it on my own and I shouldn’t cheat and take short-cuts’.”

A lack of experience with AI could carry a cost when students enter the labour market. In August the researchers added a survey of 1,143 hiring managers to their study, revealing that managers value high-performing women with AI expertise 8% more than those without. This sort of premium does not exist for men, suggesting that there are rewards for women who are willing to relax their self-imposed ban.

Tera Allas of McKinsey, a consultancy, worries that by the time AI is firmly embedded into modern working life, it might be designed to appeal more to men, who are its main users—potentially shutting women out in the long term. But not everyone is as concerned. Despite the fact that the early internet was dominated by men, for example, young American women were more online than their male counterparts by 2005. On top of this, Danielle Li of the Massachusetts Institute of Technology notes that the studies do not actually show whether men’s current Chat GPT use translates into better or more productive work. At the moment, the technology may be more of a digital toy, she says. Perhaps, then, high-achieving women are simply better at avoiding distraction. ■

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This article appeared in the Finance & economics section of the print edition under the headline “A new gender gap”

Finance & economics August 24th 2024

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Scientists Have a New Theory About Why Orcas Are Attacking Boats

A pod of orcas damaged a boat and left its two-person crew stranded. It was the latest in a string of attacks that research suggests could be used for hunting practice.

By Lynsey Chutel

Reporting from London

The orcas have struck again — this time ramming a sailboat off Spain’s northwest coast, rescue workers said on Tuesday.

A pod of orcas damaged the rudder of a sailboat, leaving its two-person crew stranded in the waters off Cape Finisterre Sunday, according to an emailed statement from the rescue workers. It is the latest in a string of attacks by pods of orcas swimming around the Iberian Peninsula.

While the sailboat, the Amidala, did not sink, pods of orcas have sunk several vessels in recent years. Researchers still do not know whether the attacks are playful or malicious, but a new theory based on studying the troublesome pods of orcas suggests that they could be using the boats as practice targets for new hunting techniques. Other competing theories still exist.

Regardless of the orcas’ intentions, the behavior is enough to worry sailors journeying in the highly trafficked waters around North Africa, Spain and Portugal.

The Amidala, manned by a crew of two Belgians, encountered an unknown number of orcas on Sunday afternoon. They sent a mayday distress call to the Finisterre Maritime Rescue Center, which towed the vessel back to shore, the center said.

The sailboat’s damaged rudder, and poor weather conditions in the area, made the rescue more arduous, with waves reaching up to nearly 10 feet and winds hitting speeds of 40 miles per hour. A female crew member on the Amidala suffered injuries to her hand as the sailboat was being towed, and she was transferred to a rescue vessel, the rescue center said. After more than four hours, the Amidala made it back to shore.

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• Published: 22 May 2019

Herbs and Spices- Biomarkers of Intake Based on Human Intervention Studies – A Systematic Review

• Rosa Vázquez-Fresno   ORCID: orcid.org/0000-0003-2635-7035 1 ,
• Albert Remus R. Rosana 1 ,
• Tanvir Sajed 2 ,
• Tuviere Onookome-Okome 1 ,
• Noah A. Wishart 1 &
• David S. Wishart 1 , 2  

Genes & Nutrition volume  14 , Article number:  18 ( 2019 ) Cite this article

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Culinary herbs and spices have been used as both food flavoring and food preservative agents for centuries. Moreover, due to their known and presumptive health benefits, herbs and spices have also been used in medical practices since ancient times. Some of the health effects attributed to herbs and spices include antioxidant, anti-microbial, and anti-inflammatory effects as well as potential protection against cardiovascular disease, neurodegeneration, type 2 diabetes, and cancer. While interest in herbs and spices as medicinal agents remains high and their use in foods continues to grow, there have been remarkably few studies that have attempted to track the dietary intake of herbs and spices and even fewer that have tried to find potential biomarkers of food intake (BFIs). The aim of the present review is to systematically survey the global literature on herbs and spices in an effort to identify and evaluate specific intake biomarkers for a representative set of common herbs and spices in humans. A total of 25 herbs and spices were initially chosen, including anise, basil, black pepper, caraway, chili pepper, cinnamon, clove, cumin, curcumin, dill, fennel, fenugreek, ginger, lemongrass, marjoram, nutmeg, oregano, parsley, peppermint and spearmint, rosemary, saffron, sage, tarragon, and thyme. However, only 17 of these herbs and spices had published, peer-reviewed studies describing potential biomarkers of intake. In many studies, the herb or spice of interest was administrated in the form of a capsule or extract and very few studies were performed with actual foods. A systematic assessment of the candidate biomarkers was also performed. Given the limitations in the experimental designs for many of the published studies, further work is needed to better evaluate the identified set of BFIs. Although the daily intake of herbs and spices is very low compared to most other foods, this important set of food seasoning agents should not be underestimated, especially given their potential benefits to human health.

Spices are the dried, pleasantly aromatic parts of the plants. More specifically, as defined by the Food and Drug Administration organization (FDA), spices are: “aromatic vegetable substances, in the whole, broken, or ground form, whose significant function in food is seasoning rather than nutrition” [ 1 ]. The main difference between a herb and a spice is that a spice comes from any part of a plant other than the leaves while a herb always comes from the leaves [ 1 ]. Spices typically come from the dried part of a plant such as buds, flowers (cloves, saffron); bark (cinnamon); root (ginger, turmeric); fruits/berries (cloves, chili, black pepper); or seeds (cumin) that contain volatile oils or aromatic scents and flavors [ 1 , 2 ] (see Table  1 ). Most of the known herbs and spices originate from Mediterranean countries, the Middle East or Asia, and many have been used since ancient Egyptian and Roman times [ 3 ].

Herbs and spices have played, and continue to play, important roles as flavoring agents, food preservatives and medicines for centuries. Over the last few decades, research into their health benefits has increased significantly, as many herbs and spices are known to possess properties associated with reducing the risk of developing chronic diseases. In particular, some of the potential health benefits of herbs and spices include conferring protection against cardiovascular disease, neurodegenerative conditions, chronic inflammation, cancer, obesity, and type 2 diabetes [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. A number of herbs and spices have also been noted for their strong antioxidant, anti-microbial, and anti-inflammatory properties [ 4 , 7 , 15 ]. Moreover, the flavoring properties of many herbs and spices tend to reduce the use of salt as a flavoring agent (i.e., reduced sodium intake) which has additional cardiovascular health benefits [ 16 ].

Most of the positive health effects of herbs and spices towards preventing or ameliorating chronic diseases such as cancer, cardiovascular disease, arthritis, and neurodegeneration appear to be mediated through the direct action of their constituent phytochemicals (particularly polyphenols or polyphenol breakdown products) targeting specific receptors or enzymes involved in various anti-inflammatory pathways or immune responses [ 10 ]. Herbs and spices (especially in their dried form) contain high levels of polyphenols [ 6 ] and other physiologically active phytochemicals. The predominant class of polyphenols found in herbs and spices are the phenolic acids and flavonoids (mainly flavones and flavonols) [ 17 ]. Relative to other polyphenol-rich foods such as broccoli, dark chocolate, red, blue and purple berries, grapes or onions—herbs and spices generally contain somewhat higher levels of these compounds. For instance, oregano has 935.3 mg of total phenolic content per 100 g of fresh weight (FW) in the fresh form (F) while in the dried form (D) has 6367 mg/100 g. Similarly, high polyphenolic levels are seen in rosemary [1082.4 mg/100 g (F) vs. 2518 mg/100 g (D)], thyme [1173.28 mg/100 g (F) vs. 1815 mg/100 g (D)], and parsley [89.27 mg/100 g (F) vs. 1584 mg/100 g (D)]. Likewise, cloves have 16,047.25 mg/100 g, cinnamon 9700 mg/100 g, and turmeric 2117 mg/100 g (all FW). In contrast, other non-herbs and foods such as dark chocolate contain 1859.8 mg/100 g FW, while raw blackcurrants contain 820.6 mg/100 g FW and broccoli just 198.6 mg/100 g FW.

Polyphenols, terpenoids, and other spice-derived alkaloids (such as capsaicinoids) are also known to possess antibacterial, antiviral, and antifungal properties [ 18 ]. This is one reason why herbs and spices are so frequently used as preservative agents in food [ 19 ]. The antimicrobial properties of herbs and spices have been attributed to their unique volatile oils and oleoresins [ 20 ]. For instance, comparative studies involving cloves, cinnamon, oregano, rosemary, sage, and thyme showed that thyme oil was particularly active against Aeromonas hydrophila— a pathogen widely distributed in the environment, domestic animals, and food [ 21 ]. Likewise, essential oils found in thyme, oregano, mint, cinnamon, and cloves were found to possess strong antibacterial properties against several food-borne bacteria and fungi [ 22 ].

The number of herbs with known or potential anti-inflammatory activity is quite significant. Of the 25 herbs and spices analyzed in this review, 21/25 (84%) had at least one published study supporting an anti-inflammatory finding. The spices that are most frequently identified as having anti-inflammatory effects are thyme, oregano, rosemary, sage, basil, mint, turmeric, dill, parsley, cinnamon, clove, nutmeg, lemon grass, ginger, chili pepper, fenugreek, and pepper [ 4 , 23 ]. Many of the anti-inflammatory compounds found in herbs and spices, such as curcumin, gingerol, and capsaicin, appear to operate by inhibiting one or more of the steps linking pro-inflammatory stimuli with cyclooxygenase (COX) activation [ 10 ]. While the mechanisms behind some of the health benefits in herbs and spices are becoming clearer over time, the vast majority of herbs and spices still have rather ill-defined health benefits and yet-to-be-identified chemical “actors” [ 4 ].

Given the widespread use of herbs and spices and given their known (and potential) health benefits, there is clearly a need to better understand the consumption patterns of herbs and spices. Population-wide average dietary intake of common spices varies considerably around the world. For instance, Europeans consume an estimated at 0.5 g/person per day, Australians and New Zealanders consume between 1.3–1.9 g/day, and residents of Africa consume 1.8 g/day. Moderate consumers of herbs and spices are found in the Middle East and Eastern Asia with daily consumption of 2.6 and 3.1 g/person, respectively. The highest consumers of herbs and spices are found in India, South Africa, and Latin America with an average of 4.4 g/day [ 23 , 24 ]. In India, turmeric consumption, alone, has been estimated to be 1.5 g/person per day [ 25 ]. While consumption of herbs and spices is generally higher in Southern countries such as India, Mexico, Peru, China, and Thailand, herb and spice intake has been increasing in many developed countries in Northern Europe and North America, due to changing food habits and a growing preference for ethnic or spicy food [ 26 , 27 ].

While broad estimates of herb and spice consumption are useful, more detailed information of what herbs/spices and how much of each are being consumed would be much more useful. In this regard, the development and identification of biomarkers of food intake (BFI) for specific herb and spice consumption would help advance the field. In particular, herb-specific or spice-specific BFIs would permit better exposure estimates for much more comprehensive and far more detailed epidemiological studies of the influence of herbs and spices on human health. This review is focused on finding and evaluating specific nutritional biomarkers for a representative set of 25 common herbs and spices used worldwide [ 3 , 10 ].

Selection of herbs and spices

This set of 25 was selected based on reported estimates of consumption volume in North America and Europe as well as the frequency with which these spices and herbs were cited in the literature. The 25 herbs and spices that were examined include anise, basil, black pepper, caraway, Capsicum sp. (chili pepper and paprika), cinnamon, clove, cumin, curcumin, dill, fennel, fenugreek, ginger, lemongrass, marjoram, nutmeg, oregano, parsley, peppermint and spearmint, rosemary, saffron, sage, tarragon, and thyme (Table  1 ).

Primary literature search

A systematic BFI review should consist of an extensive literature search (ELS) for each food or food group, which will select from all the putative markers proposed in the available scientific literature only the most promising candidate biomarkers based on their likely specific presence in the food and/or food group [ 28 ]. The structure of the present guidelines for conducting an ELS on putative and candidate BFIs is reported elsewhere [ 29 ], which follows the methods proposed by the European Food Safety Authority (EFSA) for conducting systematic reviews for food and feed safety assessments [ 30 ], as well as the ‘Cochrane handbook for systematic review on interventions’ [ 31 ], with proper modifications for handling BFIs. The PRISMA statement for reporting and discussing the results [ 32 ] was also used. Original research papers and reviews were searched in three databases: PubMed, Scopus, and the ISI Web of Knowledge using combinations of the grouped search terms (biomarker* OR marker* OR metabolite* OR biokinetics OR biotransformation) AND (trial OR experiment OR study OR intervention) AND (human* OR men OR women OR patient* OR volunteer* OR participant*) AND (urine OR plasma OR serum OR blood OR excretion) AND (intake OR meal OR diet OR ingestion OR consumption OR eating OR drink* OR administration) as reported in in Additional file  1 : Table S1, together with specific keywords related to herbs and spices food group (Additional file  1 :Table S2) . The specific search terms for specific herbs and spices included both their common and scientific names so as to be as comprehensive as possible . The specific keywords for the herbs and spices of interest were the following: (“anise” OR “Pimpinella anisum” OR “basil” OR “Ocimum basilicum” OR “black pepper” OR “Piper nigrum” OR “caraway” OR “Carum carvi” OR “chili pepper” OR “Capsicum annuum” OR “Capsicum baccatum” OR “Capsicum chinense” OR “Capsicum frutescens” OR “Capsicum pubescens” OR “cinnamon” OR “Cinnamomum” OR “clove” OR “Syzygium aromaticum” OR “cumin” OR “Cuminum cyminum” OR “turmeric” OR “Curcuma longa” OR “dill” OR “Anethum graveolens” OR “fennel” OR “Foeniculum vulgare” OR “fenugreek” OR “Trigonella foenum-graecum” OR “ginger” OR “Zingiber officinale” OR “lemongrass” OR “Cymbopogon” OR “marjoram” OR “Origanum majorana” OR “nutmeg” OR “Myristica fragrans” OR “oregano” OR “Origanum vulgare” OR “parsley” OR “Petroselinum crispum” OR “peppermint” OR “Mentha x piperita” OR “rosemary” OR “Rosmarinus officinalis” OR “saffron” OR “Crocus sativus” OR “sage” OR “Salvia officinalis” OR “spearmint” OR “Mentha spicata” OR “tarragon” OR “Artemisia dracunculus” OR “thyme” OR “Thymus vulgaris”. To improve the accuracy of the search and to help exclude unrelated papers, several other keywords were used including NOT (Ginger [Author] OR Parsley [Author] OR Sage [Author] OR Dill [Author] OR Pimpinella [Author] OR Basil [Author] OR Artemisia [Author] OR Cumin [Author] OR Thyme [Author]). The default search fields for each of the databases were [All Fields] for PubMed, [Article Title/ Abstract/ Keywords] for Scopus, and [Topic] for ISI Web of Science, respectively. This literature search was conducted between November 2015 and January of 2016, followed by a second validation phase and update in January 2018. The literature search was limited to papers in the English language with no restrictions being applied for the publication dates. Results of this literature search for potential biomarkers of herbs and spices are shown in Table  2 .

Exclusion criteria

Papers were excluded if they investigated the effect on human physiology of the selected herbs and spices, the presence or effect of toxicants, if they referred to unspecific markers or if they were based on in vitro or animal studies.

BFI identification and classification

A second search step was used to evaluate the apparent specificity of the markers in the list. The remaining list of potential biomarkers was used for a second literature search in the three bibliographic databases used also for the primary search. This was done in order to identify other foods containing the potential biomarkers or their precursors, as well as foods otherwise associated with these compounds. For the second web-based literature search, the “marker name” was used as keyword, together with AND (biomarker* OR marker* OR metabolite* OR biokinetics OR biotransformation). Further filters, such as (urine OR plasma OR serum OR blood OR excretion) AND (intake OR meal OR diet OR ingestion OR consumption OR eating OR drink* OR administration) AND (human* OR men OR women OR patient* OR volunteer* OR participant* OR subject*) were added based on the results obtained. At the end of this selection process, the usefulness, and weakness of each biomarker compounds were evaluated, and the most promising biomarkers were scored to assess their validity as BFIs according to the system reported below.

Marker validation score

In order to further assess the validity of the biomarker candidates, a set of consensus evaluation criteria, from the FoodBAll consortium was employed [ 33 ]. Specifically, the suitability of each biomarker was assessed by answering a set of questions reported elsewhere [ 33 ], which reflect the analytical and biological criteria that the proposed biomarkers should fulfill in order to be considered valid. Such questions have been answered for the most promising biomarkers and the results are reported in Table  3 . Possible answers were Y (yes), N (no), or U (unknown or uncertain). The potential markers were scored for plausibility and uniqueness (question 1); kinetics and dose-response relationship (question 2), kinetics of postprandial response (question 3a) and longer-term kinetics (question 3b). All markers were further evaluated for their robustness in complex diets or a real exposure situation (question 4) and reliability (question 5), which refers to the concordance with other measures of intake for the food or food group in question (such as other existing validated biomarkers or dietary instruments). The analytical aspects of each BFI were investigated through an evaluation of their chemical stability (question 6), their analytical performance (question 7), and reproducibility in different labs (question 8).

The research papers that identified, described, or evaluated potential biomarkers of intake for the set of 25 herbs and spices were further screened by one or more skilled researchers as described in Fig.  1 . The initial PubMed search retrieved 527 matches, the Web of Science search generated 370 matches, and the Scopus search generated 284 matches, resulting in a total of 1181 hits. This number was reduced to 946 after the removal of duplicates. Subsequent screening of the titles and abstracts by the skilled researchers reduced the number of papers to 54. Further evaluation excluded 6 papers and a secondary search identified 1 more paper leading to a total of 49 papers that were included in this review (Fig.  1 ). Additional papers were identified from the reference lists in these papers and from reviews or book chapters identified through the literature search. This secondary search was used to evaluate the apparent specificity of the marker.

Flow diagram of the study selection

From this total of 49 papers, 18 BFI papers were found for turmeric and curcumin, 6 papers were found for peppermint, 4 papers were found for thyme, 3 papers for ginger, Capsicum and parsley, 2 papers for anise and saffron; and 1 paper each was found for cinnamon, fennel, nutmeg, oregano, marjoram, rosemary and sage, and finally one paper which examined basil, tarragon and fennel (Table  2 ). No potential BFI papers were found for black pepper, caraway, clove, cumin, dill, fenugreek, lemongrass, and spearmint.

A systematic validation of the candidate intake biomarkers is assessed and presented in Table  3 . It should be noted that the search criteria were primarily targeted for BFIs in humans, but, in some cases, a small number of papers in which the BFI study was performed in animals were also investigated. These papers were used to provide supportive information to the studies performed in humans; however, the biomarkers observed only in animal studies were not considered eligible for further BFI validation. Figure  2 summarizes many of the findings of this review. It includes the most representative or strongly validated metabolites identified for each herb and spice, the molecule formula, the HMDB ID, and/or Phytohub code (if exists) and the biofluid or tissue in which each BFI has been found.

Anise is a seed spice derived from a flowering plant belonging to the family Apiaceae , which is native to the Eastern Mediterranean region and Southwest Asia. The distinctive licorice flavor and aroma from anise comes from anethole. Anethole is a phenylpropene derivative found in anise ( Pimpinella anisum ) and fennel ( Foeniculum vulgare ). Anethole occurs naturally in high concentrations in volatile oils such as anise oil (80–90%), star anise oil (over 90%), and fennel oil (80%) [ 34 ]. Anethole exists in both a cis and a trans isomer with the trans isomer being more abundant. It is the main component of the anise essential oil (80–90%), with minor components including para-anisaldehyde, estragole, and pseudoisoeugenyl-2-methylbutyrates, among others [ 35 ]. In Mediterranean countries, the popularity of alcoholic and non-alcoholic anise-flavored beverages has led to a much greater consumption of trans- anethole [ 36 ]. Anethole is also used in medicines as an expectorant, an antitussive and an antispasmodic for treating gastrointestinal tract illnesses. As a result, anise is found in a number of pharmaceutical products.

Just two papers have reported potential anise intake biomarkers. The most complete study was conducted in 1988 [ 37 ], where Caldwell and co-workers performed an acute human study administrating trans -anethole (using a synthesized radio-labeled 14 C compound). The major routes of elimination of 14 C were in the urine (54–69% of the administered dose) and as exhaled 14 CO 2 (13–17%). The principal metabolite (> 90% of urinary 14 C) was 4-methoxyhippuric acid (also known as anisic acid), accompanied by much smaller amounts of 4-methoxybenzoic acid (or also known as p -anisic acid, an oxidation product of anethole) and up to three other unknown compounds. As the authors stated, metabolism of anethole in man was unaffected by changes in dose size, and is dominated by the ɷ-oxidation pathway ultimately leading to 4-methoxyhippuric acid, and by oxidative O-demethylation, leading to the exhalation of 14 CO 2 [ 36 ].

The only other research article to look into anise BFIs was an observational study that measured the content of anethole in the blood after the intake of alcoholic anise-based beverages [ 37 ]. This study rigorously monitored a single individual, wherein the subject consumed the alcoholic drink ouzo over three different days under controlled conditions. In addition to this controlled single-participant study, the authors also looked at the blood collected from 50 motor vehicle drivers who claimed to have consumed drinks containing anethole (ouzo, raki and the German aniseed liqueur “Küstennebel”). The anethole concentrations detected for the tested volunteer showed rapid resorption of anethole as well as rapid elimination. Anethole concentrations above the detection level of 3.6 ng/ml serum were detected in the selected volunteer for 3 h after ceasing consumption of 120 ml of Helenas ouzo and for 3 h after ceasing consumption of 200 ml of regular ouzo, and for 7 h after ceasing consumption of 360 ml of regular ouzo. For the 50 motor vehicle drivers, 10 out of 50 serum samples had anethole concentrations of between 5.4 and 17.6 ng/ml. Of these, eight corresponded to confirmed cases of ouzo consumption, one of raki consumption and one of German aniseed liqueur “Kustennebel” consumption. The authors concluded that anethole can be reliably detected in blood/serum samples after consumption of spirits containing anethole. In no case was a positive result for anethole found where 40 ml or less of spirits containing anethole had been consumed or where the time difference between the cessation of drinking and the taking of the blood sample was greater than 4 h.

Based on these two studies, we can conclude that anethole seems to be a robust and reliable blood BFI for anise consumption as assessed by observational studies involving the consumption of anise-based drinks. While a single, high-quality marker for specific food intake is ideal, the addition of other (unrelated) biomarkers to create a multi-component biomarker panel can substantially improve a biomarker’s sensitivity and specificity [ 33 ]. In this regard, two compounds, 4-methoxyhippuric acid and 4-methoxybenzoic acid have been specifically detected in urine after direct anethole intake. However, these two compounds are actually metabolites of anethole and so are unlikely to add to anethole’s sensitivity/specificity. We also believe that further studies are needed to confirm that these two compounds are seen with actual anise-based food intake. It is also worth noting that anethole is found in fennel, basil, and tarragon [ 38 ], and it is widely present in pharmaceutical products and as a flavoring additive. Therefore, anethole and its metabolites may not be sufficiently specific BFIs for anise intake.

Capsicum sp.

Chili pepper.

The chili pepper is a fruit spice derived from plants from the genus Capsicum , originated in Mexico and brought to Asia by Portuguese navigators during the sixteenth century. The five domesticated species of pepper are Capsicum annuum , C. frutescens, C. chinense , C. pubescens , and C. baccatum. Chili peppers have a taste that is pungent, hot, and somewhat sweet (depending on the variety and type). Mild or sweet peppers contain similar constituents as Capsicum but with little or no pungent components. Chili peppers are used as food colorants, flavoring agents, as predator repellants, and a source of pain relief. The compounds responsible for the “hot” flavor of chili peppers are called capsaicinoids, with capsaicin being the best known. Capsaicin occurs naturally in plants of the Solanaceae family. It is commonly used in both food and medicine, but its strong pungency limits the quantity that can be employed. Capsicum contains up to 1.5% (by weight) of pungent compounds, commonly composed of capsaicin, dihydrocapsaicin, and others. Other constituents present in chili peppers are carotenoids, vitamins A, C, and small amounts of volatile oils with more than 125 known components. Another class of capsaicin-like compounds found in chili peppers and non-pungent chili peppers are the capsinoids. Capsinoids have an estimated “hot taste threshold” that is about 1/1000 that of capsaicin making it possible to use capsinoids in food applications without the intense heat effect found in capsaicins [ 39 ]. Many positive health benefits have been ascribed to both capsaicin and capsinoids, including anticancer, anti-inflammatory, and analgesic effects [ 40 ].

We found two published studies that explored possible BFIs associated with chili pepper consumption. In a cross-over study with 12 volunteers [ 41 ], capsaicin was detected in plasma by HPLC analysis after the administration of 5 g of capsaicin derived from chili pepper. This pharmacokinetic study showed that capsaicin was rapidly absorbed (being detected at 10 min) after ingestion and also rapidly metabolized (not detected in blood after 90 min). Another study, conducted by Bernard et al. [ 42 ], analyzed the metabolites present in plasma by LC-MS/MS after the administration of a capsule of a variety of non-pungent (sweet) pepper (CH-19) extract. The compounds identified were the capsinoids capsiate, dihydrocapsiate and nordihydrocapsiate, and a capsinoid metabolite, vanillyl alcohol. However, these compounds were below the limit of quantification, so the authors could not perform proper kinetic studies.

Based on these data, capsaicin, the main compound responsible for the hot taste of chili peppers, can be considered a specific BFI for chili peppers. However, we believe more data are required and further studies should be performed to confirm the utility of capsaicin as a BFI. With regard to the non-pungent compounds of the “sweet” varieties of Capsicum , (i.e., capsinoids) additional dose-response studies are needed to consider them as plausible BFIs since the concentrations measured in the single reported study were too low to perform kinetic analyses.

Paprika is a ground spice made from the red, air-dried fruits of the larger and sweeter varieties of the plant Capsicum annuum , which is also called bell pepper or sweet pepper. Paprika can also be modified with the addition of more pungent chili peppers and cayenne pepper. Originating in central Mexico, paprika was brought to Spain in the sixteenth century. Paprika spices can range from mild to hot, depending on the variety of the source plant. The flavor also varies from country to country—but almost all plants grown produce the sweet variety. The red, orange, or yellow color of paprika is due to its content of carotenoids. The intense color of paprika makes it an ideal and natural food colorant for many dishes.

Only one study was found that looked into the identification of biomarkers of food intake for paprika. Nishino and co-workers [ 42 ] measured paprika carotenoids in the plasma and erythrocytes of five volunteers who were supplemented with paprika for 4 weeks. The results showed that several, non-unique carotenoids such as lutein, zeaxanthin, β -cryptoxanthin (also found in vegetables such as carrots and tomatoes) could be detected in the paprika-supplemented volunteers. However, the authors also detected other carotenoids specific for paprika, such as cryptocapsin, capsanthin, capsorubin (just found in paprika and lily pollen), cucurbitaxanthin A (found just in paprika and pumpkins), and finally capsanthone (a possible oxidative product of capsanthin). Paprika carotenoids, particularly capsanthin and capsorubin, have been reported to have a strong antioxidant activity [ 43 , 44 ]. Based on these results, cucurbitaxanthin A, capsanthin, capsanthone, and cryptocapsin could be potential paprika-specific carotenoid biomarkers. However, further analyses using untargeted MS-based approaches should be conducted to evaluate other possible biomarkers of paprika intake.

Cinnamon is a bark spice obtained from the inner bark of several tree species from the genus Cinnamomum . Only a few Cinnamomum species are grown commercially (largely from Asia) for spice. Cinnamon is native to India, Sri Lanka, Bangladesh, and Myanmar, and it was imported to Egypt as early as 4000 years ago [ 45 ]. In addition to its common culinary use as a condiment and flavoring material, cinnamon is widely known for its anti-diabetic and glucose lowering effects [ 46 ]. The flavor of cinnamon is due to an aromatic essential oil that is largely composed of cinnamaldehyde (up to 90%); however, there are at least 80 other compounds known to be in cinnamon oil, including cinnamyl alcohol, cinnamyl acetate, eugenol, and various coumarins that contribute to its overall flavor and aroma [ 47 ].

Only one study has been performed in humans to identify BFIs of cinnamon intake [ 48 ]. While cinnamaldehyde might have been expected to be a useful BFI, it is quickly metabolized to cinnamic acid [ 49 ], making it unusable as a cinnamon biomarker. On the other hand, coumarin was deemed to be a potentially useful BFI for cinnamon. Because coumarin has a very strong first-pass effect in the liver, with only a small percentage reaching systemic circulation, the authors chose its main metabolite, 7- hydroxycoumarin as a measure of relative bioavailability. In the study by Abraham et al. [ 40 ], 7-hydroxycoumarin was assessed as a biomarker of cinnamon consumption in both urine and plasma via HPLC-MS/MS analysis. The conversion of coumarin to 7-hydroxycoumarin is catalyzed by cytochrome P450 2A6 (CYP2A6) [ 50 ]. 7-hydroxycoumarin and its phase II metabolite, 7-hydroxycoumarin glucuronide, are rapidly excreted via the kidneys [ 51 ]. Therefore, the total amount of 7-hydroxycoumarin (free and bound as a glucuronide) in urine could serve as an indirect measure of the extent of cinnamon consumption.

Coumarin possesses a pleasant spicy odor of fresh hay or vanilla [ 48 ]. The occurrence of coumarin has been reported in a number of bedding plants such as Anthoxanthum odoratum (sweet vernal grass), Asperula odorata (sweet woodruff), Dipterix odorata (tonka bean), Eupatorium triplinerve (white snakeroot), Hierochloe odorata (holy grass), Melilotus coerulea (sweet trefoil), M. officinalis (common melilot), Melittis melissophyllum (bastard balm), Primula elatior (oxlip), and Trilisa odoratissima (deer tongue). However, none of these plants are usually used as edible foods; thus, the main source of coumarin in the diet is cinnamon [ 52 ]. Coumarin, which is frequently used in perfumes, is also a well-known hepatotoxin (based on animal studies). Interestingly, different species of cinnamon have different levels of coumarin. For example, C. cassia cinnamon contains up to 1% coumarin, whereas the more expensive and less frequently used true cinnamon ( Cinnamomum verum ) contains only trace levels (0.004%) [ 53 , 54 ]. Today, many commercially available food products are spiced with the cheaper C. cassia cinnamon and consequently contain high levels of coumarin. It is notable that German Christmas cookies (which contain considerable amounts of C. cassia cinnamon) have a coumarin content that often exceeds the maximum tolerable dose intake (TDI 0.1 mg/kg body weight).

Based on the available data and based on the fact that the food matrix effect has been well tested, 7-hydroxycoumarin appears to be a plausible specific and robust biomarker of cinnamon intake. Additional cumulative/kinetic aspects of this biomarker need to be performed and most likely an inter-laboratory validation needs to be completed to fully validate this compound as a cinnamon BFI. However, the use of this metabolite as a BFI for cinnamon is confounded by the fact that it depends on the species of cinnamon being used. We believe that other cinnamon compounds (such as cinnamaldehyde and cinnamic acid or the essential oils as cinnamyl alcohol, cinnamyl acetate and eugenol)) should also be explored as potential biomarkers as, so far, the only reported cinnamon BFI study was limited to measuring coumarin and its derivatives.

Fennel, basil, and tarragon

While fennel, basil, and tarragon are very distinct herbs, coming from very different plant species, they share a number of common chemicals and consequently they tend to be grouped together in food intake studies. This is why we have chosen to group these three herbs under a single topic heading.

Fennel is a seed (and bulb) spice, as well as a leaf herb, that is derived from Foeniculum vulgare . This is a small flowering plant that was originally indigenous to the shores of the Mediterranean, but which has since become widely naturalized in many parts of the world. Fennel is a highly aromatic and flavorful herb/spice and is one of the primary ingredients of absinthe. The distinctive licorice flavor and aroma from fennel comes from anethole. Other compounds known to be in fennel include estragole, fenchone, 1,8-cineole (eucalyptol), and p -allylphenol. In addition to its use in culinary applications, fennel has long been used as a medicinal herb to treat gastrointestinal illnesses and upper respiratory tract infections as well as to increase milk production in breastfeeding mothers through the consumption of fennel tea.

Basil ( Ocimum basilicum ) is a culinary herb belonging to the botanical family Lamiaceae . It is a culinary herb that is prominently featured in Italian cuisine as well as many Southeast Asian cuisines. Depending on the species and cultivar, the leaves may taste somewhat like anise, with a strong, pungent, often sweet smell. Thai basil is also a condiment in the Vietnamese noodle soup. Basil has been used traditionally as a medicinal herb in the treatment of headaches, coughs, diarrhea, constipation, warts, worms, and kidney disorders [ 55 ]. It is also a source of aroma compounds and essential oils containing biologically active constituents that possess antimicrobial and antifungal properties [ 56 , 57 ]. Linalool is the main constituent of the essential oil of O. basilicum (28.6–60.6%), followed by estragole, methyl cinnamate, epi-α-cadinol, α-bergamotene, γ-cadinene (3.3–5.4%), germacrene D (1.1–3.3%), and camphor (1.1–3.1%). Other compounds such as myrcene, pinene, terpineol, 1,8-cineole, eugenol, and methyleugenol have been identified in basil leaves [ 56 , 58 , 59 ].

Tarragon ( Artemisia dracunculus ), also known as estragon, is a perennial herb belonging to the Asteraceae (daisy) family. It is widespread across much of Eurasia and North America, and is cultivated for culinary and medicinal purposes. Two well-described “cultivars” (Russian and French) are widely used. “Dracunculus” which in Latin meaning “little dragon” is believed to describe its coiled, serpentine root, and/or the shape of the leaves, which is reminiscent of a dragon’s tongue [ 60 ]. In vitro pharmacological studies indicate that tarragon has antibacterial, antifungal, and antiplatelet activity [ 61 ]. In vivo pharmacological studies have shown that tarragon has anti-inflammatory, hepatoprotective, antihyperglycemic, and antioxidant activity [ 61 ]. The major components of Russian tarragon are reported to be terpinen-4-ol, sabinene, and elemicin. Methyleugenol and estragole are usually present in tarragon oils at about 10 and 3%, respectively. However, estragole is one of the predominant compounds in the essential oil of French tarragon, constituting up to 82% [ 61 ]. Trans -anethole (21.1%), α-trans-ocimene (20.6%), limonene (12.4%), α-pinene (5.1%), and allo-ocimene (4.8%) are the other main components of tarragon [ 62 ].

Two studies have explored or assessed potential biomarkers of fennel (alone) or fennel, tarragon, and basil intake in humans. The first one, by Zeller et al. [ 63 ], studied the metabolism of estragole in humans consuming fennel tea. The metabolites identified in the urine of subjects were estragole, 1′-hydroxyestrogle, trans -anethole (also reported in anise [ 36 , 37 ]), and p -allylphenol (also found in betel leaf oils and in oil of bay). However, the authors were unable to report concentrations for these compounds or to correlate them with fennel dosage. In terms of the specificity of these compounds, estragole, in addition to being found in fennel, is a known component of several herbs such as tarragon, basil, and anise. Estragole, which is structurally similar to safrole, is rapidly metabolized to 1′-hydroxyestragole and is quickly excreted as its glucuronic acid conjugate.

In the second study by Barfi et al. [ 38 ], the authors developed and validated a multi-step method to extract trans -anethole, estragole, and para -anisaldehyde (three major components of fennel, basil and tarragon) from biofluids and then applied this extraction technique to real human plasma and urine samples. All three compounds were found in plasma and urine after the consumption of either 15 ml of fennel extract, 15 ml of tarragon extract or 15 ml of brewed basil.

While studies of fennel, basil, and tarragon phytochemicals and essential oils have identified several potentially unique compounds for each of these herbs, the same cannot be said of the BIFs that have been, so far, identified. To date, all of the food intake compounds identified for fennel, basil, and tarragon consumption [ 38 , 63 ] are not sufficiently specific to identify one from the other or any of them from other widely consumed herbs. This is because all of the reported compounds found in human biofluids, so far, are also found in other herbs and spices (such as anise). Therefore, we conclude that no specific BFI for fennel, basil, or tarragon intake has, to date, been discovered or described in the literature.

Ginger ( Zingiber officinale ) is a root or rhizome-based spice derived from the ginger plant, a member of the turmeric family (both are from Zingiberaceae ). Ginger is believed to have originated in India and is widely used as a culinary additive as a hot, fragrant spice as well as a popular medicine. In addition to ginger’s well-known use as a treatment for nausea, many components in ginger have been found to have anti-inflammatory, antibacterial, antipyretic, antilipidemic, antitumorigenic, and antiangiogenic effects [ 64 , 65 , 66 ]. Ginger’s flavor and aroma come from its volatile oils ( ∼ 1 to 3% of the weight of fresh ginger) and non-volatile pungent oleoresins. A variety of active components have been identified in the oleoresins of ginger including zingerone, gingerols (6-, 8-, and 10-gingerols), and shogaols (6-, 8-, and 10-shogaols) [ 67 ]. Gingerols (especially 6-gingerol) are the major pungent components in the fresh ginger rhizome. In dried ginger, the quantity of shogaols are significantly increased as evidenced by the reduction of the ratio of 6-gingerol to 6-shogaol from 10:1 in fresh ginger to 1:1 in dried ginger [ 68 ]. In particular, zingerone is produced from gingerols during drying, having lower pungency and a spicy-sweet aroma.

A total of three studies have been reported on potential BFIs for ginger or ginger extracts. The earliest study by Zick et al. [ 69 ] found that 6, 8-, and 10-gingerols and 6-shogaol are absorbed after oral ginger extract dosing and can be detected as glucuronide and sulfate conjugates [ 69 ]. Yu and co-workers [ 55 ] detected free 10-gingerol and 6-shogaol in the human plasma, whereas the majority of the 6-, 8-, and 10-gingerols and 6-shogaol existed as glucuronide and sulfate metabolites after oral dosing of 2 g ginger extracts [ 70 ]. No free 6-gingerol was detected in plasma despite it being the most abundant component of ginger extracts (2.64%). In comparison, although 6-shogaol makes up 2.25% and 10-gingerol only accounts for 1.22% of most ginger extracts, 6-shogaol and 10-gingerol were readily detected in human plasma. Pharmacokinetic studies showed very short half-lives for these four analytes and their metabolites (1–3 h in human plasma). Due to their short half-lives, no accumulation was observed for 6-, 8-, and 10-gingerols and 6-shogaol (and their metabolites) in either plasma or colon tissues even after multiple daily dosing. A third biomarker intake study was focused on the metabolism of shogaol [ 60 ]. The results of this study (Table  2 ) show that it was possible to detect all the major thiol-conjugated metabolites of shogaol in human urine using LC-MS/MS [ 71 ]. The authors suggested the mercapturic acid pathway as a major metabolic route for shogaols in humans.

Based on the available data, 6-, 8-, and 10-gingerol glucuronides and sulfates along with 6-shogaols appear to be plausible, specific, and robust biomarkers of ginger intake. More studies are needed to confirm that they are also seen with actual ginger-based food intake. Additional cumulative/kinetic aspects of these biomarkers need further evaluation and most likely an inter-laboratory validation is required to make these compounds fully validated BFIs for ginger consumption.

Nutmeg is a fragrant flavoring spice coming from the seed of Myristica fragrans ( belonging to the Myristicaceae family ), an evergreen tree indigenous to the Banda Islands in the Moluccas (or Spice Islands) of Indonesia. Until the mid-nineteenth century, the small island group of the Banda Islands, was the only location of the production of nutmeg and mace in the world. This made nutmeg a particularly prized and costly spice in European medieval cuisine. The nutmeg essential oil is obtained by steam distillation of ground nutmeg, and it is used widely in the perfumery and pharmaceutical industries. This volatile fraction typically contains sabinene (21.38%), 4-terpineol (13.92%), and myristicin (13.57%), as well as portions of safrole, elimicin, terpineol, α-pinene d-camphene, limonene, linalool, and isoeugeunol [ 72 ]. Psychotropic effects have been described after ingestion of large doses of nutmeg, which are attributable to metabolic formation of amphetamine derivatives from the main nutmeg ingredients elemicin, myristicin, and safrole.

Only one study was found for the evaluation of nutmeg ingestion. Beyer and co-workers [ 73 ] evaluated nutmeg administration in animals and then performed an observational toxicological study to identify the metabolites in the urine of a human subject after the individual ingested the powder derived from 5 nutmeg seeds. In the human urine sample, the following metabolites were identified by GC-MS: O-demethyl elemicin, O-demethyl dihydroxy elemicin, demethylenyl myristicin, dihydroxy myristicin, and demethylenyl safrole. Neither amphetamine derivatives nor the main nutmeg ingredients could be detected in the rat urine nor in human urine samples [ 73 ].

Myristicin is a natural organic compound not only present in nutmeg oil, but also, to a lesser extent, in members of the Umbelliferae family such as carrots, parsley, celery, dill, parsnip, and black pepper [ 74 ]. The measured amount of myristicin in nutmeg and mace is very high—13,000 mg/kg (nutmeg) and 27,000 mg/kg (mace). On the other hand, it is much less in dill and parsley (1200 mg/kg and 727 mg/kg, respectively), and very low in celery (0.33 mg/kg), carrots (0.16 mg/kg), and parsnip (0.002 mg/kg) [ 74 ]. Zheng et al. [ 75 ] found that in an in vivo animal study conducted on mice, myristicin had the ability to increase the activity of the detoxifying system (potential cancer chemoprevention). This finding was replicated in another study [ 76 ]. Elemicin has been identified as an essential oil composition of carrots [ 77 ], parsley, elemi oil, banana, anise, and oregano [ 78 ]; however, the major route of elemicin intake appears to be nutmeg [ 79 ]. Lastly, safrole is a major chemical constituent (85%) of the aromatic oil of sassafras root bark ( Sassaras albidum ). It is also a minor component or trace constituent in mace, nutmeg, cinnamon, black pepper, cocoa, anise, and a number of other spices [ 80 ].

Because nutmeg is the primary known dietary source of these compounds [ 81 ], many of the metabolites of myristicin, elemicin, and safrole either alone or in combination (as a multi-marker panel) could be considered as good candidate BFIs of nutmeg intake. However, since the only study that exists on nutmeg intake is an observational study, additional controlled kinetic studies should be conducted, and further analytical performance validation should be done before these BFIs can be fully validated.

Oregano, marjoram, rosemary, and thyme

Oregano, marjoram, rosemary, and thyme are culinary herbs derived from members of the Lamiacea e plant family, which also includes basil, mint, sage, lavender, and others. Due to their phylogenetic proximity and the similarity of the compounds identified in studies of these herbs, we decided to present the results and discuss them together.

Oregano ( Origanum vulgare ) is a native herb to temperate western and southwestern Eurasia and the Mediterranean region. It has an aromatic, warm, and slightly bitter taste. Among the chemical compounds contributing to the flavor of oregano are carvacrol, thymol, limonene, pinene, ocimene, and caryophyllene [ 82 ]. Oregano also contains polyphenols, including caffeic, p -coumaric, and rosmarinic acid, which confer antioxidant activity and prevents lipid peroxidation [ 4 ]. It is widely used in Mediterranean cuisine, the Philippines, and Latin America, especially in Argentina. A related herb from Origanum oonites , which is better known as marjoram, is a plant species found in Sicily, Greece, and Turkey. Marjoram has similar flavors as oregano.

Rosemary ( Rosmarinus officinalis ) is native to the Mediterranean and Asia. The leaves are used as a flavoring agent in a variety of foods in traditional Mediterranean cuisine. They have a bitter, astringent taste, and a very characteristic aroma. Rosemary contains a number of phytochemicals, including rosmarinic acid, camphor, caffeic acid, ursolic acid, betulinic acid, carnosic acid, and carnosol [ 83 ]. Major essential oils present in rosemary oil are borneol (26.5%), α-terpinene (15.6%), and α-pinene (12.7%) [ 84 ].

Thyme ( Thymus vulgaris ) is also a member of the Lamiaceae family, and it has been used in foods mainly for flavor, aroma, and food preservation. Thyme has also been used in folk medicine since the times of the ancient Egyptians, Greeks, and Romans. The leafy parts of thyme are often added to meat, fish, and food products and also used as herbal medicinal products. The essential oils of common thyme contain 20–58% thymol and p- cymene (15–28%) as the most prevalent compounds, followed by linalool (0.7–6.5%), γ-terpinene (4–10%), carvacrol (1–4%), myrcene (1–3%), 1,8-cineole (0.8%), and borneol (0.7–1.7%) [ 85 , 86 , 87 ]. Thymol is the compound that provides the distinct flavor of thyme. It is also found in oregano and is used as one of many additives in cigarettes.

Oregano, rosemary, thyme, along with sage and mint are known to share several polyphenols and essential oils. Shared polyphenols include caffeic acid, chlorogenic acid, ferulic acid, p -coumaric acid, p -hydroxybenzoic acid, protocatechuic acid, and rosmarinic acid [ 83 ]. Some of the essential oils that are common to many herbs in the Laminaceae family are thymol (thyme, oregano, marjoram), carvacrol (thyme, oregano, marjoram), carnosic acid (rosemary and sage), carnosol (rosemary and sage), and rosmanol (rosemary and sage) [ 4 ].

Oregano, thyme, and rosemary are well known for their beneficial health properties. For example, carnosic acid and some of the diterpenes abundant in rosemary and sage appear to exert anti-obesity effects (including body weight and lipid-lowering effects) [ 88 ]. Likewise, thymol and carvacrol (oregano, thyme), carnosic acid, carnosol, rosmanol, (rosemary, sage), and epirosmanol (rosemary) have been shown to prevent lipid peroxidation and to have anti-inflammatory activity [ 4 , 89 , 90 , 91 , 92 , 93 , 94 ]. Rosmarinic acid (found in oregano, sage, basil, rosemary, thyme and mint) exhibits anti-inflammatory effects while ferulic acid, caffeic acid, and p -coumaric acid inhibit LDL peroxidation [ 4 ]. Several compounds found in herbs from the Laminaceae family also exhibit antimicrobial activity, such as thymol, carvacrol, carnosol, rosmanol, and caffeic acid [ 7 ].

With regard to BFIs for these four herbs (thyme, marjoram, oregano, rosemary), a total of four studies were found that evaluated thyme intake, one study was found for marjoram intake, and one for oregano (evaluated in mice) and one for rosemary (evaluated in rats). In terms of oregano BFI intake, carvacrol, one of the principal components of oregano, was detected by LC-MS/MS in both murine plasma and brain after oregano extract administration [ 95 ]. Carvacrol was also found after ingestion of thyme, in a study that involved two different experimental models: (1) in vitro fermentation and (2) human intervention (in feces) [ 96 ]. These authors found that the in vitro fermentation showed limited degradation of thymol and carvacrol while the human intervention study, which used thyme phenol-enriched olive oil, increased the levels of phenylpropionic and hydroxyphenylpropionic acids in human feces, confirming in vivo microbial degradation of rosmarinic acid and eriodictyol . Based on these data, carvacrol can be considered a specific biomarker of thyme and oregano intake.

A human study looking at BFIs for marjoram measured urinary metabolites of 6 healthy volunteers, each of whom took a single dose of marjoram extract. In this study, the urinary metabolites identified by an HPLC-coulometric electrode array detector (CEAD) [ 97 ] were mainly polyphenol compounds such as protocatechuic acid, p -hydroxybenzoic, caffeic, ferulic, syringic, vanillic, p -coumaric, 3,4-dihydroxyphenylacetic, m -hydroxyphenylacetic acids. These polyphenols are also found in many other plant foods and beverages such as tea, wine, coffee, cereals, cocoa, and in general in vegetables and fruits ( http://phenol-explorer.eu ).

In the BFI evaluation studies of thyme, thymol [ 96 , 98 ], and its derived metabolites (thymol sulfate, thymol glucuronide) [ 99 ], along with a number of polyphenols and polyphenolic metabolites including hydroxyphenyl propionic acid sulfate, coumaric acid sulfate, caffeic acid sulfate, ferulic acid sulfate, hydroxybenzoic acid dihydrophenylpropionic acid sulfate were identified in both rats [ 98 ] and humans [ 99 ]. Rosmarinic acid was also detected in plasma after thyme administration in a controlled randomized trial performed on Wistar rats [ 98 ]. Rosmarinic acid is found in both thyme and rosemary and can be considered as a biomarker of intake for both spices. Romo-Vaquero and collaborators [ 100 ] evaluated the gut, liver, plasma, and small intestine of 24 Zucker rats after both acute and subchronic administration of rosemary extract. Although the main bioactive compound of rosemary is carnosic acid [ 101 ], other derived metabolites (shown in Table  2 ) were also detected in this Zucker rat study. Because the two studies we found for rosemary and oregano administration were performed on animals, the compounds identified are simply being reported here for completeness. The data cannot be used to infer human BFIs for these two herbs. More studies in humans for rosemary and oregano are needed to better understand the metabolites and establish a set of specific BFI for humans.

Based on the data described here, we can conclude that several polyphenols and essential oils are shared between oregano, marjoram, rosemary and thyme. Most of these polyphenols are also common to other fruits and vegetables, so they cannot be considered specific biomarkers for these herbs. While rosmarinic acid is a very specific polyphenol for this family ( Laminaceae ), no rosamarinic acid could be detected in humans after consumption due to its rapid metabolism. With regard to essential oils, thymol and thymol sulfate in plasma and urine and thymol glucuronides in urine seem to be plausible biomarkers of thyme intake. However, these compounds are also present in oregano. Given the rather sparse number of studies done in humans for these four herbs, it is clear that additional human intervention studies are needed to evaluate if several compelling candidate biomarkers (i.e., carvacrol, carnosic acid, carnosol, rosmanol and derivatives) seen in animals can also be confirmed in human studies.

Parsley ( Petroselinum crispum ) is an herb belonging to the Apiaceae family. It is native to the central Mediterranean region. Fresh parsley has a clean, green aroma with a versatile fresh taste that is slightly peppery with an aftertaste of green apple. Parsley is a source of several flavonoids, especially luteolin and apigenin [ 102 , 103 ]. Apigenin is associated with anti-inflammatory activities as it appears to downregulate or inhibit cyclo-oxygenoase-2 (COX-2) [ 104 ]. Apigenin has also been identified as a potential cancer chemopreventive agent [ 105 ]. The major essential oil found in parsley leaves is 1,3,8- p -menthatriene, but other components are also present in lesser amounts including myristicin and limonene, among others [ 106 , 107 ].

Two research articles were found that focused specifically on measuring BFIs of parsley [ 108 , 109 ]. The first article focused on the development of a method to analyze apigenin and the apigenin metabolite acacetin (4′-methoxyapigenin) in human samples using an HPLC–UV method [ 108 ] while the second article focused on an intervention study [ 109 ] that measured these two compounds after the consumption of parsley. In this randomized crossover trial, parsley consumption together with a low flavone diet revealed a strong correlation with urinary apigenin excretion [ 108 ]. In addition to these two BFI parsley studies, several other studies have also assessed apigenin intake. One study [ 102 ], which looked at the ingestion of apigenin-rich foods like parsley, found that apigenin was elevated in urine, plasma, and red blood cells (RBCs). Although apigenin could be identified in plasma and RBCs, it was barely detectable (i.e., close to the limit of detection). On the other hand, apigenin in urine was easily identified in all individuals [ 102 ]. In another study that used a randomized crossover design for the administration of parsley, apigenin could not be detected in plasma because it was below the lower the limit of detection for the type of assay and instrument used [ 110 ].

Apigenin is a flavone not only found in parsley, but also in other vegetables from the same family ( Apiacea ), such as celery, and in lesser amounts in parsnip, carrots, and fennel. So while parsley certainly has a high content of apigenin, due to the poor specificity of this polyphenolic compound, we conclude that apigenin would not be a suitable BFI of parsley intake. Therefore, we conclude that there are no useful BFIs of parsley intake that have yet been discovered or reported in the literature.

Peppermint and spearmint are herbs that belong to the Laminacea family. Spearmint ( Mentha spicata ) is believed to be the oldest of the mints. It is a species of mint native to much of Europe and Asia (the Middle East, the Himalayas, China) that is now found in many parts of Northern and Western Africa, North America, and South America. On the other hand, peppermint ( Mentha × piperita ) is a hybrid mint herb. In particular, it is a cross between watermint and spearmint, and is indigenous to Europe and the Middle East. Both spearmint and peppermint have a fresh, minty, weedy, aroma. The taste is spicy, minty cool, sweet, and slightly pungent [ 111 ]. The active constituents of spearmint include spearmint oil, various flavonoids (diosmin, diosmetin), phenolic acids, and lignans. The most abundant compound in spearmint oil is carvone, which gives spearmint its distinctive smell. Spearmint oil also contains significant amounts of limonene, dihydrocarvone, and 1,8-cineol [ 112 ]. Unlike peppermint oil, spearmint oil contains minimal amounts of menthol and menthone. Conversely, peppermint has a high menthol content (40.7%), along with menthone (23.4%), and other essential oils such as menthyl acetate (4.2%), 1,8-cineole (5.3%), limonene (2.6%), menthofuran (3.7%), and β-caryophyllene (1.7%) [ 113 , 114 ]. Peppermint leaves are often used alone or with other herbs in herbal teas (tisanes, infusions), ice cream, confectionery, chewing gum, toothpastes, and shampoos. Menthol activates cold-sensitive receptors in the skin and mucosal tissues, and is the primary source of the cooling sensation that follows the topical application of peppermint oil [ 115 ]. Peppermint also contains terpenoids and flavonoids such as eriocitrin, hesperidin, and kaempferol 7-O-rutinoside.

Interestingly, six research papers were found that studied the administration of peppermint (oil), but no studies were found that assessed spearmint administration. All six peppermint studies evaluated menthol and its glucuronide conjugate after administration of peppermint oil using a targeted approach. The main goal of these studies was to find a way to delay the absorption and increase the efficacy in treating spastic colon and irritable bowel syndrome. Menthol is fat-soluble and therefore is rapidly absorbed from the proximal small intestine when taken orally [ 116 ]. This makes it particularly useful for targeting disorders of the intestine. One of the first studies to look at peppermint oil ingestion was performed in 1984 [ 117 ] in which a comparison was done between the oral administration of gelatine capsules containing peppermint oil versus a Colpermin preparation (Tillotts Laboratories), a commercial peppermint preparation. The comparison was done in six healthy volunteers and repeated in six ileostomy subjects. The authors measured the levels of menthol in urine and found that Colpermin led to a more delayed-release of menthol compared to a gelatine capsule [ 117 ]. A second study conducted 3 years later, compared the Colpermin preparation with another new capsule administration ( Mintec SK&F Ltd.). The authors affirmed that the Colpermin preparation delivered menthol more effectively to the distal small intestine and ascending colon than the Mintec formulation [ 116 ]. In 1990, Kaffenberger [ 118 ] studied the administration of 180 mg of peppermint oil in an enteric-coated capsule, identifying menthol glucuronide in urine by GC-FID [ 118 ].

In another study focusing on the kinetics of menthol metabolism [ 119 ], the authors used 13 C glucose administered with peppermint oil to detect 13 C-menthol glucuronide. In a later study, the same authors used deuterated water administered with peppermint to detect menthol glucuronide by 2 H-NMR spectroscopy [ 120 ]. Finally, the most recent study analyzed urine and plasma by GC-MS after intragastric administration of peppermint oil [ 121 ]. Approximately, 70% of the administered menthol and its metabolites were excreted in the urine, and this amount fluctuated independent of the dose. The main metabolite identified in plasma and urine was menthol glucuronide along with lesser amounts of mono-hydroxylated menthol glucuronic acid and di-hydroxylated menthol glucuronic acid.

While menthol is highly abundant in peppermint (40%), it can also be found in sunflower petals (essential oils), tarragon (0.1%) [ 122 ], basil, and thyme (traces). However, due to the high menthol content in peppermint compared to the other two herbs and given that sunflower petals are not an edible food, menthol can be considered a specific marker of peppermint. Given that menthol glucuronide is also detectable in urine, this compound could also be a suitable biomarker of peppermint intake, particularly after capsular oral administration. However, further analysis in peppermint administration is needed for a suitable evaluation of menthol as potential food intake biomarker. In the case of spearmint, because no studies have yet been performed for spearmint BFIs, it is clear that spearmint interventions studies need to be undertaken.

Saffron is among the world’s most costly spices. It comes from the dried flower stigma of Crocus sativus . This is a flower that is native to Southwest Asia but which is now cultivated in Greece, India, Iran, Morocco, and Spain. Saffron is mainly used as a seasoning and coloring agent in food, particularly in Persian, Indian, European, and Arab cuisines. Saffron contains more than 150 volatile and aroma-yielding compounds. Safranal (2,6,6-trimethyl-1,3-cyclohexadiene-1-carboxaldehyde) is the major compound (70%) in the volatile fraction of saffron [ 123 , 124 ]. Saffron also has a number of non-volatile active components many of which are carotenoids, including zeaxanthin, lycopene, and various α- and β-carotenes. However, the golden yellow-orange color of saffron is primarily the result of the carotenoid α-crocin, a glycosyl ester of crocetin. Picrocrocin (4-(β-d-glucopyranosyloxy)-2,6,6-trimethyl-1-cyclohexene-1-carboxaldehyde) has also been found in saffron spice from 0.8 to 26.6% on a dry basis. This compound is responsible for saffron’s bitter taste [ 124 ]. In addition, saffron contains two important vitamins: riboflavin and thiamine. Riboflavin values range from 56 to 138 μg/g, and are the highest reported for any food. Thiamine values range from 0.7 to 4 μ g/g, which are well within the range of values reported in many vegetables [ 125 ]. Saffron extracts and tinctures have been used as antispasmodic agents, gingival sedatives, nerve sedatives, expectorants, stimulants, and aphrodisiacs.

Only one study has explored BFIs for saffron [ 126 ]. This was a single dose study that looked at saffron products in the plasma of four healthy volunteers using solid phase extraction—high-performance liquid chromatography (SPE-HPLC). Saffron was administered in the form of saffron tea [ 126 ]. Crocetin was tracked from the plasma of subjects and was found to be rapidly absorbed, being detected in systemic circulation after 2 h of administration, with the compound still being present for up to 24 h. A separate pharmacokinetic study that used purified crocetin extracted from Gardenia jasminoides fruit showed a strong dose-dependent absorption profile into the bloodstream of 10 healthy adult subjects [ 127 ].

While crocetin is also present in Gardenia jasminoides , this particular flower is not considered a common edible food so, in this regard, crocetin could be considered a specific BFI of saffron in plasma. The analytical performance of this biomarker has been well documented. However, additional studies are needed with regard to cumulative aspects (robustness in complex meals). Likewise, a comparison with other markers for the same food could certainly help with validating this BFI.

Sage or Salvia officinalis is a medicinal plant belonging to the Lamiaceae family. It is an aromatic herb native to the Mediterranean region but now widely distributed throughout the world. Sage has been used in traditional medicine for the treatment of seizures, ulcers, gout, rheumatism, inflammation, dizziness, tremors, paralysis, diarrhea, and hyperglycemia [ 128 ]. Sage has a savory, slightly peppery flavor. It is strongly aromatic, and is characterized by a medicinal, lemony, or bitter taste. It is used for seasoning and flavoring in many different foods including sausages and stuffing. The major components present in sage are α-thujone (11.55–19.23%), viridiflorol (9.94–19.46%), 1,8-cineole (8.85–15.60%), camphor (5.08–15.06%), manool (5.52–13.06%), β-caryophyllene (2.63–9.24%), α-humulene (1.93–8.94%), and β-thujone (5.45–6.17%) [ 129 ]. Some of the major phenolic compounds found in sage are rosmarinic acid, caffeic acid, carnosol, and carnosic acid. All of these polyphenols are also present in rosemary, thyme, or oregano as previously discussed.

Only one BFI study has been performed on sage in humans [ 130 ]. In this acute study, a single female volunteer was involved in a pharmacokinetic evaluation of 1,8-cineole after ingestion of sage tea [ 130 ]. The compounds identified in plasma and urine by GC-MS and LC-MS were 1,8-cineole and a number of its derivatives (2-hydroxy-1,8-cineole, 3-hydroxy-1,8-cineole, 7-hydroxy-1,8-cineole, 9-hydroxy-1,8-cineole). 1,8-cineole is also known as eucalyptol, and is a major component of essential oils from Eucalyptus polybractea . This monoterpene is present in numerous spices, such as rosemary, sage, basil, and laurel. It is also used in pharmaceutical preparations to treat coughs, muscular pain, neurosis, rheumatism, asthma, and urinary stones [ 131 ].

As mentioned earlier, other compounds present in rosemary and thyme are also present in sage. Interestingly, there are no intervention studies reporting any of these compounds after sage intake. While 1,8-cineole is detectable in urine after sage intake, it is important to note that 1,8-cineole is found in several other herbs belonging to the Laminacea family. Therefore, 1,8-cineole and its derivates cannot be considered to be specific for sage intake. Furthermore, its rapid metabolism makes it a poor BFI for most members of the Laminacea family. We conclude that there are no useful BFIs for sage intake that have yet been discovered or reported in the literature.

Turmeric (curcumin)

Turmeric is a rhizomatous herbaceous perennial plant ( Curcuma longa ) belonging to the ginger family, Zingiberaceae. It is native to Southeast Asia. Turmeric is a key ingredient in many Asian dishes and is used mainly as a coloring agent. The most notable phytochemical components of turmeric root include compounds called curcuminoids, such as curcumin (diferuloylmethane), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC). Curcumin is a polyphenolic molecule that constitutes 3.14% (on average) of powdered turmeric Curcumin is what gives the spice its yellow color [ 132 ]. The rhizome oils of turmeric contain more than 40 identifiable compounds, with the major constituents being α-turmerone (30–32%), aromatic-turmerone (17–26%), and β-turmerone (15–18%) [ 133 ].

Curcumin is a particularly well-studied spice. A total of 18 research papers were found for this review just for curcumin. This interest is likely due to the multiple biological or health activities attributed to it, including antioxidant, anti-inflammatory, and anti-tumor activities [ 134 ]. Recent clinical studies with curcumin have demonstrated additional health benefits relating to treating immune deficiencies, improving cardiovascular health, treating depression [ 135 ], combating Alzheimer’s disease, treating diabetes [ 136 ], arthritis, and inflammatory bowel disease [ 137 , 138 ]. Curcumin has very low oral bioavailability, which is primarily due to its poor solubility, low absorption, rapid metabolism, and systemic elimination. As a result, most ingested curcumin is excreted through the feces unmetabolized. The small portion that is absorbed is extensively converted to its water-soluble metabolites, glucuronides, and sulfates. These metabolites include curcumin-O-glucuronide (COG), curcumin-O-sulfate (COS) [ 25 , 138 ], [ 139 ], [ 6 , 140 , 141 ], and tetrahydrocurcumin (THC) [ 138 , 142 , 143 ]. Apart from glucuronidation and sulfation, other biotransformations could occur, which yield other unspecific metabolites such as ferulic acid and vanillic acid [ 132 ]. COG, the major curcumin metabolite, is relatively hydrophilic compared to curcumin due to its conjugation to glucuronic acid [ 141 ].

Several pharmacokinetic studies with healthy volunteers [ 139 , 144 , 145 ] and colorectal cancer patients [ 6 ] revealed that curcumin has a plasma T max between 1 and 4 h, with conjugates persisting for up to 36 h after 10 g of curcumin intake [ 139 ]. Sharma et al. [ 145 ] determined that there was no detectable curcumin or any of its metabolites in the blood or urine of patients after the administration of 440—2200 mg of “curcuma” extract per day (containing 36–180 mg of curcumin) in advanced colorectal cancer patients. Another study performed by Cheng et al. [ 144 ] demonstrated that the peak concentrations of curcumin in serum after administration of 4, 6, and 8 g of curcumin (given in the form of tablets) were 0.51, 0.64, and 1.77 μM, respectively. However, doses below 4 g were barely detectable. Lao et al. [ 146 ] could not detect curcumin in the serum of volunteers with doses ranging from 0.5 to 8.0 g of curcumin.

Due to curcumin’s poor absorption, poor bioavailability, and fast excretion, several studies have explored different vehicles for curcumin administration to increase its bioavailability. Oral administration of curcumin in “C3 complex,” which consists of 450 mg of curcumin, 30 mg of demethoxycurcumin (DMC), and 20 mg of bisdemethoxycurcumin (BDMC) [ 6 ] was extensively tested by several research groups [ 6 , 139 , 141 , 143 , 145 , 146 , 147 ]. Nearly all groups were able to detect COG up to 24 h after oral administration of 4 g of curcumin. However, no curcumin could be detected for the same subjects after the same time period [ 141 ]. This suggests that curcumin-O-glucuronide (COG) has a much higher half-life and is more suitable as a curcumin/turmeric BFI.

Another interesting study of curcumin bioavailability has been conducted by Jager et al. [ 138 ]. These researchers studied the absorption of formulated curcumin versus unformulated curcumin. Their formulated curcumin used a combination of a hydrophilic carrier, cellulosic derivatives, and natural antioxidants. This formulation was found to significantly increase curcuminoid levels in the blood in comparison to the unformulated product [ 138 ]. Theracurmin, a colloidal nanoparticle dispersion of curcumin, is reported to have a much higher bioavailability (27-fold higher) than any other available preparations [ 148 ]. A recent pharmacokinetic study conducted in both mice and humans [ 149 ], looked at fresh turmeric-derived curcuminoids versus dry turmeric-derived curcuminoids. These researchers showed that fresh curcuminoids permitted better plasma delivery and better absorption. Baum and co-workers suggested that curcumin consumed with food appears to accelerate its absorption [ 132 ].

Almost all of turmeric/curcumin intake studies that we found were performed in blood (plasma or serum). A smaller number of studies looked at other biofluids or excreta such as urine and feces. In almost all cases, curcumin was barely detected. Moderately suitable biomarkers of curcumin consumption were reported in plasma after the intake of formulated curcumin, such as BDMC, DMC, THC, COG, and COS, as opposed to unformulated administration. However, in feces and colon tissue, only curcumin itself could be detected. In conclusion, formulated curcumin, curcumin biotransformation products, and curcuminoids can be detected in plasma and in feces, but due to the fact that curcumin was administered in a formulated preparation, these biomarkers cannot be considered robust BFIs of turmeric/curcumin consumption.

As far as we are aware, this is the first comprehensive review of biomarkers of food intake for common herbs and spices. We believe it provides a useful overview of what is known, how most herb and spice BFI studies are done, and what needs to be done to improve the current state of knowledge of herb and spice BFIs. Based on our analysis, we found that most BFI studies of herbs and spices were typically performed through the administration of capsules, tablets or other “artificial” forms. In many cases, these studies administered a particularly abundant, carefully purified chemical component of the herb or spice, not in the form of the whole food. Technically, this means that this particular compound or family of compounds was/were evaluated in a supervised manner, not in an untargeted manner using the whole food (spice or herb) of interest. This suggests that potentially synergistic or antagonistic factors concerning the consumption of the herb or spice along with possible matrix effects in terms of absorption and bioavailability were not typically evaluated in these studies. Given that herbs and spices are normally consumed in combination with other foods, the influence of other food constituents taken in the same meal was not particularly well addressed in any of the studies that we reviewed. Because our focus was on human metabolism and biomarkers of human consumption, we restricted our reviews to human intervention trials. For the most part, animal models were not considered, except for a few specific cases where interesting or compelling biomarkers was reported. Overall, we were surprised by how little work has been done on BFIs in herbs and spices. From an initial list of 25 herbs and spices, we found that only 6 had useful or sufficiently robust BFI studies, and in many cases only a single study was completed. Relatively few fully validated BFIs were identified, although several promising or putative BFIs were described, and these will likely be confirmed if further validation studies are completed. Based on our data, it is clear that further research needs to be performed in the evaluation of herbs and spices in human intervention studies.

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FoodBAll is a project funded by the BioNH call (grant number 529051002) under the Joint Programming Initiative, “A Healthy Diet for a Healthy Life.” The project is funded nationally by the respective Research Councils including a grant from the Canadian Institutes of Health Research (CIHR) to DSW.

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The search of literature was performed by RVF. The articles were reviewed and selected by ARR, TS, and RVF. The preparation of the tables was done by TOO, NW, and RVF. The first draft was prepared by RVF and revised by DSW. The final manuscript following several revisions by all co-authors was finally accepted by all of them.

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Vázquez-Fresno, R., Rosana, A.R.R., Sajed, T. et al. Herbs and Spices- Biomarkers of Intake Based on Human Intervention Studies – A Systematic Review. Genes Nutr 14 , 18 (2019). https://doi.org/10.1186/s12263-019-0636-8

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Why is Research on Herbal Medicinal Products Important and How Can We Improve Its Quality?

Olavi pelkonen.

1 Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.

2 Department of Renal Medicine, King's College London, London, UK.

Tai-Ping Fan

3 Department of Pharmacology, University of Cambridge, Cambridge, UK.

Research on herbal medicinal products is increasingly published in “Western” scientific journals dedicated primarily to conventional medicines. Publications are concerned mainly not only on the issues of safety and interactions, but also on efficacy. In reviews, a recurring complaint has been a lack of quality studies. In this opinion article, we present the case of Chinese herbal medicines as an example, as they have been extensively used in the global market and increasingly studied worldwide. We analyze the potential reasons for problems and propose some ways forward. As in the case of any drug, clinical trials for safety, efficacy, and/or effectiveness are the ultimate demonstration of therapeutic usefulness of herbal products. These will only make scientific sense when the tested herbal products are authentic, standardized, and quality controlled, if good practice guidelines of evidence-based medicine are followed, and if relevant controls and outcome measures are scientifically defined. Herbal products are complex mixtures, and for such complexity, an obvious approach for mechanistic studies is network pharmacology based on omic tools and approaches, which has already begun to revolutionize the study of conventional drugs, emphasizing networks, interactions, and polypharmacological features behind the action of many drugs.

INTRODUCTION

A recent PubMed search (done in September 2013) using the key word herbal medicinal products (HMPs) gave rise to 30,917 hits, with about 2700 of them published in 2013. The first (most recent) 10 papers deal with type II diabetes or diabetic nephropathy, comparison between Europe and China on the safety of materials, the European Union (EU) herbals directive, plant metabolomics in quality assessment, various activities of selected herbs, and integrative nanomedicine.[ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ] Examples of typical articles published in a Western medical journal are either original papers on interaction potential,[ 11 , 12 ] or systemic and general reviews on the use of herbal medicines in various conditions,[ 13 , 14 ] on the quality, efficacy, and safety,[ 15 ] on herb–drug interactions[ 16 , 17 ] or herbal side effects, especially in hepatotoxicity.[ 18 ] A recurring theme in conclusions of these reviews was the lack of adequate scientific data to judge efficacy and/or safety and the less-than-desirable quality of the published data. At least in the Western scientific establishment, there is a rather strong impression that research on herbals has been rather haphazard and sporadic, when compared with conventional medicines, and often also outdated and wanting of quality.

CURRENT CONDITION OF HERBAL RESEARCH

What is behind the current condition of herbal research.

There are some obvious, although not thoroughly surveyed, reasons for the current condition of research on herbals. The first is lack of sustainable funding in this area. In the USA, the situation is probably improving. Since 1999, National Center for Complementary and Alternative Medicine (NCCAM) at National Institutes of Health (NIH) has been funded US$ 50-128.8 million per annum, which has been dedicated to complementary and alternative medicines including herbal medicines. The above-mentioned “less-than-desirable quality” is also due to lack of funding and functional mechanisms for interregional, intersectoral, and interdisciplinary collaborations on training and sustaining people to do high-quality herbal research and on dissemination, implementation, and further refinement of good practices, resulting in the sporadic feature of research and various expertise needed for high-quality herbal medicine research scattered around different parts of the world.

Changing research and market for herbal medicines – Chinese herbal medicines as an example

There are a number of reasons to think that HMPs have a potential to become a significant part of efforts to advance drug discovery and development. In particular, pharmacologists shuffling through recent issues of international journals have certainly become aware of an increasing contribution of research from China, often dealing with traditional Chinese herbal medicines or their components. This mere observation testifies the emphasis of the Chinese scientific establishments on the research of their 2000-year medicinal heritage.

It has been estimated that total value of the world market for herbal products stands at around $83 billion and Europe accounts for over 50% of the total.[ 19 ] Also, the use of Chinese herbal products is a worldwide phenomenon and Europe has a long history of their use and research.[ 20 ] For instance, in 2008, China announced a major economic stimulus package, including an investment of US$ 124 billion in healthcare. Due to the deep cultural roots of herbal products in China with its 1.3 billion people and the strong commitment of the State to further develop their use in both domestic and global settings, it is anticipated that in the coming years, a larger global market for herbal products will be created.[ 21 ] Chinese herbal products are important for Europe because after Asia, Europe is the second largest import/export market of these products,[ 20 ] and in China alone, approximately 100,000 herbal formulae and over 11,000 individual medicinal plants have been documented, which are generally hailed as rich natural resources for developing new drugs, including new lead compounds and new types of multi-component drugs.[ 22 , 23 ]

Changing attitudes of regulators in the EU and the USA toward HMPs

In the EU, HMPs have been granted an official medicine status by the European Medicines Agency through legislation in 2001 and its Committee on Herbal Medicinal Products was established in 2004. Since then, more than 100 HMPs have undergone scientific assessment, which in most cases have resulted in a regulatory status either as a well-established use or a traditional use. These classifications relate to the time a product has been on the market in the EU and elsewhere and also to the nature and adequacy of scientific evidence.

In the USA, most HMPs still fall under the legislation of botanical products, i.e. they are under food legislation. Historically, the US Food and Drug Administration (FDA) has been reluctant to approve herbal products as prescription drugs due to their complexity, but this has now changed since Veregen (sinecatechins), the first herbal product derived from green tea (綠茶 Lǜ Chá; Camellia sinensis), was approved by the FDA in late 2008 for certain types of external genital or perianal warts,[ 24 , 25 ] followed by Crofelemer approved in December 2012 for the relief of diarrhea in HIV/AIDS patients taking antiretrovirals.[ 23 ] In 2010, it was estimated that approximately 25% of botanical investigational new drug (IND) applications submitted to the FDA were derived from Chinese herbal medicines.[ 26 ] Indeed, as a group of specialist FDA officials have concluded, although new botanical drugs pose many challenges for both industry and the FDA, these challenges can be successfully met.[ 25 ] Currently, a number of standardized Chinese herbal products have been under clinical trials in the USA, including PHY906 (黃芩湯 Huáng Qín Tāng) for cancer patients, which has passed a multicenter, open-label, dose escalation phase I/II trial,[ 27 ] and Dantonic ® (丹參滴丸 Dān Shēn Dī Wán), which is undergoing phase III trial for the prevention and treatment of stable angina.[ 28 ] In addition, after a multicenter trial and a liver re-biopsy study in Asia demonstrating good safety and efficacy profiles,[ 29 , 30 ] Fuzheng Huayu is now in a phase II clinical trial for patients with hepatitis C–induced liver fibrosis in America.[ 31 ] In keeping with the positive attitude of the FDA, the NIH also emphasizes the importance of traditional and alternative medicines through establishing NCCAM, with a budget of US$ 120.7 million for 2013.[ 32 ] The industrial sector also reacted to the promising prospects of Chinese herbal products. For example, Pfizer and GlaxoSmithKline have greatly increased their investments into further developments based on Chinese herbal medicines.[ 33 , 34 ]

Why are new approaches needed?

There are several reasons why new approaches are needed to tackle challenges in drug development and clinical treatment. Possibly the most important reason is the emergence of chronic diseases as major causes of morbidity and mortality in developed countries and increasingly also in developing countries. Most chronic diseases are not single entities. Instead, there are usually several etiological factors and multiple mechanisms within numerous molecular pathways and networks behind various manifestations of the disease.[ 35 , 36 ] Preventing and treating these major chronic diseases have led to the use of multiple drugs to tackle different targets and various symptoms, which furthermore have been associated with an increasing frequency of adverse interactions and side effects.[ 37 ] While drug development has generated novel drugs (albeit rather slowly), the outcome of drug treatment has not improved to an expected extent, judged on the basis of risks and benefits. It seems that one of the reasons for the less-than-satisfactory success of drug development during the recent decades has been the single-target–single-compound or one-disease–one-drug paradigm based on the emphasis of molecular biological approaches and tools.[ 38 ] Molecular biology has been extremely successful in finding and pinpointing potential drug targets, but the consequent development of exceedingly potent and selective compounds has not fulfilled expectations in clinical reality. Consequently, it seems desirable to cover multiple targets at the same time with multiple active principles, but at a balanced and personalized manner.

HERBAL MEDICINES AS MULTI-TARGET DRUGS FOR COMPLEX DISEASES

Herbal medicines are complex drugs with multiple potential targets and actions.

To treat a complex chronic disease would require covering multiple targets, and in conventional drug therapy, this leads to polypharmacy. In this light, it has to be stressed that herbal medicines, just for the sake of them being based on plant-derived products, are chemically complex mixtures containing multiple major and minor constituents with multiple potential targets and mechanisms. European tradition has been slow in recognizing these new possibilities perhaps because of the currently ongoing consolidation of the EU legislation concerning well-established and traditional medicines. Meanwhile, some other traditional medicines, such as those used in Asia,[ 39 ] not only provide invaluable knowledge resulting in new Western drugs and drug leads,[ 40 ] but also highlight different approaches characterized by personalized medicine and the use of complex herbal products.[ 25 ] Accumulating evidence suggests that using omic methods, including genomics, transcriptomics, epigenomics, proteomics, metabolomics, etc., to revisit traditional medicines will lead to new insights and offer opportunities for new types of medicine.[ 41 , 42 ]

What is an appropriate conceptual background?

For complex medicines, the current reductionist approach (which has worked admirably with conventional single drugs) is ill suited for analyzing the actions and interactions of multiple chemicals with multiple targets at different levels of an organism. Instead, a systems approach is required, be it called systems or network biology, medicine or pharmacology, whose “goal is to understand in a precise, predictive manner, how drugs modulate cellular networks in space and time and how they impact human pathophysiology.”[ 43 ] Development of drug–target and drug–ligand networks to reveal an essentially polypharmacological nature of conventional drugs and the application of the ensuing polypharmacology to disease networks have resulted in a new, more comprehensive view of drugs as multitarget molecules, with often overlapping on-target and off-target actions.[ 44 , 45 , 46 ] For this concept to be applicable to complex herbal products, one has to replace only a multitude of conventional drugs (which is usually derived from the database of FDA-approved drugs) with HMPs with multiple components. There are already a few examples of the application of network pharmacology in the analysis of multiple targets and actions of a specific HMP.[ 47 ]

What kind of scientific tools are needed?

The above conceptual background for drugs is still based to a large extent on in silico exercises, even if some of its predictions have been studied and often successfully proven by experiments.[ 45 , 46 ] Models and networks need to be populated by experimental data, which come from studies using various omic techniques, and naturally by bioinformatics for retrieving, storing, and handling of the huge amount of data.

As a legacy of the multibillion dollar human genome sequencing projects, technological innovations have exponentially increased affordability of genomic and transcriptomic studies. Meanwhile, shotgun proteomics,[ 48 ] targeted proteomics,[ 49 , 50 ] and multiplexed quantitative proteomics using isobaric tags[ 51 ] have made the proteomics technology faster, more sensitive, and much more affordable than ever before. To illustrate the affordability of the metabolomic technology, an international company specialized in metabolomic service charges US$ 350 per sample, including sample processing, high-performance liquid chromatography/mass spectrometry (HPLC/MS), gas chromatography/mass spectrometry (GC/MS) analysis, statistical analysis, pathway mapping, and data interpretation. Finally, analysis of omic data or integrated data from different omic levels can now be addressed using a systems biology approach.[ 52 ]

The omic techniques are increasingly being used in connection with functional screening assays, which are able to measure phenotypes, i.e., complex physiological and pathological traits and perturbations.[ 53 ] A recent analysis suggested that the majority of recent first-in-class drugs are actually developed with the help of phenotypic screening assays.[ 54 ] It is envisaged that in the long run, it is possible to build a screening scheme in which various subcellular and cellular assays are used in conjunction with most modern analytical data-rich techniques, e.g. omics, imaging, and chemical analytical tools, to enable a comprehensive screening paradigm. One such example is the suggestion to screen complex herbal products with respect to absorption, distribution, metabolism, and excretion (ADME) and pharmacokinetic characteristics in a stepwise manner, envisaged to lead to the prediction of pharmacokinetic behavior of a product before actual clinical trials.[ 55 ]

THE WAY FORWARD

The way forward – gp-tcm as an example.

To promote good practice in the research of traditional Chinese medicine (TCM), with a particular focus on Chinese herbal medicines, the Good Practice in Traditional Chinese Medicine Research in the Post-genomic Era consortium, widely known as GP-TCM, was launched by the European Commission under its Seventh Framework Programme (FP7) on 1 May 2009.[ 56 ] With two of us (QX, TPF) as coordinator and deputy coordinator, respectively, this 3.5-year FP7 coordination action project discussed state of the art and produced guidelines for studies of Chinese herbal medicines, with an emphasis on using an omic approach. The consortium voted confidence in the omic and network pharmacology technologies in the research of complex herbal products and had their main findings published in the open-access GP-TCM Journal of Ethnopharmacology special issue.[ 57 , 58 ] For example, the consortium noted that an omic approach was granted a patent for quality control of complex herbal products in 2003 (Patent Cooperation Treaty No.: GB00/00428), was successfully applied to control the quality and investigate the mechanisms of action of Huangqin Tang (黃芩湯 Huáng Qín Tāng), a Chinese herbal medicine formula of four herbs,[ 27 , 59 , 60 ] and was also explored in personalized diagnosis and for rescuing drug discovery.[ 41 , 42 ] To ensure sustainable collaborations in the development and refinement of good practices beyond the lifespan of GP-TCM (May 2009-October 2012), the FP7 consortium also led the establishment of a new not-for-profit organization, known as the GP-TCM Research Association.[ 61 ] Launched in April 2012, this association has officially succeeded the missions and legacies of the FP7 GP-TCM project since November 2012. It will remain a devoted link between Europe, China, and other parts of the world, especially dedicated to dissemination, validation, and further development of good practice guidelines through interregional, interdisciplinary, and intersectoral collaborations.

Search for promising leads and useful assays

As pharmacologists/toxicologists (OP, TPF) and nephrologist (QX), we became interested in Chinese herbal medicines for different reasons, but all based on evidence. For example, in a UK-China collaboration led by King's College London, anti- and pro-fibrotic activities of herbs used in TCM were studied systematically using objective, quantitative, and novel assays, based on reports in the literature[ 62 ] and also guided by the theories and practice of TCM.[ 63 ] Extracts of 17 herbal formulae and 11 individual herbs as well as 5 herbal compounds were found to be anti-fibrotic and extracts of 3 herbs were found to be pro-fibrotic.[ 62 , 63 ] Thus, there are real activities in herbal entities. The question is how to improve the quality of research on herbals, especially complex herbal mixtures, so that they can be used more efficaciously and more safely.

Another interesting example is our observation on herbal regulation of angiogenesis. Ginseng (人參 Rén Shēn) is a commonly used nutraceutical. Intriguingly, existing literature reports both wound-healing and anti-tumor effects of ginseng extract through opposing activities on the vascular system. To elucidate this apparently contradictory perplexity, the University of Cambridge led an international team and merged a chemical fingerprinting approach with a deconstructional study of the effects of pure molecules from ginseng extract on angiogenesis.[ 64 , 65 ] A mass spectrometric compositional analysis of American, Chinese, and Korean ginseng, and Sanqi (notoginseng) revealed distinct “sterol ginsenoside” fingerprints, especially in the ratio between a triol, Rg 1 , and a diol, Rb 1 , the two most prevalent constituents, with the dominance of Rg 1 leading to angiogenesis, but Rb 1 exerting an opposing effect. This study explained, for the first time, the ambiguity about the effects of ginseng in vascular pathophysiology based on the existence of opposing active principles in the extract. Differential gene expression profile of human endothelial cells revealed Rg 1 promotes angiogenesis via the modulation of genes that are involved in cytoskeletal dynamics, cell–cell adhesion, and migration. Further work demonstrates that Rg 1 stimulates angiogenesis via endothelial nitric oxide synthase (eNOS)[ 66 ] and vascular endothelial growth factor through the glucocorticoid receptor,[ 67 ] while Rb 1 and Rg 3 inhibit angiogenesis by up-regulating pigment epithelium-derived factor through the β estrogen receptor.[ 68 ] It is noteworthy that some metabolites of ginsenosides are novel inhibitors of breast cancer resistance protein.[ 69 ]

Another angiogenesis modulator is Angelica sinensis (當歸 Dāng Guī), which contains alkylphthalides, ferulic acid, and polysaccharides. Previous reports showed that n -butylidenephthalide (BP), an alkylphthalide derived from the volatile oil of Radix A. sinensis (VOAS), exhibited anti-platelet, anti-anginal, and anti-cancer activities. We have recently reported that BP and VOAS are anti-angiogenic.[ 70 , 71 ] In contrast, Lam et al .,[ 72 ] showed that an aqueous extract of Radix A. sinensis (AQAS), which contained 60% polysaccharide, was pro-angiogenic. These studies clearly highlight the fact that a single medicinal plant contains a variety of bioactive compounds, sometimes with opposite pharmacological activities.

Research at University of Oulu has been especially focused on pharmaco/toxicokinetic and safety assessment of HMPs, which poses great challenges due to their complex nature. The chemogenomic approach could provide important predictions also for potential harmful effects, as recently demonstrated for some TCM and Ayurvedic medicines by Mohd Fauzi et al .[ 73 ] However, these essentially in silico predictions have to be confirmed and eventually validated by experimental and/or clinical studies, in which omic approaches might be invaluable in surveying and delineating various toxicities and underlying mechanisms of actions.[ 74 ] The in vitro metabolism, transport, and interaction assays used for conventional drugs under development have been successfully applied and modified for the study of HMPs.[ 75 , 76 , 77 ] However, currently, it is possible to predict the behavior or responses of the complete HMPs on the basis of their individual components only to a limited extent. It is obvious that the presence of multiple components will give rise to interactions at all levels of kinetics and dynamics of HMPs, for good or bad.

Good practices and a paradigm change in complex herbal medicine research are necessary

Based on the above analysis, we are convinced that HMPs are both interesting and important. Looking forward, good practices and a paradigm change are necessary to study HMPs in a productive way. Examples have been set regarding traditional herbal medicines by some pioneering groups, and in particular, by the GP-TCM project funded by the EU, establishing the necessary framework to facilitate the change. The GP-TCM Research Association is expected to play a major role in moving forward good practices in this increasingly important area. To further facilitate this, European funding like those provided by the NCCAM in the USA will be needed. Admittedly, the one-disease–one-drug concept will still benefit by the new approach in that promising leading compounds will be identified and used for further development. However, this is not enough because complex chronic diseases need complex therapeutic solutions, and complex herbal medicines may play a significant role in supplying such solutions and lead to efficient and safe prevention and treatment. At least they are worthy of a fair trial.

What are the implications of the above perspectives and arguments to clinical pharmacology? Thus far, clinical trials on HMPs have provided a rather indefinite and even bleak view about their therapeutic benefits. However, it is quite possible that the current gold standard, a placebo-controlled randomized double-blinded trial, is unable to provide a relevant outcome about medicines that are primarily intended for personalized and holistic use, as is the case with Chinese herbal medicines. Nonetheless, the FP7 GP-TCM project has agreed on a guideline on randomized controlled clinical trials of Chinese herbal medicines,[ 78 ] which should serve as a plausible starting point for further development. In any case, whatever the form of the clinical trial is, at least the major results emanating from omic experiments and systems analyses should be considered and incorporated into the design of clinical trials, especially regarding relevant surrogate markers as clinical endpoint measures and for mechanisms.

ACKNOWLEDGMENTS

This manuscript was supported by the GP-TCM project funded by the European Commission under the FP7 grant agreement No. 223154. Dr. Qihe Xu was the coordinator of the project,Dr. Tai-Ping Fan was the deputy coordinator of the project, Professor Olavi Pelkonen was a member of the management and science committee.

Herbal infusions and health: A review of findings from human studies, mechanisms and future research directions

Nutrition & Food Science

ISSN : 0034-6659

Article publication date: 16 January 2020

Issue publication date: 18 August 2020

Increasingly, interest in and the uptake of herbal infusions has advanced, namely, owing to their bioactive properties and potential links to health. Given this, the purpose of the present review was to collate evidence from human trials for five popular herbal infusions.

Design/methodology/approach

The systematic review comprised ten human trials (560 participants), investigating inter-relationships between herbal infusions consumption and health. Only human studies involving German chamomile ( Matricaria chamomilla L. Asteraceae ), ginger ( Zingiber officinale Roscoe Zingiberaceae ), lemon balm ( Melissa officinalis L. Lamiaceae ), peppermint ( Mentha x spicata L. Lamiaceae )/spearmint ( Mentha spicata L. Lamiaceae ) and rosehip ( Rosa canina L. Rosaceae ) teas were included in the present paper.

Most herbal infusions serve as a good source of flavonoids and other polyphenols in the human diet. Studies included in this paper indicate that herbal infusions (1-3 cups tended to be drank daily; infusion rates up to 15 min) could benefit certain aspects of health. In particular, this includes aspects of sleep quality and glycaemic control (German chamomile), osteoarthritic stiffness and hormone control (spearmint), oxidative stress (lemon balm) and primary dysmenorrhea (rosehip).

Research limitations/implications

Ongoing research is needed using homogenous herbal infusion forms, brewing rates and volumes of water to further reinforce these findings. In the meantime, herbal infusions could provide a useful supplementary approach to improving certain aspects of well-being.

Originality/value

The present paper collates evidence from human trials for five popular herbal infusions.

• Anti-oxidants
• Herbal infusions
• Polyphenols

Etheridge, C.J. and Derbyshire, E. (2020), "Herbal infusions and health: A review of findings from human studies, mechanisms and future research directions", Nutrition & Food Science , Vol. 50 No. 5, pp. 969-985. https://doi.org/10.1108/NFS-08-2019-0263

Emerald Publishing Limited

Copyright © 2019, Christopher John Etheridge and Emma Derbyshire.

Published by Emerald Publishing Limited. This article is published under the Creative Commons Attribution (CC BY 4.0) licence. Anyone may reproduce, distribute, translate and create derivative works of this article (for both commercial and non-commercial purposes), subject to full attribution to the original publication and authors. The full terms of this licence may be seen at: http://creativecommons.org/licences/by/4.0/legalcode

Introduction

Herbal infusions have long been used in traditional medicine and are a popular global beverage choice ( Poswal et al. , 2019 ). Now, in the era of globalisation, regional and ethnic barriers have been removed and specialist infusions have become universally available ( Chandrasekara and Shahidi, 2018 ). For example, in the UK, herbal infusions account for approximately 36 per cent of all varieties consumed ( Mintel, 2019 ).

The consumption of herbal beverages is gaining popularity driven by the fact that many are rich sources of natural bioactive compounds, such as alkaloids, carotenoids, coumarins, flavonoids, polyacetylenes and terpenoids ( Chandrasekara and Shahidi, 2018 ). Subsequently, more people consume these infusions as daily beverages for health purposes ( Li et al. , 2013 ). The aphorism that “Nature is the best chemist” has a long historic pedigree ( Abuhamdahab and Chazota, 2008 ).

Accruing evidence suggests that bioactives present in herbals infusions could have a diverse range of biological effects, including potential anti-bacterial, anti-oxidant, anti-inflammatory, anti-allergic, anti-thrombotic and vasodilatory actions, as well as anti-mutagenic, anti-carcinogenic and anti-ageing effects ( Chandrasekara and Shahidi, 2018 ). The Rotterdam cohort comprised 2,424 adults, found that herbal tea consumers (36.3 per cent) had reduced levels of liver stiffness – a proxy for liver fibrosis, which was independent of several other lifestyle and environmental factors ( Alferink et al. , 2017 ).

Increasingly, more people are beginning to take control of their own health. For example, the European Social Survey found that complementary and alternative medicine (CAM) treatments were used by 25.9 per cent of the general population with women and those with a higher level of education more likely to use these ( Kemppainen et al. , 2018 ). In another study, 80 per cent of 480 respondents from German General Practitioner practices were more likely to use home remedies before using pharmaceutical products – these included hot lemon drinks and chamomile tea ( Parisius et al. , 2014 ). Recently, it was also purported that herbal tea phytochemicals could have synergistic potential, helping to manage medical conditions when used alongside conventional medicines ( Malongane et al. , 2017 ).

Given the shift towards integrated medicine and growing interest in herbal infusions and health, the present review collates evidence from human trials and mechanistic studies to better understand inter-relationships between herbal infusions and health. A recent scoping review collating evidence from 21 studies (including observational studies) showed that herbal tea consumption could confer some preventative and clinical benefits ( Poswal et al. , 2019 ).

In the present review, we focus on five specific herbal infusions: chamomile ( Matricaria chamomilla L. Asteraceae ), ginger ( Zingiber officinale Roscoe Zingiberaceae ), lemon balm ( Melissa officinalis L. Lamiaceae ), peppermint ( Mentha x spicata L. Lamiaceae )/spearmint ( Mentha spicata L. Lamiaceae ) and rosehip ( Rosa canina L. Rosaceae ) teas and evidence from human trials, although we also support this with mechanistic studies.

Materials and methods

A literature search was conducted to identify human trials examining inter-relationships between herbal infusions and markers of health. A National Centre for Biotechnology Information (PubMed) search was undertaken to identify these studies using the selection filter.

Filters were applied to extract English language publications. Search terms applied were: “herbal tea/infusion/tisane”, “chamomile tea/infusion/tisane”, “ginger tea/infusion/tisane”, “lemon balm/ Melissa officinalis tea/infusion/tisane”, “peppermint/spearmint tea/infusion/tisane” and “rosehip/rose tea/infusion/tisane”. The filter was set to only identify human clinical trials. The reference lists of relevant publications were also searched. Relevant mechanistic studies were also discussed for each of the herbal tea forms to supplement evidence.

author and country of research;

study population (number of participants, age, gender and health status at baseline);

study design;

the intervention applied (dose/cups of herbals tea provided);

infusion conditions (length of time, water temperature);

health outcomes; and

study findings ( Table I ).

Publications were excluded, if they were not one of the named five infusions or were multiple/combined interventions, e.g. two herbal teas extracts or pilot studies. Studies were also omitted where capsules/supplements of concentrated sources of herbal extracts were used rather than “tea” as infusions or in beverage form. When full texts were not available, these were purchased. Latin binomials were checked using the Kew Medicinal Plant Names Services database ( www.mpns.science.kew.org ).

Data extraction

The present review followed the preferred reporting items for systematic reviews and meta-Analyses (PRISMA) statement ( Moher et al. , 2009 ). Publications were omitted, if PRISMA benchmarks were not included in the trial publication but instead published elsewhere. Relevant data extracted from the studies included the amount of herbal infusions given within the intervention and compliance. The Jadad scale and criteria was then applied and used to develop quality scores for each human trial ( Jadad et al. , 1996 ). Quality scores were graded between 1 and 5 with higher scores being indicative of higher quality ( Table II ).

The PubMed search identified 264 publications. Of these, 254 papers were discarded after reviewing the abstracts and article content, as they did not meet the inclusion criteria. This left ten human trials for general review. The algorithm of qualifying publications is shown in Figure 1 .

Of these, three studies were conducted in Taiwan, China ( Chang and Chen, 2016 ; Chao et al. , 2011 ; Tseng et al. , 2005 ) three in Iran ( Zemestani et al. , 2016 ; Rafraf et al. , 2015 ; Zeraatpishe et al. , 2011 ) and one in Turkey ( Akdogan et al. , 2007 ), Japan,( Yui et al. , 2017 ) Canada ( Connelly et al. , 2014 ) and the UK ( Grant, 2010 ). Of the ten studies identified, seven were good quality and ranking 3 or higher on the Jadad scale ( Table II ) ( Chang and Chen, 2016 ; Zemestani et al. , 2016 ; Rafraf et al. , 2015 ; Yui et al. , 2017 ; Connelly et al. , 2014 ; Grant, 2010 ; Tseng et al. , 2005 ).

German chamomile tea

German chamomile ( Matricaria chamomilla L. Asteraceae ) should not be confused with Roman chamomile [ Chamaemelum nobile (L.) Asteraceae ]. It is one of the most ancient and popular single ingredient herbal teas known to man ( McKay and Blumberg, 2006a ). From a historical perspective, chamomile has been used to help ease ailments such as hay fever, inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, gastrointestinal disorders, rheumatic pain and haemorrhoids ( Srivastava et al. , 2010 ). It is estimated that in the UK alone, over 450,000 cups of chamomile tea are drank daily – the equivalent of over 165,000,000 cups a year ( Nielsen, 2019 ).

Three randomised controlled trials (RCTs) studied the effects of German chamomile tea consumption on aspects of health. In these trials, participants drank either one 300 ml cup of chamomile tea (of German origin) daily ( Chang and Chen, 2016 ) or three 150 ml cups daily immediately after meals ( Zemestani et al. , 2016 ; Rafraf et al. , 2015 ). The first trial recruiting 80 women 6 weeks postpartum found that drinking just 1 cup (300 ml) of German chamomile tea (infused for up to 15 min) appeared to have a sedative-hypnotic effect improving sleep quality and symptoms of depression after 2 weeks of consumption ( Chang and Chen, 2016 ).

Two trials focussed on the markers of glycaemic control in patients with type 2 diabetes mellitus (T2DM) ( Zemestani et al. , 2016 ; Rafraf et al. , 2015 ). One found that after 8 weeks of German chamomile tea consumption thrice daily (150 ml each time) significantly reduced serum insulin, total cholesterol, triglyceride, low-density lipoprotein cholesterol and glycosylated haemoglobin (HbA1c) levels in adults with T2D at baseline versus the hot water group ( Rafraf et al. , 2015 ). Another similar trial showed that total anti-oxidant capacity, superoxide dismutase, glutathione peroxidase and catalase activities increased significantly by 7 per cent, 26 per cent, 37 per cent and 45 per cent, respectively, after 8 weeks of drinking German chamomile tea ( Zemestani et al. , 2016 ).

Regarding active ingredients, dried German chamomile flowers provide an array of phenolic compounds including flavonoids: apigenin, quercetin, patuletin, luteolin and their glucosides ( Srivastava et al. , 2010 ) which some of their medical properties could be attributed to. Recently, German chamomile tea has been identified as a source of structurally diverse polysaccharides, including inulin, fructo-oligosaccharides and pectin, which are well-established prebiotics ( Chaves et al. , 2019 ). Mechanistically, laboratory studies have similarly shown that German chamomile has cholesterol-lowering and anxiolytic effects ( McKay and Blumberg, 2006a ). In vivo work ( Villa-Rodriguez et al. , 2017 ) shows that German chamomile tea inhibits digestive enzymes related to sugar release along with sugar transport pathways (GLUT2 and GLUT5), potentially managing sugar absorption and metabolism. Together, this could explain some of the findings from the identified RCTs.

Ginger ( Zingiber officinale Roscoe Zingiberaceae ) is a rhizome (root) with a long history of use in traditional medicine, which has been attributed to its constituents: 6-gingerol, 6-shogaol, 6-paradol, zingerone and dehydrozingerone ( Choi et al. , 2018 ). It has been postulated that ginger could modulate obesity by increasing thermogenesis and lipolysis, suppressing lipogenesis, inhibiting intestinal fat absorption and controlling appetite ( Ebrahimzadeh Attari et al. , 2018 ). Ginger is also thought to have gastroprotective effects which have been linked to its phenolic, free radical scavenging and inhibition of lipid peroxidation properties ( Haniadka et al. , 2013 ).

While a growing number of studies have looked at ginger per se in relation to health, few trials have focussed on ginger tea. One study ( Chao et al. , 2011 ) found that stroke volume increased and pulse pressure decreased in non-heat constitution subjects (neutral and partial cold body temperature) after drinking 250 ml aged ginger tea compared with baseline, indicating effects on sympathetic activity.

Most mechanistic studies refer to ginger rather than ginger tea. It is known that ginger extract and its constituent components have anti-oxidant properties that could be attributed to their hydroxyl structure ( Si et al. , 2018 ). In vitro both [6]-shogaol and [6]-gingerol, the major active components in ginger, significantly trapped methylglyoxal (a reactive metabolite derived from glucose and lipids), which can contribute to protein glycation and the formation of advanced glycation end products. While these effects look promising, ongoing research using ginger “tea” is now needed.

Lemon balm tea

Lemon balm ( Melissa officinalis L. Lamiaceae ) is a perennial herb. It is also sometimes referred to as “bee balm”, “garden balm”, “Melissa” or “melissengeist” ( Rasmussen, 2011 ). Lemon balm has been used both historically and contemporarily as a modulator of cognition and mood, including its anxiolytic effects ( Scholey et al. , 2014 ).

Two human trials have used lemon balm tea in their intervention. In an open-label parallel trial, 28 healthy Japanese subjects drank either one 200 ml cup of lemon balm or barley tea (the control) daily for over 6 weeks. In the lemon balm group, brachial-ankle pulse wave velocity (an indicator of arterial stiffness) reduced significantly while female skin cheek elasticity improved ( Yui et al. , 2017 ). A before–after clinical trial ( Zeraatpishe et al. , 2011 ) provided 55 radiology staff with a lemon balm infusion twice daily (each 100 ml) for over 30 days. Consumption led to significant improvements in plasma catalase, superoxide dismutase and glutathione peroxidase, protecting against oxidative stress, while DNA damage, myeloperoxidase and lipid peroxidation were reduced ( Zeraatpishe et al. , 2011 ).

These findings suggest that lemon balm infusion could have physiological benefits. Other work has shown that lemon balm per se possesses high amount of anti-oxidant activity through its chemical compounds potentially alleviating oxidative stress-related disease ( Miraj et al. , 2017 ). Some research has found that delivering lemon balm as a water-based drink (but not tea) observed some improvements in mood and/or cognitive performance ( Scholey et al. , 2014 ).

Regarding mechanisms, laboratory research shows that lemon balm extract activates peroxisome proliferator-activated receptors, which have key roles in the regulation of whole body glucose and lipid metabolism ( Weidner et al. , 2014 ). In a cell model, lemon balm extract promoted melanogenesis, helping to possibly prevent UVB damage which could be linked to some of the skin elasticity effects ( Perez-Sanchez et al. , 2016 ). Overall, lemon balm appears to have multi-faceted effects though the forms and dosages required to initiate these effects warrant further study.

Spearmint/peppermint tea

There are two main forms of Mentha drunk as infusions – Mentha spicata L. Lamiaceae (spearmint) and Mentha x piperita L. Lamiaceae (peppermint) ( Akdogan et al. , 2007 ). Spearmint has traditionally been used for various kinds of illnesses in herbal medicine and flavouring in the food industry ( Akdogan et al. , 2007 ). Peppermint is also one of the most popular and widely consumed herbal teas or tisanes ( McKay and Blumberg, 2006b ). Mentha leaves provide the phenolic rosmarinic acid (rosA) and flavonoids including eriocitrin, hesperidin and luteolin ( McKay and Blumberg, 2006b ).

Three human trials focussed on Mentha teas and aspects of health. Two trials examined the effects of spearmint tea on female androgen levels ( Grant, 2010 ; Akdogan et al. , 2007 ). A 30-day RCT comprised 42 females with hirsutism found that spearmint tea consumption (2 cups daily) led to significant reductions in total and free testosterone levels, improved luteinising hormone (LH) and follicle stimulating hormone (FSH) levels and the patient’s subjective assessment of hirsutism ( Grant, 2010 ). An intervention study comprised 21 hirsute patients provided with 2 cups of spearmint tea daily had similar effects. Significant reduction in free testosterone and increase in LH, FSH and oestradiol after 5 days were observed compared with baseline ( Akdogan et al. , 2007 ). These findings imply that that spearmint tea has anti-androgenic properties but longer studies are needed.

In another trial, 62 participants with medically diagnosed osteoarthritis were randomised to drink high-rosA spearmint tea or commercial spearmint tea twice daily over 16 weeks. Daily ingestion of both high-rosA and commercial spearmint teas significantly improved stiffness and physical disability scores in subjects with knee osteoarthritis, but only the high-rosA tea significantly decreased pain ( Connelly et al. , 2014 ).

Mechanistically, peppermint tea has also been found to modulate hormone levels in animal research. In further laboratory studies, peppermint tea exposure also reduced total testosterone and increased FSH and LH levels ( Akdogan et al. , 2004 ). In other work, high-rosA Mentha has been found to be an effective inhibitor of lipopolysaccharide-induced inflammation seen in cartilage explants ( Pearson et al. , 2010 ). Other laboratory work suggests plausible anti-inflammatory effects ( Arumugam et al. , 2008 ).

Rosehip tea

Rosehip ( Rosa canina L. Rosaceae ) is an abundant source of vitamin C and polyphenolic compounds – components that could prevent oxidation-related disease ( Tumbas et al. , 2012 ). The wild rosehip fruit is also naturally high (12.9-35.2 mg/100g) in lycopene, the pigment found in tomatoes ( Bohm et al. , 2003 ).

The use of rosehip tea to alleviate menstrual pain has long been a part of traditional folk knowledge ( Tseng et al. , 2005 ). One six-month RCT, comprised 130 teenagers with primary dysmenorrhoea (menstrual cramps), found that 2 cups of rosehip tea daily (each 300 ml) consumed 1 week before and 5 days after commencing menstruation reduced perception of menstrual pain, distress and anxiety and reported greater psychophysiological well-being compared to placebo ( Tseng et al. , 2005 ). Findings suggest that rosehip tea could be an effective non-pharmacological strategy for women with primary dysmenorrhoea.

Further research now needs to study biochemical markers such as hormone levels. Mechanistic studies are lacking, but some research has investigated effects of brewing conditions. It was found that the optimal “brewing conditions” for rosehip tea was an infusion time of 6-8 min and temperature 84-86°C which resulted in the tea providing 3.15 mg 100 ml −1 of ascorbic acid, 61.44 mg 100 ml −1 of total phenolic content and 2,591  µ mol of ferric reducing anti-oxidant power ( Ilyasoglu and Arpa, 2017 ). These valuable findings should be embedded when designing future rosehip tea trials and their methods.

Herbal infusions have gained popularity, particularly amongst health conscious consumers and have diffused into the common market – now being consumed alongside other popular beverages such as tea, coffee and cocoa which are also prepared using plant materials ( Chandrasekara and Shahidi, 2018 ). The present review shows that a growing number of studies, including human RCTs, have investigated herbal infusion consumption in relation to aspects of health and wellness.

It should be appreciated that seven of the ten studies conducted were good quality ( Table II ). RCTs using herbal infusions as an intervention can be challenging to undertake. For example, most studies were “single” blinded and this was typically the investigator rather than the patient. Blinding herbal infusions can be difficult, as many herbal infusions have distinct flavours and sensory properties.

The health outcomes studied have been wide-ranging from improvements in glycaemic control and lipid profile (German chamomile) to aspects of women’s health (German chamomile, peppermint and rosehip tea) ( Table I ). Of the evidence available, the studies investigating inter-relationships between German chamomile tea consumption and glycaemic/lipid control look particularly promising ( Zemestani et al. , 2016 ; Rafraf et al. , 2015 ). These RCTs were well-conducted and high quality, ranking five on the Jadad scale ( Table II ).

Similarly two trials focussing on spearmint tea were also ranked as being “high-quality” with 1 cup daily for reducing stiffness in patients with knee osteoarthritis ( Connelly et al. , 2014 ) and 2 cups daily for improving hormone levels and symptoms of hirsutism in patients with polycystic ovary syndrome (PCOS) at baseline ( Grant, 2010 ). There a strong body of evidence showing that PCOS can impact negatively on quality of life, with hirsutism being presented as a factor contributing to this ( Aliasghari et al. , 2017 ). Given this, the drinking of spearmint tea could play an important role in supporting the management of such conditions.

Other human trials also yielded interesting findings. For example, lemon balm tea could help to prevent glycation-associated tissue damage in blood vessels and skin of healthy adults ( Yui et al. , 2017 ). Based on the work by Chang et al. (2016), German chamomile tea could be recommended to postpartum women as a supplementary approach to alleviating depression and sleep quality problems. Similarly, rose tea could potentially benefit females with dysmenorrhea, which can be a painful and debilitating condition affecting between 45 and 95 per cent of menstruating women ( Tseng et al. , 2005 ; Iacovides et al. , 2015 ).

Elsewhere there appears to be emerging evidence for other herbal infusions too. Such benefits, by and large, may be attributed to their polyphenol and flavonoid profiles. For example, cinnamon ( Cinnamomum verum J. Presl Lauraceae ) tea reduced postprandial blood sugar levels in one trial, which was thought to be because of its polyphenol content and high anti-oxidant capacity ( Bernardo et al. , 2015 ). Echinacea ( Echinacea spp. Asteraceae ) tea – made from the leaves (not root) of two Echinacea species – in a randomised, double-blind trial was effective at relieving early onset cold and flu symptoms, though intakes were higher (5-6 cups) in this particular trial ( Lindenmuth and Lindenmuth, 2000 ). Amongst prehypertensive and mildly hypertensive adults, hibiscus tea ( Hibiscus sabdariffa L. Malvaceae ) – three 240 ml cups daily over six weeks significantly reduced systolic blood pressure ( McKay et al. , 2010 ).

Overall, a growing number of trials are being conducted to investigate herbals teas and health. Interestingly, interest in organic teas also appears to be gaining momentum. A survey of 202 Chinese shoppers revealed that consumers perceiving organic tea as a healthy option and as a status symbol were more likely to report organic tea purchase intentions ( James et al. , 2019 ). Synergistic combinations of herbal teas could also confer health benefits. For example in one study, a mixture of two South African indigenous herbal teas (bush tea – Athrixia phylicoides DC and special tea – Monsonia burkeana Planch. ex Harv ) were reported to have high anti-oxidant activities that could play a role in the management of health conditions such as diabetes ( Mathivha et al. , 2019 ). Given the array and combinations of herbal infusions available, the evidence will take time to build.

In the meantime, herbal teas appear to be a valuable source of phytochemicals, such as flavonoids and other polyphenols, in the human diet. Generally, their consumption also tends to be without additional sugar or milk. As such, herbal tea consumption is a useful way to obtain anti-oxidants and bio-actives without providing surplus energy or sugar. Presently in the UK, herbal infusions are not mentioned specifically in the Eatwell Guide. This states that the public should: “Aim to drink 6-8 glasses of fluid every day. Water, lower fat milk and sugar-free drinks including tea and coffee all count” ( PHE, 2018 ). There is scope, as evidence accumulates, to further embed herbal infusions within such guidelines.

Future research

Regarding future research, multiple daily consumptions may be needed to generate further effects. In the present studies, benefits were observed at fairly low levels of herbal infusion consumption (1-3 cups daily). Higher intakes could lead to more detectable changes in markers of health. It should be considered, however, that better standardisation is needed in terms of what constitutes “a cup”, as this ranged in size from 100 to 300 ml. It has been mentioned previously that interventions should be well characterised to aid uniformity and enable a common body of evidence to be developed ( Dwyer and Peterson, 2013 ).

Tea forms should also be used that can be more generalisable to daily life. For example, a recent quality assessment of marketed chamomile tea found that it was crude flowers that were most likely to be adulterated by other plant materials compared to German chamomile tea bags ( Guzelmeric et al. , 2017 ). Bearing this in mind, baseline biochemical analysis of the tea interventions would be worthy before progressing on to trials. Following on from this, modes of tea preparation – including weight of herbal product – the volume of water added and infusion times should be kept as consistent as possible.

Self-reported assessments of health and well-being can be somewhat subjective, so ongoing biomarkers of health are needed in future work. Mechanistic studies should continue to determine which tea bioactive constituents generate health effects and whether these act alone or in combination ( Dwyer and Peterson, 2013 ). These should also be conducted using the tea per se , as most have focussed on the herb or plant itself rather than tea in beverage form.

Being in the era of anti-biotic resistance, there is great potential to further study the anti-microbial properties and activities of herbal teas. A recent in vitro study found that rosehip, mint, Echinacea tea bags, cinnamon, black and green teas, amongst others were active against most of the studied microorganisms ( Hacioglu et al. , 2017 ). Interestingly, however, rosehip (and pomegranate blossom) were antagonistic with some anti-biotics indicating that they would be better consumed alone for their anti-microbial activities and avoided when on a course of anti-biotics ( Hacioglu et al. , 2017 ).

There is growing interest in whether herbal infusions could contribute to healthy living and preventative health. Our review collating evidence from human trials demonstrated that drinking 1-3 cups daily of certain herbal infusions could confer health benefits. In particular, German chamomile tea appears to improve anti-oxidant status and glycaemic/lipid profiles. German chamomile, spearmint and rose teas could also benefit aspects of women health including sleep quality, hormonal control and primary dysmenorrhea. Evidence for ginger and lemon balm also look promising but ongoing human trials are needed.

Algorithm for database search results

Human studies investigating herbal tea consumption and health