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Botanical Safety Handbook, 2^nd ed.

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Front Matter

Dedication

This book is dedicated to the memory of Mary Frances Picciano, Ph.D., former Senior Nutrition Research Scientist at the Office of Dietary Supplements, National Institutes of Health. Her interest, foresight, and willingness to have the Office of Dietary Supplements support a partnership with the American Herbal Products Association and the University of Massachusetts made this work possible.

Preface To The First Edition

Increased attention on herbal products, both in the marketplace and in the legislative arena, has created a need for wider public access to data regarding the safety of botanicals. The passage of the Dietary Supplement Health and Education Act in October, 1994, furthered the need for such information, as this law authorizes the use of cautionary labeling for dietary supplements, including those that contain herbs.

The American Herbal Products Association (AHPA), through its Standards Committee, convened a special SubCommittee (hereinafter “the Committee”) to address this need. The Committee members identified considerable safety data in varied texts and journals and discovered that some attempts to classify herbs had been undertaken in several other countries. No comprehensive compilation or review of this data for botanical ingredients sold in the North American marketplace, however, was available in a useful format.

The goal of the present work is to find a rational platform for the evaluation of herb safety, neither assuming that all natural substances are inherently safe, as some popular references suggest, nor blindly accepting reports of toxicity from uncritical sources. In undertaking this task, the Editors met with information that presented significant challenges. Many authors utilize unreferenced data, perpetuate historical inaccuracies or display inherent biases against the use of botanicals. Also, contemporary reviews of the toxicity of many herbs are not available. Nonetheless, the Editors are confident that the body of information presented here is largely accurate. It is our sincere hope that readers of this work will find it to be a valuable reference and will address all useful criticisms to our attention.

In sponsoring this effort, the American Herbal Products Association addresses the common interest of industry, the public, and regulatory agencies in assuring safe access to a wide range of herbs and herbal products. This document provides accurate data to guide manufacturers and consumers in safe utilization of herbal products. As the most broadly established trade association in the herbal marketplace, AHPA has, by supporting and sponsoring the creation of this work, furthered the herb industry’s leadership role in promoting the responsible use of herbs.

Preface

This second edition of AHPA’s Botanical Safety Handbook represents a significant modification from the first edition, published in 1997. At the same time, the second edition reflects the continued commitment of the American Herbal Products Association (AHPA) to provide accurate information about the safe use of herbs in a practical and accessible format.

The original edition classified botanical ingredients in four safety classifications to differentiate those that can be safely consumed when used appropriately from those for which some contraindication or other restriction is known, as well as those that should be used only under the guidance of a qualified expert. A handful of entries in that edition were also placed in a separate class if the editors had insufficient data for classification. The revised edition largely retains this safety classification system, with the exception that if the review process did not provide enough information to make a knowledgeable decision on any specific herb, that species was removed from the text.

The present edition also includes a separate classification system to address what is known about the potential for an herb to interact with any drugs. Each of the herbs listed here is identified in one of three interaction classes to differentiate between those for which no clinically relevant interactions are expected and those for which clinically relevant interactions are biologically plausible or are, in fact, known to occur.

Botanical products continue to be broadly used throughout the world. In the United States, most herbs are sold in loose form or as tablets, capsules, or tinctures, and regulated as dietary supplements (this product class that also includes vitamins, minerals, amino acids, and numerous other ingredients). Many herbs are also common flavorings for foods, or are used in teas. In addition, a handful of herbs provide active ingredients in non-prescription drugs. The U.S. marketplace for herbal products in the supplement category has increased significantly in the years since publication of the first edition, and the retail value of this product category grew from $3 billion in 1996 (Muth et al. 1999) to $5 billion in 2010 (Anon. 2011).

An even more significant change in the past 15 years has been the emergence of the internet and online scientific databases as tools for accessing scientific information. The first edition of this book relied almost entirely on secondary references (i.e., books and other summaries of traditional or scientific information), and the editors of that document used their personal collections of such texts to compile the information needed to make safety determinations for the plants addressed in it. On the other hand, the process for compiling information for this second edition, as described in the introduction, involved a much more thorough review of primary references (i.e., published research papers, case reports, and other original literature). Thus, while the first edition included just 280 references to evaluate the over 500 plants addressed therein, this revision cites 301 references just in its treatment of St. John’s wort herb (Hypericum perforatum), ginkgo leaf and seed (Ginkgo biloba), and garlic bulb (Allium sativum).

Any attempt to provide a summary of safety information on botanicals will encounter certain prejudices and inaccuracies in the published record. One such prejudice, often repeated in reviews of herbal medicines and dietary supplements, is the view that consumers have been led to believe the myth that “anything natural is safe” (Barnes 2003; Dasgupta and Bernard 2006). While one survey of consumer attitudes in Canada found that 7 percent of respondents completely agree that there is no risk associated with products made with natural ingredients (Anon. 2005), there are no published analyses of consumer beliefs that indicate that there is broad acceptance of any such assumption.

It is, however, true that many of the plants that enjoy broad culinary and traditional therapeutic usage are generally safe. We can safely season our food with any number of herbs to make a meal more flavorful. We can appreciate a delicious cup of peppermint leaf or rose hips tea, or safely take an herbal supplement containing dandelion root, saw palmetto berries, or any number of other herbs. Although allergies and individual reactions have been recorded for a few herbs that are widely used in foods and supplements, such individual concerns are also seen with many other foods, and do not diminish the safety profile of the many herbs that are widely regarded as safe.

On the other hand, and as everyone knows, there are any number of plants that are highly toxic, even deadly. Every savvy North American hiker knows to stay away from poison ivy (Toxicodendron spp.) when walking in the woods. The death sentence imposed on Socrates by an Athenian jury 2,400 years ago was carried out with a fatal dose of poison hemlock (Conium maculatum). The poison curare, a blend of several equatorial rain forest plants (e.g., species of Chondrodendron, Curarea and Strychnos) is used by some South American hunter cultures to make their arrows more deadly (Schultes and Raffauf 1990). And in the “concrete jungle” of Los Angeles, two young boys died in 2000 from ingesting a few leaves of the ubiquitous oleander (Nerium oleander) (Garrison 2000). Federal law and good common sense, however, prevent the use of any such highly toxic plants in products that are readily available to consumers.

The revised edition of the AHPA Botanical Safety Handbook fills the need for a reference that neither promulgates the myth that all herbs are always safe, since they are “natural,” nor accepts without review every case report or conceptual theory that draws an unsubstantiated or illogical conclusion of harm from an herb or herbal product. In assembling this revision, significant effort has gone into sorting out references that are factual from those that are inaccurate. Texts that communicate that all natural substances are inherently safe would not have been included here, though in fact no such documents were encountered. More effort was needed to avoid blind acceptance of reports that purport to identify herbal safety concerns with unreferenced statements or incomplete records of specific herbal preparations, which are unfortunately quite common, even in peer-reviewed scientific journals. Such references may nonetheless be included in this text to provide readers with a complete record, though efforts were made to highlight any perceived flaws.

Even as the consumer market for herbal supplement products expands and scientific information becomes more accessible, the goals of the second edition of AHPA’s Botanical Safety Handbook are essentially the same as those of the original edition. Companies that market herbal products are bound by federal regulations to disclose known safety concerns that may result from a product’s use. Health care providers, especially those lacking in training or experience in the use of herbs, are in need of accurate data if they are to provide guidance to their patients who use herbs. And consumers of herbs and herbal products need readily understandable information to assist them in making safe and appropriate health care choices. AHPA’s Botanical Safety Handbook, 2nd ed. is designed to provide the information needed by each of these audiences.

It should be recognized, however, that this reference is not an herbal user’s guide. Numerous excellent references exist that provide information on the uses and benefits of herbs. Readers of the present document are advised to seek out these references, or to consult with experts qualified by training and experience, for advice on when and how to use herbs for their health benefits.

The editors are confident that the body of information presented in this second edition of the AHPA Botanical Safety Handbook is largely accurate, and hope that readers of this work will find it to be a valuable reference. Useful criticisms will nonetheless be welcome, and should be addressed to the attention of the editors.

LITERATURE CITED

Anon. (Ipsos-Reid). 2005. Baseline Natural Health Products Survey Among Consumers: Final Report. Health Canada, Natural Health Products Directorate.

Anon. 2011. Organic wins big in 2010. Nutrition Business Journal 16(6):1-8.

Barnes J. 2003. Quality, efficacy and safety of complementary medicines: Fashions, facts and the future. Part II: Efficacy and safety. Br. J. Clin. Pharmacol. 55:331-340.

Dasgupta A. and D.W. Bernard. 2006. Herbal remedies: effects on clinical laboratory tests. Arch. Pathol. Lab. Med. 130:521–528.

Garrison, J. 2000. Two Toddlers Died from Oleander Poisoning, Coroner Says. Los Angeles Times: July 26, 2000.

Muth, M.K., D.W. Anderson, J.L. Domanico, J.B. Smith, and B. Wendling. 1999. Economic characterization of the dietary supplement industry. Contract No. 223-96-2290: Task Order 3. Final Report. Research Triangle Park, NC: Research Triangle Institute.

Schultes, R.E. and R.F. Raffauf. 1990. The healing forest. Portland, OR: Dioscorides Press.

Acknowledgements

Appreciation was expressed in the first edition of the Botanical Safety Handbook to three individuals who were essential to AHPA’s decision to take on the task of creating this document. This appreciation is restated now to Daniel Gagnon, for his vision and persistence; to John Hallagan, for the encouragement borne of his own experience; and to the late William Appler, for so clearly seeing the value of this text when it was just an idea.

The members of this edition’s Expert Advisory Council met together on a regular basis for nearly five years, all on their own time, and without any financial compensation. The expertise and experience embodied in these individuals is unsurpassed, and without them the work could not have proceeded beyond a collection of references, as it was through their efforts that these references were evaluated and organized into the present text. Biographies of each of these individuals follow.

Additional specific guidance was occasionally solicited from a number of other experts, and thanks are due to: Dennis Awang, Dan Bensky, Paul Bergner, Mary Bove, Eric Brand, Josef Brinckmann, Francis Brinker, Chanchal Cabrera, Todd Caldecott, John Chen, Sigrun Chrubasik, Emily Cohen, Cynthia Copple, De-Qiang Dou, Lana Dvorkin-Camiel, Andrew Ellis, Thomas Avery Garran, Christopher Hobbs, David Hoffmann, Prashanti de Jager, K.P. Khalsa, Vasant Lad, Reinhard Länger, Wilson Lau, Phyllis Light, Amanda McQuade Crawford, Russell Molyneux, Vikram Naharwar, Robert Newman, Xie Peishan, Sebastian Pole, Bill Schoenbart, Atreya Smith, Ed Smith, James Snow, Alan Tillotson, Jonathan Treasure, Nancy Turner, Donnie Yance, Eric Yarnell, and Yifang Zhang.

Thanks are also due to the generations of herbalists and scientists around the world whose research and experience has provided the basis for our understanding of the safety of medicinal plants. Their work and publications have created a significant foundation for our understanding of the safety of the botanicals reviewed in the present text.

Appreciation is also due to Joseph Betz, Ph.D. and the late Mary Frances Picciano, Ph.D. of the Office of Dietary Supplements (ODS) at the National Institutes of Health. Dr. Betz shared his ideas on the makeup of the Expert Advisory Council and on the importance of addressing the potential for an herb to modify the effect of a drug taken concomitantly, commonly referred to as an herb-drug interaction (a topic that was outside of the scope of the first edition). Dr. Picciano facilitated ODS’s significant financial support of the revision process and ensured that the planned revision met high academic and scientific standards.

A number of research assistants helped to acquire and manage the thousands of documents reviewed in this project. A work of this scope would not have been possible without the enthusiastic assistance of Jamie Blair, Brittney Laramee, Annie Winkler, Ryan Rogan, Rye Zemelsky, Kathleen Broadhurst, Jennifer Kehoe, Margo Voskanian, Jennifer Hast, and Abigail Haines. Thanks are also due to Constance Parks and Bill Schoenbart for their detailed reading and editing of the manuscript.

Financial Supporters

AHPA appreciates our patrons. This work was made possible with financial supporter from the Office of Dietary Supplements at the National Institute of Health, and in-kind contributions by the Medical Plant Program at the University of Massachusetts, Amherst.

Financial contributions to support this effort were also made by numerous AHPA member companies and individuals identified below.

Visionaires

Benefactors

Champions

Editors

Zoë Gardner, M.S., Ph.D.(c)

Research & Development Manager, TRADITIONAL MEDICINALS

Fascinated by the connection between people and plants, Zoë Gardner has been studying, researching, and teaching on the production, conservation, quality, safety, and appropriate use of medicinal plants since 1998.

After completing her undergraduate degree in Environmental Studies at the Audubon Expedition Institute, Zoë helped to establish the Medicinal Plant Program at the University of Massachusetts, earning her master's degree there in Plant & Soil Sciences.

More recently, Zoë joined the Research & Development Department at Traditional Medicinals, a leading producer of botanical dietary supplements. A self-proclaimed "herb nerd," Zoë is currently completing her Ph.D. on medicinal plant quality and safety.

Michael McGuffin

President, AMERICAN HERBAL PRODUCTS ASSOCIATION

Michael's introduction to herbs dates to the sassafras he gathered in his youth. His interest in plant toxicology began when he misidentified the toxic Nicotiana glauca in a Venice, California alley as a Western cousin of poke weed.

Michael has been active in the herbal industry since 1974, having managed retail and manufacturing businesses in this field. Elected to the board of the American Herbal Products Association (AHPA) in 1990, he was hired as AHPA's president in 1999. He is the managing editor of both editions of AHPA's Botanical Safety Handbook (1997; 2013) and of Herbs of Commerce, 2nd Edition (2000).

Michael serves on the boards of the American Herbal Pharmacopoeia and United Plant Savers and in various advisory positions. He has lived in the same Venice house since 1980, and keeps a large garden and an active kitchen.

Introduction

The second edition of AHPA’s Botanical Safety Handbook provides information on a number of safety factors that may affect an individual’s decision to ingest any of the herbal1 substances listed in this work. The information was prepared through a process that involved identification of relevant publications on each botanical, as well as review by experts qualified by training and experience in the traditional and therapeutic use of herbs and herbal products.

Each of the botanical ingredients2 included in this text is classified into one or more Safety Class, and also into an Interaction Class, details of which are described below. These classifications, as well as a synopsis of pertinent information from reviewed references, are presented in a QUICK REFERENCE SUMMARY, which provides basic data needed to understand safety issues associated with each botanical. This summary is followed by a section titled REVIEW DETAILS in which more in-depth information is presented when available. Thorough descriptions of the templates and contents of each of these sections are provided later in this introduction.

Determination of herb safety.

In developing this document, the voices and experience of various organizations and individuals were considered. A primary source of guidance and inspiration for the first edition of this text was the work of the World Health Organization (WHO). In 1991, WHO’s Programme on Traditional Medicines presented Guidelines for the Assessment of Herbal Medicines at the Sixth International Conference of Drug Regulatory Authorities. These guidelines, which were subsequently reviewed and adopted by WHO, propose that the safety of herbal medicine be assessed according to the following principle:

“..that if the product has been traditionally used without demonstrated harm, no specific restrictive regulatory action should be undertaken unless new evidence demands a revised risk-benefit assessment” (WHO 1991).

The editors of the first edition adopted this principle from the WHO Guidelines and this view has been maintained for the compilation of the present work.

In his classic text, The Problem of Poisonous Plants, J.M. Kingsbury provides further direction by calling attention to the fact that there are many instances in which a plant contains a measurable amount of a toxic substance, though the plant may be poisonous only if consumed in excessive quantities. He notes:

“In order for a plant to be functionally poisonous, it must not only contain a toxic secondary compound, but also possess effective means of presenting that compound to an animal in sufficient concentrations, and the compound must be capable of overcoming whatever physiological or biochemical defenses the animal may possess against it. Thus the presence of a known poison principle, even in toxicologically significant amounts, in a plant does not automatically mean that either man or a given species of animal will ever be effectively poisoned by the plant” (Kingsbury 1979).

In examining the relevance of Kingsbury’s position, it is of interest to revisit the means by which concerns for the safety of herbs arise. Toxicity studies are often conducted by feeding abnormally high quantities of an herb or isolated constituent of an herb to laboratory animals. For example, Bensky and Gamble report in their monograph on mulberry leaves that “Long-term use of 250 times the normal human dose in mice produced both liver and kidney damage” (Bensky and Gamble 1986). Data based on excessive consumption have little relevance to the practical use of herbal supplements, and such findings are clearly not pertinent to normal human consumption patterns. In addition, information is sometimes available that identifies an LD50 for an herb, herbal preparation, or isolated compound (i.e., the “lethal dose” at which 50 percent of test animals are killed by the studied substance), but often fails to specify the concentration or form of the specific material used. Such incomplete data cannot be accurately applied to safety evaluations of human consumption.

Significant toxicity data exist for isolated constituents of a wide variety of commonly available foods, as well as herbs. Potatoes, as a member of the Solanaceae family, contain trace amounts of the toxic glycoalkaloid solanine, especially in green parts of the potato tuber (Turner and Szczawinski 1991). Although the symptoms of solanine poisoning are serious, potatoes themselves are generally considered to be a safe food. While consumption of as little as five grams of nutmeg can cause marked hallucinations (Sangalli and Chiang 2000), no safety concerns prevent us from enjoying a sprinkle of this characteristic flavor on our holiday eggnog. Similarly, no safety concern is associated with a candy flavored with peppermint oil, though as many as 26 toxins are reported to have been observed in the plant (Duke 1989). Safety concerns for herbal products need not be extrapolated from constituent profiles with any more alarm than is appropriate for foods.

In following the principles espoused by WHO and incorporating the ideas delineated by Kingsbury, it is imperative that herb safety be assessed according to the intended use of the substance within the historical context of its use. In establishing safety classifications, this work has intentionally refrained from automatically applying information on the toxicity of isolated constituents or considering excessive or irresponsible consumption patterns. The decision to place an herb in a restrictive safety class was made only if the use of the herb in a normal dosage range is documented as presenting a safety concern, or if the amount of a harmful or potentially harmful constituent obtainable from the crude plant is of sufficient quantity to be problematic.

Addressing potential drug interactions.

The issue of herb-drug interactions was specifically excluded from the first edition of this work, since at that time very little accurate information had been developed on this subject. In the years since then, this topic has been much more prominently studied. Some early publications on the subject were largely speculative, but researchers have now begun to develop scientifically based data that have measured actual effects of several herbs on the metabolism of selected drugs or on drug metabolizing enzymes. At the same time, emerging research on many specific botanicals has confirmed that no drug interactions should be expected with these herbs.

Drug interactions are generally divided into two categories: pharmacodynamic interactions, in which the physiological effects of drugs or botanicals interact (including additive and opposing effects), and pharmacokinetic interactions, in which an interaction affects a drug’s absorption, metabolism, or excretion, and changes the amount and duration of a drug’s bioavailability (see CYP450 and P-gp interactions profile in Appendix 3). While pharmacodynamic interactions are generally predictable based on the pharmacological effects of drugs and botanicals, pharmacokinetic interactions, until identified through testing or well-documented case reports, generally cannot be predicted.

This work focuses primarily on pharmacokinetic interactions, although a small number of pharmacodynamic interactions are also listed, especially when such interactions may have significant health consequences (e.g., additive effects on heart medications or antiplatelet drugs). In pharmacokinetic herb-drug interactions, the severity of an interaction is generally based on the toxicity of the drug being used or the consequences if the therapeutic dose is not achieved. When herbs are used with drugs that have a narrow therapeutic window (i.e., small difference between the effective dose and the toxic dose, such as with digoxin, warfarin, lithium, cyclosporine, phenytoin, and theophylline), supervision by a qualified healthcare practitioner is strongly advised.

Both pharmacodynamic and pharmacokinetic interactions may have positive effects, such as increasing the efficacy or bioavailability of drugs or botanicals. Such positive therapeutic interactions are not covered in this text, unless the interaction also poses a safety concern.

Selection of the Expert Advisory Council

Methods and considerations for safety evaluations that are outlined in the U.S. Institute of Medicine’s (IOM) Framework for Evaluating the Safety of Dietary Supplements provided guidance in the literature collection and review processes that went into the creation of this text (IOM 2005). This IOM document also highlights the importance of using experts from a number of fields related to dietary supplements. Consistent with this advice, an advisory panel of qualified experts was assembled at the outset of this project. All members were selected for their extensive knowledge and experience in areas such as medicine, clinical herbalism, pharmacology, biochemistry, or traditional herbal medicine systems (e.g., traditional Chinese medicine or Ayurvedic medicine). When knowledge of a particular topic or botanical was not found in the Expert Advisory Council, the experience and opinions of outside experts was solicited.

Literature review methods

Systematic literature searches were conducted in several electronic databases from January 2007 to May 2010, using search terms developed in cooperation with a technical information specialist from the National Library of Medicine, as follows:

PubMed
([Latin name] OR [standardized common name]) AND (adverse effects OR adverse reaction OR safety OR tolerability OR drug interactions OR herb-drug interactions OR poisoning OR toxic OR toxicity OR toxicology OR drug toxicity OR teratogen* OR contraindicat* OR cytochrome OR p450 OR pregnancy OR lactation OR breast feeding OR breast milk OR pharmacodynamics OR “[MeSH term]/adverse effects” OR “[MeSH term]/toxicity” OR (Case Reports[ptyp]))
EMBASE and Biological Abstracts
([Latin name] OR [standardized common name]) AND (‘adverse drug reaction’ OR ‘safety’ OR ‘tolerability’ OR ‘drug tolerability’ OR ‘herb drug interaction’ OR ‘drug interaction’ OR ‘drug contraindication’ AND ‘contraindication’ OR ‘poisoning’ OR ‘intoxication’ OR ‘drug toxicity’ OR ‘toxic’ OR ‘toxicity’ OR ‘toxicology’ OR ‘teratogen’ OR ‘teratogenic’ OR ‘teratogenicity’ OR ‘cytochrome’ OR ‘pregnancy’ OR ‘lactation’)
TOXNET
([Latin name] OR [standardized common name]) AND (teratogen* OR adverse effects OR safety OR tolerability OR drug interactions OR poisoning OR toxicity OR cytochrome OR contraindications OR pregnancy OR lactation) NOT PubMed

Literature selected from these searches for review included meta-analyses, systematic reviews, other reviews, clinical trials, human, animal and in vitro pharmacological studies related to safety (including drug interaction studies), toxicity studies including reproductive and developmental toxicity studies, epidemiological studies, and ethnobotanical surveys. Articles on combination products and homeopathic products were generally excluded. No language restrictions were imposed, so publications in other languages were included whenever possible, but the review focused on English language publications.

Besides this extensive literature review, numerous other publications were consulted. These consisted primarily of authoritative references on the traditional use of herbal medicines, and also included regulatory documents, ethnobotanical records, pharmacopoeial texts, and writings on toxicology, food ingredients, and other relevant topics.

Literature was identified, obtained, and summarized by the research editor. Full literature summaries were presented to the Expert Advisory Council, and other experts as needed, for review and assignment of safety and interaction ratings, contraindications, and precautions. Ratings were assigned by the Expert Advisory Council bearing in mind the history of use of the botanical under review.

No formal assessment of the validity of each reference was undertaken in this process, although the levels of evidence afforded by different types of publications (i.e., case report vs. randomized, placebo-controlled double-blind study) were actively considered during the review process. In addition, it was observed that some identified publications were of limited value, especially those that lack sufficient detail about the specific herbal preparation addressed, and case reports that postulate a causal relationship between a specific herbal ingredient and a reported adverse effect, without consideration for confounding factors such as patient history or concomitant drug use. Some such references were nonetheless retained, though the editors attempted to call attention to their perceived flaws.

Additional articles in scientific journals that were published subsequent to the 2007 to 2010 review were also considered for several entries during the editing stages that followed the process described above.

The Review Process and Classification

The herbal ingredients included in this edition are very nearly the same as those included the first edition, published in 1997. Some other herbs were added in order to include ingredients that have become more prominent in the U.S. marketplace in the interim. A few herbs addressed in the first edition are not included here, usually because no relevant contemporary publications were found and evidence from historical sources was lacking or insufficient.

Classifications are included for each part of the plant³ identified in an entry, and are for dried plant material, unless otherwise stated. Classifications address only the identified part of the herb in its whole, cut, or powdered form, as a raw material or as an ingredient in a finished product (tablets, capsules, teas, etc.); or as a decoction, tincture, or extract prepared from that plant part by a traditional process. Concentrated extracts, extracts with added compounds, or compounds isolated from botanicals may be expected to have different physiological effects and safety and interaction considerations than the source botanical, and classifications should not be extrapolated to other such ingredients without additional review.

Classifications are generally based on data that are associated with use of the specific herb and in the quantities generally consumed for a health promoting or therapeutic effect. Any cautions may therefore be somewhat overstated for an herb which appears in the market in a smaller amount as part of a combination product, or for herbs that are used as flavorings in less than therapeutic quantities.

Each herb is placed in two classes based on all of the information included, along with the experience of the Expert Advisory Council. The first is the Safety Class, which evaluates the safety of a particular herb. For The second is the Interaction Class, which provides information on what is currently known about the potential for an herb to alter the effect of prescription or non-prescription drugs when the herb and drug are used concomitantly. Central to the appropriate application of this document is the understanding that classifications are based on an assumption of rational, informed use of herbs and herbal products.

Classes are defined below, and are followed by bullet points which list criteria and considerations for inclusion in each particular class.

Safety Classes

Class 1. Herbs that can be safely consumed when used appropriately.

History of safe traditional use
No case reports of significant adverse events with high probability of causality
No significant adverse events in clinical trials
No identified concerns for use during pregnancy or lactation
No innately toxic constituents
Toxicity associated with excessive use is not a basis for exclusion from this class
Minor or self-limiting side effects are not bases for exclusion from this class

Class 2.⁴ Herbs for which the following use restrictions apply, unless otherwise directed by an expert qualified in the use of the described substance:

2a: For external use only

Toxicity demonstrated with crude preparation taken orally at traditional dose
Adverse event data in humans with probability of causality of toxicity (e.g., hepatotoxicity, nephrotoxicity, neurotoxicity) associated with oral use

2b: Not to be used during pregnancy

Traditional use contraindicates
Traditional use as an abortifacient or uterine stimulant
Relevant adverse event data in humans exists and has probability of causality
Data in animals suggesting teratogenicity or other adverse effects on the fetus or mother, with reasonable application to humans
For plants with common food uses, standard dose is in excess of typical food amounts

2c: Not to be used while nursing

Traditional use contraindicates
Relevant adverse event data in humans exists and has probability of causality
Potential hepatotoxicity or neurotoxicity
Bioavailability of constituents of concern in breast milk has been demonstrated

2c: Not to be used while nursing

Traditional use contraindicates
Relevant adverse event data in humans exists and has probability of causality
Potential hepatotoxicity or neurotoxicity
Bioavailability of constituents of concern in breast milk has been demonstrated

2d: Other specific use restrictions as noted

Information exists that use may be unsafe for specific populations
Dosage level outside of a standard range known to cause adverse effects

Class 3. Herbs to be used only under the supervision of a qualified expert. The following labeling is recommended for Class 3 herbs: “To be used only under the supervision of an expert qualified in the appropriate use of this substance.” Labeling must include proper use information: dosage, contraindications, potential adverse effects and drug interactions, and any other relevant information related to the safe use of the substance.

Narrow therapeutic range
Identified safety concerns in many populations

Interaction Classes

Class A. Herbs for which no clinically relevant interactions are expected

No case reports of suspected interactions with probability of causality
No clinically relevant interactions in human pharmacological studies, if any

Class B. Herbs for which clinically relevant interactions are biologically plausible

Human or animal pharmacological study data suggests potential for clinically relevant interaction
Multiple case reports have suggested a potential interaction concern
Cell culture or biochemical assays establish a basis for biologically plausible mechanism of interaction

Class C. Herbs for which clinically relevant interactions are known to occur

Human pharmacological study has demonstrated interaction with a specific drug or supplement
Human pharmacological study has demonstrated clinically relevant effects on drug metabolizing enzymes or drug transporter proteins
Case reports of suspected interactions have a probability of causality

Limitations of Scope

This work specifically excludes the following data, conditions, and related products:

Excessive consumption. Safety and interaction classifications given here are for normally consumed amounts, and cannot be assumed to have relevance for any quantity. Also, any concerns that are significant only in excessive or immoderate use are not relevant to assignation of classifications, though these may be referred to in an Editors’ Note.
Safety or toxicity concerns based on isolated constituents. As is the case with many common foods, some herbs are known to contain constituents that, in isolation, exhibit toxicity. Data based solely on constituents are not considered relevant to safety classification except in those cases where such compounds are known to accumulate, or where consumption patterns are sufficient to provide cause for health concerns. The presence of a constituent has been identified in a Notice if knowledge of the constituent is relevant to the safe use of an herb.
Toxicity data based solely upon intravenous or intraperitoneal administration. The majority of herbal products consumed by the public are taken orally and with adequate dosage instructions. The physiological effects of injectable preparations are not relevant to oral consumption. Information associated with other forms of administration was reviewed but was not considered as a sole basis for classifications, and classifications should be assumed to address oral administration, unless otherwise stated.
Traditional Chinese and Ayurvedic contraindications. In Chinese and Ayurvedic therapeutic traditions, most herbs have contraindications based on an individual’s constitutional strengths and weaknesses, seasons, climate, and other factors that can only be understood in the context of the specific tradition. These traditional concerns have not been included in the text unless they can also be interpreted in a modern biomedical context, such as contraindication in pregnancy.
Gastrointestinal disturbances. Reports of nausea or emesis from excessive doses, or occasional and/or minor gastrointestinal disturbances, have been noted but have not been considered in establishing safety classification, unless frequency or severity of such reactions warrants consideration.
Idiosyncratic reactions. Any plant substance, whether used as food or medicine, has the potential to stimulate a negative response in unpredictably sensitive individuals. Safety classifications do not take into account such idiosyncratic responses, unless there is evidence to suggest that such an idiosyncratic reaction may be predictable.
Allergic reactions. Certain plants in the Asteraceae, Apiaceae, and other plant families possess a relatively high degree of allergenicity, and specific mention of this is provided in the text for certain plants, such as feverfew herb (Tanacetum parthenium) and Echinacea spp. flowering tops. A plant’s allergic potential, however, is not generally considered a basis for restrictive safety classification. Persons with a known allergy to ragweeds are nonetheless advised to observe caution in the consumption of all plants of the Asteraceae family, especially flowering parts.
Contact dermatitis. The primary focus of this work is on herbal products for oral ingestion. Except in cases where there is a history of external therapeutic use, coupled with a record of associated dermatitis (e.g., mustard plasters), such concerns are beyond the scope of this document.
Well-known toxic plants with known safety concerns that are not broadly traded. Many of the plants which are listed in standard toxicological texts as highly poisonous are not included in this document. Although isolates and constituents of some of these might be included in prescription drugs, they are not found in products which are otherwise accessible in a retail setting. Among the plants excluded are Adonis vernalis, Claviceps purpurea, Chondrodendron tomentosum, Colchicum autumnale, Conium maculatum, Croton tiglium, Datura spp., Gelsemium sempervirens, Hyoscyamus niger, Nicotiana spp., Rauwolfia spp., Stramonium spp., Strophanthus kombe, and Strychnos nux-vomica.
Homeopathic herbal preparations. Homeopathic products are classified as over-the-counter or prescription drugs and are regulated under the Homeopathic Pharmacopoeia of the United States. Safety concerns that arise for an herb in crude form may not apply to homeopathic preparations of the same herb, and this document does not address herbal products in homeopathic forms.
Essential oils. Essential oils are concentrations of specific volatile compounds. While many essential oils have a well-documented history of safe use by appropriately skilled persons, they often present toxicological concerns which are absent or moderate in the crude plant materials from which the oil is derived. Except for a small number of essential oils that have a history of internal use, the classification of essential oils is beyond the scope of this document.
Herbal products to which chemically-defined active substances, including chemically-defined isolated constituents of an herb, have been added. Safety of such products should be determined by manufacturers and marketers prior to market introduction.
Environmental factors, additives, or contaminants. Classifications do not consider potential adulteration of botanical materials, although known adulterations which present health risks may be listed in an Editors’ Note. Safety concerns of this sort must be addressed by the manufacturing practices of suppliers and manufacturers, who are responsible for assuring that herbal products are not contaminated or adulterated.

LITERATURE CITED

Bensky, D., and A. Gamble. 1986. Chinese herbal medicine: Materia medica. Seattle: Eastland Press.

Duke, J.A. 1989. CRC handbook of medicinal herbs. Boca Raton, FL: CRC Press.

IOM. 2005. Dietary supplements; A framework for evaluating safety. Institute of Medicine and National Research Council of the National Academies. Washington, D.C.: National Academies Press.

Kingsbury, J.M. 1979. The problem of poisonous plants. New York: Columbia University Press.

Sangalli, B., and W. Chiang. 2000. Toxicology of Nutmeg Abuse. J Toxicol Clin Toxicol 38 (6):671-678.

Turner, N., and A. Szczawinski. 1991. Common poisonous plants and mushrooms of North America. Portland, OR: Timber Press.

WHO. 1991. WHO Guidelines for the assessment of herbal medicines. WHO/TRM/91.4. Geneva: World Health Organization.

¹ The terms “herbal” and “botanical” are used interchangeably throughout this work. Go back.

² Or occasionally, groups of ingredients. Examples are listings for more than one plant part from a specific taxa, when the safety concerns for these are not different, or groups of two or more species within a genus, when these have common safety profiles. Go back.

³ Plant parts identified as “herb” consist of the leaf and stem of the identified plant, and this term is generally used only for non-woody plants. A plant part identified as “above-ground parts” means all of the plant above the ground, so it generally includes not only leaf and stem, but also flowers, fruits, and seeds, depending on the state of maturity of the plant at the time of harvest. All other plant parts (e.g., bark, leaf, root) are each identified with the generally used botanical term. Go back.

⁴ Herbs placed in any of the subparts of Class 2 may also be placed in other of these subparts. Go back.

Organization Of The Data

Listings are alphabetically arranged by Latin name. More than one species of a genus are combined into a single listing in those cases where two or more species are used interchangeably, or where the issues relevant to safe use are the same or nearly the same for related species. Some herbs supply more than one useful part. These parts are listed and classified together only in those cases where the safety issues of all parts are sufficiently similar; otherwise, separate listings are included for each plant part.

Following the Latin name is the botanical family name. In instances where synonymous Latin names may be encountered in relevant references, one or more of these may be listed as a Synonym (Syn).

AIt is not unusual for a plant to have many common names, a fact which can confound the understanding of an herb’s uses and potential safety concerns. AHPA published Herbs of Commerce, 2nd Edition (McGuffin et al. 2000) to address this concern, by assigning a single common or usual name to each herb, denoted in each listing in the current text as its standardized common name (SCN). Additional familiar common names are listed as other common names (OCN), though this field is generally not intended to be exhaustive. Ayurvedic names (AN) and pinyin names (PN) for botanical ingredients commonly used in Ayurvedic or traditional Chinese medicine are also included; note that Ayurvedic names tend to identify the plant itself, while pinyin names usually identify a specific plant part. With occasional exceptions, nomenclature in this work is derived from Herbs of Commerce, 2nd Edition.

Following the plant’s names is the Part of the plant for which the safety and interactions classifications that follows are made. Occasional specific information is included for those herbs that require special processing.

The remainder of each listing is divided into two sections, the QUICK REFERENCE SUMMARY, which provides a concise, clinically relevant summary of the scientific information and traditional knowledge on the safety of each species or set of species, and the REVIEW DETAILS section, which provides details on the information presented in the summary.

Each entry’s QUICK REFERENCE SUMMARY includes the following elements. Each of the fields printed below in bold are always included, and state “None known” in the absence of any information relevant to the entry. All other fields are optional, and are included only for those entries where information in the described area is relevant.

Safety Class: Each entry is assigned one or more of the Safety Classes described earlier in this introduction.
Interaction Class: Each herb is also assigned an Interaction Class as described previously.
CONTRAINDICATIONS: Any situations, conditions, or populations in which the botanical should not be used are listed here.
OTHER PRECAUTIONS: Special considerations for use are identified in this field. These may include, for example, common idiosyncratic effects (e.g., allergic reactions), adverse effects that may be undesirable but are not typically dangerous, or other conditions that require some specific caution, as stated.
DRUG AND SUPPLEMENT INTERACTIONS: This section gives details on known or suspected interactions in order to provide further information on any possible or probable interactions noted in an Interaction Class B or C. Note, however, that possible interactions that have low levels of evidence, or drugs for which a lack of interactions has been demonstrated, are generally listed under Pharmacological Considerations.
Standard Dose: Quantitative dosage information is included here only for those plants which list a recommendation that excessive dosage be avoided. The dose is usually given in the quantity and form for direct consumption or for preparation as a tea or decoction and is based on the herb in its dried (dehydrated) form, unless otherwise stated. Equivalent dosage in the form of tinctures and extracts must be calculated based on the concentration of such extracts on a dry weight basis. Standard Dose should not be taken to be the equivalent of a dosage limitation. Rather, this dosage should be seen as related to the concept of “serving size.” Although Standard Dose may be relevant to the determination of appropriate dosage limits, a thorough examination of other specific factors would be required prior to setting such levels.
Notice: Certain plant constituents, such as caffeine or pyrrolizidine alkaloids, and herbs with known physiological actions, such as emetics and nervous system stimulants, may present safety considerations in numerous species. Rather than address such concerns in detail for each individual species, a Notice identifies these constituents or actions and directs the reader to a thorough discussion of each such subject in Appendix 1, 2, or 3.
Editors’ Notes: Supplemental information relevant to the safe use of an herb, such as specific labeling recommendations, information regarding preparation, content of a chemical compound of potential concern, exceptions to use restrictions, possible adulteration, and other information are all included in this section, if required. Some discussion of the details, quality, or applicability of cited references may also be included here.
ADVERSE EVENTS AND SIDE EFFECTS. Recorded adverse changes in health, including any abnormal signs or symptoms, that have been reported to have occurred in association with the use of a particular herb are listed at this field. Side effects are defined as predictable effects of an herb that are not the principal effect for which the herb was taken (e.g., some people experience heartburn after ingestion of ginger). Adverse events, which include any health-related event associated with the use of a product that is perceived as harmful to the user, may or may not be related to an herb that was being taken at the time of an event. While some adverse events temporally associated with usage may be attributable to the herb consumed (e.g., nausea, vomiting, and central nervous system disturbances with overdose of raw Ginkgo biloba seed), many adverse events identified in case reports are not likely to be related to the associated herb. Sufficient detail is often lacking in case reports to determine whether a particular herb was likely the cause of any adverse event, and a case report cannot be considered to be in and of itself evidence that the reported adverse event was caused by the identified herb. All case reports in this text refer to human cases, unless they are listed under animal studies or otherwise specified.
PHARMACOLOGICAL CONSIDERATIONS. If the physiological effects or other pharmacological activity of an herb may be relevant to the safe use of that herb, this information is reported here. Preference is given to data from human and animal use, although in vitro data that may be relevant to clinical use is also listed here. Low-level evidence for potential drug interactions is also typically included here.
PREGNANCY AND LACTATION. As available, information on the safety of herbs during pregnancy or while nursing is provided in this field. For a number of the Class 1 herbs, substantial data or traditional use suggests that these may be safely used in pregnancy and lactation. For other botanicals, less data and clinical experience is available regarding their use in pregnancy or lactation. The absence of formal data and clinical experience regarding the use of a botanical in pregnancy or lactation, in and of itself, was not justification to contraindicate the botanical in these conditions. In such cases, the editors and Expert Advisory Council have used their best judgment in conjunction with the available literature to make the most appropriate determination. The following statement is included in those entries for which data and clinical experience for the botanical were lacking or less robust than desired:
No information on the safety of this herb in pregnancy or lactation was identified in the scientific or traditional literature. While this review did not identify any concerns for use while pregnant or nursing, safety has not been conclusively established.

The REVIEW DETAILS section for each entry is divided into five primary fields, each of which has its own organization. The reader will observe considerable redundancy when reading an herb’s QUICK REFERENCE SUMMARY and its REVIEW DETAILS sections together, as each of these is designed to be complete in itself. Thus, while the QUICK REFERENCE SUMMARY provides enough information to understand an herb’s safety and interaction profile, the Review Details section provides a more in-depth discussion of the data that was reviewed for the entry.

Some of the specific elements of this section are always present (again shown in bold font below) and when there is no relevant information known for a specific entry, that fact is affirmatively stated (e.g., “No clinical trials of drug or supplement interactions were identified”). All other elements are optional, and are again included only for those entries where information in the described area is relevant to the listing.

I. Drug and Supplement Interactions
- Clinical trials of drug or supplement interactions
- Case reports of suspected drug or supplement interactions
- Animal trials of drug or supplement interactions
II. Adverse Events
- Adverse events reported in clinical trials
- Case reports of adverse events
III. Pharmacology and Pharmacokinetics
- Human pharmacological studies
- Animal pharmacological studies
- In vitro pharmacological studies
IV. Pregnancy and Lactation
V. Toxicity Studies
- Acute toxicity
- Short-term toxicity
- Subchronic toxicity
- Chronic toxicity
- Genotoxicity
- Cytotoxicity

Each entry closes with a listing of the LITERATURE CITED for that particular entry.

McGuffin, M., J. Kartesz, A. Leung, and A.O. Tucker. 2000. Herbs of commerce. 2nd ed. Silver Spring, MD: American Herbal Products Association.

Disclaimer

The editors and the Expert Advisory Council of the Botanical Safety Handbook have endeavored to ensure that the information contained in this document accurately represents contemporary knowledge on the safe use of herbal ingredients. In developing this work, particular care was given to identifying references that provide accurate information, and efforts were made to present a balanced view of all available scientific information.

The safe oral consumption of any substance can depend to a great deal on the health of an individual consumer, as well as to the quantity of the substance consumed. In addition, idiosyncratic or allergic reactions are often unpredictable. Any person who consumes an herb listed in this reference based on its classifications does so at his or her own risk, and should consult a health care provider in the event of an adverse response.

There is no obligation at this time for AHPA members to adopt the specific information contained here in their product labeling. Rather, this document is presented as a guideline, providing data to assist member and non-member manufacturers in developing labels that fully inform consumers. Verification of all data and classifications for the purpose of label development is the responsibility of the manufacturer.

Appendices

Appendix I.

Herbal Constituent Profiles

Alkenylbenzenes

Written by Soaring Bear, Ph.D.

Alkenylbenzenes, also known as allylbenzenes or allylphenols, contribute to the flavor of some plants. Alkenylbenzenes found in medicinal plants include, among others, asarone, estragole, safrole, and methyleugenol. β-asarone is found in species of Acorus and Asarum. Traces of estragole can be found in herbs such as tarragon (Artemisia dracunculus), basil (Ocimum basilicum), and fennel (Foeniculum vulgare) (EMEA 2005). Safrole is a minor component of aromatic oils of nutmeg (Myristica fragrans), cinnamon leaf (Cinnamomum verum), and camphor (Cinnamomum camphora), and a major constituent of sassafras (Sassafras albidum) essential oil (Keeler and Tu 1983). Safrole is also found in black pepper (Piper nigrum) and in trace amounts in basil (Ocimum basilicum) (Farag and Abo-Zeid 1997; Leung and Foster 1996).

Adverse effects

There is some controversy regarding the safety of the use of plants containing alkenylbenzenes, with some of them limited in usage by regulatory authorities. Extract of sassafras was used for many years as a flavoring agent in the soft-drink industry, providing one of the familiar natural root beer flavors. In 1960, however, researchers began to question the safety of safrole (Barceloux 2008). Animal studies showed an increase in liver tumors in animals fed the purified compound safrole in relatively high amounts (0.01 to 0.1 % of the diet) for extended periods of time (2 years, equivalent to approximately 68 years of human exposure) (Abbott et al. 1961; Hagan et al. 1967; Hagan et al. 1965; Long et al. 1963).

A 1961 report, “Toxic and possible carcinogenic effects of 4-allyl-1,2-methylenedioxybenzene (safrole) in rats,” led to further in vitro studies that culminated in a ban by the FDA (CFR 2011; Homburger et al. 1961). Safrole’s potential damage of DNA has not been confirmed in humans, yet it is of such substantial consequence that public health agencies are inclined to err on the side of safety. Safrole is also used as a precursor in the synthesis of the insecticide synergist piperonyl butoxide and for the clandestine manufacture of MDMA (ecstasy) (Barceloux 2008), which raises suspicions about politicization of the regulation.

Animal studies with isolated estragole raised similar concerns with regulatory agencies regarding the association between estragole and liver cancer, although estragole has been regarded as a “weak inducer” in regards to liver cancer. Metabolic studies indicate that in high doses (150 – 600 mg/kg), the production of 1'-hydroxyestragole, expressed as percentage of the dose, is about 5 – 10 times higher than that at lower doses (0.05 – 50 mg/kg). European authorities have recommended on precautionary grounds that the content of estragole and methyleugenol in foods be reduced as far as possible (BGVV 2002). The Committee on Herbal Medicinal Products of the EMEA issued a public statement on the use of herbal medicinal products containing estragole and concluded that, “The present exposure to estragole resulting from consumption of herbal medicinal products (short time use in adults at recommended posology) does not pose a significant cancer risk” (EMEA 2005).

Generally in toxicology, there is some threshold dose below which toxicity is inconsequential and above which our normal detoxification systems are overwhelmed. There is evidence that small quantities of alkenylbenzenes are quickly broken down by the cytosolic and microsomal epoxide hydrolases of the liver and that the potential hazard to humans of low doses of allylbenzenes (e.g., β-asarone, estragole, and safrole) is minimal. The question of exactly how much is too much has not yet been answered.

Mechanism of Action

Alkenylbenzenes are not directly hepatotoxic or hepatocarcinogenic. Cytochrome P450 enzymes in the liver oxidize the double bond of alkenylbenzenes to an epoxide, which is mostly conjugated by glutathione for excretion, but at levels exceeding the detoxification capacity, the overflow can be reactive electrophilic and mutagenic sulfuric acid esters that give rise to DNA adducts. The propenyl analogues isosafrole, anethole and methylisoeugenol, which cannot undergo 1-hydroxylation, are not genotoxic (Hasheminejad and Caldwell 1994).

Relative to other carcinogens, the hazard of alkenylbenzenes is small yet present. One study compared the number of liver tumors (hepatomas) induced in mice by a set of compounds with well known carcinogenic effects. Diethylnitrosamine and aflatoxin B1 respectively induced 1100 and 350 hepatomas per micromole per gram of body weight, whereas the estragole and safrole hydroxyl-metabolites respectively induced 32 and 20 hepatomas per micromole per gram of body weight (Wiseman et al. 1987).

Herbs listed in the Botanical Safety Handbook that contain alkenylbenzenes:

Acorus calamus rhizome of the asarone-containing triploid or tetraploid varieties
Acorus gramineus rhizome
Artemisia dracunculus herb
Cinnamomum camphora wood distillate
Foeniculum vulgare fruit
Pimpinella anisum fruit

Piper nigrum fruit
Ocimum basilicum leaf
Ocimum gratissimum aboveground parts
Ocimum tenuiflorum leaf
Sassafras albidum root

Literature Cited

Abbott, D.D., E.W. Packman, J.W.E. Harrisson, and B.M. Wagner. 1961. Chronic oral toxicity of oil of sassafras and safrole. Pharmacologist 3:62.

Barceloux, D.G. 2008. Medical toxicology of natural substances: foods, fungi, medicinal herbs. New York: John Wiley and Sons.

BGVV. 2002. Reduce estragole and methyleugenol contents in foods. German Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV). Berlin.

CFR. 2011. Code of federal regulations, Title 21 Part 189.180, 2011 ed. Substances generally prohibited from direct addition or use as human food. Safrole. Washington, DC: U.S. Government Printing Office.

EMEA. 2005. Final position paper on the use of herbal medicinal products containing estragole. European Agency for the Evaluation of Medicinal Products, Committee on Herbal Medicinal Products. EMEA/HMPC/137212/2005.

Farag, S.E.A., and M. Abo-Zeid. 1997. Degradation of the natural mutagenic compound safrole in spices by cooking and irradiation. Nahrung 41:359–361.

Hagan, E.C., W.H. Hansen, O.G. Fitzhugh, et al. 1967. Food flavourings and compounds of related structure. II. Subacute and chronic toxicity. Food Cosmet. Toxicol. 5 (2):141-57.

Hagan, E.C., P.M. Jenner, W.I. Jones, et al. 1965. Toxic properties of compounds related to safrole. Toxicol. Appl. Pharmacol. 7 (1):18-24.

Hasheminejad, G., and J. Caldwell. 1994. Genotoxicity of the alkenylbenzenes α- and β-asarone, myristicin and elemicin as determined by the UDS assay in cultured rat hepatocytes. Food Chem. Toxicol. 32 (3):223-231

Homburger, F., T. Kelley, G. Friedler, and A.B. Russfield. 1961. Toxic and possible carcinogenic effects of 4-allyl-1,2-methylenedioxybenzene (safrole) in rats on deficient diets. Med. Exp. Int. J. Exp. Med. 4:1-11.

Keeler, R.F., and A.T. Tu. 1983. Plant and fungal toxins. New York: Marcel Dekker.

Leung, A.Y., and S. Foster. 1996. Encyclopedia of common natural ingredients used in food, drugs, and cosmetics. 2nd ed. New York: Wiley.

Long, E.L., A.A. Nelson, O.G. Fitzhugh, and W.H. Hansen. 1963. Liver tumors produced in rats by feeding safrole. Arch. Pathol. 75 (6):595–604.

Wiseman, R.W., E.C. Miller, J.A. Miller, and A. Liem. 1987. Structure-activity studies of the hepatocarcinogenicities of alkenylbenzene derivatives related to estragole and safrole on administration to preweanling male C57BL/6J. x C3H/HeJ F1 mice. Canc. Res. 47 (9):2275-2283.

Berberine

Written by Lisa Ganora

Berberine is a bitter, yellow compound belonging to the subclass of the isoquinoline alkaloids known as the protoberberines. Berberine has a positively-charged quaternary amine group and thus is quite soluble in water. Berberine is found in a number of medicinal plants including goldthread (Coptis spp.), goldenseal (Hydrastis canadensis), barberry (Berberis spp.), Oregon grape (Mahonia spp.), phellodendron (Phellodendron spp.), California poppy (Eschscholzia californica), celandine (Chelidonium majus), and bloodroot (Sanguinaria canadensis). Traditionally, berberine-rich herbs have been used as bitter choleretic and cholagogue, astringent, anti-inflammatory, antimicrobial, anticarcinogenic and antidiabetic agents. Berberine-rich herbs have been used for conditions involving the mucous membranes in the digestive, reproductive, ocular, and respiratory systems. Berberine also has activity on the cardiovascular system, with antihypertensive, antiatherosclerotic, anti-arrhythmic, and anti-aggregatory effects.

Adverse effects

Berberine is not usually considered to be harmful at clinical doses (Imanshahidi and Hosseinzadeh 2008). However, some authors suggest that berberine-rich herbs should be contraindicated during pregnancy and lactation, based on the fact that higher doses of berberine can strongly displace bilirubin both from human serum albumin in vitro and at a dosage over 2 mg/kg intraperitoneally administered to rats (Chan 1993). High concentrations of unconjugated bilirubin can accumulate in and cause damage to human brain tissue. If an excessive dose of berberine were to be ingested during pregnancy, this could be of concern especially for neonates with pre-existing jaundice or hereditary diseases (such as Gilbert’s syndrome and Crigler-Najjar syndrome) which also involve hyperbilirubinemia.

There is some controversy regarding the clinical significance of berberine’s bilirubin-displacing effect. Chinese literature from the 1970s and 1980s reported an association between the maternal and neonatal use of formulas containing Coptis chinensis (approx. 7 – 9 % berberine content) and an increased incidence of kernicterus in infants with neonatal jaundice (Chan 1993; Upton 2001). There is also a widespread belief in China that formulas containing Coptis can be hazardous to infants born with an erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency, in whom such formulas could cause hemolytic anemia. However, it is unclear if Coptis or some other substance in the formulas commonly given to neonates could be responsible for such an effect (Yeung et al. 1990). A review of traditional Chinese medicine use in cases of neonatal jaundice identified one case that associated exposure to coptis with fatal hemolysis and kernicterus in a baby (Fok 2001). There are no reports in the contemporary literature of these conditions being associated with berberine-containing Western herbs such as goldenseal, barberry, and Oregon grape. Mills and Bone, however, recommend that berberine-containing herbs not be used during pregnancy except with professional supervision (Mills and Bone 2005).

Another rationale for contraindicating berberine during pregnancy is based on a few older reports claiming that it could induce uterine contractions in mice (Furuya 1957; Imaseki et al. 1961). A recent literature search found no contemporary reports of such activity ascribed to the use of berberine-containing herbs. Some studies (using several types of isolated tissue) have found berberine to have a contractile effect on smooth muscle, while others have found it to be antispasmodic and relaxant (Tice 1997). Hydrastine, a related alkaloid found along with berberine in goldenseal, was historically employed as a uterine astringent and hemostatic by the Eclectic physicians (Felter and Lloyd 1898). At least one historical source notes that goldenseal was not observed to cause or enhance contractions when used for this purpose (Shoemaker 1906).

In high doses, isolated berberine salts are moderately toxic; the LD50 for intraperitoneally administered berberine chloride dihydrate (BCD) was reported to be 30 mg/kg in the mouse and 205 mg/kg in the rat (Jahnke et al. 2006). The LD50 of orally administered berberine sulfate was reported to be greater than 1000 mg/kg in the rat (Kowalewski et al. 1975). These dosages are far beyond what one would obtain from the clinical use of berberine-containing herbs, which typically contain concentrations ranging from 0.5 to 6% in goldenseal root and 4 to 7% in coptis (Chang and But 1986; Upton 2001).

In an evaluation of reproductive toxicity, isolated berberine salts were given by oral gavage to pregnant mice over the course of eleven days. The maternal lowest-observed-adverse-effect-level (LOAEL) was determined to be 841 mg/kg daily of BCD (equivalent to approximately 698 mg of pure berberine). No signs of developmental toxicity were observed until the dosage reached approximately 938 mg BCD/kg/day, and these were limited to a 5 to 6 % decrease in average fetal body weight; there was no evidence of teratogenicity (Price and George 2003). Another evaluation found no adverse effects at dosages up to 1,000 mg/kg/day of BCD in rats. The authors noted that the no-observed-adverse-effect-level (NOAEL) for both rats and mice was approximately 500 times greater than the amount of berberine that one would obtain from herbs used as dietary supplements (Jahnke et al. 2006).

A 2005 reproductive screening in rats, which found no adverse effects from a hydroethanolic extract of goldenseal at a dosage of 1.86 g/kg daily (reported as 65 times the recommended human dose), concluded that toxic levels of berberine were unlikely to be reached in the plasma due to poor intestinal absorption (Yao et al. 2005). In humans, symptoms of berberine overdose are reported to include hypotension, bradycardia, dyspnea, and gastrointestinal disturbances (Lau et al. 2001).

Mechanism of action

Berberine has demonstrated a number of anti-inflammatory and anti-cancer properties in numerous different cell lines and tissue types. A recent investigation identified NF-κβ modulation as a major mechanism underlying these effects. Berberine was found to suppress NF-κβ activation when induced by several different pro-inflammatory and carcinogenic agents. This activity led to the down-regulation of gene products responsible for blocking apoptosis in cancer cells, for promoting inflammation via COX-2 induction, and for enabling tumor metastasis (Pandey et al. 2008).

In a mechanism distinct from that of the statin drugs, berberine can significantly reduce plasma levels of LDL cholesterol. The mechanism involves upregulation of the low-density lipoprotein receptors (LDLR) in the liver. The LDL receptor system coordinates cholesterol metabolism, allowing excessive LDL cholesterol to be cleared from the bloodstream (Goldstein and Brown 2009). Berberine was found to extend the half-life of LDLR mRNA (without having an effect on gene transcription), resulting in a strong increase in LDLR protein expression (Abidi et al. 2006). A clinical study of hypercholesterolemic patients in China found that an oral dose of one gram of berberine/day for three months lowered total cholesterol by 29%, LDL by 25%, and triglycerides by 35% (Kong et al. 2004).

Herbs listed in the Botanical Safety Handbook that contain berberine:

Berberis vulgaris root, root bark
Chelidonium majus herb
Corydalis yanhusuo tuber
Hydrastis canadensis rhizome, root
Mahonia aquifolium root
Mahonia nervosa root
Mahonia repens root

Coptis chinensis rhizome
Coptis groenlandica rhizome
Phellodendron amurense bark
Phellodendron chinense bark
Sanguinaria canadensis rhizome, root

Literature Cited

Abidi, P., W. Chen, F.B. Kraemer, H. Li, and J.W. Liu. 2006. The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms. J. Lipid Res. 47 (10):2134-2147.

Chan, E. 1993. Displacement of bilirubin from albumin by berberine. Biol. Neonate 63 (4):201-208.

Chang, H.-M., and P.P.H. But. 1986. Pharmacology and applications of Chinese materia medica. English ed. Singapore: Philadelphia, PA, USA.

Felter, H.W., and J.U. Lloyd. 1898. King's American dispensatory. Cincinnati: Ohio Valley Co.

Fok, T.F. 2001. Neonatal jaundice—traditional Chinese medicine approach. J. Perinatol. 21 Suppl 1:S98-S100, 104-7.

Furuya, T. 1957. Pharmacological action, including toxicity and excretion of berberine hydrochloride and its oxidation product. Bull. Osaka Med. School 3:62-7.

Goldstein J.L. and M.S. Brown. 2009. The LDL receptor. Arterioscler. Thromb. Vasc. Biol. 29(4):431-8.

Imanshahidi, M., and H. Hosseinzadeh. 2008. Pharmacological and therapeutic effects of Berberis vulgaris and its active constituent, berberine. Phytother. Res. 22 (8):999-1012.

Imaseki, I., Y. Kitabatakea, and T. Taguchi. 1961. Studies on the effect of berberine alkaloids on intestine and uterus in mice. Yakugaku Zasshi 81:1281-4.

Jahnke, G.D., C.J. Price, M.C. Marr, C.B. Myers, and J.D. George. 2006. Developmental toxicity evaluation of berberine in rats and mice. Birth Defects Res. B 77 (3):195-206.

Kong, W., J. Wei, P. Abidi, et al. 2004. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nature Medicine 10:1344-1351.

Kowalewski, Z., A. Mrozikiewicz, T. Bobkiewicz, K. Drost, and B. Hladon. 1975. Studies of toxicity of berberine sulfate. Acta Polon. Pharmaceut. 32 (1):113-120.

Lau, C.W., X.Q. Yao, Z.Y. Chen, W.H. Ko, and Y. Huang. 2001. Cardiovascular actions of berberine. Cardiovasc. Drug Rev. 19 (3):234-244.

Mills, S., and K. Bone. 2005. The essential guide to herbal safety. St Louis: Elsevier

Pandey, M.K., B. Sung, A.B. Kunnumakkara, et al. 2008. Berberine modifies cysteine 179 of I kappa B alpha kinase, suppresses nuclear factor-kappa B-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res. 68 (13):5370-5379.

Price, C.J., and J.D. George. 2003. Final study report on the developmental toxicity evaluation for berberine chloride dihydrate (CAS no. 5956-60-5) administered in the feed to Swiss (cd-1) mice on gestational days 6 through 17. Gov. Rep. Announce. Index (20):112.

Shoemaker, J. 1906. A practical treatise on materia medica and therapeutics: With especial reference to the clinical application of drugs. 6th ed. Philadelphia: F.A. Davis.

Tice, R. 1997. Goldenseal (Hydrastis canadensis L.) and two of its constituent alkaloids berberine and hydrastine; Review of toxicological literature. Research Triangle Park, NC: Integrated Laboratory Systems.

Upton, R. 2001. Goldenseal root: Hydrastis canadensis; Standards of analysis, quality control, and therapeutics. Santa Cruz, CA: American Herbal Pharmacopoeia.

Yao, M., H.E. Ritchie, and P.D. Brown-Woodman. 2005. A reproductive screening test of goldenseal. Birth Defects Res. B 74 (5):399-404.

Yeung, C.Y., F.T. Lee, and H.N. Wong. 1990. Effect of a popular Chinese herb on neonatal bilirubin protein-binding. Biol.Neonate 58 (2):98-103.

Caffeine

Written by Zoë Gardner, Ph.D.(c)

Caffeine is an alkaloid classified as a methylxanthine, a group of closely related compounds including caffeine, theophylline, and theobromine, that have similar physiological effects. Caffeine is the most widely consumed and researched psychoactive substance in the world. The worldwide average daily intake of caffeine is 159 mg per person, with Americans consuming approximately 168 mg daily, while the Dutch are the heaviest consumers at an average of 414 mg per day (Fredholm et al. 1999).

Adverse effects

Ingestion of caffeine results in a number of physiological effects including central nervous system stimulation, acute elevation of blood pressure, increased metabolic rate, increased gastric and colonic activity, and diuretic activity (Higdon and Frei 2006; James 2000). Long-term use of caffeine usually results in tolerance to some of the physiological and behavioral effects (Griffiths and Mumford 1996). See Appendix 2 for more information on the diuretic activity of caffeine.

Overdose of caffeine may result in caffeine intoxication with symptoms including nervousness, anxiety, restlessness, insomnia, gastrointestinal upset, tremors, and a rapid heart rate (APA 1994). Symptoms of caffeine intoxication may be similar to those of anxiety or other mood disorders (Greden 1974). In rare cases, caffeine overdose can be fatal, although such cases are generally from intentional self-poisoning with caffeine pills or tablets rather than from drinking caffeine-containing beverages (Holmgren et al. 2004; Mrvos et al. 1989).

Regular use of caffeine produces physical dependence on caffeine, and withdrawal symptoms are common with reduction or cessation of caffeine (Hughes et al. 1998; Strain et al. 1994). Withdrawal symptoms begin to occur 12 to 24 hours after abstaining from caffeine consumption. The most common symptom of withdrawal is headache, with fatigue, decreased energy, decreased alertness, a depressed mood, irritability, and other related symptoms also being commonly reported (Juliano and Griffiths 2004).

Studies on the effects of caffeine on blood pressure indicate that caffeine causes an acute rise in blood pressure, usually occurring 30 minutes to 4 hours after ingestion (Nurminen et al. 1999). The blood-pressure raising effects may be more pronounced in persons with high blood pressure (Nurminen et al. 1999). With routine consumption of caffeine, most individuals develop tolerance to the blood-pressure raising effects, while some do not (James 1994; Lovallo et al. 2004). Studies on the effects of caffeine or coffee on blood pressure have mixed results. Some studies show a mild elevation of blood pressure after caffeine consumption (James 2004), while others show no effect or a habituation to the effect. In addition, the effects of coffee on blood pressure may be different than those of caffeine, since coffee contains other compounds, such as polyphenols, soluble fiber and potassium, which typically have a beneficial effect on the cardiovascular system (Geleijnse 2008).

The effects of caffeine on human reproduction and pregnancy have been widely studied. While current reviews suggest a lack of adverse effects of caffeine on fetal development and pregnancy outcomes (Christian and Brent 2001; Peck et al. 2010), women are generally advised to limit caffeine intake to approximately 300 mg daily during pregnancy and 200 to 300 mg daily while nursing (AAP 2001; ADA 2008; PDR 2006).

The American Herbal Products Association has established a trade requirement (AHPA 2011) that dietary supplement products that contain caffeine*, whether as a direct ingredient or as a constituent of herbal ingredients, conform to all of the following:

The label of caffeine-containing dietary supplements discloses the presence of caffeine in the product.
The label or labeling of caffeine containing dietary supplements, except for such supplements as are described in paragraph 3 below, discloses the quantity of caffeine per recommended serving of the dietary supplement, stated in both milligrams per serving and in equivalent approximate cups of coffee, where 100 mg of caffeine represents one cup of coffee.
The label of caffeine-containing dietary supplements discloses the presence of caffeine, but not necessarily the quantity of caffeine per recommended serving, if at least one of the following conditions is met:
- The caffeine-containing dietary ingredient is an herb or herbal source ingredient that is less concentrated than a 1:1 weight/weight or weight/volume concentration ratio of raw herb to dietary ingredient; or
- The amount of caffeine per recommended serving of the caffeine-containing dietary supplement is less than 25 mg.
Caffeine-containing dietary supplements are formulated and labeled in a manner to recommend a maximum of 200 mg of caffeine per serving, not more often than every 3 to 4 hours.
The following or similar statement is included on the label of any dietary supplement that contains caffeine in sufficient quantity to warrant such labeling:

Too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heartbeat. Not recommended for use by children under 18 years of age.

*Consisting of caffeine and all so-called caffeine analogues that include, but are not limited to, the following terms: caffeine, guaranine, mateina, mateine, methyltheobromine, thein, theine, 1,3,7-trimethylxanthine, 1,3,7-trimethyl-2,6-dioxopurine, and 7-methyltheophylline.

Drug interactions

Caffeine is metabolized by the isoenzyme CYP1A2. Drugs that inhibit this isoenzyme (including fluvoxamine, ciprofloxacin, cimetidine, amiodarone, fluoroquinolones, furafylline, interferon, methoxsalen, and mibefradil) may slow the metabolism of caffeine. In persons drinking multiple cups of coffee daily, high levels of caffeine could accumulate (Carrillo and Benitez 2000).

Mechanism of action

Methylxanthines, including caffeine, stimulate the central nervous system and the heart, elicit a diuretic effect in the kidneys, and relax smooth muscles.

Caffeine works in part by competing with adenosine, a neurotransmitter that accumulates in the brain during periods of wakefulness and helps to induce sleep. Caffeine binds to the adenosine receptors, effectively blocking the adenosine, thus promoting alertness and reducing the ability to fall asleep. Changes in motor activity are due to the effect of caffeine on neurotransmitters in the basal ganglia, an area of the brain responsible for motor control and other activities (Fisone et al. 2004).

Average amount of caffeine per 8 oz. cup

Green tea
Black tea
Espresso (single shot)
Brewed coffee
Cola beverage 25 – 40 mg
25 – 55 mg
60 – 75 mg
70 – 125 mg
23 – 31 mg

(China et al. 2008; McCusker et al. 2003)

Herbs listed in the Botanical Safety Handbook that contain caffeine:

Camellia sinensis leaf, stem
Coffea arabica seed kernel
Cola acuminata seed
Cola nitida seed

Ilex paraguariensis leaf
Paullinia cupana seed

Literature Cited

AAP. 2001. The transfer of drugs and other chemicals into human milk. American Academy of Pediatrics Committee on Drugs. Pediatrics 108 (3):776-789.

ADA. 2008. Position of the American Dietetic Association: Nutrition and lifestyle for a healthy pregnancy outcome. J. Am. Diet. Assoc. 108:553-61.

APA. 1994. Diagnostic and statistical manual of mental disorders: DSM-IV. Washington D.C.: American Psychiatric Association.

Carrillo, J.A., and J. Benitez. 2000. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin. Pharmacokin. 39 (2):127-153.

China, J.M., M.L. Merves, B.A. Goldberger, A. Sampson-Cone, and E.J. Cone. 2008. Caffeine content of brewed teas. J. Analyt. Toxicol. 32 (8):702-704.

Christian, M.S., and R.L. Brent. 2001. Teratogen update: evaluation of the reproductive and developmental risks of caffeine. Teratol. 64 (1):51-78.

Fisone, G., A. Borgkvist, and A. Usiello. 2004. Caffeine as a psychomotor stimulant: mechanism of action. Cell Molec. Life Sci. 61 (7):857-872.

Fredholm, B.B., K. Bättig, J. Holmén, A. Nehlig, and E.E. Zvartau. 1999. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev. 51 (1):83-133.

Geleijnse, J.M. 2008. Habitual coffee consumption and blood pressure: an epidemiological perspective. Vasc. Health Risk Manag. 4 (5):963-70.

Greden, J.F. 1974. Anxiety or caffeinism: a diagnostic dilemma. Am J. Psych. 131 (10):1089.

Griffiths, R.R., and G.K. Mumford. 1996. Caffeine reinforcement, discrimination, tolerance, and physical dependence in laboratory animals and humans. In Pharmacological aspects of drug dependence: toward an integrated neurobehavioral approach, edited by Schuster, C.R. and M.J. Kuhar. New York: Springer.

Higdon, J.V., and B. Frei. 2006. Coffee and health: a review of recent human research. Crit. Rev. Food Sci. Nutr. 46 (2):101-23.

Holmgren, P., L. Nordén-Pettersson, and J. Ahlner. 2004. Caffeine fatalities—four case reports. Forensic Sci. Int. 139 (1):71-73.

Hughes, J.R., A.H. Oliveto, A. Liguori, J. Carpenter, and T. Howard. 1998. Endorsement of DSM-IV dependence criteria among caffeine users. Drug Alc. Depend. 52 (2):99-107.

James, J.E. 1994. Chronic effects of habitual caffeine consumption on laboratory and ambulatory blood pressure levels. J. Cardiovasc. Risk 1:159-164.

James, J.E. 2000. Acute and chronic effects of caffeine on performance, mood, headache, and sleep. Neuropsychobiol. 38 (1):32-41.

James, J.E. 2004. Critical review of dietary caffeine and blood pressure: A relationship that should be taken more seriously. Psychosom. Med. 66 (1):63-71.

Juliano, L.M., and R.R. Griffiths. 2004. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacol. 176 (1):1-29.

Lovallo, W.R., M.F. Wilson, and A.S. Vincent. 2004. Blood pressure response to caffeine shows incomplete tolerance after short-term regular consumption. Hypertension 43:760-765.

McCusker, R.R., B.A. Goldberger, and E.J. Cone. 2003. Technical note: Caffeine content of specialty coffees. J. Analyt. Toxicol. 27 (7):520-522.

Mrvos, R.M., P.E. Reilly, B.S. Dean, and E.P. Krenzelok. 1989. Massive caffeine ingestion resulting in death. Vet. Hum. Toxicol. 31 (6):571-2.

Nurminen, M.L., L. Niittynen, R. Korpela, and H. Vapaatalo. 1999. Coffee, caffeine and blood pressure: A critical review. Eur. J. Clin. Nutr. 53:831−839.

PDR. 2006. Physicians' Desk Reference for Nonprescription Drugs and Dietary Supplements. 27th ed. Montvale, NJ: Medical Economics Co.

Peck, J.D., A. Leviton, and L.D. Cowan. 2010. A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: A 2000 – 2009 Update. Food Chem. Toxicol. 48 (10):2549-76.

Strain, E.C., G.K. Mumford, K. Silverman, and R.R. Griffiths. 1994. Caffeine dependence syndrome: evidence from case histories and experimental evaluations. J.A.M.A. 272 (13):1043.

Cyanogenic Glycosides

Written by Michael McGuffin; revised by Zoë Gardner, Ph.D.(c)

Cyanogenic glycosides are sugar-containing compounds with a nitrile group (hydrogen triple-bonded to nitrogen). After being metabolized, these compounds can release cyanide (in the form of hydrocyanic acid), a substance that can, in significant amounts, be toxic to humans and other animals. The best-known cyanogenic glycoside, amygdalin, is found in the seeds of many common fruits of the Rosaceae family, such as cherries, apples, peaches, apricots, almonds and pears (Vetter 2000).

Several common food plants, including bamboo shoots, cassava, and lima beans, contain cyanogenic glycosides (FSANZ 2004; Ologhobo et al. 1984). Medicinally, a number of plants containing cyanogenic glycosides, including black cherry bark (Prunus serotina) and loquat leaf (Eriobotrya japonica), have traditionally been used as cough remedies (Mills and Bone 2000). Foods and botanicals containing low levels of cyanogenic glycosides are generally not dangerous to consume.

Adverse effects

Cyanide is released during the metabolism of cyanogenic glycosides. The best established and probably most important toxic action of cyanide is incapacitation of the cell’s mechanism for using oxygen, resulting in chemical asphyxiation (oxygen deprivation) (Nelson 2006).

Of the plants included in this text that contain this class of glycosides, the seeds of several species of Prunus present the most, and possibly the only, concern. Peach kernels contain 2 to 6 percent amygdalin, while apricot kernels contain up to 8 percent amygdalin (Encarna et al. 1998; Femenia et al. 1995; Gunders et al. 1969; Holzbecher et al. 1984; Machel and Dorsett 1970). The toxic dose for apricot seeds has been reported as 10 to 20 seeds in children and 40 to 60 seeds in adults, though removal of the seed skin and heating of the seeds reduce the amygdalin content (Bensky et al. 2004; Chen and Chen 2004). Levels of cyanogenic glycosides in other species listed below are generally not of toxicological concern.

The LD₅₀ of hydrocyanic acid is 3.7 mg/kg in mice and 4 mg/kg in dogs, while the LD50 of amygdalin, the compound found in apricot seeds, is 522 mg/kg in rats (Milne 1995; Newton et al. 1981). Based on the concentration of amygdalin in apricot seeds, a toxic dose would be equivalent to 34 – 39 g of amygdalin in an adult of normal weight. An adult would need to consume 425 – 480 grams of apricot seeds, for example, in order to reach this toxic intake level.

The symptoms of cyanide poisoning are well known from industrial exposure or exposure to cyanide in smoke from residential or industrial fires. Early signs and symptoms of acute cyanide poisoning include attempts of the respiratory, neurologic, and cardiovascular systems to overcome tissue hypoxia (whole body oxygen deprivation). These include transient increases in blood pressure and heart rate, hyperventilation, shortness of breath, heart palpitations, and headache. Late symptoms or symptoms of severe poisoning include neurologic, respiratory, and cardiovascular depression, as tissues fail to compensate for their inability to use oxygen (Borron 2006; Nelson 2006). A number of sources review the available treatment protocols for cyanide poisoning (Cummings 2004; Goldfrank and Flomenbaum 2006; Hall et al. 2009).

Mechanism of action

Plants containing cyanogenic glycosides do not contain detectable free hydrocyanic acid. Instead, the glycosides and enzymes that break down the glycosides are stored separately until the plant tissue is crushed, chewed, wilted, or otherwise disturbed, at which time the glycosides and enzymes come together, and cyanide (in the form of hydrocyanic acid) is released (Ganora 2009; Thayer and Conn 1981).

Cyanide is a normal waste product of protein degradation, and humans are able to detoxify about 1 mg/kg of cyanide per hour (Aminlari et al. 2007; Nelson 2006). Additionally, the acidic environment of the human stomach is not optimal for β-glucosidase, the main enzyme that liberates hydrocyanic acid from cyanogenic glycosides. Ruminant animals, such as cows, are more susceptible to poisoning from plants containing cyanogenic glycosides due to the relatively neutral pH of the ruminant digestive tract (Ganora 2009; Majak 1992).

Different methods of processing have been developed for reducing the cyanide content in food products. Cassava, a root crop widely used as a staple food in tropical countries, contains two cyanogenic glycosides and must be processed prior to consumption. Processing is done through a combination of several steps that may include crushing, soaking, drying, fermenting, or roasting (Cardoso et al. 2005; Lancaster et al. 1982).

Herbs listed in the Botanical Safety Handbook that contain cyanogenic glycosides:

Eriobotrya japonica leaf (0.06% amygdalin)
Hydrangea arborescens root (1 – 3% hydrangin)
Linum usitatissimum seeds (0.1 to 1.5% linustatin and neolinustatin)
Prunus armeniaca seed (up to 8% amygdalin)
Prunus persica seed (2 – 6% amygdalin; leaf, 0.5 to 1.5% amygdalin)
Prunus serotina dried bark (prunasin yielding up to 0.15% hydrocyanic acid)
Prunus spinosa seeds and fresh flowers (minor amounts)
Sambucus canadensis leaves, bark, seeds, and raw unripe fruits (minor amounts)
Sambucus nigra leaves, bark, seeds, and raw unripe fruits (minor amounts)
Turnera diffusa leaf (0.26% tetraphyllin B)

Literature Cited

Aminlari, M., A. Malekhusseini, F. Akrami, and H. Ebrahimnejad. 2007. Cyanide-metabolizing enzyme rhodanese in human tissues: comparison with domestic animals. Compar. Clin. Pathol. 16 (1):47-51.

Bensky, D., S. Clavey, and E. Stöger. 2004. Chinese herbal medicine: Materia medica. 3rd ed. Seattle: Eastland Press.

Borron, S.W. 2006. Recognition and treatment of acute cyanide poisoning. J. Emerg. Nurs. 32 (4 Suppl):S12-8.

Cardoso, A.P., E. Mirione, M. Ernesto, et al. 2005. Processing of cassava roots to remove cyanogens. J. Food Comp. Anal. 18 (5):451-460.

Chen, J.K., and T.T. Chen. 2004. Chinese medical herbology and pharmacology. City of Industry, CA: Art of Medicine Press.

Cummings, T.F. 2004. The treatment of cyanide poisoning. Occ. Med. 54 (2):82.

Encarna, G., B. Lorenzo, S. Constanza, and M. Josefa. 1998. Amygdalin content in the seeds of several apricot cultivars. J. Sci. Food Agric. 77 (2):184-186.

Femenia, A., C. Rossello, A. Mulet, and J. Canellas. 1995. Chemical composition of bitter and sweet apricot kernels. J. Agric. Food Chem. 43 (2):356-361.

FSANZ. 2004. Cyanogenic glycosides in cassava and bamboo shoots. Technical Report Series No. 28, Food Standards Australia New Zealand. Canberra.

Ganora, L. 2009. Herbal constituents: Foundations of phytochemistry. Louisville, CO: HerbalChem Press.

Goldfrank, L.R., and N. Flomenbaum. 2006. Goldfrank's toxicologic emergencies. New York: McGraw-Hill Professional.

Gunders, A.E., A. Abrahamov, E. Weisenberg, S. Gertner, and S. Shafran. 1969. Cyanide poisoning following ingestion of apricot (Prunus armeniaca) kernels. Harefuah 76 (12):536-8.

Hall, A.H., J. Saiers, and F. Baud. 2009. Which cyanide antidote? Crit. Rev. Toxicol. 39 (7):541-552.

Holzbecher, M.D., M.A. Moss, and H.A. Ellenberger. 1984. The cyanide content of laetrile preparations, apricot, peach and apple seeds. Clin. Toxicol. 22 (4):341-347.

Lancaster, P.A., J.S. Ingram, M.Y. Lim, and D.G. Coursey. 1982. Traditional cassava-based foods: survey of processing techniques. Econ. Bot. 36 (1):12-45.

Machel, A.R., and C.I. Dorsett. 1970. Cyanide analyses of peaches. Econ. Bot. 24:5-2.

Majak, W. 1992. Metabolism and absorption of toxic glycosides by ruminants. J. Range Manag. 45 (1):67-71.

Mills, S., and K. Bone. 2000. Principles and practice of phytotherapy: Modern Herbal Medicine. New York: Churchill Livingstone.

Milne, G.W.A. 1995. CRC handbook of pesticides. Boca Raton, FL: CRC Press.

Nelson, L. 2006. Acute cyanide toxicity: mechanisms and manifestations. J. Emerg. Nurs. 32:S8-11.

Newton, G.W., E.S. Schmidt, J.P. Lewis, R. Lawrence, and E. Conn. 1981. Amygdalin toxicity studies in rats predict chronic cyanide poisoning in humans. West. J. Med. 134 (2):97.

Ologhobo, A.D., B.L. Fetuga, and O.O. Tewe. 1984. The cyanogenic glycoside contents of raw and processed limabean varieties. Food Chem. 13 (2):117-128.

Thayer, S.S., and E.E. Conn. 1981. Subcellular localization of dhurrin β-glucosidase and hydroxynitrile lyase in the mesophyll cells of sorghum leaf blades. Plant Physiol. 67 (4):617.

Vetter, J. 2000. Plant cyanogenic glycosides. Toxicon 38 (1):11-36.

Pyrrolizidine Alkaloids

Written by Michael McGuffin; revised by Zoë Gardner, Ph.D.(c)

Pyrrolizidine alkaloids (PAs) are compounds found in a number of plant species that have been associated with liver toxicity. Based on their chemistry, different PAs may be saturated or unsaturated (the difference between the two is determined by whether a chemical bond between two particular carbons in the central ring structure is double or single). Saturated PAs, such as those found in Euphrasia spp. and Echinacea spp., are nontoxic. Unsaturated PAs, such as those in Senecio species, are recognized as causing liver toxicity when ingested in sufficient amounts. Certain unsaturated PAs are more toxic than others.

Adverse effects

Initial concern regarding PAs was probably based on cases of livestock poisoning due to consumption of Senecio and Amsinckia (Cheeke 1988; Johnson et al. 1985). Supplies of grain have been contaminated by PA-containing weeds in grain fields, leading to outbreaks of PA toxicity, causing acute cases of liver damage in persons eating the contaminated grain (Prakash et al. 1999). Serious liver damage has also occurred after chronic consumption of PA-containing medicinal plants that have traditionally been used for therapeutic purposes.

The herbs most widely used in the United States that contain PAs are comfrey root and leaf (Symphytum spp.), coltsfoot leaf and flower (Tussilago farfara), and borage leaf (Borago officinale). The amounts and relative safety of PAs in these plants and in the various plant parts vary widely. For example, in comfrey, the concentration of alkaloids is measured at about 10 times higher in the root than in the leaf (Tyler 1994). Moreover, echimidine, the most toxic of the alkaloids found in comfrey, is present in Symphytum asperum and S. x uplandicum but is absent in most samples of S. officinale (Awang et al. 1993; Huizing et al. 1982; Jaarsma et al. 1989). Although a number of species of Eutrochium (recently reclassified from Eupatorium) are known to contain PAs (Zhang et al. 2008), the PA content of several species used in the U.S. (E. fistulosum, E. purpureum, and E. maculatum) has not been adequately investigated. For other plants, such as borage, the amounts of PAs are generally cited to be “low,” although reliable information on the concentration of PAs in these plants is lacking.

While some of these alkaloids have shown carcinogenic and mutagenic properties, and kidney toxicity has been reported (Fu et al. 2004), the primary concern for use of these herbs is the potential for serious liver damage, specifically hepatic veno-occlusive disease (a condition in which veins in the liver become blocked). This potentially fatal condition manifests symptoms such as abdominal pain, swelling of the liver and spleen, accumulation of fluid in the abdominal cavity, elevated levels of bilirubin, jaundice, cirrhosis of the liver, and liver failure (Chen and Huo 2010; McDermott and Ridker 1990).

Cautious restrictions on the use of all of the herbs containing unsaturated (toxic) PAs have been recommended by the American Herbal Products Association, with suggestions to limit use to external application on unbroken skin only, and to refrain from use while nursing (AHPA 2011). All use is contraindicated in pregnancy and in persons with a history of liver disease.

Mechanism of action

PAs are metabolized in the liver by the drug metabolizing isoenzyme CYP3A4 to form N-oxides and conjugated dienic pyrroles (alkylating compounds that are highly reactive with proteins and nucleic acids). The complex of pyrroles with proteins and nucleic acids may remain in tissues and cause chronic injury, while the N-oxides may be transformed into epoxides and toxic necines. Substances that induce CYP3A4 may enhance the toxicity of PAs, while inhibitors of this isoenzyme may reduce the toxicity. The development of veno-occlusive disease remains poorly understood, although studies suggest that endothelial cell injury, cytokines, and hemostatic derangement are all involved. A strict dose-dependent association between PA consumption and veno-occlusive disease development may not be present, and not all persons taking PAs develop the disease (Chen and Huo 2010).

An animal study demonstrated that the systemic bioavailability of PAs after external use is about 20 to 50 times lower than that after oral ingestion, although absorption may be increased after application to inflamed, cut, or abraded skin (Brauchli et al. 1982).

Herbs listed in the Botanical Safety Handbook that contain unsaturated pyrrolizidine alkaloids¹:

Alkanna tinctoria root
Borago officinalis² herb
Eutrochium fistulosum herb, root, and rhizome
Eutrochium maculatum herb, root, and rhizome
Eutrochium purpureum³ herb, root, and rhizome

Symphytum asperum⁴ leaf, root
Symphytum officinale⁴ leaf, root
Symphytum x uplandicum⁴ leaf, root
Tussilago farfara⁴ flower, leaf

¹ Note that although medicinal species of Petasites, including purple butterbur (Petasites hybridus) and Arctic butterbur (Petasites frigidus), are not listed in this text, these species also contain pyrrolizidine alkaloids. PA-free extracts of Petasites species are available, and PA-free products are considered appropriate for internal use.

² Processing of borage seed oil eliminates PAs.

³ Presence and type of PAs has not been confirmed.

⁴ PA-free extracts of Symphytum spp., Tussilago farfara, and other botanicals are available commercially.

Literature Cited

AHPA. July 2011. Code of Ethics & Business Conduct. Silver Spring, MD: American Herbal Products Association.

Awang, D.V.C., B.A. Dawson, J. Fillion, M. Girad, and D. Klindack. 1993. Echimidine content of commercial comfrey. J. Herbs Spices Med. Plants 2 (1):21-34.

Brauchli, J., J. Luthy, U. Zweifel, and C. Schlatter. 1982. Pyrrolizidine alkaloids from Symphytum officinale L. and their percutaneous absorption in rats. Experientia 38 (9):1085-7.

Cheeke, P.R. 1988. Toxicity and metabolism of pyrrolizidine alkaloids. J. Animal Sci. 66 (9):2343-50.

Chen, Z., and R.-H. Huo. 2010. Hepatic veno-occlusive disease associated with toxicity of pyrrolizidine alkaloids in herbal preparations. Neth. J. Med. 68 (6):252-60.

Fu, P.P., Q. Xia, G. Lin, and M.W. Chou. 2004. Pyrrolizidine alkaloids—genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab. Rev. 36 (1):1-55.

Huizing, H.J., T.W.J. Gadella, and E. Kliphuis. 1982. Chemotaxonomical investigations of the Symphytum officinale polyploid complex and S. asperum (Boraginaceae): The pyrrolizidine alkaloids. Plant Systemat. Evol. 140 (4):279-292.

Jaarsma, T.A., E. Lohmanns, T.W.J. Gadella, and T.M. Malingre. 1989. Chemotaxonomy of the Symphytum officinale agg. (Boraginaceae). Plant Sys. Evol. 167 (3-4).

Johnson, A.E., R.J. Molyneux, and G.B. Merrill. 1985. Chemistry of toxic range plants. Variation in pyrrolizidine alkaloid content of Senecio, Amsinckia, and Crotalaria species. J. Agric. Food Chem. 33 (1):50-55.

McDermott, W.V., and P.M. Ridker. 1990. The Budd-Chiari syndrome and hepatic veno-occlusive disease: Recognition and treatment. Arch. Surg. 125 (4):525-527.

Prakash, A.S., T.N. Pereira, P.E.B. Reilly, and A.A. Seawright. 1999. Pyrrolizidine alkaloids in human diet. Mutat. Res. 443 (1-2):53-67.

Tyler, V. 1994. Herbs of choice. Binghamton, NY: Pharmaceutical Products Press.

Zhang, M.L., M. Wu, J.J. Zhang, et al. 2008. Chemical constituents of plants from the genus Eupatorium. Chem. Biodivers. 5 (1):40-55.

Salicylates

Written by Michael McGuffin; revised by Zoë Gardner, Ph.D.(c)

Salicylates are phenolic acids derived from salicylic acid, and include salicin (in Salix species), populin (in Populus species), methyl salicylate (in Gaultheria and Betula species), and acetylsalicylic acid (aspirin). Salicylic acid was first synthesized in 1860, and the salicylate-containing plants were soon supplanted by the synthetic analog, acetylsalicylic acid (Weissmann 1991). Salicylates are commonly consumed for pain relief, especially for low intensity pain, with an estimated 40,000 metric tons of aspirin being consumed worldwide every year (Warner and Mitchell 2002).

Adverse effects

Concern regarding the consumption of the salicin-containing plants is addressed here primarily to assure that the known adverse effects of aspirin have been examined in relationship to these naturally occurring related compounds. While persons with known sensitivity to aspirin and other salicylates should exercise caution with these plants, there is no evidence that the types of reactions known to be associated with the pharmaceutical salicylates is observed with Salix or any other salicin-rich plant. A study using serum from human volunteers taking willow bark extract (providing 240 mg of salicin daily for 28 days) did note a modest effect on platelet aggregation, but it was less than the effect seen with 100 mg per day aspirin (acetylsalicylic acid) (Krivoy, et al. 2001). At this dose, there is reassurance that salicin will not adversely affect bleeding, though there have not been studies conducted in patients with disorders of thrombotic function. It also suggests that salicin should not be used as a substitute for aspirin in the prevention of heart attacks and strokes.

The concentration of salicylates in most botanicals listed here is quite low, and salicylate overdose is unlikely except in the case of wintergreen essential oil (which contains 98% methyl salicylate), for which multiple cases of overdose have been reported after oral and topical use (Chan 1996; Chyka et al. 2007; Stevenson 1937). Symptoms of mild salicylate poisoning (serum concentrations of 30 – 50 mg/dl) include deep breathing (hyperpnea), nausea, vomiting, tinnitus, and dizziness. Moderate poisoning (serum concentrations of 50 – 70 mg/dl) can produce symptoms of rapid breathing (tachypnea), fever, sweating, dehydration, incoordination, and listlessness. With severe intoxication (> 75mg/dl), symptoms may include coma, seizures, hallucinations, stupor, cerebral edema, dysrhythmias, heart failure, low blood pressure, decreased urine production (oliguria), or kidney failure (Pearlman and Gambhir 2009).

Mechanism of action

Most research has focused on the ability of salicylates to suppress the synthesis of prostaglandins, hormones thought to play an integral role in pain, inflammation, and fever. Two specific enzymes, cyclooxygenase 1 and 2 (COX1 and COX2), are considered to be predominant in this process. COX1 occurs in platelets, blood vessels, and other organs; COX2 acts primarily in inflamed tissue.

Aspirin is the most commonly used salicylate. It blocks the synthesis of prostaglandins through the acetylation of cyclooxygenase, especially COX1, by an irreversible transfer of the acetyl group into the enzyme (Hardman and Limbird 1996). Salicylic acid and salicylates (such as salicin) that lack an acetyl group are not as effective as aspirin in inhibiting platelet aggregation. Therefore, there is little concern for salicin-containing plants causing hematological disturbances. Conversely, these plants are not appropriate as a preventative treatment against stroke, a benefit associated with aspirin consumption.

Herbs listed in the Botanical Safety Handbook that contain salicylates:

Betula lenta leaf and bark
Filipendula ulmaria herb
Gaultheria procumbens leaf
Populus balsamifera ssp. balsamifera leaf buds
Salix alba bark

Salix daphnoides bark
Salix fragilis bark
Salix pentandra bark
Salix purpurea bark

Literature Cited

Chan, T.Y. 1996. Potential dangers from topical preparations containing methyl salicylate. Hum. Exp. Toxicol. 15 (9):747-50.

Chyka, P.A., A.R. Erdman, G. Christianson, et al. 2007. Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin. Toxicol. 45 (2):95-131.

Hardman, J.G., and L.E. Limbird, eds. 1996. Goodman's and Gilman's the pharmacological basis of therapeutics. New York: McGraw Hill.

Krivoy, N., E. Pavlotzky, S. Chrubasik, E. Eisenberg, and G. Brook. 2001. Effect of Salicis Cortex Extract on Human Platelet Aggregation. Planta Med. 2001; 67(3): 209-212.

Pearlman, B.L., and R. Gambhir. 2009. Salicylate intoxication: A clinical review. Postgrad. Med. 121 (4):162-8.

Stevenson, C.S. 1937. Oil of wintergreen (methyl salicylate) poisoning: report of three cases, one with autopsy, and a review of the literature. Am. J. Med. Sci. 193 (6):772-88.

Warner, T.D., and J.A. Mitchell. 2002. Cyclooxygenase-3 (COX-3): Filling in the gaps toward a COX continuum? P.N.A.S. U.S. 99 (21):13371-3.

Weissmann, G. 1991. Aspirin. Sci. Amer. 264 (1):84-90.

Tannins

Written by Michael McGuffin

Tannins are a broad class of complex phenolic compounds that are comprised of two chemical groups: the hydrolyzable tannins (gallotannins) and the condensed tannins (proanthocyanidins). Tannins bind to and precipitate proteins, producing the astringent activity of tannin-containing herbs. Tannins are natural components of many herbs and common foods, and some tannins are used in the processing of foods, alcoholic beverages, and medicines. Condensed tannins are found in grapes (Vitis vinifera), green tea (Camellia sinensis), hawthorn (Crataegus spp.), and many other plants, while hydrolyzable tannins are found in pomegranate (Punica granatum), green and black tea (Camellia sinensis), white oak (Quercus alba), witch hazel (Hamamelis virginiana), and cranesbill (Geranium maculatum). Both types of tannins have astringent properties, providing the basis for many of the historical medicinal uses of the plants containing them.

Adverse effects

Tannins are broadly distributed throughout the plant kingdom, occurring in the barks, roots, leaves, fruits, seeds, and other parts of many different species. Only those plants which are reported to contain at least 10% tannins have been identified as relevant to this discussion of the potential adverse effects of tannin consumption.

Tannins have been shown to reduce the availability of certain nutrients. In the digestive tract, tannins form complexes with proteins, starch, and digestive enzymes, thereby reducing the nutritional values of ingested foods. Condensed tannins, in particular, inhibit digestive enzymes, although the major effects of condensed tannins within the digestive tract are thought to be due to the formation of less digestible complexes with dietary proteins, rather than by inhibition of digestive enzymes (Chung et al. 1998a). Tannins are also known to reduce the absorption certain vitamins and minerals, notably iron (Chung et al. 1998a; Disler et al. 1975; Salunkhe et al. 1990). To optimize nutrient absorption, supplements or beverages that contain tannins should be taken separately from meals.

Most of the known adverse effects related to tannins are specifically recorded for consumption of tannic acid, an ethereal or hydroalcoholic extract of nutgalls (from Quercus spp.), and include gastrointestinal disturbances and kidney damage, as well as severe necrotic conditions in the liver (Gilman et al. 1985; Osol and Farrar 1955). While these concerns may be theoretically relevant to the use of high tannin content herbs, only the digestive irritating properties of tannins are traditionally associated with the consumption of these other plants.

Both carcinogenic and anti-cancer properties of tannins have been reported in experimental settings that measured the effect of tannins on laboratory animals (Chung et al. 1998a; Chung et al. 1998b). Condensed tannins, also called proanthocyanidins, are recognized to have significant anti-oxidant activity and potential anti-cancer activity (Nandakumar et al. 2008).

Mechanism of action

The therapeutic activities of tannins are associated with their ability to bind with and precipitate proteins and to force dehydration of mucosal tissues. In external use, these actions allow the formation of a protective layer of harder, constricted cells; internally, both normal and pathologic secretions of all types are reduced. During internal use, tannins alter the fluidity of the bowel contents, hence their use as anti-diarrheal remedies.

Herbs listed in the Botanical Safety Handbook that contain over 10% tannins:

Agrimonia eupatoria herb
Alchemilla xanthochlora herb
Arctostaphylos uva-ursi leaf
Camellia sinensis leaf and stem
Castanea dentata leaf
Corylus avellana leaf and bark
Corylus cornuta leaf and bark
Epilobium parviflorum herb
Juglans nigra leaf
Krameria argentea root
Krameria lappacea root
Polygonum bistorta root
Potentilla erecta rhizome
Punica granatum fruit husk
Quercus alba bark
Quercus petraea bark
Quercus robur bark
Rheum officinale rhizome and root
Rheum palmatum rhizome and root
Rheum tanguticum rhizome and root
Rubus fruticosus leaf
Rumex acetosa leaf
Rumex acetosella leaf

Eucalyptus globulus leaf
Euphrasia rostkoviana herb
Euphrasia stricta herb
Filipendula ulmaria herb
Geranium maculatum root
Hamamelis virginiana bark and leaf
Heuchera micrantha root
Ilex paraguariensis leaf
Rumex crispus root
Rumex hymenosepalus root
Rumex obtusifolius root
Salix alba bark
Salix daphnoides bark
Salix fragilis bark
Salix pentandra bark
Salix purpurea bark
Schinus molle bark
Schinus terebinthifolius bark
Terminalia arjuna bark
Terminalia bellerica fruit
Terminalia chebula,/ fruit
Uncaria gambir leaf and twig

Literature Cited

Chung, K.T., C.I. Wei, and M.G. Johnson. 1998a. Are tannins a double-edged sword in biology and health? Trends Food Sci. Tech. 9 (4):168-175.

Chung, K.T., T.Y. Wong, C.I. Wei, Y.W. Huang, and Y. Lin. 1998b. Tannins and human health: a review. Crit Rev Food Sci. Nutr. 38 (6):421-464.

Disler, P.B., S.R. Lynch, R.W. Charlton, et al. 1975. The effect of tea on iron absorption. Gut 16 (3):193-200.

Gilman, A.G., L.S. Goodman, T.W. Rall, and F. Murad, eds. 1985. Goodman and Gilmans' the pharmacological basis of therapeutics. New York: Macmillan Publishing Company.

Nandakumar, V., T. Singh, and S.K. Katiyar. 2008. Multi-targeted prevention and therapy of cancer by proanthocyanidins. Cancer Lett. 269 (2):378-387.

Osol, A., and G. Farrar. 1955. The dispensatory of the United States of America, 25th ed. Philadelphia: JB Lippincott Company.

Salunkhe, D.K., J.K. Chavan, and S.S. Kadam. 1990. Dietary tannins: Consequences and remedies. Boca Raton, FL: CRC Press.

Thujone

Written by Lisa Ganora

Thujone (which occurs as both α-thujone and its isomer, β-thujone) is a bicyclic monoterpene ketone found as a constituent of certain volatile oils. α-Thujone is a modulator of GABA_A and 5-HT₃ receptors; high doses are neurotoxic and cause epileptiform convulsions in mammals (Dettling et al. 2004). β-Thujone is less active in this respect. Because of toxicological concerns, isolated thujone is banned in many countries as a food additive. Contemporary EU regulations limit its content in sage-containing foods to 25 mg/kg, while bitters may contain 35 mg/L of thujone (ECSCF 2003). In a draft document issued in January 2011, the European Medicines Agency recommended that thujone intake from herbal medicines be limited to 6 mg per day, and indicated that higher amounts may be acceptable if deemed appropriate on a case by case basis (EMA 2011).

One analysis found that the total thujone content in essential oil of common garden sage (Salvia officinalis) ranged from 9 to 44 percent (Perry et al. 1999), while wormwood (Artemisia absinthium) essential oil has been reported to contain anywhere from 0 to 90 percent total thujone (Lachenmeier et al. 2006). Thuja (Thuja occidentalis) oil may have up to 73 percent total thujone (Naser et al. 2005), tansy oil (Tanacetum vulgare) up to 81 percent (Rohloff et al. 2004), and yarrow (Achillea millefolium) oil from 0 to 27 percent α-thujone and 0 to 11 percent β-thujone (Orav et al. 2006). Depending on any given plant’s developmental stage, chemotype, and geographical origin, there can be wide variations in total thujone content as well as in the proportion of α-thujone to β-thujone.

It was formerly assumed that thujone (from A. absinthium) was responsible for the alleged psychotropic activity and toxicity of absinthe; this notion has recently been refuted by multiple analyses demonstrating that insignificant concentrations of the compound are present in both historical and contemporary examples of the beverage. It is now generally believed that absinthe’s high ethanol content, and perhaps the presence of chemical adulterants (e.g., copper salts added as green dyes to inferior grades of absinthe) or other potential toxins, were responsible for any actual neurological effects (Lachenmeier et al. 2008).

Adverse effects

Thujone has very low solubility in water; therefore little can be found in aqueous preparations (e.g., teas); however, it can be present in hydroethanolic extracts having a high percentage of ethanol, and especially in distilled products (Tegtmeier and Harnischfeger 1994).

In a toxicological assessment of thujone in mice, no adverse effects were found at concentrations below 5 mg/kg body weight, given orally for fourteen weeks (Council of Europe 1999). The LD₅₀ for orally administered thujone in the rat has been reported as 192 to 500 mg/kg (ECSCF 2003).

Numerous investigations have established that essential oil of wormwood can cause convulsions in animals (Padosch et al. 2006). A case report relates that the ingestion of approximately 10 mL of the oil produced seizures, mental confusion, and agitation in a 31 year old man; this was followed by apparent rhabdomyolysis and subsequent acute renal failure which resolved after treatment (Weisbord et al. 1997). In another case, a 2-year-old ingested up to 15 mL of dilute Thuja oil; the resulting seizures responded to treatment with lorazepam and phenytoin, and she was released after fifteen hours in the hospital with no apparent adverse sequelae (Friesen and Phillips 2006).

In a recent investigation, an ethanol drink high in thujone (100 mg/L) was demonstrated to have a negative effect on attention performance in human volunteers and to counteract the anxiolytic effects of ethanol alone; a low-thujone (10 mg/L) preparation did not have these properties (Dettling et al. 2004).

Mechanism of action

α-Thujone, which binds at a non-competitive blocker site, has been established as a reversible modulator of GABAA receptors. This monoterpene has an analeptic effect similar to picrotoxinin and the pesticide dieldrin, both GABAA receptor antagonists. In the case of all three compounds, binding and toxicity is blocked by diazepam, phenobarbital, and ethanol. β-Thujone was found to have a 2.3-fold lower binding affinity and has demonstrated lesser toxicity in mice (Hold et al. 2000). It seems likely that thujone’s activity on GABA_A receptors is largely responsible for its seizure-promoting effects.

One study has reported that α-thujone reduced the activity of cloned human 5-HT₃ receptors, resulting in an inhibition of serotonergic responses. It is not yet known if this mechanism contributes to the observed neurological effects of the compound (Deiml et al. 2004).

It was formerly suggested that thujone might interact with cannabinoid receptors in the CNS to bring about a psychotropic effect. Despite internet marketing claims, this idea has been discredited by a study which found that thujone has low affinity for cannabinoid receptors and does not demonstrate cannabimimetic properties (Meschler and Howlett 1999).

In chick embryo liver cells, thujone has demonstrated porphyrogenic activity; on this basis, it has been suggested that it could be hazardous to patients with acquired or genetic defects of heme synthesis in the liver (Bonkovsky et al. 1992).

In human cells, the thujone isomers are metabolized by several cytochrome P-450 enzymes, including CYP2D6 and CYP3A4. 7-Hydroxy-α-thujone and 7-hydroxy-β-thujone are the major metabolites, followed by their 4-hydroxylated congeners (Jiang et al. 2006). These metabolites have significantly reduced GABA_A binding affinity compared to their parent compounds and are therefore considered to be less toxic (Hold et al. 2000). Little is known about the pharmacokinetics of thujone in humans.

Herbs listed in the Botanical Safety Handbook that contain thujone:

Achillea millefolium herb
Artemisia absinthium herb
Artemisia capillaris herb
Artemisia douglasiana herb
Artemisia lactiflora herb
Artemisia scoparia herb
Artemisia vulgaris herb
Evernia furfuracea¹ thallus

Evernia prunastri¹ thallus
Hyssopus officinalis herb
Platycladus orientalis cacumen
Salvia officinalis leaf
Tanacetum vulgare² herb
Thuja occidentalis leaves

¹ May contain thujone

² Some chemotypes contain thujone

Literature Cited

Bonkovsky, H.L., E.E. Cable, J.W. Cable, et al. 1992. Porphyrogenic properties of the terpenes camphor, pinene, and thujone (with a note on historic implications for absinthe and the illness of Vincent van Gogh). Biochem. Pharmacol. 43 (11):2359-2368.

Council of Europe, 1999. Revised detailed datasheet on thujone. Document RD 4.2/14-44.

Deiml, T., R. Haseneder, W. Zieglgansberger, et al. 2004. Alpha-thujone reduces 5-HT3 receptor activity by an effect on the agonist-induced desensitization. Neuropharmacol. 46 (2):192-201.

Dettling, A., H. Grass, A. Schuff, et al. 2004. Absinthe: Attention performance and mood under the influence of thujone. J. Stud. Alcohol 65 (5):573-581.

ECSCF. 2003. Opinion of the Scientific Committee on Food on thujone. European Commission Scientific Committee on Food. SCF/CS/FLAV/FLAVOUR/23 ADD2 Final.

EMA. 2011. Public statement on the use of herbal medicinal products containing thujone: draft. European Medicines Agency, Committee on Herbal Medicinal Products. EMA/HMPC/732886/2010.

Friesen, M., and B. Phillips. 2006. Status epilepticus following pediatric ingestion of Thuja essential oil. LCLT abstracts of the European Association of Poisons Centres and Clinical Toxicologists XXVI International Congress. 219.

Hold, K.M., N.S. Sirisoma, T. Ikeda, T. Narahashi, and J.E. Casida. 2000. Alpha-thujone (the active component of absinthe): gamma-aminobutyric acid type A receptor modulation and metabolic detoxification. P.N.A.S. U.S. 97 (8):3826-3831

Jiang, Y.Y., X. He, and P.R.O. de Montellano. 2006. Radical intermediates in the catalytic oxidation of hydrocarbons by bacterial and human cytochrome P450 enzymes. Faseb J. 20 (4):A42-A42.

Lachenmeier, D.W., D. Nathan-Maister, T.A. Breaux, et al. 2008. Chemical composition of vintage preban absinthe with special reference to thujone, fenchone, pinocamphone, methanol, copper, and antimony concentrations. J. Agric. Food Chem. 56 (9):3073-3081.

Lachenmeier, D.W., S.G. Walch, S.A. Padosch, and L.U. Kroner. 2006. Absinthe—a review. Crit. Rev. Food Sci. Nutr. 46 (5):365-377.

Meschler, J.P., and A.C. Howlett. 1999. Thujone exhibits low affinity for cannabinoid receptors but fails to evoke cannabimimetic responses. Pharmacol. Biochem. Behav. 62 (3):473-480.

Naser, B., C. Bodinet, M. Tegtmeier, and U. Lindequist. 2005. Thuja occidentalis (Arbor vitae): A review of its pharmaceutical, pharmacological and clinical properties. Evid.-Based Compl. Altern. Med. 2 (1):69-78.

Orav, A., E. Arak, and A. Raal. 2006. Phytochemical analysis of the essential oil of Achillea millefolium L. from various European countries. Nat. Prod. Res. 20 (12):1082-1088.

Padosch, S.A., D.W. Lachenmeier, and L.U. Kroner. 2006. Absinthism: a fictitious 19th century syndrome with present impact. Subst Abuse Treat Prev Policy 1 (1):14.

Perry, N.B., R.E. Anderson, N.J. Brennan, et al. 1999. Essential oils from Dalmatian sage (Salvia officinalis L.): Variations among individuals, plant parts, seasons, and sites. J. Agric. Food Chem. 47 (5):2048-2054.

Rohloff, J., R. Mordal, and S. Dragland. 2004. Chemotypical variation of tansy (Tanacetum vulgare L.) from 40 different locations in Norway. J. Agric. Food Chem. 52 (6):1742-1748.

Tegtmeier, M., and G. Harnischfeger. 1994. Methods for the reduction of thujone content in pharmaceutical preparations of artemisia, salvia and thuja. Eur. J. Pharm. Biopharm. 40 (5):337-340.

Weisbord, S.D., J.B. Soule, and P.L. Kimmel. 1997. Poison on line—acute renal failure caused by oil of wormwood purchased through the internet. N.E.J.M. 337 (12):825-827.

Appendix II.

Herbal Action Profiles

Abortifacients

Written by Michael McGuffin, revised by Aviva Romm, M.D. and Tieraona Low Dog, M.D.

Abortifacients are agents that are used to induce abortion and terminate pregnancy. Herbal abortion is not a recommended method of intentional pregnancy termination.

Adverse effects

There is a long history of use of select botanicals as abortifacients. Research on the use of botanicals to induce abortion is extremely limited, and most information on the topic comes from historical or empirical reports. Little reliable data exists on the effectiveness, toxic levels, or possible effects of these plants on the developing fetus.

Abortifacient or potential harmful effects to a fetus typically require very high amounts of a botanical or botanical formula over a continuous period of time. Thus, ingesting small amounts of the herbs listed below during pregnancy, except in rare cases, is not a cause for alarm. In addition, some of the herbs listed below as abortifacients, such as saffron (Crocus sativus), safflower (Carthamus tinctorius), and Roman chamomile (Chamaemelum nobile) may be safely used during pregnancy in amounts typically consumed in foods or beverages.

Mechanism of Action

Abortifacients have many different mechanisms of action. Some abortifacients act indirectly, meaning that they induce abortion through peripheral systems such as the endocrine, cardiovascular, gastrointestinal, or nervous systems. Others are direct-acting abortifacients that target the uterus, endometrium, and/or fetus, causing abortion to commence. It is not possible to generalize the action, efficacy, or safety of plants listed in this text as abortifacients, since the mechanisms of action of these plants has not been well studied (Bingel and Farnsworth 1980).

Certain abortifacients have drastic purgative effects or are gastrointestinal irritants that can produce reflex uterine contraction. Many volatile oils, such as oil of tansy (Tanacetum vulgare), and saponin glycosides, such as those found in bethroot (Trillium erectum), act in this manner.

Herbs listed in the Botanical Safety Handbook with potential abortifacient action:

Andrographis paniculata herb
Carthamus tinctorius flower
Catharanthus roseus herb
Caulophyllum thalictroides root
Chamaemelum nobile flower
Chrysopogon zizanoides root
Crocus sativus stigma
Cytisus scoparius flowering tops
Gossypium herbaceum root bark

Gossypium hirsutum root bark
Juniperus virginiana leaf, berry
Mentha pulegium leaf, essential oil
Podophyllum peltatum root
Podophyllum hexandrum root
Ruta graveolens herb
Tanacetum vulgare herb
Thuja occidentalis leaves

Literature Cited

Bingel, A., and N. Farnsworth. 1980. Botanical Sources of Fertility Regulating Agents: Chemistry and Pharmacology. In Progress in hormone biochemistry and pharmacology edited by Briggs, M. and A. Corbin. St. Albans, VT: Eden Medical Research

Rao, R.B., and R.S. Hoffman. 2002. Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacient. Vet. Hum. Toxicol. 44 (4):221-2.

Rao, R.B., R.S. Hoffman, R. Desiderio, et al. 1998. Nicotinic toxicity from tincture of blue cohosh (Caulophyllum thalictroides) used as an abortifacient. J. Toxicol. Clin. Toxicol. 36 (5):455.

Sullivan, J.B., B.H. Rumack, H. Thomas, Jr., R.G. Peterson, and P. Bryson. 1979. Pennyroyal oil poisoning and hepatotoxicity. JAMA 242(26):2873-4.

Bulk-forming Laxatives

Written by Michael McGuffin; revised by Eric Yarnell, N.D.

Bulk-forming laxatives are substances that promote bowel evacuation by increasing the bulk volume and water content of the stool. These are generally considered to be the safest laxative agents.

Adverse effects

Bulk-forming laxatives are contraindicated in bowel obstruction and must be taken with adequate liquid to avoid paradoxical constipation and esophageal or bowel obstruction (Frohna 1992; Herrle et al. 2004; Noble and Grannis 1984; Schapira et al. 1995). Cases of esophageal or bowel obstruction typically occur in persons with abnormal esophageal or intestinal narrowing or in persons who took the laxative product with insufficient liquid (Angueira and Kadakia 1993; Frohna 1992; Herrle et al. 2004).

The U.S. Food and Drug Administration (FDA) requires specific labeling of products classified as over-the-counter drug products that contain certain of the herbs listed here, including agar (Gelidiella acerosa and Gelidium spp.), guar gum (Cyamopsis tetragonolobus), and psyllium (Plantago spp.) if these are marketed in a “dry or incompletely hydrated form,” such as capsules and powders. The designated labeling is as follows:

Choking: Taking this product without adequate fluid may cause it to swell and block your throat or esophagus and may cause choking. Do not take this product if you have difficulty in swallowing. If you experience chest pain, vomiting, or difficulty in swallowing or breathing after taking this product, seek immediate medical attention (CFR 2011).

Additional language is required under the directions for use, as follows:

Directions: (Select one of the following, as appropriate: “Take” or “Mix”) this product (child or adult dose) with at least 8 ounces (a full glass) of water or other fluid. Taking this product without enough liquid may cause choking. See choking warning.

Although the above labeling is not specifically required by FDA for dietary supplements, it is suggested that the above or significantly similar language be included on the label of dietary supplements that contain bulk-forming laxative ingredients and posted at the point of sale in any retail setting where any of these are sold in bulk.

Bulk-forming laxatives may inhibit the absorption of other drugs. The drugs usually associated with this consideration are aspirin, digitalis and other cardiac glycosides, antibiotics, thyroid hormones, and anticoagulants. To ensure complete absorption of drugs, bulk-forming laxatives and other drugs should be taken several hours apart (Brunton et al. 2006). The absorption of dietary nutrients, including calcium, iron, zinc, sodium, and potassium, can also be inhibited (ESCOP 2003). Appropriate supplementation must therefore be considered when using bulk-forming laxatives for extended periods. For individuals accustomed to a low-fiber diet, gradual use of less refined fiber in the diet is recommended before using bulk fiber agents.

Mechanism of action

Bulk-forming laxative herbs include gel-forming fibers such as psyllium husk (Plantago spp.) and flax seed (Linum usitatissimum). Gel-forming fibers contain a form of starch called mucilage, composed of mucopolysaccharides, and roughage or indigestible plant fiber called cellulose. These plant starches are hydrophilic, absorbing water or other liquid to form a mucilaginous or gel-like substance. Because these herbs also expand on contact with liquid, they add moisture and bulk to stools in the colon (Brunton et al. 2006; Williams et al. 2006).

Bulk-forming laxatives that contain mucilage have additional minor benefits complementing their primary effect of relieving constipation. Mucilaginous herbs are demulcent, meaning that they are soothing to inflamed mucosal surfaces (Brunton et al. 2006). Demulcents form a temporary gelatinous barrier which protects the intestinal wall from irritation caused by caustic material in the intestines, thus allowing repair of the adjoining tissues.

Besides providing the demulcent properties associated with these plants' mucilage content, the indigestible cellulose fiber of bulk-forming laxatives plays additional roles related to diet and digestion. Fiber absorbs dietary fats, decreasing the absorption of cholesterol into the bloodstream. In addition, since dietary fiber from bulk laxatives cannot be digested, these herbs add a feeling of fullness without calories. Fiber also slows the release of dietary sugar from the digestive tract into the blood stream, assisting in the stabilization of blood sugar (Brennan 2005; Singh 2007; Sirtori et al. 2009).

Herbs listed in the Botanical Safety Handbook as bulk forming laxatives:

Gelidiella acerosa (thallus)
Gelidium amansii (thallus)
Gelidium cartilagineum (thallus)
Gelidium crinale (thallus)
Gelidium divaricatum (thallus)
Gelidium pacificum (thallus)

Gelidium vagum (thallus)
Linum usitatissimum (seed)
Plantago arenaria (seed, seed husk)
Plantago asiatica (seed, seed husk)
Plantago ovata (seed, seed husk)

Literature Cited

Angueira, C., and S. Kadakia. 1993. Esophageal and duodenal bezoars from Perdiem. Gastrointest. Endosc. 39 (1):110-1.

Brennan, C.S. 2005. Dietary fibre, glycaemic response, and diabetes. Molec. Nutr. Food Res. 49 (6):560-570.

Brunton, L.L., J.S. Lazo, and K.L. Parker. 2006. Goodman & Gillman’s The Pharmacological Basis of Therapeutics, 11th ed. New York: McGraw-Hill.

CFR. 2011. Code of federal regulations, Title 21 Part 201.319, 2011 ed. Specific labeling requirements for specific drug products. Water-soluble gums, hydrophilic gums, and hydrophilic mucilloids (including, but not limited to agar, alginic acid, calcium polycarbophil, carboxymethylcellulose sodium, carrageenan, chondrus, glucomannan ((B-1,4 linked) polymannose acetate), guar gum, karaya gum, kelp, methylcellulose, plantago seed (psyllium), polycarbophil tragacanth, and xanthan gum) as active ingredients; required warnings and directions. Washington, DC: U.S. Government Printing Office.

ESCOP. 2003. ESCOP Monographs: The scientific foundation for herbal medicinal products. 2nd ed. New York: Thieme.

Frohna, W.J. 1992. Metamucil bezoar: an unusual cause of small bowel obstruction. Am. J. Emerg. Med. 10 (4):393-5.

Herrle, F., T. Peters, C. Lang, et al. 2004. Bolus obstruction of pouch outlet by a granular bulk laxative after gastric banding. Obes. Surg. 14 (7):1022-4.

Noble, J.A., and F.W. Grannis, Jr. 1984. Acute esophageal obstruction by a psyllium-based bulk laxative. Chest 86 (5):800.

Schapira, M., J. Henrion, P. Jonard, et al. 1995. Esophageal bezoar: report of five more cases. Endoscopy 27 (4):342.

Singh, B. 2007. Psyllium as therapeutic and drug delivery agent. Int. J. Pharmaceut. 334 (1-2):1-14.

Sirtori, C.R., C. Galli, J.W. Anderson, E. Sirtori, and A. Arnoldi. 2009. Functional foods for dyslipidaemia and cardiovascular risk prevention. Nutr. Res. Rev. 22 (02):244-261.

Williams, P.A., G.O. Phillips, A.M. Stephen, and S.C. Churms. 2006. Gums and mucilages. In Food polysaccharides and their applications, edited by Stephen, A.M., G.O. Phillips and P.A. Williams. Boca Raton, FL: CRC Press.

Diuretics

Written by Zoë Gardner, Ph.D.(c), reviewed by Roy Upton, RH (AHG), DAyu and Lana Dvorkin-Camiel, Pharm.D., R.Ph.

A diuretic is a substance that increases the volume and/or rate of urinary output.

Botanicals with diuretic activity can be divided into two general categories: Those that induce urinary output and thus fluid loss through excretion of sodium ions (natriuretics), and those that induce urinary output without impacting electrolyte balance (aquaretics).

In conventional medicine, diuretics are employed to assist the kidneys in eliminating excess fluid from the body, fluid that accumulates in conditions such as congestive heart failure, pulmonary edema, and liver failure (Brunton et al. 2006). To be clinically useful for such indications, a diuretic must also cause excretion of sodium or sodium chloride ions in order to cause substantial fluid output (Wright 2007). Diuretics may also be employed for relief of conditions such as mild primary hypertension or to increase the flow of urine in cases of urinary tract infections and other conditions of the urinary tract (Brunton et al. 2006; Yarnell 2001).

The listing of herbs as diuretics in this text is generally based on traditional use and clinical observation. While there are a number of botanicals for which diuretic activity has been confirmed, formal research is lacking on the specific activity (i.e., natriuretic or aquaretic) and degree of effect of most of these (Wright et al. 2007). This makes it difficult to provide clear guidance on which species and what dosage may cause the level of diuresis that invokes the concerns typically ascribed to diuretics. At the same time, there is evidence to suggest that select botanical diuretics (e.g., dandelion leaf; Taraxacum officinale) do not result in the potassium loss common to many conventional diuretics (Racz-Kotilla et al. 1974). The magnitude of diuretic activity of the species listed here is considered by many to be generally more mild than those of pharmaceutical diuretics (Racz-Kotilla et al. 1974; Wright et al. 2007). Therefore, formal investigation would be helpful in determining the clinical efficacy, potential adverse effects profile, and potential advantage of using botanical as compared to conventional diuretics.

Adverse effects

The potential adverse effects associated with diuretics are generally related to shifts in electrolyte balances. Although botanical diuretics are generally not as strong as pharmaceutical diuretics, and have not been associated with many of the adverse effects (i.e., hypotension, dehydration, and significant electrolyte loss) of pharmaceutical diuretics, botanical diuretics may theoretically cause electrolyte imbalances (Brunton et al. 2006; Wright et al. 2007). Therefore, individuals with conditions that may cause electrolyte imbalances (i.e., congestive heart failure, liver failure, kidney failure, etc.) should be cautious when taking diuretic herbs or do so under medical supervision, as shifts in electrolyte balance may exacerbate the disease state.

Use of diuretics is generally cautioned in persons taking drugs with narrow therapeutic ranges (small differences between the effective and toxic doses), such as warfarin, steroids (i.e., prednisone), digoxin, tacrolimus, cyclosporine, valproic acid, phenytoin, and carbemazepine, as shifts in serum levels of sodium and potassium may affect serum levels of these drugs. Serum electrolyte shifts, notably sodium, can also cause an increase in serum lithium levels, and may result in lithium toxicity (Finley et al. 1995). Use of lithium with diuretics is not recommended, but if taken concomitantly, serum drug and electrolyte levels need to be monitored closely. Corticosteroids or licorice may amplify the potassium-depleting effects of diuretics (Brunton et al. 2006; Isbrucker and Burdock 2006).

Concomitant use of diuretic herbs with prescription loop diuretics, thiazide diuretics, osmotic diuretics, and potassium-sparing diuretics may cause excessive fluid loss. Reductions in potassium levels caused by diuretics may increase the toxicity of cardiac glycosides, such as digoxin, and their combination should be avoided (Anon 2010).

Diuretics may irritate or exacerbate symptoms of kidney stones, and professional guidance is recommended when employing these therapies for this condition (Chitme et al. 2010). Some naturopathic treatment protocols suggest that kidney stones smaller than 5 mm in size may be passed with the assistance of herbal diuretics, but such protocols should only be followed under the supervision of a qualified health professional (Yarnell 2001).

Mechanism of action

Due to lack of research, it is not yet known whether botanical diuretics have the same or different mechanisms of action as non-botanical diuretic drugs.

Herbs listed in the Botanical Safety Handbook as diuretics:

Agathosma betulina leaf
Agathosma crenulata leaf
Agathosma serratifolia leaf
Alisma plantago-aquatica rhizome
Anethum graveolens herb and fruit
Apocynum androsaemifolium root
Apocynum cannabinum root
Asparagus officinalis rhizome
Asparagus racemosus rhizome
Betula pendula leaf
Betula pubescens leaf
Boerhavia diffusa root
Camellia sinensis leaf and stem
Juniperus osteosperma fruit
Juniperus oxycedrus fruit
Nardostachys jatamansi rhizome and root
Parietaria judaica herb
Parietaria officinalis herb
Paullinia cupana seed
Petroselinum crispum root
Phyllanthus amarus whole plant
Phyllanthus fraternus whole plant
Phyllanthus niruri whole plant
Polygala senega root
Polygala sibirica root
Polygala tenuifolia root
Portulaca oleracea herb
Prunus spinosa seeds and fresh flowers

Chamaesyce hirta herb
Coffea arabica seed kernel
Cola acuminata seed
Cola nitida seed
Coffea arabica seed
Daucus carota fruit
Equisetum arvense herb
Equisetum hyemale herb
Equisetum telmateia herb
Gossypium herbaceum root bark
Gossypium hirsutum root bark
Ilex paraguariensis leaf
Juniperus communis fruit
Juniperus monosperma fruit
Ribes nigrum leaf
Satureja hortensis leaf
Satureja montana leaf
Selenicereus grandiflorus flowers and stem
Solidago canadensis var. lepida herb
Solidago gigantea herb
Solidago virgaurea herb
Stephania tetrandra root
Tanacetum vulgare herb
Taraxacum officinale leaf, root
Tinospora cordifolia root, stem, and leaf
Tribulus terrestris fruit
Urtica dioica leaf
Zea mays stigma

Literature Cited

Anon. 2010. Digoxin: serious drug interactions. Prescrire Int. 19 (106):68-70.

Brunton, L.L., J.S. Lazo, and K.L. Parker. 2006. Goodman & Gillman’s the pharmacological basis of therapeutics, 11th ed. New York: McGraw-Hill.

Chitme, H.R., S. Alok, S.K. Jain, and M. Sabharwal. 2010. Herbal treatment for urinary stones. Int. J. Pharm. Sci. Res. 1 (24-31).

Combest, W., M. Newton, A. Combest, and J.H. Kosier. 2005. Effects of herbal supplements on the kidney. Urol. Nurs. 25 (5):381-6.

Finley, P.R., M.D. Warner, and C.A. Peabody. 1995. Clinical relevance of drug interactions with lithium. Clin. Pharmacokin. 29 (3):172-191.

Isbrucker, R.A., and G.A. Burdock. 2006. Safety and risk assessment on the consumption of licorice root. Regul. Toxicol. Pharmacol. 46:168-192.

Racz-Kotilla, E., G. Racz,, and A. Solomon. 1974. The action of Taraxacum officinale extracts on the body weight and diuresis of laboratory animals. Planta Med 26(3):212-7.

Supuran, C.T., A. Scozzafava, and J. Conway, eds. 2004. Carbonic anhydrase—Its inhibitors and activators. Boca Raton, FL: CRC Press.

Wright, C.I., L. Van-Buren, C.I. Kroner, and M.M.G. Koning. 2007. Herbal medicines as diuretics: A review of the scientific evidence. J. Ethnopharmacol. 114 (1):1-31.

Yarnell, E. 2001. Naturopathic urology and men’s health. Wenatchee, WA: Healing Mountain Publishing.

Emetics

Written by Michael McGuffin; revised by Zoë Gardner, Ph.D.(c)

An emetic is a substance that induces vomiting in a sufficient dose. Emetics have two primary functions. The first is to empty the stomach, especially in cases of ingestion of non-caustic poisons; the second is as an expectorant for respiratory diseases, primarily to expel mucus and phlegm from the bronchioles. Historically, use in respiratory conditions was mainly in children with conditions such as asthma, bronchitis, and diphtheria before they were able to expectorate effectively. Doses for this latter use are significantly smaller than doses used to empty the stomach.

Adverse effects

The concerns related to herbs with emetic potential are of importance only when they are consumed in dosage levels sufficient to produce vomiting. Such use is typically limited in duration to one or several doses, and use of emetics for more than three to four days can produce dehydration and severe electrolyte imbalances. Continual retching action from chronic vomiting will strain the abdominal and stomach muscles and the diaphragm, causing severe cramping and potential development of hernias (Rakel 1996; Hardman & Limbird 1996; Katcher et al. 1983). Chronic use by persons with eating disorders may lead to generalized muscle weakness, diarrhea, mild tremors, fluid retention, dehydration, and metabolic disturbances (hypokalemia, hypochloremic acidosis, elevation of creatinine phosphokinase) (Manno and Manno 1977; Quang and Woolf 2000).

Emetics are contraindicated in those with aneurysms, hernia, arteriosclerosis, or in cases of hemorrhage. The use of emetics is often associated with depression of central motor functions, and so is best used under appropriate medical supervision.

The following guidelines have been developed for the use of ipecac (Cephaelis ipecacuanha), one of the most common botanical emetics used, but are applicable to any botanical being used for emetic purposes in the case of poisonings. Ipecac (and other emetics) should not be used unless directed by a qualified healthcare professional (physician, poison control center, or other professional), and should not be used if:

A patient is comatose or has altered mental status and the risk of breathing in the stomach contents is high. The patient is having convulsions.
The substance ingested is capable of causing altered mental status or convulsions.
The substance ingested is a caustic or corrosive agent.
The substance ingested is a low viscosity petroleum distillate with the potential for pulmonary aspiration.
The patient has a medical condition that may be exacerbated by vomiting (e.g., severe high blood pressure, slow heart rate, or tendency for bleeding) (Manoguerra and Cobaugh 2005).

Other guidelines list additional “relative contraindications” beyond the “absolute contraindications” listed above. These guidelines indicate that ipecac should not be used if:

The patient is already vomiting.
More than one hour has passed since ingestion of the product of concern.
The patient is susceptible to bleeding or hemorrhaging (bleeding diathesis).
An oral antidote to the consumed poison is available.
The patient is less than 6 months of age.
The patient is elderly or has a history of heart disease.
The patient ingested cardiotoxic drugs (i.e., calcium-channel blockers, beta blockers) (Quang and Woolf 2000).

While emetics such as ipecac were, in the past, remedies of choice for emptying the stomach in the case of poisonings, more recent recommendations indicate that emetics should not be used in certain circumstances, and that other treatment methods may be preferable (Manoguerra and Cobaugh 2005; Quang and Woolf 2000). Activated charcoal and emetics should not be administered together since the charcoal can absorb the emetic substance and reduce the emetic effect and because the charcoal will be expelled through vomiting (Hardman and Limbird 1996).

Ipecac contains the compound emetine, which may adversely affect the heart. In the event that vomiting does not occur after administration of ipecac, gastric lavage (stomach pumping) should be performed to avoid a toxic reaction to emetine (Manno and Manno 1977).

Mechanism of action

There are two primary classes of emetics: Those that work on the vomiting centers in the medulla (central emetics), and those which act directly on the stomach itself (gastric emetics). There are botanical emetics that fall into each class, although the mechanism of action of most botanical emetics is not fully understood. Central emetics act by affecting a section of the brain stem known as the chemoreceptor trigger zone. This zone is affected by certain chemical abnormalities in the body and sends a signal to the vomiting centers, which stimulate and coordinate the process of vomiting. Gastric emetics, such as ipecac, act as irritants in the gastrointestinal tract and signal the vomiting center via the vagus nerve (Hardman and Limbird 1996).

Herbs listed in the Botanical Safety Handbook as emetics:

Apocynum androsaemifolium root
Apocynum cannabinum root
Asclepias tuberosa root
Cephaelis ipecacuanha rhizome
Lobelia inflata herb
Lobelia siphilitica herb
Melia azedarach fruit, root bark
Podophyllum peltatum root

Genista tinctoria herb and flower
Ipomoea purga root
Iris versicolor rhizome and root
Iris virginica rhizome and root
Podophyllum hexandrum root
Sanguinaria canadensis root

Literature Cited

Hardman, J.G., and L.E. Limbird, eds. 1996. Goodman & Gilman's the pharmacological basis of therapeutics. New York: McGraw-Hill.

Katcher BS, Young LY, Koda-Kimble MA. 1983. Applied therapeutics - the clinical use of drugs, 3rd ed. Spokane, WA: Applied Therapeutics.

Manno, B.R., and J.E. Manno. 1977. Toxicology of ipecac: a review. Clin. Toxicol. 10 (2):221-42.

Manoguerra, A.S., and D.J. Cobaugh. 2005. Guideline on the use of ipecac syrup in the out-of-hospital management of ingested poisons. Clin. Toxicol. 43 (1):1-10.

Quang, L.S., and A.D. Woolf. 2000. Past, present, and future role of ipecac syrup. Curr. Opin. Pediatr. 12 (2):153-62.

Rakel R, editor. 1996. Conn's Current Therapy. Philadelphia: W.B. Saunders Co.

Emmenagogues and Uterine Stimulants

Written by Tieraona Low Dog, M.D.

Emmenagogues are agents used to promote menstrual flow. Uterine stimulants are used to cause a woman's uterus to contract, or to increase the frequency and intensity of the contractions.

As a category, emmenagogues are not well defined, and their mechanisms of action have not been well studied or understood. Emmenagogues are principally used for amenorrhea, a condition that can be due to a wide variety of causes. Logically thinking through the etiology of amenorrhea, the category could include herbs with inherent nutritive value, herbs that have a calming effect on the nervous system, herbs that enhance or promote circulation, agents that induce or increase uterine contractions (uterine stimulants), and herbs that interact with the hypothalamic-adrenal-gonadal axis (part of the neuroendocrine system). Examples might include the following:

Amenorrhea secondary to anemia or malnourishment might be treated with nutritive herbs (i.e., nettles, red clover, dong quai).
Amenorrhea secondary to trauma or great emotional stress might be treated with nervines (i.e., chamomile, motherwort, bupleurum).
Amenorrhea due to pregnancy might be addressed using herbs with abortifacient or uterine stimulant activity (e.g., pennyroyal, artemisia, cotton root bark). Abortifacient activity may involve reduction in maternal progestagen and testosterone levels, as well as an increase in immunoreactive cells (Al-Dissi et al. 2001; Boareto et al. 2008; Mukherjee et al. 1996; Talwar et al. 1997).

In Traditional Chinese Medicine, blood-moving herbs, or "herbs which invigorate the blood," are thought to increase menstrual blood flow by regulating the blood vessels in the uterus or stimulating the general blood circulation (e.g., safflower (Carthamus tinctorius) flower and myrhh (Commiphora wightii) gum resin (Bensky et al. 2004; Chen and Chen 2004).

The broad variation in herbs used to “bring about menstruation” makes it impossible to generalize mechanistic activity.

Adverse effects

Depending upon the plant and the intended use, one could predict to some degree the adverse effects that might occur. Herbs that are widely known to be used as abortifacients and/or uterine stimulants should be avoided during pregnancy and in women with menorrhagia (heavy menstrual bleeding) (Chalker and Downer 1992).

Uterine stimulants for labor induction should always be used under the direct supervision of a qualified and experienced individual. If used improperly, these herbs could potentially lead to such complications as uterine hypercontractility, uterine rupture and maternal hypotension (Kelsey and Prevost 1994).

Adverse effects in pregnancy from emmenagogues that do not have abortifacient activity, such as chamomile or catmint, are unlikely when they are used at normal and customary doses. The same is true for the culinary herbs, such as thyme, parsley and rosemary, when they are used to flavor food.

The editors of this text acknowledge that there is a lack of consensus regarding which herbs should be listed as emmenagogues, and that safety is a grey area when it comes to their use in pregnancy. The editors actively discourage the use of any emmenagogue as an abortifacient due to the potential for serious and significant risk to both mother and fetus; they encourage the herbal, medical and research communities to explore the category more fully and conduct studies that would help to clarify mechanisms of action and safety.

Herbs listed in the Botanical Safety Handbook as emmenagogues or uterine stimulants:

Emmenagogues

Angelica archangelica root and fruit
Angelica atropurpurea root and fruit
Anthriscus cerefolium herb
Artemisia abrotanum herb
Artemisia douglasiana herb
Artemisia lactiflora herb
Artemisia vulgaris herb
Caulophyllum thalictroides root
Chamaemelum nobile flower
Ferula assa-foetida oleo-gum-resin
Ferula foetida oleo-gum-resin
Forsythia suspensa fruit
Gentiana lutea root
Hyssopus officinalis herb
Inula helenium root
Leonurus cardiaca herb
Satureja montana leaf
Tanacetum vulgare herb
Taxus brevifolia needles
Thymus vulgaris herb

Leonurus heterophyllus herb
Leonurus sibiricus herb
Marrubium vulgare herb
Mentha pulegium leaf and essential oil
Monarda clinopodia herb
Monarda didyma herb
Monarda fistulosa herb
Monarda pectinata herb
Monarda punctata herb
Nardostachys jatamansi rhizome, root
Nepeta cataria herb
Petroselinum crispum leaf
Polygala senega root
Rosmarinus officinalis leaf
Ruta graveolens herb
Satureja hortensis leaf
Zanthoxylum americanum bark
Zanthoxylum clava-herculis bark

Uterine stimulants

Achyranthes bidentata root
Capsella bursa-pastoris herb
Carthamus tinctorius flower
Commiphora mukul gum resin
Commiphora wightii gum resin
Corydalis yanhusuo tuber
Cytisus scoparius flowering tops

Gossypium herbaceum root bark
Gossypium hirsutum root bark
Leonurus heterophyllus herb
Leonurus sibiricus herb
Ziziphus jujuba var. spinosa seed

Literature Cited

Al-Dissi, N.M., A.S. Salhab, and H.A. Al-Hajj. 2001. Effects of Inula viscosa leaf extracts on abortion and implantation in rats. J. Ethnopharmacol. 77 (1):117-121.

Bensky, D., S. Clavey, and E. Stöger. 2004. Chinese herbal medicine: Materia medica, 3rd edition. 3rd ed. Seattle: Eastland Press.

Boareto, A.C., J.C. Muller, A.C. Bufalo, et al. 2008. Toxicity of artemisinin (Artemisia annua L.) in two different periods of pregnancy in Wistar rats. Repro. Toxicol. 25 (2):239-246.

Chalker, R., and C. Downer. 1992. A woman's book of choices: Abortion, menstrual extraction, RU-486. New York: Four Walls Eight Windows.

Chen, J.K., and T.T. Chen. 2004. Chinese medical herbology and pharmacology. City of Industry, CA: Art of Medicine Press.

Kelsey, J.J., and R.R. Prevost. 1994. Drug-Therapy During Labor and Delivery. Am. J. Hosp. Pharm. 51 (19):2394-2402.

Mukherjee, S., N.K. Lohiya, R. Pal, M.G. Sharma, and G.P. Talwar. 1996. Purified neem (Azadirachta indica) seed extracts (Praneem) abrogate pregnancy in primates. Contraception 53 (6):375-378.

Talwar, G.P., S. Shah, S. Mukherjee, and R. Chabra. 1997. Induced termination of pregnancy by purified extracts of Azadirachta Indica (Neem): mechanisms involved. Am. J. Reprod. Immunol. 37 (6):485.

Photosensitizing

Written by Zoë Gardner, Ph.D.(c)

Photosensitizing substances cause the development of abnormally heightened reactivity of the skin or eyes to sunlight. Exposure to either the substance or light alone is not sufficient to induce the reaction, which may include rashes, blistering, skin irritation, swelling, or hyperpigmentation. Such reactions may occur after topical application or ingestion of the photosensitizing substance (Moore 2002).

A number of plants that may cause reactions after topical exposure do not pose any risk after internal use. For example, furanocoumarin compounds, such as those present in fragrant angelica (Angelica dahurica), have photosensitizing effects after contact with skin, although no cases of photosensitivity after ingestion of fragrant angelica are known (Bensky et al. 2004). While certain plants elicit photosensitivity in most people, the majority of photosensitizing plants listed in this text affect sensitive or otherwise predisposed people (i.e., those who are fair skinned) or those undergoing phototherapy (laser or UV treatment).

Adverse effects

There are two distinct types of photosensitizing reactions associated with the use of photosensitizing agents: phototoxic reactions and photoallergic reactions. Phototoxic reactions are dose dependent and may occur several minutes or hours after exposure to sunlight. These reactions are limited to sun-exposed skin and generally resemble severe sunburns, sometimes accompanied by erythema (reddening of the skin), edema (swelling and fluid retention), and blistering. Skin pigmentation may also occur (Stein and Scheinfeld 2007). Phototoxic reactions are generally associated with products containing psoralens (linear furocoumarins), although other compounds, such as hypericin in St. John’s wort (Hypericum perforatum), may contribute to photosensitivity (Brockmöller et al. 1997; Stein and Scheinfeld 2007). Psoralens are found in more than two dozen plant sources, including species of the Rutaceae (i.e., Ruta graveolens, Citrus aurantifolia, and C. bergamia), Apiaceae (i.e., Ammi majus and Apium graveolens), Fabaceae (Psoralea spp.), and Moraceae (Ficus carica) families (Bollero et al. 2001; Egan and Sterling 1993; Eickhorst et al. 2007; Maso et al. 1991; Thomson et al. 2007; Wagner et al. 2002; Wang et al. 2002).

Photoallergic reactions occur after light causes a substance to change from one that is non-allergenic to one that is allergenic. These reactions are less common than phototoxic reactions and are not dependent on the dose (which may be very small) of the substance taken or the amount of light exposure, but do require prior sensitization. Photoallergic reactions typically occur 24 hours or more after initial exposure and present as an eczema-like rash that may spread beyond the sun-exposed skin (Nigel et al. 2003; Stein and Scheinfeld 2007). Photoallergic reactions are exhibited as skin conditions characteristic of allergic contact dermatitis, with the reaction limited to sun-exposed areas of the body. However, when the reactions are severe or prolonged, they may extend into covered areas of skin (Stein and Scheinfeld 2007).

Photosensitivity associated with the use of common herbs such as St. John’s wort generally occurs at doses many times higher than standard recommended dosages, though there are exceptions. While photosensitivity reactions may occur after oral use of some botanicals, reactions are more common after topical use or accidental topical exposure. Fair-skinned individuals are more susceptible to developing photosensitivity than others. Severe reactions may occur during exposure to high levels of ultraviolet (UV) light, and especially during therapeutic UV treatment (Beattie et al. 2005).

Mechanism of action

Phototoxic reactions occur by light activation of plant compounds such as psoralens. The psoralen or other compound in the skin absorbs energy which increases the energy state of the compound’s electrons, creating an excited state. As the electrons return to ground state, energy is released that incites an inflammatory response and damages cellular molecules and organelles. Damage may occur from formation of radicals or by production of singlet oxygen, which then oxidizes cell structures (Stein and Scheinfeld 2007).

Photoallergic reactions occur after light causes a conversion from a non-allergenic substance to an allergenic substance (Nigel et al. 2003; Stein and Scheinfeld 2007). Radiant energy converts a compound (from a botanical or drug) in the skin into a photoactive compound, initiating an immunologic, cell-mediated hypersensitivity reaction. This can occur through the production of stable photodrugs, one of which acts as a hapten that conjugates with a carrier molecule to form an antigen (a substance that elicits production of antibodies). Alternatively, the compound may be converted by radiant energy to a higher energy state and, upon return to resting state, the released energy promotes conjugation of a compound to a carrier protein, forming a completely new antigen (Stein and Scheinfeld 2007).

Herbs listed in the Botanical Safety Handbook with potential photosensitizing action:

Angelica pubescens root
Apium graveolens fruit
Citrus ×aurantifolia peel
Citrus bergamia peel

Cullen corylifolia seed
Hypericum perforatum herb
Ruta graveolens herb

Literature Cited

Beattie, P.E., R.S. Dawe, N.J. Traynor, et al. 2005. Can St John's wort (hypericin) ingestion enhance the erythemal response during high-dose ultraviolet A1 therapy? Br. J. Dermatol. 153 (6):1187-91.

Bensky, D., S. Clavey, and E. Stöger. 2004. Chinese herbal medicine: Materia medica, 3rd edition. 3rd ed. Seattle: Eastland Press.

Bollero, D., M. Stella, A. Rivolin, et al. 2001. Fig leaf tanning lotion and sun-related burns: case reports. Burns 27 (7):777-9.

Brockmöller, J., T. Reum, S. Bauer, et al. 1997. Hypericin and Pseudohypericin: Pharmacokinetics and Effects on Photosensitivity in Humans. Pharmacopsych. 30:94-101.

Egan, C.L., and G. Sterling. 1993. Phytophotodermatitis: a visit to Margaritaville. Cutis 51 (1):41.

Eickhorst, K., V. DeLeo, and J. Csaposs. 2007. Rue the herb: Ruta graveolens-associated phytophototoxicity. Dermatitis 18 (1):52-5.

Maso, M.J., A.M. Ruszkowski, J. Bauerle, V.A. DeLeo, and F.P. Gasparro. 1991. Celery phytophotodermatitis in a chef. Arch. Dermatol. 127 (6):912.

Moore, D.E. 2002. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management. Drug Safety 25 (5):345-372.

Nigel, S., S.R. Knowles, and N.H. Shear. 2003. Drug eruptions: approaching the diagnosis of drug-induced skin diseases. J. Drugs Dermatol. 2 (3):278 -299.

Stein, K.R., and N.S. Scheinfeld. 2007. Drug-induced photoallergic and phototoxic reactions. Exp. Opin. Drug Safe. 6 (4):431-443.

Thomson, M.A., P.W. Preston, L. Prais, and I.S. Foulds. 2007. Lime dermatitis from gin and tonic with a twist of lime. Contact Derm. 56 (2):114-5.

Wagner, A.M., J.J. Wu, R.C. Hansen, H.N. Nigg, and R.C. Beiere. 2002. Bullous phytophotodermatitis associated with high natural concentrations of furanocoumarins in limes. Am. J. Cont. Derm. 13 (1):10-14.

Wang, L., B. Sterling, and P. Don. 2002. Berloque dermatitis induced by "Florida water". Cutis 70 (1):29-30.

Stimulant Laxatives

Written by Michael McGuffin, updated by Eric Yarnell, N.D.

Stimulant laxatives are agents used to relieve constipation by local stimulation and contraction of the smooth muscle of the lower bowel. This results in increased peristalsis that empties stools more quickly.

Adverse effects

Short-term side effects of stimulant laxative consumption may include intestinal cramps, uterine contractions, and watery diarrhea. Continuous use for more than 10 days can cause dependency, resulting in colonic atonicity requiring the aid of stimulant laxatives to have bowel movements. When used in excess or for long periods, the resultant loss of fluids and electrolytes, especially potassium, can cause pathological alterations to the colon, kidney malfunction, or heart palpitations. Patients taking cardiac glycosides are particularly susceptible to cardiotoxicity (De Smet 1993).

The American Herbal Products Association (AHPA) recommends the following labeling for products that contain Aloe spp. latex, Frangula alnus bark, Frangula purshiana bark, Rhamnus catahrtica fruit, Rheum spp. root/rhizome, and Senna spp. fruit (pod) and leaf:

NOTICE: Do not use this product if you have abdominal pain or diarrhea. Consult a health care provider prior to use if you are pregnant or nursing a baby. Discontinue use in the event of diarrhea or watery stools. Do not exceed recommended dose. Not for long-term use.

The State of California has established labeling requirements that supersede the AHPA recommendation for products sold in California. All dietary supplements that contain any of the above listed ingredients are required to bear the following label (California 2010):

NOTICE: This product contains [name of substance(s) and common name(s) if different]. Read and follow directions carefully. Do not use if you have or develop diarrhea, loose stools, or abdominal pain because [insert common name] may worsen these conditions and be harmful to your health. Consult your physician if you have frequent diarrhea or if you are pregnant, nursing, taking medication, or have a medical condition.

Beyond these regulations, stimulant laxatives must not be given to patients with eating disorders, and every attempt should be made to determine if such patients are abusing them. Chronic abuse by such patients has resulted in severe muscle damage, kidney failure, and death. Urine tests exist to detect the presence of anthraquinones in such patients (Roerig et al. 2010).

Cathartic laxatives can turn the urine and/or stool a red or dark color (Roerig et al. 2010). While this does not represent any health problem, people taking laxatives should be warned of this, so they do not mistake the color for blood and seek unnecessary health care.

The majority of evidence supports that, although anthraquinone-containing glycosides cause dark patches in the colon that can last for months (known as pseudomelanosis coli), this is not a precursor to nor does it increase the risk of colorectal cancer (Sonnenberg and Müller 1993).

While most stimulant laxatives have traditionally been contraindicated in pregnancy due to concerns regarding stimulation of the uterus, senna (Senna alexandrina) and sickle-pod senna (Senna obtusifolia, S. tora) has shown a lack of adverse effects on pregnancy or the fetus when used according to the recommended dosage schedule (Ács et al. 2010; ESCOP 2003). Thus, senna laxatives are now considered appropriate for use during the second and third trimesters of pregnancy (ESCOP 2003; Prather 2004). Due to the potential genotoxicity of certain anthraquinones, however, it is recommended that use of senna be avoided in the first trimester of pregnancy or used under professional supervision (ESCOP 2003).

Mechanism of action

The action of stimulant laxative herbs is, in most cases, due primarily to their content of anthraquinones. The one exception among the herbs listed in this category is castor oil (from Ricinus communis), the action of which is due to ricinoleic acid (Brunton et al. 2006).

Stimulant laxatives increase the motility of the colon, induce changes in the surface cells of the colon, and cause the loss of water and electrolytes. Although intensive research has been performed, the exact mechanism of action is still unclear. However, herbs that contain anthraquinones do affect the colonic mucosa and produce a laxative effect. Anthraquinones disturb the equilibrium between the absorption of water from the intestinal lumen (via an active sodium transport) and the secretion of water into the lumen by the hydrostatic blood pressure or a prostaglandin-dependent chloride secretion. Anthraquinone glycosides utilize the intestinal flora to produce a laxative effect and are stronger in action than anthraquinone aglycones, which are absorbed in the stomach and duodenum (De Smet 1993). Both aglycones and glycosides occur in Aloe, Rhamnus, and Rheum.

Herbs listed in the Botanical Safety Handbook as stimulant laxatives:

Aloe ferox latex
Aloe vera latex
Frangula alnus bark
Frangula purshiana bark
Ipomoea purga root
Iris versicolor rhizome, root
Iris virginica rhizome, root
Podophyllum peltatum root
Podophyllum hexandrum root
Reynoutria multiflora unprocessed root tuber

Aloe perryi latex
Rhamnus cathartica fruit
Rheum officinale rhizome, root
Rheum palmatum rhizome, root
Rheum tanguticum rhizome, root
Ricinus communis seed oil
Senna alexandrina fruit (pod), leaf
Senna obtusifolia fruit (pod), leaf
Senna tora fruit (pod), leaf

Literature Cited

Ács, N., F. Bánhidy, E.H. Puhó, and A.E. Czeizel. 2010. No association between severe constipation with related drug treatment in pregnant women and congenital abnormalities in their offspring: A population based case control study. Congen. Anom. 50 (1):15-20.

Brunton, L.L., J.S. Lazo, and K.L. Parker. 2006. Goodman & Gillman’s the pharmacological basis of therapeutics, 11th ed. New York: McGraw-Hill.

California. 2010. State of California, Title 17, California Code of Regulations, Section 10750.

De Smet, P.A.G.M. 1993. Adverse effects of herbal drugs volume 2. Berlin: Springer.

ESCOP. 2003. ESCOP Monographs: The scientific foundation for herbal medicinal products. 2nd ed., completely rev. and expand ed. New York: Thieme.

Prather, C.M. 2004. Pregnancy-related constipation. Curr. Gastroenterol. Reports 6 (5):402-404.

Roerig, J.L., K.J. Steffen, J.E. Mitchell, and C. Zunker. 2010. Laxative Abuse: Epidemiology, Diagnosis and Management. Drugs 70 (12):1487-1503.

Sonnenberg, A., and A. Müller. 1993. Constipation and cathartics as risk factors of colorectal cancer: A meta-analysis. Pharmacology 47 (Supp 1):224-33.

Appendix III.

Herbal Interaction Profiles

Pharmacokinetic drug interactions: CYP450 and P-glycoprotein

Written by Bill Gurley, Ph.D. and Zoë Gardner, Ph.D.(c)

Drug interactions are generally split into two classes. The first are pharmacodynamic interactions, which are interactions that happen due to additive or opposing effects of two different substances. Pharmacodynamic interactions can be predicted based on the biological activities of the different drugs or herbs (i.e., stimulants and sedatives have opposing effects). The second type of interactions, pharmacokinetic interactions, are unrelated to the therapeutic activity of the herbs and drugs being taken. Pharmacokinetic interactions involve enzymes or transporter proteins that metabolize drugs or compounds from herbs and foods or transport these substances into and out of cells. Several herbs and foods, and a number of drugs, can change the activity of these enzymes and proteins, which can be inhibited or induced, in turn influencing the blood levels of specific drugs or other compounds. While some changes in activity may be minor, with little change in the efficacy of herbs or drugs involved, other changes may produce clinically relevant interactions. In pharmacokinetic interactions, the severity of an interaction is based on the potential toxicity of the drug being used (in the case of increased blood levels of a drug) or the consequences of the therapeutic dose not being achieved (in the case of decreased blood levels of a drug). Until identified through testing or well-documented case reports, these interactions generally cannot be predicted. Once identified, however, these interactions can be easily avoided.

Once understood, herb-drug interactions may also be used therapeutically. Inhibition of drug metabolizing enzymes or transporter proteins, for example, can help increase or maintain levels of certain drugs in the blood or in cells, allowing for a reduced dose (and sometimes reduced side effects) of drugs or increased therapeutic activity (Dresser et al. 2000; Padowski and Pollack 2010). Therapeutic interactions are an emerging area of research, although few human studies have been completed (Bano et al. 1987; Kasibhatta and Naidu 2007).

While some foods and herbs, such as grapefruit (Citrus ×paradisi), St. John’s wort (Hypericum perforatum), and schisandra (Schisandra sphenanthera), have been shown to affect CYP450 enzymes or P-glycoprotein in a clinically significant manner, some other botanicals, such as black cohosh and milk thistle, have shown a lack of metabolic interactions in human studies (Fuhr et al. 2007; Gurley et al. 2006a; Gurley et al. 2006b; Gurley et al. 2008; Rajnarayana et al. 2004; Rao et al. 2007).

Cytochrome P450

The cytochrome P450 enzymes are known as a “superfamily” of enzymes found in nearly all living organisms. These enzymes are important in metabolizing a variety of compounds from foods, medicines, environmental contaminants, and compounds produced in the body. In humans, cytochrome P450 enzymes are primarily responsible for the initial metabolism (phase I) of many drugs to prepare them for conjugation (phase II) and then elimination. These enzymes are important for understanding potential drug interactions and an individual’s response to certain drugs (Danielson 2002).

CYP-based drug interactions

Certain CYP enzymes may be induced or inhibited by conventional drugs or by compounds in plants, leading to an increase or decrease in the activity of the enzyme. If a CYP enzyme is induced, plasma levels of drugs metabolized by that enzyme may be decreased, which, in turn, may result in plasma levels too low to be effective. For example, the compound hyperforin in St. John’s wort induces CYP3A4 and reduces plasma levels of cyclosporine, a drug used for immune system suppression in patients who have had organ transplants (Mai et al. 2004). This interaction has resulted in sub-therapeutic levels of cyclosporine, causing organ rejection in transplant patients (Barone et al. 2000; Breidenbach et al. 2000). Conversely, if a CYP enzyme is inhibited, metabolism of a drug metabolized by that enzyme will be slowed and plasma levels will increase, leading to potential overexposure and drug toxicity. Grapefruit juice is a well known inhibitor of CYP3A4 (David et al. 1998) and thus should not be consumed by patients taking drugs metabolized by CYP3A4.

Induction or inhibition of CYP enzymes occurs at different levels, with some inhibitors or inducers producing weak effects and others producing strong effects. For drugs with narrow therapeutic indices (a small difference between the effective dose and the toxic dose), a potentially “weak” induction or inhibition could result in significant adverse side effects (Huang et al. 2007). By understanding the effects of herbal products and drugs on different CYP enzymes and cross-referencing with known substrates, inducers, and inhibitors, potentially dangerous interactions can be avoided.

Effects on CYP enzymes have been shown to last several days, with patients drinking a single glass of grapefruit juice showing normal enzyme activity after three days, while those taking St. John’s wort for two weeks had normal enzyme activity one week after stopping St. John’s wort (Greenblatt et al. 2003; Imai et al. 2008). Such a multi-day time to return to normal enzyme activity suggests that simply separating ingestion of a CYP-metabolized drug and a CYP inducer or inhibitor by several hours is not sufficient to prevent interactions, and that products affecting CYP enzymes should not be used during treatment with CYP-metabolized drugs.

While most concern has been placed on herbs that can modify the effects of drugs, drugs may also modify the activity of herbs or herbal compounds. For example, drugs that inhibit CYP1A2 may slow the metabolism of caffeine (Carrillo and Benitez 2000; Christensen et al. 2002). While this is not likely to pose any risk with average caffeine consumption, persons taking a drug that inhibits CYP1A2 and drinking large amounts of coffee (10 cups or more daily) may experience prolonged or more pronounced effects of caffeine.

P-glycoprotein

P-glycoprotein (P-gp), also known as ABCB1, or multi-drug resistance protein 1 (MDR1), is a multi-drug efflux pump (a protein that removes drugs and related compounds from cells) that can move a wide variety of compounds across cellular membranes. P-gp is concentrated in the excretory tissues (liver and kidney) and in barrier tissues (intestines, blood-brain barrier, placental barrier, blood-testes barrier, and blood-ovary barrier), helping to detoxify or protect certain organs and the fetus (Cordon-Cardo et al. 1989; Fojo et al. 1987; Thiebaut et al. 1987). P-gp is also concentrated in tumor cells and is primarily responsible for multi-drug resistance found in some patients undergoing chemotherapy (Bellamy 1996).

P-glycoprotein-based drug interactions

Like CYP450 enzymes, P-gp can be both inhibited and induced. Induction of P-gp can lead to low plasma levels of P-gp-transported drugs, potentially reducing the efficacy of the drug. For example, St. John’s wort has been shown to induce P-gp, leading to reduced plasma levels of digoxin, a drug transported by P-gp and used to treat heart failure and abnormal heart rhythms (Durr et al. 2000; Johne et al. 1999). Inhibition of P-gp can lead to higher intracellular (inside the cell) levels of drugs transported by P-gp, resulting in potential drug toxicity.

Differences in human, animal, and in vitro study findings

To determine potential CYP450 interactions, in vitro, animal, and human studies are used, each with varying levels of accuracy for predicting clinically relevant interactions. While most research to date has been in vitro, the results of in vitro studies are often quite different from animal and human studies. Such differences may be caused by chemicals added to in vitro studies to promote uptake of some compounds that can exaggerate experimental findings by changing solubility that would otherwise limit uptake. In vitro studies sometimes use phytochemical concentrations that exceed those achieved in humans or other animals, or focus on isolated compounds that do not reflect the phytochemical complexity typical of extracts that may contribute to the bioactivity. Many compounds and extracts also undergo extensive metabolism in the intestines or liver, which may also change the bioactivity (Brinker 2009; Hines 1999; Markowitz et al. 2008; Venkataramanan et al. 2006). While animal studies may be more accurate in predicting clinically relevant drug interactions, these studies cannot be taken as conclusive, since large, non-physiological doses are often administered and, due to species variation in metabolism and transport, results are rarely generalizable to humans (Brinker 2009; Venkataramanan et al. 2006). In considering interaction ratings for herbs in this text, the types of evidence (human, animal, or in vitro) available were important for determining the level of concern for a potential interaction.

Literature Cited

Bano, G., V. Amla, R.K. Raina, U. Zutshi, and C.L. Chopra. 1987. The effect of piperine on pharmacokinetics of phenytoin in healthy volunteers. Planta Med. 53 (6):568-9.

Barone, G.W., B.J. Gurley, B.L. Ketel, M.L. Lightfoot, and S.R. Abul-Ezz. 2000. Drug interaction between St. John's wort and cyclosporine. Ann. Pharmacother. 34 (9):1013-6.

Bellamy, W.T. 1996. P-Glycoproteins and multidrug resistance. Ann. Rev. Pharmacol. Toxicol. 36 (1):161-183. Breidenbach, T.H., V. Kliem, M. Burg, et al. 2000. Profound drop of cyclosporin A whole blood trough levels caused by St. John's wort (Hypericum perforatum). Transplantation 69 (10):2229-30.

Brinker, F. 2009. Managing and interpreting the complexities of botanical research. HerbalGram 82:42-9. Carrillo, J.A., and J. Benitez. 2000. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin. Pharmacokinet. 39:127-153.

Christensen, M., G. Tybring, K. Mihara, et al. 2002. Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin. Pharmacol. Ther. 71 (3):141-152.

Cordon-Cardo, C., J.P. O'Brien, D. Casals, et al. 1989. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. P.N.A.S. U.S. 86 (2):695.

Danielson, P.B. 2002. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr. Drug Metab. 3 (6):561-597.

David, G.B., J. Malcolm, O. Arnold, and J.D. Spence. 1998. Grapefruit juice-drug interactions. Br. J. Clin. Pharmacol. 46 (2):101-110.

Dresser, G.K., J.D. Spence, and D.G. Bailey. 2000. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin. Pharmacokinet. 38 (1):41-57.

Durr, D., B. Stieger, G.A. Kullak-Ublick, et al. 2000. St John's Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clin. Pharmacol. Ther. 68 (6):598-604.

Fojo, A.T., K. Ueda, D.J. Slamon, et al. 1987. Expression of a multidrug-resistance gene in human tumors and tissues. P.N.A.S. U.S. 84 (1):265.

Fuhr, U., S. Beckmann-Knopp, A. Jetter, H. Luck, and U. Mengs. 2007. The effect of silymarin on oral nifedipine pharmacokinetics. Planta Med. 73 (14):1429-1435.

Greenblatt, D.J., L.L. von Moltke, J.S. Harmatz, et al. 2003. Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice. Clin. Pharmacol. Ther. 74 (2):121-129.

Gurley, B., M.A. Hubbard, D.K. Williams, et al. 2006a. Assessing the clinical significance of botanical supplementation on human cytochrome P450 3A activity: comparison of a milk thistle and black cohosh product to rifampin and clarithromycin. J. Clin. Pharmacol 46 (2):201-13.

Gurley, B.J., G.W. Barone, D.K. Williams, et al. 2006b. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Drug Metab. Dispos. 34 (1):69-74.

Gurley, B.J., A. Swain, M.A. Hubbard, et al. 2008. Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Mol. Nutr. Food Res. 52 (7):755-63.

Hines, E. 1999. Standardizing botanical extracts: can the part exceed the whole? Pharmaceut. Formulat. Qual. 3:28-33. Huang, S.M., R. Temple, D.C. Throckmorton, and L.J. Lesko. 2007. Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin. Pharmacol. Ther. 81 (2):298-304.

Imai, H., T. Kotegawa, K. Tsutsumi, et al. 2008. The recovery time-course of CYP3A after induction by St John's wort administration. Br. J. Clin. Pharmacol 65 (5):701-707.

Johne, A., J. Brockmoller, S. Bauer, et al. 1999. Pharmacokinetic interaction of digoxin with an herbal extract from St. John's wort (Hypericum perforatum). Clin. Pharmacol. Ther. 66 (Oct):338-345.

Kasibhatta, R., and M.U.R. Naidu. 2007. Influence of piperine on the pharmacokinetics of nevirapine under fasting conditions: a randomised, crossover, placebo-controlled study. Drugs R&D 8 (6):383-391.

Mai, I., S. Bauer, E.S. Perloff, et al. 2004. Hyperforin content determines the magnitude of the St John's Wort–cyclosporine drug interaction. Clin. Pharmacol. Ther. 76 (4):330-340.

Markowitz, J.S., L.L. von Moltke, and J.L. Donovan. 2008. Predicting interactions between conventional medications and botanical products on the basis of in vitro investigations. Molec. Nutr. Food Res. 52 (7):747-754.

Padowski, J.M., and G.M. Pollack. 2010. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Meth. Mol. Biol. 596:359-84.

Rajnarayana, K., M. Reddy, J. Vidyasagar, and D. Krishna. 2004. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Arzneim-Forsch 54 (2):109-113.

Rao, B.N., M. Srinivas, Y.S. Kumar, and Y.M. Rao. 2007. Effect of silymarin on the oral bioavailability of ranitidine in healthy human volunteers. Drug Metabol. Drug Interact. 22 (2-3):175-85.

Thiebaut, F., T. Tsuruo, H. Hamada, et al. 1987. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. P.N.A.S. U.S. 84 (21):7735.

Venkataramanan, R., B. Komoroski, and S. Strom. 2006. In vitro and in vivo assessment of herb drug interactions. Life Sci. 78 (18):2105-2115.

Mucilages

Written by Zoë Gardner, Ph.D.(c)

Definition

Mucilages are polysaccharides that form gels or viscous solutions when mixed with water. These compounds are highly branched and form large hydrophilic (water-loving) cage-like structures that are capable of trapping water (Williams et al. 2006). After being mixed with water, mucilaginous herbs swell to many times their original size as the water is absorbed (Mills and Bone 2000).

Mucilage-based drug interactions

Mucilages are a source of dietary fiber, and, like certain other sources of soluble fiber, are capable of inhibiting the absorption of some drugs (Brunton et al. 2006). To ensure complete absorption of drugs, mucilaginous plants should be taken at least one hour after other drugs or supplements (Wichtl 2004).

Mucilages may also inhibit the absorption of certain nutrients, so diabetics taking mucilaginous herbs should continue to monitor blood sugar levels (Ziai et al. 2005).

Drinking a glass of water with mucilaginous plants (especially when taken in powdered or granular form) is important to prevent the plant material from swelling in clumps and causing an obstruction in the esophagus or intestines (Angueira and Kadakia 1993; Frohna 1992; Herrle et al. 2004). Many mucilaginous herbs are also used as bulk-forming laxatives. See Appendix 2 for further information.

Herbs listed in the Botanical Safety Handbook containing mucilages*:

Alcea rosea root
Aloe ferox leaf gel
Aloe perryi leaf gel
Aloe vera leaf gel
Althaea officinalis root, leaf and flower
Laminaria digitata thallus
Laminaria hyperborea thallus
Laminaria japonica thallus

Laminaria setchellii thallus
Laminaria sinclairii thallus
Linum usitatissimum seed
Malva sylvestris leaf and flower
Nereocystis luetkeana thallus
Plantago arenaria seed, seed husk
Plantago asiatica seed, seed husk
Plantago ovata seed, seed husk
Trigonella foenum-graecum seed
Ulmus rubra bark

*Many other herbs, such as mullein (Verbascum thapsus) and cinnamon (Cinnamomum verum), contain small amounts of mucilages that are unlikely to interfere with drug or nutrient absorption.

Literature Cited

Angueira, C., and S. Kadakia. 1993. Esophageal and duodenal bezoars from Perdiem. Gastrointest. Endosc. 39 (1):110-1.

Brunton, L.L., J.S. Lazo, and K.L. Parker. 2006. Goodman & Gillman’s the pharmacological basis of therapeutics, 11th ed. New York: McGraw-Hill.

Frohna, W.J. 1992. Metamucil bezoar: an unusual cause of small bowel obstruction. Am J. Emerg. Med. 10 (4):393-5.

Herrle, F., T. Peters, C. Lang, et al. 2004. Bolus obstruction of pouch outlet by a granular bulk laxative after gastric banding. Obes. Surg. 14 (7):1022-4.

Mills, S., and K. Bone. 2000. Principles and practice of phytotherapy: Modern herbal medicine. New York: Churchill Livingstone.

Wichtl, M. 2004. Herbal Drugs and Phytopharmaceuticals: A handbook for practice on a scientific basis. 3rd ed. Boca Raton, FL: CRC Press.

Ziai, S.A., B. Larijani, S. Akhoondzadeh, et al. 2005. Psyllium decreased serum glucose and glycosylated hemoglobin significantly in diabetic outpatients. J. Ethnopharmacol. 102 (2):202-7.

Piperine

Written by Zoë Gardner, Ph.D.(c)

Piperine is an alkaloid found in black pepper (Piper nigrum), long pepper (Piper longum), cubeb (Piper cubeba) and grains-of-paradise (Aframomum melegueta), and is responsible in part for the pungent taste of these spices. In addition to being found naturally in these botanicals, isolated piperine is sometimes added to other herbal products to help increase absorption and bioavailability.

Piperine-based drug interactions

The compound piperine has been shown to increase the bioavailability of a number of drugs and other substances. Human studies have indicated that piperine generally increases the absorption and plasma concentrations and reduces the elimination rate of drugs including phenytoin (Bano et al. 1987; Pattanaik et al. 2006; Velpandian et al. 2001), carbamazepine (Pattanaik et al. 2009), propranolol (Bano et al. 1991), theophylline (Bano et al. 1991), rifampicin (Zutshi et al. 1985), nevirapine (Kasibhatta and Naidu 2007), and the supplements coenzyme Q10 (Badmaev et al. 2000) and curcumin (Shoba et al. 1998). Increases in the plasma levels of these substances have ranged from 30 to 120 percent. The standard dose of piperine used in human studies is 20 mg daily, though one study measured a delay in elimination of phenytoin in human subjects fed soup with black pepper (Velpandian et al. 2001). In many cases, increases in bioavailability can result in enhanced therapeutic effects, while in the case of drugs with a narrow therapeutic window (a small difference between the effective dose and the toxic dose), piperine and piperine-containing herbs may need to be used with caution.

Animal studies have shown that piperine can increase the bioavailability of the drug fexofenadine (Jin and Han 2010), the compounds curcumin, from turmeric (Shoba et al. 1998), and EGCG, from green tea (Lambert et al. 2004).

Mechanism of action

Piperine’s mechanism of enhancing bioavailability is not yet fully understood, although it is generally attributed to increased absorption, which may be due to alteration in membrane lipid dynamics and changes in the conformation of enzymes in the intestine (Khajuria et al. 2002).

An animal study demonstrated that piperine slowed the gastric emptying time and gastrointestinal transit time of solid foods (Bajad et al. 2001). An in vitro study suggested that piperine inhibited both the drug metabolizing isoenzyme CYP3A4 and the drug transporter protein P-gp (Bhardwaj et al. 2002; Han et al. 2008). Several studies have suggested that piperine acts as an MAO inhibitor (Rahman and Rahmatullah 2010).

Herbs listed in the Botanical Safety Handbook that contain piperine:

Aframomum melegueta fruit, seed
Piper cubeba unripe fruit
Piper longum fruit
Piper nigrum fruit

Literature Cited

Badmaev, V., M. Majeed, and L. Prakash. 2000. Piperine derived from black pepper increases the plasma levels of coenzyme q10 following oral supplementation. J. Nutr. Biochem. 11 (2):109-113.

Bajad, S., K.L. Bedi, A.K. Singla, and R.K. Johri. 2001. Piperine inhibits gastric emptying and gastrointestinal transit in rats and mice. Planta Med. 67 (2):176-179.

Bano, G., V. Amla, R.K. Raina, U. Zutshi, and C.L. Chopra. 1987. The effect of piperine on pharmacokinetics of phenytoin in healthy volunteers. Planta Med. 53 (6):568-9.

Bano, G., R.K. Raina, U. Zutshi, et al. 1991. Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers. Eur. J. Clin. Pharmacol. 41 (6):615-617.

Bhardwaj, R.K., H. Glaeser, L. Becquemont, et al. 2002. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J. Pharmacog. Exp. Ther. 302 (2):645-50.

Han, Y., T.M. Chin Tan, and L.Y. Lim. 2008. In vitro and in vivo evaluation of the effects of piperine on P-gp function and expression. Toxicol. Appl. Pharmacol. 230 (3):283-9.

Jin, M.J., and H.K. Han. 2010. Effect of piperine, a major component of black pepper, on the intestinal absorption of fexofenadine and its implication on food-drug interaction. J. Food Sci. 75 (3):H93-6.

Khajuria, A., N. Thusu, and U. Zutshi. 2002. Piperine modulates permeability characteristics of intestine by inducing alterations in membrane dynamics: influence on brush border membrane fluidity, ultrastructure and enzyme kinetics. Phytomed. 9 (3):224-231.

Lambert, J.D., J. Hong, D.H. Kim, V.M. Mishin, and C.S. Yang. 2004. Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice. J. Nutr. 134 (8):1948.

Pattanaik, S., D. Hota, S. Prabhakar, P. Kharbanda, and P. Pandhi. 2006. Effect of piperine on the steady-state pharmacokinetics of phenytoin in patients with epilepsy. Phytother. Res. 20 (8):683-686.

Pattanaik, S., D. Hota, S. Prabhakar, P. Kharbanda, and P. Pandhi. 2009. Pharmacokinetic interaction of single dose of piperine with steady-state carbamazepine in epilepsy patients. Phytother. Res. 23 (9):1281-6.

Rahman, T., and M. Rahmatullah. 2010. Proposed structural basis of interaction of piperine and related compounds with monoamine oxidases. Bioorg. Med. Chem. Lett. 20 (2):537-40.

Shoba, G., D. Joy, T. Joseph, et al. 1998. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med. 64:353-356.

Velpandian, T., R. Jasuja, R.K. Bhardwaj, J. Jaiswal, and S.K. Gupta. 2001. Piperine in food: interference in the pharmacokinetics of phenytoin. Eur. J. Drug Metab. Pharmacokinet. 26 (4):241-7.

Zutshi, R.K., R. Singh, U. Zutshi, R.K. Johri, and C.K. Atal. 1985. Influence of piperine on rifampicin blood levels in patients of pulmonary tuberculosis. J. Assoc. Physicians. India 33 (3):223-4.

Appendix IV.

Safety of Botanicals in Pregnancy and Lactation

Written by Aviva Romm

Introduction

Herbs have been used by women during pregnancy, to help prepare for birth, and to promote lactation since time immemorial, with texts and treatises dating at least back to ancient Egypt (O'Dowd 2001). Herbal medicines are still commonly used by childbearing women for a variety of reasons, for example, ginger to treat “morning sickness,” raspberry leaf (Rubus spp.) as a uterine tonic, or echinacea (Echinacea spp.) for colds (Ernst 2002; Gibson et al. 2001; Hepner et al. 2002; Pinn and Pallett 2002). Studies suggest the safety of these commonly used herbs during pregnancy. Two human clinical trials evaluated raspberry leaf for its effects on labor outcome and did not demonstrate any adverse effects (Parsons et al. 1999; Simpson et al. 2001). An observational study showed no harmful effects of echinacea when used during various stages of pregnancy (Gallo et al. 2000), and numerous studies have evaluated ginger root (Zingiber officinale) for the reduction of nausea and vomiting of pregnancy, finding it both safe and effective at the doses used (dried rhizome 1000 – 1500 mg per day) (Bryer 2005). There is considerable evidence that modern obstetric professionals such as midwives and obstetricians are recommending herbs during pregnancy, particularly for labor stimulation and for other concerns as well (Allaire et al. 2000; Chez and Jonas 1999; Hardy 2000; Hepner et al. 2002; Low Dog 2009; Pinn and Pallett 2002; Romm 2009b). Because pregnancy is the most sensitive time in human development, and many substances cross the placenta, questions have been raised about the safety of herbal medicines taken during pregnancy.

Similar safety concerns are raised about the safety of herbal remedies used by breastfeeding mothers. About one percent of any substance a lactating mother ingests will be passed to her baby through the breast milk; thus, while many herbs would likely be safe, we must also be mindful about the maternal ingestion of some herbal products during lactation. Consideration should also be given to the age of the infant, as there are considerable differences between the liver and kidney function of a 4-week old and a 12-month old infant (Humphrey and McKenna 1997).

Most herbs have not been evaluated for safety in the childbearing cycle; thus, there is little scientific evidence to support or refute their safety during this time. Ethical considerations surrounding experimentation on pregnant women and the need for large sample sizes severely limit human clinical investigation during pregnancy (Hepner et al. 2002; Low Dog 2009; Romm 2009b). This chapter elucidates some of the key issues surrounding the use of herbs during pregnancy and lactation, and explains the careful process involved in creating the pregnancy and lactation safety ratings found in this book.

Contraindicated herb lists and botanical safety classifications

The herbal literature is rife with lists of herbs contraindicated in pregnancy and lactation. There are limitations inherent in most lists, particularly in their lack of specifics as to how, when, and why each herb is contraindicated. Herbs may sometimes be broadly contraindicated in pregnancy yet in actuality be only contextually contraindicated. For example, some herbs are absolutely contraindicated during the first and second trimesters but may be reasonably used during labor, or they may be safe in small doses for a very limited duration. Culinary herbs, appearing on many contraindicated lists, represent no harm to the fetus or mother when ingested in the small amounts typically used as food seasonings,. Herbs such as goldenseal root (Hydrastis canadensis) may be used topically with no risk but should be avoided for internal use, yet are contraindicated on such lists with no differentiation, leading to confusion about safety. Certain contraindications have become pervasive myths; for example, the frequent contraindication of chamomile (Matricaria recutita) in pregnancy due to its alleged action as an abortifacient (McKenna et al. 2002). In fact, chamomile provides an excellent example of how misapplication of a scientific finding can lead to unjustified contraindication of a safe herb. A study conducted in 1979 found that a concentrated extract of the compound α-bisabolol caused birth defects at high doses. No birth defects were seen at lower doses, and the dose of α-bisabolol required to cause defects is far greater than would be possible to ingest by someone drinking the tea. However, based on this single study, chamomile continues to be improperly contraindicated for consumption during pregnancy (Low Dog 2004).

Finally, herbs may be contraindicated based on limited or conflicting information. For example, information on traditional use indicates that ashwagandha (Withania somnifera) is used as both an “abortifacient” (Badhwar and Chopra 1946; Casey 1960; Chadha 1976) and as a “pregnancy tonic” (Kapoor 1990; Tirtha 1998; Upton 2000). However, no details are available regarding plant part, doses used, and duration of use. A more recent study in animals indicated a lack of adverse effects of ashwagandha in pregnancy (Sharma et al. 1986). To complicate matters, certain herbs that are contraindicated by western herbalists for use during pregnancy may be routinely used in traditional medicines of non-western cultures. For example, dong quai is prescribed in blood tonic formulas for pregnant women in China, and listed in official Chinese and Japanese texts for the prevention of miscarriage, yet is considered contraindicated for use in pregnancy by some western herbalists (Brinker 2001; Mills and Bone 2005).

Safety of herbs in pregnancy and lactation

There is a lack of human clinical trials on the safety or efficacy for many botanical therapies during pregnancy. Risks associated with the use of herbs during pregnancy include:

Toxicity to the mother which might indirectly affect the embryo/fetus
Direct teratogenicity, mutagenicity, or fetal toxicity
Abortifacient activity
Poor neonatal outcomes
Delayed administration of necessary medical therapy in favor of herbs, regardless of their safety (Mills and Bone 2005; Romm 2009b).

In general, most herbs on the market in the U.S. have a relatively high track record of safety, with few case reports of adverse effects (Hansten 2000). Negative outcomes have been reported for only a very limited number of herbal products used by women in or about to be in labor (Beal 1998; Ernst 2002; Mabina et al. 1997; Romm 2009a). When apparent adverse events have occurred, cause and effect have been difficult to establish due to a wide range of confounding factors (Ernst and Schmidt 2002). Adverse events have typically involved the consumption of known toxic herbs, contaminated or adulterated herbal products, or inappropriate use or dosage of specific botanical therapies. However, lack of proof of harm is not synonymous with proof of safety. Some of the harmful effects of herbs may not be readily apparent until after they have been discontinued, or may only occur with cumulative use. Some researchers therefore believe that, in the absence of scientific proof of safety, herbs that are used for therapeutic reasons should be avoided during pregnancy (Ernst 2002). However, many practitioners, including herbalists, naturopaths, and midwives, continue to use herbs based on historical data and observational evidence, tempered by the knowledge that many pharmaceutical preparations recommended during pregnancy also carry unknown risks (Low Dog 2004; Romm 2009b).

After much careful consideration, the editors of this text deemed that the most reasonable standard on which to base pregnancy safety ratings is a combination of the best available evidence including:

Clinical evidence in the medical/scientific literature
Animal and in vitro studies
Case reports
Known and suspected mechanisms of action of the herb
Safety and bioavailability of the herb in the form most likely to be used (i.e., powder, tea, tincture, concentrated extract, etc.)
Dose of the herb typically ingested and typical duration of use
Clinical (empiric, observational) consensus of safety/risk
Chemical constituent profile
- teratogenicity
- toxicity
- bioavailability
- mutagenicity
- extractability
Historical information and traditional use as derived from a circumscribed set of approved texts and sources

There are virtually no formal studies that can definitively make a determination that a particular herb, or drug for that matter, is absolutely safe during pregnancy. There are also a number of botanicals for which there are little data or clinical experience regarding their use in pregnancy and lactation. It is the opinion of the editors that the absence of formal data and clinical experience regarding the use of a botanical in pregnancy or lactation, in and of itself, is not justification to contraindicate the botanical in pregnancy and lactation. In cases where there is neither substantial historical nor scientific data, the editors have used their best judgment in looking at the totality of the data available to make the most appropriate determination. However, consumers and health professionals should be cautioned about taking any botanical in pregnancy and lactation regardless of its classification. This is especially true for those botanicals for which there is insufficient traditional or scientific evidence of safety. For such botanicals, the following Editors’ Note was included to highlight the relative lack of data specifically regarding use in pregnancy and lactation, but also a lack of data to suggest that any safety concern exists:

No information on the use of wild lettuce during pregnancy or lactation was identified in the scientific or traditional literature. While this review did not identify any concerns for pregnant or lactating women, safety has not been conclusively established.

Herbal medicines may be used during lactation for a variety of concerns, ranging from increasing the quantity of breast milk (lactagogues) to the treatment of any number of postpartum or common general conditions. The risks of using herbs during lactation appear to be less significant than in pregnancy, as only very small quantities of plant constituents ingested by the mother actually pass into the breast milk, and risks of birth defects and abortifacient activity are no longer present (Humphrey 2009). However, quantification of chemical constituents from herbal medicines appearing in breast milk has not been conducted for most herbs, so some element of caution is still required. As with pregnancy, it is prudent to avoid known toxic herbs or those with possible effects on still developing biological systems, such as the nervous and endocrine systems. The editors of this text have taken these points into consideration when assigning safety classifications to herbs in pregnancy and lactation.

Emmenagogues, uterine stimulants, abortifacients and partus preparator

Much of the literature on these categories comes from late 19th century references, such as Felter & Lloyd's King's American Dispensatory (Felter and Lloyd 1898), as well as the experience of contemporary practicing herbalists.

Historically, as in modern times, the term emmenagogue has referred to a plant or substance that was used with the intention of bringing about menstruation (Santow 2001). For this reason, many of these herbs have been contraindicated during pregnancy. While some of these herbs were undoubtedly used as abortifacients, it is also quite plausible that a number were used to nourish and strengthen a woman who might have lost her menstrual cyclicity due to anemia, malnourishment, or severe stress. This has led to considerable disagreement about what should and shouldn’t be called an emmenagogue. Those that are considered to be unsafe during pregnancy include rue (Ruta graveolens), Scotch broom (Cytisus scoparius), tansy (Tanacetum vulgare), thuja (Thuja occidentalis), wormwood (Artemisia absinthium), and pennyroyal (Mentha pulegium).

Uterine tonics have been used historically with the belief that they improve the strength and tone of the uterine muscle, while uterine stimulants were thought to bring on menses or induce labor. Although both of these are important categories in modern herbal therapeutics, there is little understanding or research regarding their mechanism of action, effective doses, or safety. Some herbs, such as dong quai (Angelica sinensis), are considered by some sources to be emmenagogues but are also believed to have both uterine relaxant and uterine stimulatory activity, and are used in Chinese and Japanese herbal formulas for the prevention of miscarriage (Chen and Chen 2004; Liang 2004; Upton 2003; Zhu 1998). Clearly, this is an area where more research is needed. Herbs that are intentionally being used to induce labor should be administered under the direct supervision of a qualified and experienced individual, usually a midwife, knowledgeable in such therapies.

Abortifacients are herbs used to facilitate a miscarriage or induce abortion. How effective these herbs are for inducing abortion is unknown; however, the amount required to terminate pregnancy is likely enough to pose significant risk to the mother’s health, including kidney and liver damage, and may not result in a successful abortion attempt. However, because the risks of these herbs to the fetus are unknown, women who have attempted to abort unsuccessfully may be well advised to obtain a clinical abortion. Abortifacients should be entirely avoided during pregnancy, and herbal abortion is not a recommended method of intentional pregnancy termination (also see Abortifacients in Appendix 2).

Partus preparators are herbs generally taken during the last few weeks of pregnancy and were historically used to facilitate a timely delivery. Blue cohosh (Caulophyllum thalictroides) is the herb most commonly used for this purpose. Case reports of adverse events, along with the activity of different compounds present in blue cohosh (see entry for Caulophyllum thalictroides) suggest that it should be avoided as a partus preparator, with use limited to short term application to induce or augment labor, and then only with the proper guidance and monitoring of an expert qualified in the appropriate use of the selected herb or formula (Jones and Lawson 1998; Wright 1999).

Teratogens and mutagens

Teratogens are substances that cause structural abnormalities and other birth defects in the fetus. There is extremely limited knowledge about which herbs may act as teratogens. Most of what is known is derived primarily from animal studies, observation of teratogenesis in grazing animals, and from human ingestion of suspected harmful herbal products. The primary means for identifying the propensity for this type of reaction is through toxicological screenings or through pharmacovigilance programs (monitoring of drugs and supplements for adverse effects).

Mutagens are substances that cause genetic mutations in cells. The potential for mutagenicity is typically discerned through in vitro assays followed by animal studies. In both types of tests, isolated compounds rather than whole herbs are most often investigated. While in vitro tests can be useful, they are generally quite limited for extrapolation to human use. The presence of a mutagen in an herb does not automatically contraindicate its use in pregnancy. There are many commonly consumed plants such as basil (Ocimum basilicum), black pepper (Piper nigrum), coffee (Coffea arabica), tomatoes (Solanum lycopersicum), and potatoes (Solanum tuberosum) that contain compounds with mutagenic potential (ACHS 1996). However, consumption of these in pregnancy is not contraindicated when consumed as a normal part of the diet, and the presence of such compounds in a food or herb does not mean that this substance crosses the placenta or reaches the fetus in appreciable or clinically significant quantities.

Phytoestrogens

Phytoestrogens are weak forms of plant estrogens found in numerous plants, including common foods such as beans and other legumes (most notably soy foods) and dark leafy greens (Franke et al. 1994; Kuiper et al. 1998). Some traditional Asian diets, which include large amounts of tofu and other soy products, are particularly high in phytoestrogens, but abnormal levels of fetal and neonatal problems have not been observed when compared to other populations. Nonetheless, there is concern that consumption of concentrated doses of phytoestrogens (i.e. isolated soy isoflavones) during pregnancy may exert abnormal hormonal effects on the developing embryo or fetus, particularly in female embryogenesis, as occurred with the drug diethylstilbestrol (DES), a synthetic non-steroidal estrogen. Although the amounts found in plant sources are incomparably minute compared to DES (Kuiper et al. 1998), it is generally recommended that women not supplement with concentrated phytoestrogen products such as soy isoflavone concentrates during pregnancy. Additionally, herbs with known or suspected estrogenic activity or activity on the endocrine system, including hops, alfalfa, or red clover, are best avoided for long term use or in large doses during pregnancy.

Nervous system stimulants or depressants

Herbs which strongly affect the nervous system, including stimulants such as ephedra (Ephedra sinica), guarana (Paullinia cupana), coffee (Coffea arabica), or green and black teas (Camellia sinensis), may have adverse effects on pregnancy and the developing fetal nervous system. Caffeine should be avoided or limited to no more than 300 mg (approx. 3 cups coffee) per day during pregnancy (ADA 2008). Kava (Piper methysticum), a strong anxiolytic and sedative herb, has been implicated in a number of cases of liver toxicity (Teschke et al. 2008). While causality is uncertain, kava should be avoided during pregnancy and lactation until the relationship between kava and liver toxicity is fully understood.

Summary

Women may turn to herbs for the relief of common complaints and concerns that arise during pregnancy, childbirth, and breastfeeding. The power of herbs should be respected and, therefore, used with caution during the childbearing cycle. However, a number of herbs have been contraindicated in modern herbal literature on the basis of very limited findings and erroneous or incomplete reports. Consumers, manufacturers, and practitioners need to be educated when it comes to the safe use of herbal medicine during pregnancy and lactation. Further research needs to be conducted not only into the safety and efficacy of herbs for both the mother and her baby, but also a comparative safety analysis should be done on herbs and pharmaceuticals commonly used during pregnancy. The editors of this text have done their best to shine light on a complicated subject by providing a safety ranking to help health care professionals, manufacturers, and consumers differentiate those herbs which are generally considered safe from those which should be avoided during pregnancy and lactation.

References

ACHS. 1996. Does nature know best? Natural carcinogens and anticarcinogens in America’s food. New York: American Council on Science and Health.

Ács, N., F. Bánhidy, E.H. Puhó, and A.E. Czeizel. 2009. Senna treatment in pregnant women and congenital abnormalities in their offspring: A population-based case-control study. Repro. Toxicol. 28 (1):100-104.

ADA. 2008. Position of the American Dietetic Association: Nutrition and lifestyle for a healthy pregnancy outcome. J. Am. Diet. Assoc. 108:553-61.

Allaire, A.D., M.K. Moos, and S.R. Wells. 2000. Complementary and alternative medicine in pregnancy: a survey of North Carolina certified nurse-midwives. Obstet. Gynecol. 95 (1):19-23.

Badhwar, R.L., and I.C. Chopra. 1946. Reputed abortifacient plants of India. Ind. J. Agric. Sci. 16:342-355.

Beal, M.W. 1998. Women's use of complementary and alternative therapies in reproductive health care. J. Nurse-Midwifery 43 (3):224-234.

Brinker, F. 2001. Herb contraindications and drug interactions. 3rd ed. Sandy, OR: Eclectic Medical Publications.

Bryer, E. 2005. A literature review of the effectiveness of ginger in alleviating mild-to-moderate nausea and vomiting of pregnancy. J. Midwifery Womens Health 50 (1):e1-3.

Casey, R. 1960. Alleged antifertility plants of India. Indian J. Med. Res. 14:590-600.

Chadha, Y. 1976. The wealth of India; a dictionary of Indian raw materials and industrial products. New Delhi: Council of Scientific and Industrial Research.

Chen, J.K., and T.T. Chen. 2004. Chinese medical herbology and pharmacology. City of Industry, CA: Art of Medicine Press.

Chen, Z., and J.R. Huo. 2010. Hepatic veno-occlusive disease associated with toxicity of pyrrolizidine alkaloids in herbal preparations. Neth. J. Med. 68 (6):252-60.

Chez, R.A., and W.B. Jonas. 1999. Complementary and alternative medicine. Part I: clinical studies in obstetrics. Obstet. Gynecol. Survey 54 (11):118-22.

Ernst, E. 2002 Herbal medicinal products during pregnancy: are they safe? B.J.O.G. 109 (3):227-235.

Ernst, E., and K. Schmidt. 2002. Health risks over the internet: advice offered by “medical herbalists” to a pregnant woman. Wien. Med. Wschr. 152 (78):190-192.

Felter, H.W., and J.U. Lloyd. 1898. King's American dispensatory. Cincinnati: Ohio Valley Co.

Franke, A.A., L.J. Custer, C.M. Cerna, and K.K. Narala. 1994. Quantitation of phytoestrogens in legumes by HPLC. J. Agric. Food Chem. 42 (9):1905-13.

Gallo, M., M. Sarkar, W. Au, et al. 2000. Pregnancy outcome following gestational exposure to echinacea: a prospective controlled study. Arch. Int. Med. 160 (20):3141-3143.

Gibson, P.S., R. Powrie, and J. Star. 2001. Herbal and alternative medicine use during pregnancy: a cross-sectional survey. Obstet. Gynecol. 97 (4):S44-S45.

Hansten, P. 2000. Managing drug interactions with herbal products. A.S.H.P. Midyear Clinical Meeting. 35:102.

Hardy, M.L. 2000. Herbs of special interest to women. J. Am. Pharm. Assoc. 40 (2):234-9.

Hepner, D.L., M. Harnett, S. Segal, et al. 2002. Herbal medicine use in parturients. Anesth. Analg. 94 (3):690.

Humphrey, S. 2009. A comprehensive review of safety considerations and breastfeeding concerns for the mother-infant dyad. In Romm, A., Botanical medicines for women's health. St. Louis: Churchill Livingstone Elsevier.

Humphrey, S.I., and D.J. McKenna. 1997. Herbs and breastfeeding. Breastfeed. Abstr. 17 (2):11-12.

Jones, T.K., and B.M. Lawson. 1998. Profound neonatal congestive heart failure caused by maternal consumption of blue cohosh herbal medication. J. Pediatr. 132 (3):550-552.

Kapoor, L. 1990. CRC Handbook of Ayurvedic medicinal plants. Boca Raton, FL: CRC Press.

Kuiper, G.G.J.M., J.G. Lemmen, B.O. Carlsson, et al. 1998. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor ß. Endocrinol. 139 (10):4252-63.

Liang, L. 2004. Acupuncture & IVF. Boulder, CO: Blue Poppy Enterprises.

Low Dog, T. 2004. Women's health in complementary and integrative medicine: A clinical guide. St Louis: Elsevier.

Low Dog, T. 2009. The use of botanicals during pregnancy and lactation. Altern. Ther. Health. Med. 15 (1):54-8.

Mabina, M.H., S.B. Pitsoe, and J. Moodley. 1997. The effect of traditional herbal medicines on pregnancy outcome. S.A.J.M. 87 (8):1008-10.

McKenna, D., K. Jones, K. Hughes, and S. Humphrey. 2002. Botanical medicines: The desk reference for major herbal supplements. New York: Haworth Press.

Mills, S., and K. Bone. 2005. The essential guide to herbal safety. St Louis: Elsevier

O'Dowd, M. 2001. The history of medications for women: Materia medica woman. New York: Parthenon Publishing Group.

Parsons, M., M. Simpson, and T. Ponton. 1999. Raspberry leaf and its effect on labour: safety and efficacy. Austral. Coll. Midwives J. 12 (3):20-25.

Pinn, G., and L. Pallett. 2002. Herbal medicine in pregnancy. Comp. Ther. Nurs. Midwif. 8 (2):77-80.

Romm, A. 2009a. Blue cohosh: history, science, safety, and midwife prescribing of a potentially fetotoxic herb. New Haven: Yale University School of Medicine.

Romm, A. 2009b. Botanical medicines for women's health. St Louis: Elsevier.

Santow, G. 2001. Emmenagogues and abortifacients in the twentieth century: An issue of ambiguity. In Regulating Menstruation: Beliefs, Practices, Interpretations. In Van de Walle, É. and E.P. Renne. Chicago: University of Chicago Press.

Sharma, S.S., S. Dahanukar, and S. Karandikar. 1986. Effects of long-term administration of the roots of ashwagandha (Withania somnifera) and shatavari (Asparagus racemosus) in rats. Indian Drugs 23:133-9.

Simpson, M., M. Parsons, J. Greenwood, and K. Wade. 2001. Raspberry leaf in pregnancy: its safety and efficacy in labor. J. Midwif. Womens Health 46 (2):51-59.

Teschke, R., A. Schwarzenboeck, and K.H. Hennermann. 2008. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur. J. Gastroenterol. Hepatol. 20 (12):1182-93.

Tirtha, S. 1998. The Ayurveda encyclopedia. Bayville, NY: Ayurvedic Holistic Center.

Upton, R. 2000. Ashwagandha root: Withania somnifera: Analytical, quality control, and therapeutic monograph. Santa Cruz, CA: American Herbal Pharmacopoeia.

Upton, R. 2003. Dang gui root: Angelica sinensis (Oliv.) Diels: Standards of analysis, quality control, and therapeutics. Scotts Valley, CA: American Herbal Pharmacopoeia.

Wright, I.M. 1999. Neonatal effects of maternal consumption of blue cohosh. J Pediatr 134 (3):384-5.

Zhu, Y. P. 1998. Chinese materia medica: Chemistry, pharmacology and applications. Amsterdam: Harwood Academic Publishers.

Appendix V.

Herb Listings by Classification

Lists are provided below of all of the plants classified in the main section of the text in either Safety Class 2a, 2b, 2c, or 3, or in Interaction Class B or C. Note that the restrictions described for plants in each of these Safety Classes (as well as in Class 2d, not listed here) apply unless otherwise directed by an expert qualified in the use of the described substance.

The lists presented here are provided as a compilation of the classifications found at individual entries in the text. Additional information, including in some cases exceptions to one of these classifications, may be found at specific entries.

Safety Class 2a: For external use only.

Alkanna tinctoria root
Borago officinalis herb
Eutrochium fistulosum herb, rhizome, root
Eutrochium maculatum herb, rhizome, root
Eutrochium purpureum herb, rhizome, root
Lawsonia inermis leaf
Mentha pulegium herb essential oil
Symphytum asperum leaf, root
Symphytum officinale leaf, root
Symphytum ×uplandicum leaf, root

Safety Class 2b: Not to be used during pregnancy.

Achyranthes bidentata root
Actaea racemosa rhizome
Adiantum capillus-veneris herb
Adiantum pedatum herb
Agathosma betulina leaf
Agathosma crenulata leaf
Agathosma serratifolia leaf
Albizia julibrissin bark
Alkanna tinctoria root
Aloe ferox latex
Aloe perryi latex
Aloe vera latex
Andrographis paniculata herb
Angelica archangelica fruit, root
Angelica atropurpurea fruit, root
Anthriscus cerefolium herb
Apium graveolens fruit
Aralia racemosa rhizome
Artemisia abrotanum herb
Artemisia absinthium herb
Artemisia annua above-ground parts
Artemisia douglasiana herb
Artemisia lactiflora herb
Artemisia vulgaris herb
Asclepias asperula root
Asclepias tuberosa root
Baptisia tinctoria root
Berberis vulgaris root, root bark
Boswellia sacra gum resin
Boswellia serrata gum resin
Capsella bursa-pastoris herb
Carica papaya leaf
Carthamus tinctorius flower
Catharanthus roseus herb
Caulophyllum thalictroides root
Chamaemelum nobile flower
Changium smyrnioides root
Chelidonium majus herb
Chrysopogon zizanioides root
Cinchona calisaya bark
Cinchona officinalis bark
Cinchona pubescens bark
Cinnamomum aromaticum bark
Cinnamomum camphora distillate of the wood
Cinnamomum verum bark
Coix lacryma-jobi seed
Commiphora madagascariensis gum resin
Commiphora molmol gum resin
Commiphora myrrha gum resin
Commiphora wightii gum resin
Coptis chinensis rhizome
Coptis trifolia rhizome
Corydalis yanhusuo tuber
Crocus sativus stigma
Cullen corylifolium seed
Curculigo orchioides rhizome
Curcuma zedoaria rhizome
Cyathula officinalis root
Daemonorops draco resin
Daucus carota ssp. carota seed
Equisetum hyemale above-ground parts
Eschscholzia californica whole plant in flower
Eucalyptus globulus essential oil
Euonymus atropurpureus root bark
Eutrochium fistulosum herb, rhizome, root
Eutrochium maculatum herb, rhizome, root
Eutrochium purpureum herb, rhizome, root
Ferula assa-foetida oleo gum resin
Ferula foetida oleo gum resin
Fouquieria splendens stem
Frangula alnus bark
Frangula purshiana bark
Fraxinus americana bark
Genista tinctoria flower, herb
Glycyrrhiza echinata rhizome, root
Glycyrrhiza glabra rhizome, root
Glycyrrhiza uralensis rhizome, root
Gossypium herbaceum root bark

Gossypium hirsutum root bark
Hedeoma pulegioides herb
Hepatica nobilis var. obtusa herb
Hydrastis canadensis rhizome, root
Hyssopus officinalis herb
Iris versicolor rhizome, root
Iris virginica rhizome, root
Juniperus communis fruit
Juniperus monosperma fruit
Juniperus osteosperma fruit
Juniperus oxycedrus fruit
Juniperus virginiana berry, leaf
Larrea tridentata leaf
Leonurus cardiaca herb
Leonurus japonicus above-ground parts, herb
Leonurus sibiricus above-ground parts, herb
Ligusticum porteri rhizome
Ligusticum sinense ‘Chuanxiong’ rhizome
Ligusticum wallichii rhizome
Lobelia inflata herb
Lobelia siphilitica herb
Lomatium dissectum root
Lycopus americanus herb
Lycopus europaeus herb
Lycopus virginicus herb
Magnolia biondii flower bud
Magnolia denudata flower bud
Magnolia officinalis bark, root bark
Magnolia sprengeri flower bud
Magnolia virginiana bark
Marrubium vulgare herb
Mentha ×piperita essential oil
Mentha pulegium essential oil
Mentha pulegium herb
Monarda clinopodia herb
Monarda didyma herb
Monarda fistulosa herb
Monarda pectinata herb
Monarda punctata herb
Morinda citrifolia fruit
Mucuna pruriens root, seed
Myristica fragrans aril, seed
Nardostachys jatamansi rhizome, root
Ocimum basilicum leaf
Ocimum gratissimum above-ground parts
Paeonia suffruticosa root bark
Pausinystalia johimbe bark
Phyllanthus amarus above-ground parts, whole plant
Phyllanthus fraternus above-ground parts, whole plant
Phyllanthus niruri above-ground parts, whole plant
Picrasma excelsa bark, root, wood
Piper longum fruit
Piper methysticum rhizome, root
Polygala senega root
Polygala sibirica root
Polygala tenuifolia root
Portulaca oleracea above-ground parts
Punica granatum fruit husk
Quassia amara bark, root, wood
Rhamnus cathartica fruit
Rheum officinale rhizome, root
Rheum palmatum rhizome, root
Rheum palmatum var. tanguticum rhizome, root
Ricinus communis seed oil
Ruta graveolens herb
Salvia miltiorrhiza root
Salvia officinalis leaf
Sanguinaria canadensis rhizome, root
Sassafras albidum root
Spigelia marilandica root
Symphytum asperum leaf, root
Symphytum officinale leaf, root
Symphytum ×uplandicum leaf, root
Tanacetum parthenium herb
Tanacetum vulgare herb
Taxus brevifolia needles
Terminalia arjuna bark
Thuja occidentalis leaf
Thymus vulgaris herb
Tribulus terrestris above-ground parts
Tribulus terrestris fruit
Trigonella foenum-graecum seed
Trillium erectum root
Tussilago farfara flower bud
Tussilago farfara leaf
Uncaria tomentosa root bark, stem bark
Verbena hastata herb
Verbena officinalis ssp. officinalis herb
Viscum album herb
Withania somnifera root
Zanthoxylum americanum bark
Zanthoxylum bungeanum fruit pericarp
Zanthoxylum clava-herculis bark
Zanthoxylum schinifolium fruit pericarp
Zanthoxylum simulans fruit pericarp
Ziziphus jujuba var. spinosa seed

Safety Class 2c: Not to be used while nursing.

Alkanna tinctoria root
Aloe ferox latex
Aloe perryi latex
Aloe vera latex
Artemisia absinthium herb
Chelidonium majus herb
Euonymus atropurpureus root bark
Eutrochium fistulosum herb, rhizome, root
Eutrochium maculatum herb, rhizome, root
Eutrochium purpureum herb, rhizome, root
Frangula alnus bark
Frangula purshiana bark
Hedeoma pulegioides herb
Lycopus americanus herb
Lycopus europaeus herb
Lycopus virginicus herb
Mentha pulegium essential oil
Mentha pulegium herb

Ligusticum wallichii rhizome
Lobelia inflata herb
Pausinystalia johimbe bark
Piper methysticum rhizome, root
Rhamnus cathartica fruit
Rheum officinale rhizome, root
Rheum palmatum rhizome, root
Rheum palmatum var. tanguticum rhizome, root
Symphytum asperum leaf, root
Symphytum officinale leaf, root
Symphytum ×uplandicum leaf, root
Tanacetum vulgare herb
Thuja occidentalis leaf
Tussilago farfara flower bud
Tussilago farfara leaf

Safety Class 3: For use only under the supervision of qualified expert.

Aconitum carmichaelii prepared root
Acorus calamus rhizome
Acorus gramineus rhizome
Apocynum androsaemifolium root
Apocynum cannabinum root
Arisaema amurense prepared rhizome
Arisaema erubescens prepared rhizome
Arisaema heterophyllum prepared rhizome
Arnica latifolia root, rhizome, whole plant
Arnica montana root, rhizome, whole plant
Atropa belladonna leaf
Buxus sempervirens leaf
Cephaelis ipecacuanha rhizome
Convallaria majalis entire plant
Cytisus scoparius flowering top

Digitalis purpurea leaf
Digitalis lanata leaf
Dryopteris filix-mas rhizome
Ipomoea purga root
Melia azedarach bark, fruit, root bark
Phoradendron leucarpum herb
Phytolacca americana root
Pilocarpus jaborandi leaf
Pilocarpus microphyllus leaf
Pilocarpus pennatifolius leaf
Pinellia ternata prepared rhizome
Podophyllum hexandrum rhizome, root
Podophyllum peltatum root
Prunus armeniaca seed
Prunus persica leaf, seed, twig
Reynoutria multiflora unprocessed root tuber
Stillingia sylvatica root
Veratrum viride root

Interaction Class B: Herbs for which clinically relevant interactions are biologically plausible.

Apocynum androsaemifolium
Apocynum cannabinum root
Astragalus mongholicus root
Carthamus tinctorius flower
Commiphora wightii gum resin
Convallaria majalis entire plant
Cytisus scoparius flowering top
Ginkgo biloba leaf
Glycyrrhiza echinata rhizome, root
Glycyrrhiza glabra rhizome, root
Glycyrrhiza uralensis rhizome, root
Lycopus americanus herb
Lycopus europaeus herb
Lycopus virginicus herb
Panax quinquefolius root

Pausinystalia johimbe bark
Pilocarpus jaborandi leaf
Pilocarpus microphyllus leaf
Pilocarpus pennatifolius leaf
Piper longum fruit
Piper methysticum rhizome, root
Piper nigrum fruit
Scutellaria baicalensis root
Selenicereus grandiflorus flower, stem
Tetradium ruticarpum unripe fruit
Valeriana edulis ssp. procera rhizome, root
Valeriana jatamansi rhizome, root
Valeriana officinalis rhizome, root
Valeriana sitchensis rhizome, root
Zingiber officinale rhizome

Interaction Class C: Herbs for which clinically relevant interactions are known to occur.

Angelica sinensis root
Atropa belladonna leaf
Camellia sinensis leaf, stem
Citrus ×aurantium fruit
Coffea arabica roasted seed kernel
Cola acuminata seed
Cola nitida seed

Digitalis purpurea leaf
Digitalis lanata leaf
Hypericum perforatum flowering top, herb
Ilex paraguariensis leaf
Paullinia cupana seed
Salvia miltiorrhiza root
Schisandra chinensis fruit
Schisandra sphenanthera fruit