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Clinical Implications and Therapeutic Strategies

Quick Guide to Interactions Evaluations System

Interaction Probability Guide


1. Certain Professional Management
2. Probable Potential or Theoretical Beneficial or
3. Possible Supportive Interaction, with Professional
4. Plausible Management
5. Improbable Beneficial or Supportive Interaction, with
6. Unknown Professional Management
Beneficial or Supportive Interaction,
 Potential or Theoretical Adverse Interaction Drug-Induced Nutrient Depletion,
of Uncertain Severity Supplementation Therapeutic, with
Professional Management
 Minimal to Mild Adverse Interaction—
Vigilance Necessary Drug-Induced Nutrient Depletion,
Supplementation Therapeutic,
 Potentially Harmful or Serious Adverse
Not Requiring Professional Management
Drug-Induced Nutrient Depletion,
Impaired Drug Absorption and Bioavailability,
Supplementation Contraindicated,
Negligible Effect
Professional Management Appropriate
Impaired Drug Absorption and Bioavailability,
Prevention or Reduction of Drug Adverse
Precautions Appropriate
Impaired Drug Absorption and Bioavailability,
Prevention or Reduction of Herb or Nutrient
Avoidance Appropriate
Adverse Effect
Adverse Drug Effect on Herbal Therapeutics,
Strategic Concern
? Interaction Possible but Uncertain Occurrence
and Unclear Implications
Adverse Drug Effect on Nutrient Therapeutics,
Strategic Concern
Drug-Induced Adverse Effect on Nutrient
Function, Coadministration Therapeutic, Consensus
with Professional Management Emerging
Drug-Induced Adverse Effect on Nutrient Mixed
Function, Supplementation Therapeutic, Inadequate
Not Requiring Professional Management
Drug-Induced Effect on Nutrient Function,
Supplementation Contraindicated,
Professional Management Appropriate

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Mitchell Bebel Stargrove, ND, LAc
Private Practice, A WellSpring of Natural Health, Inc., Beaverton, Oregon
President, Resources Unlimited, Inc., Beaverton, Oregon
Founder, Editor-in-Chief, IBIS: Integrative BodyMind Information System
Adjunct Professor, Oregon College of Oriental Medicine, Portland, Oregon
Guest Lecturer, National College of Natural Medicine, Portland, Oregon

Jonathan Treasure, MA, MNIMH, RH (AHG)

Medical Herbalist, Centre for Natural Healing, Ashland, Oregon

Dwight L. McKee, MD
Diplomate, American Boards of Internal Medicine, Medical Oncology, and Hematology
Board Certified in Integrative and Holistic Medicine
Certified Nutrition Specialist, Private Practice, Aptos, California
Scientific Director, Life Plus International, Batesville, Arkansas; Cambridgeshire, England
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Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or
appropriate. Readers are advised to check the most current information provided (i) on procedures
featured or (ii) by the manufacturer of each product to be administered, to verify the recommended
dose or formula, the method and duration of administration, and contraindications. It is the
responsibility of the practitioner, relying on his or her own experience and knowledge of the patient,
to make diagnoses, to determine dosages and the best treatment for each individual patient, and to
take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the
Authors assume any liability for any injury and/or damage to persons or property arising out of or
related to any use of the material contained in this book.

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Ruth Bar Shalom, ND, LAc Lewis Mehl-Madrona, MD, PhD

Timothy C. Birdsall, ND William A. Mitchell, ND
Carlo Calabrese, ND, MPH Shauna Rey, ND
Hyla Cass, MD Peggy M. Rollo, ND, LAc
Subhuti Dharmananda, PhD Kia Sanford, MS, CN
Michael F. Holick, PhD, MD Lori Beth Stargrove, ND
Alena M. Langsjoen, MS Maret G. Traber, PhD
Peter H. Langsjoen, MD, FACC Don West, RPh
Rick Marinelli, ND, MAcOM, LAc
Russell B. Marz, ND, LAc

Special gratitude and appreciation for inspiration, participation, support, and patient perseverance to:

Lori Beth Stargrove, ND Joseph E. Pizzorno, Jr, ND

Jillellen McKee, DO Jared L. Zeff, ND, LAc
Joanne Chase Tieraona Low Dog, MD
The Bebel and Kopacz, Isenberg, and Sternheim families Wayne Jonas, MD
Raphael B. Stargrove David S. Riley, MD
Tara R. Stargrove Pamela Snider, ND
Sage S. Stargrove John Weeks
Richard W. Bebel Robert Stern, DC, CFE
Mary A. Bebel Bruce Canvasser, ND
Norbert Isenberg, PhD Heiner Freuhauf, PhD, LAc
Edith Isenberg, RN Clyde Jensen, PhD
Stephanie Sandstrom Eric F. Stephens, DAOM, LAc
Owen Treasure David M. Eisenberg, MD
Kellie White Robert Scholten, MSLIS
Jennifer Watrous Ted J. Kaptchuk, OMD
Anne Altepeter Steve Austin, ND
Roger L. McWilliams Timothy C. Birdsall, ND
Inta Ozols Alan R. Gaby, MD
Linda Duncan Jonathan V. Wright, MD
Sara Snyder Christopher A. Foley, MD
Larry Park Melvin R. Werbach, MD
Claire de la Mer Bruce N. Ames, PhD
Marilyn Wasson Candace B. Pert, PhD
Kelley Schaefer-Levi Micheal R. Ruff, PhD
Jacob S. Gill Leland Kaiser, PhD
Tatiana Lifshitz Mildred S. Seeling, MD, MPH, FACN
David Weitzer, LMT Gonzalo Flores, MAcOM, LAc
Janice Weitzer, LMT John K. Chen, PhD, PharmD, OMD, LAc
Satya Ambrose, ND, LAc Jerry Cott, PhD
Duncan Soule, MD Iris Bell, MD, PhD
David Young, DC Jackie Wootton, MEd
Grant Dawson, DC Joseph J. Jacobs, MD, MBA
John Bastyr, ND Subhuti Dharmananda, PhD
William Turska, ND Ethan Depweg, MAcOM, LAc
Robert Broadwell, ND, LAc Peter Eschwey, MAcOM, LAc
William A. Mitchell, ND Sheila Barnhart

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.

Nicki Scully Prof. D. Mahalakshmi

Mark Hallert Prof. Ganapati
Terry L. Neal Our patients
Parvinder S. Kohli Our teachers and mentors
James A. Spake, MEd, LMT National College of Natural Medicine
Prof. Wang Qingyu Oregon College of Oriental Medicine
Sri Dadaji Mahendranath The healing environs of the Pacific Northwest
Dr. T.H. Trismegistus

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Support Team and Reviewers


Lori Beth Stargrove, ND Private Practice in Cardiology
Private Practice, President, A WellSpring of Natural Health, Research in Biomedical and Clinical Aspects of Coenzyme Q10,
Tyler, Texas
Inc., Beaverton, Oregon
Affiliated with East Texas Medical Center Hospital and
Mother Francis Health System Hospital, Tyler, Texas
MANAGEMENT Rick Marinelli, ND, MAcOM, LAc
Raphael B. Stargrove Private Practice, Natural Medicine Clinic, Portland, Oregon
Clinical Professor, National College of Natural Medicine,
WebWeaver Design Portland, Oregon
Doctoral Faculty, Oregon College of Oriental Medicine,
CONTRIBUTORS Portland, Oregon
Kimberly Ann Brown, MSAOM, LAc Russell B. Marz, ND, LAc
Research Coordinator, Helfgott Research Institute, Portland, Private Practice, Tabor Hill Clinic, Portland, Oregon
Oregon Associate Professor of Nutrition, National College of Natural
Medicine, Portland, Oregon
Gonzalo Flores, MAcOM, LAc President, Omnivite Nutrition, Inc., Portland, Oregon
Private Practice, Groundspring Healing Center, Portland,
Oregon Lewis Mehl-Madrona, MD, PhD
Professor, Integrative Psychiatry, University of Arizona,
REVIEWERS Department of Medicine, Program in Integrative Medicine,
Tucson, Arizona; University of Saskatchewan College of
Ruth Bar Shalom, ND, LAc Medicine, Saskatoon, Saskatchewan
Private Practice, Holistic Medical Center, Santa Cruz,
California William A. Mitchell, ND
Co-Founder; Clinical Professor, Advanced Integrated
Timothy C. Birdsall, ND, FABNO Therapeutics, Bastyr University, Kenmore, Washington
Vice President, Integrative Medicine, Cancer Treatment Private Practice, Seattle, Washington
Centers of America, Zion, Illinois
Shauna Rey, ND
Carlo Calabrese, ND, MPH Staff Naturopathic Physician, Midwestern Regional Medical
Senior Investigator, Helfgott Research Institute, Center, Cancer Treatment Centers of America, Zion, Illinois
Portland, Oregon
Research Professor, National College of Natural Medicine, Peggy M. Rollo, ND, LAc
Portland, Oregon Private Practice, Portland, Oregon

Hyla Cass, MD Kia Sanford, MS, CN

Assistant Clinical Professor of Psychiatry, UCLA School of Private Practice, Ashland, Oregon
Medicine, Los Angeles, California
Private Practice, Pacific Palisades, California Lori Beth Stargrove, ND
Private Practice, A WellSpring of Natural Health, Inc.,
Subhuti Dharmananda, PhD Beaverton, Oregon
Director, Institute for Traditional Medicine, Portland, Oregon
Maret G. Traber, PhD
Michael F. Holick, PhD, MD Professor of Nutrition; Principal Investigator, Linus Pauling
Professor of Medicine, Physiology, and Biophysics and Director Institute, Oregon State University, Corvallis, Oregon
of the General Clinical Research Center, Boston University
Medical Center, Boston, Massachusetts Don West, RPh
Lloyd Center Pharmacy, Portland, Oregon
Alena M. Langsjoen, MS
Laboratory Director, Coenzyme Q10 Laboratory, Inc., Tyler,

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Professional Feedback

“Thorough, accurate, evidence-based information that all “This book, by acknowledged medical experts, offers evidence-
practitioners need if they or their patients use herbs or dietary based advice on a variety of interactions between conventional
supplements. Highly recommended.” drugs, dietary supplements, and herbal medications. The Dietary
Supplements Health Education Act (DSHEA) of 1994—the
Wayne Jonas, MD primary regulatory oversight for dietary supplements and
Former Head of National Center for Complementary and herbs—does not provide any of this information.
Alternative Medicine
President and Chief Executive Officer This book does. It also provides valuable information on a
Samueli Institute variety of other interactions, such as the fact that patients on
Alexandria, Virginia the cholesterollowering medications known as statins (HMG-
CoA reductase inhibitors) have depleted levels of coenzyme
“The text is well referenced, balanced, and objective and the Q10. I wholeheartedly recommend this book for its thoughtful,
use of icons and summary tables allows the clinician to quickly balanced, and well-referenced presentation integrating scientific
identify areas of potential risk, as well as potential benefit. This evidence with practical clinical experience.”
book is a major contribution to the field of integrative medicine
and an invaluable resource to practitioner and researcher alike.” David S. Riley, MD
Cofounder and Editor-in-chief, Global Advances in
From the Foreword by Health and Medicine
Tieraona Low Dog, MD Clinical Associate Professor
Director of Education, Program in Integrative Medicine University of New Mexico Medical School
Clinical Assistant Professor, Department of Medicine Albuquerque, New Mexico
University of Arizona College of Medicine Founder, Integrative Medicine Institute
Tucson, Arizona Santa Fe, New Mexico

“The most comprehensive and substantiated resource I have seen

on drug/herb/nutrient interactions. I was especially impressed
by Dr. Stargrove and his interdisciplinary team’s ranking of
the quality of the available evidence as well as their careful
consideration of beneficial interactions, not just adverse effects.
Required for every clinician serious about integrative medicine.”

Joseph E. Pizzorno, Jr ND
President Emeritus and Faculty Member
Bastyr University
Kenmore, Washington

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
To those who have inspired us,
who have welcomed us,
who have taught, and supported us,
in our challenges, growth, shortcomings, and successes;

Those with whom we share our lives and work,

with whom we play, create, grow, and endure,
as we evolve together,
in our understanding, appreciation, and respect for one another;

Those who come to us, who trust and challenge us,

who ask difficult questions and want honest responses,
who honor us with the challenge and privilege of serving them
in their healing and self-discovery;

That we may care for each and all, including ourselves,

just a little bit better,
working together in a sincere effort
toward healing, truth, and peace
in every interaction.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Quick Guide to Interactions Evaluations System

Interaction Probability Guide


1. Certain Professional Management
2. Probable Potential or Theoretical Beneficial or
3. Possible Supportive Interaction, with Professional
4. Plausible Management
5. Improbable Beneficial or Supportive Interaction, with
6. Unknown Professional Management
Beneficial or Supportive Interaction,
 Potential or Theoretical Adverse Interaction Drug-Induced Nutrient Depletion,
of Uncertain Severity Supplementation Therapeutic, with
Professional Management
 Minimal to Mild Adverse Interaction—
Vigilance Necessary Drug-Induced Nutrient Depletion,
Supplementation Therapeutic,
 Potentially Harmful or Serious Adverse
Not Requiring Professional Management
Drug-Induced Nutrient Depletion,
Impaired Drug Absorption and Bioavailability,
Supplementation Contraindicated,
Negligible Effect
Professional Management Appropriate
Impaired Drug Absorption and Bioavailability,
Prevention or Reduction of Drug Adverse
Precautions Appropriate
Impaired Drug Absorption and Bioavailability,
Prevention or Reduction of Herb or Nutrient
Avoidance Appropriate
Adverse Effect
Adverse Drug Effect on Herbal Therapeutics,
Strategic Concern
? Interaction Possible but Uncertain Occurrence
and Unclear Implications
Adverse Drug Effect on Nutrient Therapeutics,
Strategic Concern
Drug-Induced Adverse Effect on Nutrient
Function, Coadministration Therapeutic, Consensus
with Professional Management Emerging
Drug-Induced Adverse Effect on Nutrient Mixed
Function, Supplementation Therapeutic, Inadequate
Not Requiring Professional Management
Drug-Induced Effect on Nutrient Function,
Supplementation Contraindicated,
Professional Management Appropriate

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Interactions Evaluation Guide


5. Improbable
I. Probability of Clinically Significant Interaction This interaction is unlikely to occur in most individuals, all other
Interactions are by definition probable events. As with any sta- factors being equal. When taken at commonly used dosages for
tistical variable, meaningful prediction must be based on knowl- appropriate medical conditions as prescribed by health care pro-
edge of the numerator and denominator. fessional(s) trained and experienced in botanical and/or nutri-
Probabilities assigned to the interactions in the text are based tional therapeutics, the probability of clinically significant
on the following criteria of combined likelihood and clinical interaction occurring appears to be minimal.
6. Unknown
1. Certain Data are contradictory, inconclusive, or insufficient to assign
Interaction occurrence is definite. Available research and clinical probability status.
experience both indicate that purposeful coadministration is
likely to provide increased therapeutic effect in beneficial inter- INTERACTION TYPE AND CLINICAL SIGNIFICANCE GUIDE
actions. With adverse interaction, concomitant use is definitely to
be avoided, even when under the active care of an appropriately II. Type and Clinical Significance of Interaction
trained and experienced health care professional. In most cases, Generally applicable principles:
however, it is inadvisable to make sudden changes in usage if the ! If the individual’s prior medical condition has been
individual’s medical condition has been stable. stable, any changes to the therapeutic regimen involv-
ing addition or withdrawal of nutrients, botanicals, or phar-
2. Probable maceuticals should not be made abruptly. Transitions in
There is relatively high probability of this interaction occurring, protocols are de facto potential foci for interaction instabil-
all other factors being equal. Conservative practice implies con- ity that may, if ignored, significantly affect intended thera-
sidering these interactions operationally as definite, unless there peutic outcomes.
are compelling reasons to the contrary. Available evidence or ! Individuals vary in response to any pharmacological agent
clinical experience indicates that purposeful coadministration because of individual biochemical or pharmacogenomic
may enhance therapeutic intervention. With adverse interaction, variability, as well as health status and medical conditions.
concomitant use is generally to be avoided, except when under ! Professional management implies supervision by collaborat-
the active care of an appropriately trained and experienced ing health care professionals with appropriate training in
health care professional. In most cases, however, it is inadvisable nutritional and/or botanical therapeutics within an integra-
to make sudden changes in usage if the individual’s medical tive medical framework.
condition has been stable.
✗ Potential or Theoretical Adverse Interaction of Uncer-
3. Possible tain Severity
There is variable probability of this interaction occurring, depend- Interaction is theoretically possible based on known pharma-
ing on specific circumstances. Operationally, the probability of cological characteristics of each substance. Inadequate informa-
the interaction may be relatively low for most individuals; how- tion is currently available to determine clinical significance of
ever, interindividual and intraindividual variation in probable potential risk. Pending conclusive research, close supervision
occurrence of the interaction is likely, depending on multi- and regular monitoring by a health care professional are war-
factorial circumstances, including atypical dosages, certain ranted for any concomitant use.
preexisting medical conditions altering pharmacokinetic or
pharmacodynamic parameters, particular risk associated with ✗ ✗ Minimal to Mild Adverse Interaction—Vigilance
life stage susceptibilities, and pharmacogenomic and biochem- Necessary
ical variability. Interaction represents a low to moderate risk, but potential
severity warrants supervision of patient during concomitant use.
4. Plausible Concomitant use is therapeutically feasible within the context of
Interaction of plausible, but not proven, likelihood. Although multidisciplinary collaboration, along with supervision and
the mechanism and rationale of this interaction appear reason- monitoring by health care professional(s) trained in conven-
able based on current knowledge, the available evidence is tional pharmacology and experienced with clinical herbal med-
inadequate to support a conclusive judgment as to the like- icine and/or therapeutic nutrition.
lihood of its occurrence or the variables influencing the char-
acter of such an interaction. However, potential clinical ✗ ✗ ✗ Potentially Harmful or Serious Adverse
significance of the interaction may warrant careful considera- Interaction—Avoid
tion within integrative therapeutic strategies. This may be Interaction represents a significant to severe risk of adverse
based on currently accepted clinical practices among appropri- effect and should be avoided. Concomitant use should be delib-
ately qualified professionals in botanical and nutritional erately avoided outside the context of close supervision and
therapeutics, despite lack of currently available published evi- regular monitoring, including laboratory monitoring wherever
dential support. feasible, by health care professional(s) trained in conventional

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
xxiv Interactions Evaluation Guide

pharmacology and experienced with clinical herbal medicine function because of drug action. Appropriate concomitant sup-
and/or therapeutic nutrition. plementation with (or coadministration of) nutrient will coun-
ter adverse metabolic effects of drug on nutrient and may
Impaired Drug Absorption and Bioavailability, optimize therapeutic effect without compromising therapeutic
Negligible Effect efficacy of pharmaceutical intervention. Clinical management is
Interaction is adverse but of minimal clinical significance. usually not required.
Nonetheless, modification of dosage, timing, or mode of admin-
istration may reduce potential for adverse effects of interaction. Drug-Induced Effect on Nutrient Function, Sup-
plementation Contraindicated, Professional Management
Impaired Drug Absorption and Bioavailability, Appropriate
Precautions Appropriate Interaction in which prescription pharmaceutical agent inten-
Interaction is of mild to moderate severity. Modification of tionally interferes with normal physiological nutrient function
dosage, timing, or mode of administration will reduce adverse through predicted drug action. Nutrient dietary intake is
effects of interaction. typically restricted and supplementation or administration con-
traindicated to optimize therapeutic effect and avoid compro-
Impaired Drug Absorption and Bioavailability, mising therapeutic efficacy of pharmaceutical intervention.
Avoidance Appropriate
Interaction has clinically significant adverse effects. Conco- ✗ Bimodal or Variable Interaction, with Professional
mitant use should be avoided, especially outside the context of Management
close supervision and regular monitoring by health care profes- Interaction is inherently neither beneficial nor adverse,
sional(s) trained in conventional pharmacology and experienced unless ignored. Based on known pharmacological characteristics
with clinical herbal medicine and/or therapeutic nutrition. of each substance (or reasonable extrapolations therefrom),
Modification of dosage, timing, or mode of administration interaction is theoretically possible. Depending on the specific
may contribute to minimizing severity in cases in which benefit clinical contextualization (patient, population, diagnosis, set-
of concurrent administration outweighs risks. ting) and practitioner training and experience, the interaction
may be deliberately utilized by an appropriately trained and
Adverse Drug Effect on Herbal Therapeutics, experienced health care professional for increasing clinical effi-
Strategic Concern cacy with appropriate clinical management within an integrative
Interaction in which drug may interfere with therapeutic therapeutic strategy. Although clinically significant in certain
effect of herbal prescription because of the drug’s pharmacolo- circumstances, this interaction may be of only minor signifi-
gical properties. Alterations in drug dosage, timing, or other cance in other contexts.
factors may prevent, ameliorate, or compensate for adverse
effects of or interference with herbal therapeutics and optimize Note: In situations in which ‘‘Bimodal’’ is assigned to an inter-
therapeutic effect, with appropriate clinical management within action dyad in the text, the possible variations are also listed.
an integrative therapeutic strategy, without compromising ther-
apeutic efficacy of either intervention. Potential or Theoretical Beneficial or Supportive
Interaction, with Professional Management
Adverse Drug Effect on Nutritional Therapeutics, Beneficial interaction is theoretically possible based on
Strategic Concern known pharmacological data. However, inadequate substantive
Interaction in which drug may interfere with therapeutic data exist currently to determine clinical significance of poten-
effect of nutrient prescription because of the drug’s pharmaco- tial benefit. Coordinated use with appropriate clinical manage-
logical properties. Alterations in drug dosage, timing, or other ment within an integrative therapeutic strategy may
factors may prevent, ameliorate, or compensate for adverse theoretically increase therapeutic efficacy. Pending conclusive
effects of or interference with nutritional therapeutics and opti- research, concomitant use may warrant close supervision and
mize therapeutic effect, with appropriate clinical management regular monitoring by a health care professional.
within an integrative therapeutic strategy, without compromis-
ing therapeutic efficacy of either intervention. Beneficial or Supportive Interaction, with Profes-
sional Management
Drug-Induced Adverse Effect on Nutrient Func- Interaction in which intentional therapeutic use of nutrient
tion, Coadministration Therapeutic, with Professional or botanical preparation concomitantly with drug therapy
Management can provide additive or synergistic effect and increase therapeutic
Interaction in which standard-practice use of pharmaceutical efficacy for most individuals when taken at appropriate dosages
agent will usually interfere with normal physiological nutrient with professional supervision and monitoring as needed. Some
function because of predicted drug action. Appropriate individuals may derive greater benefit because of medical condi-
coadministration of nutrient, with appropriate clinical manage- tions or individual pharmacogenomic and biochemical variabil-
ment within an integrative therapeutic strategy, will counter ity. Coadministration can be therapeutically efficacious within
adverse metabolic effects of drug on nutrient and may optimize the context of multidisciplinary collaboration and supervision
therapeutic effect without compromising therapeutic efficacy of by health care professional(s) trained in conventional pharmacol-
pharmaceutical intervention. ogy and experienced with clinical herbal medicine and/or ther-
apeutic nutrition.
Drug-Induced Adverse Effect on Nutrient Func-
tion, Supplementation Therapeutic, Not Requiring Profes- Beneficial or Supportive Interaction, Not Requir-
sional Management ing Professional Management
Interaction in which standard-practice use of pharmaceutical Interaction in which concurrent administration can generally
agent will usually interfere with normal physiological nutrient be considered safe for patient self-care. Based on available

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Interactions Evaluation Guide xiv

evidence, it is improbable that the therapeutic benefit of addi- clinically significant nutrient deficiency pattern or obstructing
tive or synergistic interaction or nutritive support has the poten- the role of herbal prescription for appropriate individuals when
tial to induce an undesired and possibly adverse additive or taken at therapeutic dosages. Concomitant use is contraindi-
interference effect, although discussion and communication cated unless specifically determined as therapeutically efficacious
with prescribing physician are advised. within the context of multidisciplinary collaboration and super-
vision by health care professional(s) trained in conventional phar-
Drug-Induced Nutrient Depletion, Supplementa- macology and experienced with therapeutic nutrition.
tion Therapeutic, with Professional Management
Interaction in which appropriate use of nutrient, given clin- ? Interaction Possible but Uncertain Occurrence and
ical management within an integrative therapeutic strategy, can Unclear Implications
prevent or counter nutrient depletion caused by drug without Interaction is of uncertain character, significance, and pre-
compromising therapeutic efficacy for most individuals when dictability of occurrence, reflective of inconsistent and/or
taken at commonly used dosages. Concomitant use therapeuti- inadequate evidence. Prudence dictates avoiding concomitant
cally efficacious within the context of multidisciplinary colla- use while assuming neither risk nor benefit until more data
boration and supervision by health care professional(s) trained become available. Pending further clinical research findings, it
in conventional pharmacology and experienced with clinical is prudent to avoid concomitant use outside the context of close
therapeutic nutrition. supervision and regular monitoring by health care profes-
sional(s) trained in conventional pharmacology and experienced
Drug-Induced Nutrient Depletion, Supplemen- with clinical herbal medicine and/or therapeutic nutrition.
tation Therapeutic, Not Requiring Professional Manage-
Interaction in which simultaneous use can generally be consid-
ered safe for patient self-care. Based on examined evidence, appro- III. Strength and Quality of Source Evidence
priate therapeutic use of nutrient adjunctively with drug therapy The source material for each topic is evaluated using the follow-
likely to provide correct drug-induced nutrient depletion pattern ing composite indicators to offer an assessment of the overall
and improve therapeutic outcomes for most individuals, without character of the literature reviewed for that nutrient-drug or
interfering with drug efficacy, when taken at appropriate dosages. herb-drug pair.
Based on available evidence, it is improbable that the therapeutic
benefit of additive or synergistic interaction or nutritive support has Consensus
the potential to induce an undesired and possibly adverse additive or Interaction demonstrated by a converging consensus of clin-
interference effect, although discussion and communication with ical experience, research literature, and known pharmacology,
prescribing physician are advised. including significant findings from published clinical or
preclinical human studies of strong design, size, and relevance;
Drug-Induced Nutrient Depletion, Supplemen- well-documented and consistent case reports; and established
tation Contraindicated, Professional Management Appro- pharmacokinetic and pharmacodynamic data.
Interaction in which prescription medication intentionally Emerging
interferes with normal physiological nutrient metabolism and Interaction supported by emerging pattern of clinical experience,
may produce nutrient depletion pattern through predicted research literature, and known pharmacology, including human
drug action. Nutrient dietary intake is typically restricted and studies of adequate design, size, and relevance; limited but consis-
supplementation (or coadministration) contraindicated to opti- tent, well-documented case reports; unpublished papers and pre-
mize therapeutic effect and avoid compromising therapeutic sentations; and probable pharmacokinetics or pharmacodynamics.
efficacy of pharmaceutical intervention. Concomitant use is
generally contraindicated for most individuals. In some unusual Preliminary
circumstances, nutrient might be prescribed under appropriate Interaction suggested by preliminary data, involving fragmentary
parameters of dosage, timing, and duration, with clinical man- or partial evidence; reports derived from anecdotal clinical experi-
agement and monitoring within the context of multidisciplinary ence, preliminary research literature, or general pharmacological
collaboration and supervision by health care professional(s) principles; research findings based on animal or in vitro experimen-
trained in conventional pharmacology and experienced with tal studies; or human studies characterized by inadequate design,
therapeutic nutrition. size, and significance; limited or incomplete case reports; or extra-
polations from pharmacokinetic or pharmacodynamic data.
Prevention or Reduction of Drug Adverse Effect
Interaction in which intentional coadministration of nutrient or Mixed
herb concurrently with drug therapy within an integrative thera- Interaction proposed on the basis of partial, contradictory, or
peutic strategy can prevent, reduce, or counter adverse drug effects otherwise inconclusive evidence, including from single sources;
without compromising therapeutic efficacy for most individuals unsubstantiated or incomplete case reports; inappropriate or
when taken at appropriate dosages, under professional guidance. methodologically flawed studies; or nonsignificant data.

Prevention or Reduction of Herb or Nutrient Adverse Inadequate

Effect Interaction proposed using obsolete, discredited, specula-
Interaction in which appropriate use of medication is inten- tive, or otherwise inadequate or inappropriate evidence from
ded to prevent, reduce, or counter adverse nutrient or herb derivative or secondary sources, including conjecture or unjus-
effects in conditions characterized by nutrient overload, exogen- tified extrapolation, inappropriate or flawed methodology, or
ous toxicity, and metabolic derangement, without inducing studies of questionable relevance.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.

Dietary supplements are among the most commonly used com- foreign language). This makes it almost impossible to enter,
plementary and alternative medical therapies in the United retrieve, or analyze information from electronic databases when
States, with sales reportedly exceeding $20 billion in 2005. an adverse event is suspected. Unlike prescription and OTC
Newspapers, magazines, and the mass media feed our curiosity medications, it can be difficult to ascertain if the adverse event
for new supplements and ways to manage our health on a daily was caused by the ingredient(s) declared on the label, or actually
basis. New dietary supplement formulations flood the shelves of resulted from the accidental or intentional adulteration, substi-
pharmacies, health food stores, retail chains, and Internet out- tution, or contamination of the product with a toxic botanical,
lets. Consumers want to know what works and are willing to pay heavy metal, or pharmaceutical agent. Accurate identification of
for products that may make them feel better. However, consu- the dietary supplement is essential for determining causality;
mers are also growing frustrated with inconsistencies in product however, the point of contact for most serious adverse events is
quality and perceived lack of regulatory oversight. Surveys indi- generally a physician who has neither the training nor the funds
cate that health care professionals are both interested in learning for collecting, submitting, and paying a laboratory with expertise
about, and concerned over the widespread use of, dietary supple- in analyzing complex botanical or supplement products. This
ments. This is not surprising given the contradictory scientific further complicates evaluation of adverse event reports in the
data and provocative titles in medical journals linking supple- medical literature, because product identity is seldom verified.
ments with dangerous adverse events and lack of efficacy. In most cases, the evidence for causality is based primarily on the
Although many supplements are safely used by the public, fact that the supplement cannot be excluded, rather than clear
there is little question that the complex chemistry of botanicals evidence of toxicity. And yet, in the absence of better pharma-
and multi-ingredient formulations may have profound effects, cological data and an optimal adverse event reporting system,
both beneficial and harmful, on our human physiology. case reports remain a necessary, if problematic, mechanism for
Dietary supplements marketed in the United States before monitoring safety.
passage of the Dietary Supplements Health Education Act With the primary emphasis on adverse interactions, the
(DSHEA) in 1994 are not required to demonstrate safety or topic of beneficial interactions has received little attention. It
efficacy, an a priori belief that since these products were already is well recognized that statin medications deplete coenzyme
in the marketplace, one could assume a certain level of safety. Q10 in the body. Preliminary evidence suggests that adminis-
The assumption that these products are safe and free from tering 50 to 100 mg per day of the supplement may reduce the
adverse effects may lead to excessive dosing, concomitant use myopathies that are reported by about 20% of patients using
with prescription and over-the-counter (OTC) medications, this class of lipid-lowering medications. A growing body of
and failure to disclose supplement use to health care providers. evidence supports the administration of glutamine during che-
According to a large, federally sponsored survey, approximately motherapy to prevent neuropathy, whereas selenium was
28 million Americans are taking dietary supplements with their shown to reduce the nephrotoxicity associated with cisplatin.
prescription medications, and 69% of them have not told their Low serum folate levels decrease the effectiveness of antide-
primary care provider. As a physician who is also an herbalist, I pressant medications. An integrative approach would utilize
find that patients generally feel comfortable talking to me about therapies that reduce or mitigate the adverse effects of
their use of supplements and alternative therapies. Yet, even medications deemed necessary for the patient whenever
with my training, I constantly brush up against the edge of possible.
my knowledge and experience when a patient asks if taking It is within this climate that I enthusiastically welcome this
ginkgo, ginseng, saw palmetto, hawthorn, coenzyme Q10, book, a collaboration written by experienced clinicians within
magnesium, L-carnitine, multivitamin, and a Chinese herbal for- the fields of conventional, integrative, and natural medicine for
mulation called xin li shu kang wan will interact in any way with health professionals who wish to counsel their patients effec-
his quinapril, amiodarone, clopidrogel bisulfate, simvastatin, tively on the safe and beneficial use of dietary supplements. As
and esomeprazole! A difficult question for anyone to answer, the title suggests, this book addresses herb-drug interactions,
but even more for those without any formal training in natural nutrient-drug interactions, and drug-induced nutrient deple-
products and limited to the typical 12- to 15-minute patient tions in a clinically oriented, integrative manner. The authors
encounter. As was shown with St. John’s wort, however, herb- demonstrate an appropriate balance between recommendation
drug interactions can occur and can be very serious. and risk based on the overall strength of the scientific evidence
It would be easy to assume that if adverse events and interac- and their own clinical experience. The text is well referenced,
tions with drugs were really a problem, it would be glaringly balanced, and objective, and the use of icons and summary
apparent given the number of people using these products. tables allows the clinician to quickly identify areas of potential
However, as Chair of the United States Pharmacopeia Dietary risk, as well as potential benefit. This book is a major contribu-
Supplements Information Expert Committee, I can attest to the tion to the field of integrative medicine and an invaluable
difficulty in determining and establishing safety for many of the resource to practitioner and researcher alike.
dietary supplement ingredients in the marketplace. Many bota-
nicals and nutritional supplements lack detailed pharmacokinetic Tieraona Low Dog, MD
and pharmacodynamic data. The adverse event reporting systems Director of Education, Program in Integrative Medicine
that are currently in place for drugs are woefully inadequate for Clinical Assistant Professor, Department of Medicine
monitoring dietary supplement products, given the vast number University of Arizona College of Medicine
of complex and unique formulations in the marketplace and the Chair, United States Pharmacopeia Dietary Supplements
variety of names used on the label (i.e., Latin binomial, common, Information Expert Panel

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.

We are in the midst of a critical historic juncture in the evolu- On publication of that reference tool, clinicians increasingly
tion of medicine. Three major currents are influencing the prac- requested deeper coverage of interactions issues involving nutri-
tice of medicine, the science underlying its methodology, and ents and herbs, in response to widespread and growing use of
the relationship between caregiver and patient. First, a signifi- such products by their patients and clinicians’ desire to integrate
cant proportion of patients are exercising greater levels of self- such agents into their therapeutic repertoire. In 1997, exhorta-
education and self-care, requesting greater opportunity for tions from physicians and educators precipitated a dedicated
informed decision making and often demanding a realignment focus on interactions issues in a clinical context and catalyzed
of the usual power relationships in conventional medicine. development of the Interactions software database, subse-
Second, the emergence of personalized medicine, particularly quently published in 2000. That reference work essentially
but not only in the form of genomics, pharmacogenomics, functioned as the first edition of the research and writing that
and nutrigenomics, offers the promise of tailoring efficacy has evolved into the present publication. Through that experi-
while decreasing adverse effects in a manner that offers a ence and several years of input and feedback from health care
modern scientific approach to individualization of care beyond professionals and educators around the world, as well as inqui-
generic pathology and lowest-common-denominator generali- ries from an online reporting and resource website, the models,
zations. Third, the now well-established recognition of medical methods, and tools applied in the creation of this publication
pluralism mandates greater communication and collaboration were developed and refined. In particular, a year of intensive
between health care providers of various medical traditions investigation, dialogue, and debate produced the pioneering
from diverse cultures and philosophies, methodologies and system of interaction characterization, literature evaluation,
therapeutics. Together, these factors give a profoundly transdis- and clinical probability applied in reviewing, compiling, and
ciplinary impetus to the development of enhanced clinical stra- assessing the relevant scientific and medical literature. Thus,
tegies synthesizing the science of medicine and the art of the current volume represents the indirect outcome of almost
healing in a process-oriented approach to the individual patient. 20 years of work and 10 years of direct efforts.
Within the context of these converging influences, the issues Interactions between pharmaceutical drugs and ‘‘natural’’
arising from the potential interactions between conventional products such as nutrients and herbs constitute an area of
drug therapies and herbal and nutritional therapies present immediate concern and growing awareness wherever patients
both a challenge and an opportunity. The challenge involves are receiving health care and members of the public are engaged
unanticipated adverse drug reactions (ADRs). The opportunity in self-care through use of these substances. Many patients
involves the potential for enhancing the depth and breadth of naively assume that nutrient and herbal products are ‘‘natural’’
the mainstream medical model, ultimately improving the suc- and that this somehow implies they are ‘‘safe.’’ More disturbing
cess of clinical outcomes. After more than two decades of is the acknowledged fact that many patients often withhold
complementary and ‘‘alternative’’ medicine (‘‘CAM’’) and sub- disclosure of nutrient and herbal intake or use of nonconven-
sequent optimistic portents of an era of ‘‘integrative medicine,’’ tional care from their conventional health care providers. This
the average practitioner surveying the medical landscape for combination suggests the need for deep inquiry and analysis
substantive changes in the clinical care model usually sees only into the doctor-patient relationship and the coordination of
glimmers of vision, moments of inspiration, and select ideal medical care. In the meantime, however, clinicians need a
cases. Such aspirations may be suitable for some, but most clin- guide to working with patients using nutrients and herbs and
icians would be content simply with effective tools for under- guidelines for crafting their interventions to coordinate these
standing other disciplines, how their patients are using them, elements. This book is most directly intended to serve this need
and the implications when mixing pharmaceutical medicines among health care professionals, educators, and students
and other modalities. Nevertheless, our patients are using a throughout the whole range of medical professions. The
diverse array of medical approaches, and we all are entering a depth of coverage, the emphasis on research, and the focus on
world of transdisciplinary care and personalized medicine, com- practical implications address the needs of this professional
plexity models of physiology, and unprecedented access to audience. Secondarily, this information will be of benefit to
information. In this context, the discovery of new synergies individuals in other professions, ranging from librarians to
and unparalleled collegial collaboration offer the promise of retail staff, faced with questions from the general public regard-
enhanced patient empowerment and novel clinical strategies. ing these issues.
Ultimately, we must always keep in mind that our first and An overview of the presently available literature reveals the
only loyalty can be to our patients and their health, even if it predominance of two types of print and electronic publications
forces us to grapple with the unfamiliar and acknowledge the covering this subject matter: those intended for the professional
unconventional. market and those intended for a consumer/patient audience.
The same data may also be disseminated differently for use by
both audiences. In both cases, most publications can fairly be
PURPOSE AND FUNCTION characterized as lacking in depth and incomplete or overreach-
The present work derives from the clinical needs of practicing ing in conclusions.
health care professionals who have been compiling, analyzing, The professional literature tends to assume that patients
and publishing assessments on interactions for two decades. using nutrients and herbs (‘‘dietary supplements’’) are doing
Interactions between drugs and nutrients first became a subject so without supervision of health care professionals trained and
of review and education in 1988 during the development of experienced in the therapeutic application of nutritional and
the Integrative BodyMind Information System (IBIS) database. botanical therapies. Lack of disclosure by patients also tends
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
xiv Preface

to be the case, and greater awareness, frank discussion, and experience, and avoiding or countering those methods and
informed decision making in these areas are necessary for effec- characteristics that lead to poorly founded, overreaching, or
tive clinical management as well as patients’ perception of misleading conclusions. Ultimately, the team that produced
respect for their choices. Similarly, especially in complex and this book was determined to make realistic assessment of clinical
chronic conditions, the use of multiple providers from several relevance and evidence quality its foundation. Only a product
different health care disciplines is increasingly common. that would meet the standards of what we would feel confident
Professionals in all disciplines can increase clinical efficacy and using in our own practices would be acceptable for publication.
patient safety through open dialogue and collegial (peer-to- Thus, the research and editorial team consists of practicing
peer) collaboration. However, interactions literature is often health care professionals trained in therapeutic nutrition, bota-
prepared by health care professionals without training or experi- nical medicine, pharmacology, and pharmacognosy with experi-
ence in nutritional and botanical therapies. Therefore, the ence on a daily basis in general family practice and specialty care,
advantages of purposefully combining, strategically sequencing, with an emphasis on internal medicine, oncology, and hematol-
or deliberately avoiding such interventions are usually not ogy. This text is therefore itself a result of collaboration among
addressed in a comprehensive and practical way. In addition, practicing experts from different modalities that is emblematic
the interactions reference texts and guides developed for con- of the transdisciplinary collaboration that ultimately is required
sumers are limited in depth, often avoid critical issues, and to understand and manage drug-nutrient and drug-herb inter-
sometimes prey on readers’ fears by exaggeration and headline actions. This fact alone distinguishes this text from other pub-
hyperbole. Furthermore, the commercial context of their use lications that claim to cover the topics but present one-sided,
frequently presents an apparent conflict of interest, especially theoretical, or partial approaches that necessarily lack the trans-
when provided as aids in product selection in a retail setting. disciplinary insight and clinical relevance of this collaboration.
Similarly, these guides are presented as online educational tools Perhaps most importantly, our authors are deeply enmeshed in
appended to broader coverage of ‘‘alternative medicine’’ within collaborative care on a daily basis, bringing together health care
the context of medical, pharmaceutical, or insurance websites. professionals from multiple disciplines and combining therapies
Either situation implies significant constraints as to thorough- from multiple modalities.
ness, rigor, and efficacy because caution is justifiably the opera- In areas where the available resources appeared to be limited,
tive premise. The issue of apparent conflict of interest and immature, or flawed, the authors systematically addressed three
possible bias must always be considered in a setting funded primary needs. First, the lack of a multidisciplinary approach
and presented by commercial interests, both for what is said inherent in the existing literature leads to the common ten-
and what is avoided. Inherently, the scope, thoroughness, and dency, for example, to assert potential interactions imputed
standards of evidence tend to be different for consumer educa- from assumed pharmacological theory, without any corrobora-
tion (or promotional) publications than for professional publi- tion from clinical experience with the interacting agents. Other
cations because of the vast divergence in educational level, than research into certain well-known drug-induced nutrient
operational needs, and responsibility. Overall, the literature depletion patterns, direct clinical trials of adequate power are
available to most of the general public, whether magazines, nearly absent from literature pertaining to drug-herb and drug-
books, friends and family, or the Internet, tends to avoid nutrient interactions. Overall, the primary source evidence
recommendation of these agents at therapeutic doses or in a tends to be delayed and reactive, fragmented, or tangential to
manner that might be construed as treating diagnosed other research objectives, or simply unapparent to those not
conditions. trained and experienced in these fields. Consequently, many
By contrast, in this book we explore many methods of using interactions supported by readily available evidence are simply
nutritional and herbal interventions not only as ‘‘dietary supple- not described in most texts. Also, many interactions based on
ments’’ but also as components of comprehensive, trans- substandard or preliminary evidence are given more weight than
disciplinary therapeutic strategies. This approach diverges they deserve. In such cases, contextualization and ‘‘debunking’’
fundamentally from typical drug interactions databases mar- of the putative or alleged interactions often result from the
keted for physicians, especially those for handheld devices, necessary ‘‘reality check.’’ This problem also derives from over-
that list telegraphic warnings (often unsubstantiated) about reliance on secondary literature (e.g., reviews, meta-analyses)
‘‘supplements’’ without context or qualification. Where conco- and derivative material in topical publications. Second, no pre-
mitant administration of nutrients and herbs might harm a viously available text, including our first effort, incorporates
patient or significantly interfere with predictable effects of con- sufficient detail to assess effectively the quality of the original
ventional medications, the priority of ensuring patient safety is data; the strengths and limitations of the study design, size, and
established throughout the text by providing cautions and sug- duration; or the characteristics or even the dose, form, or other
gesting modifications based on scientific literature and clinical critical particulars of the agents involved. Third, clinical rele-
experience. vance and therapeutic implications need to be the primary goal
of analysis of all interactions.
In light of these many factors, this text relies primarily on
METHODOLOGY AND STRUCTURE evidence from clinical trials whenever possible, using reasonable
The methodology applied in developing this publication extrapolations from human research as secondary evidence and
involved two steps. First, input was gathered from among the relegating animal studies or in vitro experiments to a supportive
authors and other clinicians, as well as pharmacists and educa- role. Published case reports are assessed based on the strength
tors, as to potential interactions they were seeing in clinical of their relevance, detail, and quality. Extrapolations can be
practice and of substantive clinical relevance, particularly poten- reasonable or not. Our in-depth examination of the published
tial risk or observed therapeutic value. Second, available refer- literature revealed that the available secondary and derivative
ence works on interactions, including drug-drug interactions literature contains at worst an abundance of confusion and at
literature, were reviewed for scope, depth, methodology, and best a lack of clarity on decisive facts, such as proper identifica-
presentation. This method ensures that we incorporated the tion of a nutrient or herb and the plant part used, naturally
best of all approaches, building on those from our own occurring nutrients or whole herbs versus synthetic forms or

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Preface xviii

extracts, doses outside the range of those considered safe and emphasizing nutritional therapies in their clinical practice.
clinically effective, diverse modes of administration, and distinc- However, the therapeutic efficacy of food sources can be limited
tive or even divergent characteristics of subject populations. by several critical factors, including difficulty in achieving neces-
In particular, the repeated citation of a poor-quality case sary dose thresholds of specific nutrients or constituents on a
report, irrelevant finding, or flawed research in multiple pub- consistent basis because of volume of food sources required,
lications suggests superficial recycling of citations by secondary low rates of compliance in the regular consumption of such
authors without full text review of original sources or critical required doses of necessary food items, and, in more recent
analysis of conclusions. The pervasive interchanging as equiva- decades, declining nutrient quality of commercially available
lents of Ephedra (the plant) and ephedrine (a pharmaceutical foods.
alkaloid) provides a stark illustration of this problem and its Similarly, just as there is a large divergence between
reverberations, despite the presumed good intentions of those primary literature and the secondary literature of reviews and
making the assertions. In contrast, this text notes if studies use meta-analyses, an even greater separation exists between primary
forms of an agent that experienced practitioners would shun, or sources and editorial news coverage in both professional publica-
doses too high for safety or too low for therapeutic efficacy. tions and popular press, as well as in educational materials and
Perhaps most important is the recognition that uninformed tools available to the typical patient/consumer. In particular,
administration of agents, or combinations of agents, in a three primary limitations appear on analysis. First, the nature of
manner wholly detached from the logic, methodology, or stan- study populations is often not defined, particularly with reference
dards and guidelines of appropriate clinical practice and histor- to critical distinctions between healthy subjects and those with
ical context from which they are derived, does not constitute an diagnosed conditions. The related factors, such as genetic risk
‘‘adverse event’’ or ‘‘interaction.’’ and pharmacogenomic variability, gender and age, health status,
A significant gap often exists between the research literature and socioeconomic vulnerabilities, are only considered on rare
and clinical practice in regard to the origins and form of many occasions. Second, critical factors in study design, such as cohort
agents studied in the scientific literature. Not all nutrients or size, dose, form, duration of administration, and other poten-
botanically derived preparations can accurately be described as tially confounding influences, can significantly alter outcomes
‘‘natural’’ medicines; many do not appear in nature and are and the interpretation of findings. In many cases, these variables
more accurately placed in the province of ‘‘pharmaceutical pre- would be significant enough to create major divergences in asses-
parations’’ rather than herbs or nutrients as traditionally under- sing conclusions because characteristics of a given study could
stood or historically practiced. Thus, a gradient can be plausibly alter effects, but such characteristics were not men-
articulated spanning pharmaceutical nutrients (e.g., dl-alpha- tioned or factored into the analysis and conclusions. Third, cer-
tocopherol, i.e., racemic synthetic vitamin E), isolated prepara- tain health care professionals, most notably naturopathic
tions of naturally occurring nutrient and botanical constituents, physicians and herbalists of the Euro-American, Chinese!East
foods and herbs in whole or minimally modified forms (with Asian, and Ayurvedic traditions, employ botanical formulations
inherent diversity and variability of constituents), and nutrients and nutritional therapeutics as a primary clinical intervention.
and herbs in combinations or formulae (with even greater com- Whether in these settings or in multidisciplinary integrative
plexity). Often the isolated constituents and synthetic prepara- approaches, the use of multiple agents within a therapeutic strat-
tions or mixed isomers used in research studies contrast sharply egy is typical practice, and especially in herbal medicine, single
with the forms (whether naturally occurring or crafted in accor- agents are rarely expected to provide the properties, potency, or
dance with traditional methodologies) typically used by practi- personalization that a compound formula provides. Such treat-
tioners trained and experienced in nutritional and botanical ment strategies are very difficult to assess adequately using
therapeutics. Moreover, the issues affecting interactions analysis research models or methodologies that assume single-agent
are confounded by the recurrent paradox observed in innumer- interventions, which are uncommon in patients with chronic
able papers on broader topics in which authors voice contra- diseases and complex cases.
dictory assumptions and conclusions; first, that whole-food The methodology applied in this text emphasizes that sup-
sources are safer and more effective than, and generally prefer- plementation of nutrients (and rarely, nutritive use of herbs) in
able to, nutrients (or herbal) constituents in pill or tablet form, healthy populations is distinct from unsupervised, concomitant
but second, that foods, herbs, nonstandardized extracts or iso- use of nutrient support in individuals concurrently taking pre-
lates, or multicomponent formulae do not fit the methodology scription drugs (especially those with known nutrient-depleting
of study designs oriented to assessing single-agent pharmaceu- effects) and from purposeful coadministration of nutrients or
tical interventions. The resulting statements that naturally herbs with conventional drugs within the context of clinical
occurring and synthetic forms are equivalent, and recurrent management by health care professionals applying integrative
findings that food (or herbal) sources provide benefits not principles. Therefore, the organization of these interactions
found in synthetic supplemental or extracted forms, at least monographs involves a spectrum of categories, including
not in those specific forms studied, suggest that naturally occur- ‘‘avoidance,’’ ‘‘benefit,’’ and ‘‘management.’’
ring forms, identical in origin, to food (or plant) sources may be By incorporating summary tables as well as in-depth analysis
the missing link. Further, authors of research papers, and even of each interaction analysis, our text provides a useful combina-
more so those who read abstracts or press releases and then tion of brevity and thoroughness by presenting an accurate
write articles on these papers for the professional and lay overview as well as answering needs for deeper access to sub-
press, often fail to discriminate between studies using naturally stance and detail. We refer to this publication as a ‘‘compre-
occurring forms, dosage levels, and modes of administration hensive’’ reference work because our goal is to articulate the
typical in experienced clinical practice and studies using isolates subject in a broad and practical manner, not merely to catalogue
or synthetic variants. Consequently, ill-founded extrapolations available data without reference to origins, therapeutic context,
and unsubstantiated conclusions and warnings often result that patterns of usage, and clinical implications. In response to
diverge from the actual research findings and even more so from feedback from users of the previous software publications and
real-world clinical implications. In general, it might be stated in pursuit of strategic design goals, the current text not
that foods are a common preference among practitioners only increases the breadth and depth of the topics under

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
xvi Preface

consideration, but more importantly also applies a systematic interactions. As noted in their meta-analysis, the data used in
method of analysis and presentation aimed at enhancing the making claims of interactions are frequently inadequate and
clinical utility of the reviewed information and subsequent ana- unreliable. Thus, these authors concluded that more than two
lysis. The structure and presentation of each monograph are thirds of published reports reviewed were ‘‘unevaluable’’ and
designed to enable rapid review through summary analysis graded only 13% as ‘‘well-documented.’’ They also noted that,
and coded characterizations of the character, significance, and in contrast to most drugs that contain a single pharmacological
evidence quality of each substantiated interaction, while also agent, most herbal products in use, and thus likely to be
providing greater depth with a thorough review of evidence, involved in possible interactions, tend to contain a variety of
mechanisms, and evolution of the scientific literature on the pharmacologically active constituents. The typical use of multi-
subject. ple herbs within a formulation further complicates the possibi-
Each monograph provides basic information on physiology lities of ascribing causal relationships.
and function of the given nutrient or herbal agent, followed by The literature of nutrient-drug interactions is typically not
a summary of established interactions and a review of clinically much better in quality than that of herb-drug interactions, with
relevant data that contextualizes the discussion of interactions the possible exception of research into drug-induced nutrient
with specific drugs, including known or potential therapeutic depletions. Generally, the research cited is limited by several
uses and historical/ethnomedicine precedent, deficiency symp- factors: inadequate patient history; presence of concurrent con-
toms, dietary sources, nutrient preparations, typical therapeutic ditions or pathologies; involvement of one or more medications
and supplemental dosing, laboratory assessment, and safety pro- (particularly those with known interactions or adverse effects);
file, with nutrient adverse effects, contraindications, and precau- lack of adequate recording of such comedications; failure to
tions and warnings. The Strategic Considerations section of adequately describe, assay, or otherwise document alleged inter-
each monograph discusses the broader clinical role of the parti- actors; incomplete chronology or consideration of time relation
cular agent, emphasizing implications of interactions, and of intake among substances; and incomplete consideration of
further assesses the clinical relevance of the available data, pat- alternative explanations for adverse effects. The need for
terns of interactions, and contentious or unresolved issues; this improvements in the methodology, gathering, and analysis of
section also presents broad clinical reviews for substances for reports and research of interactions involving herbs and nutri-
which substantive interactions evidence is lacking. Each review ents will benefit all concerned and enable distinctions among
of a particular interaction dyad is divided into those with sub- harmful, beneficial, and bimodal interactions and clarify the
stantive evidence, primarily focusing on clinical trials and qua- frequency, intensity, and risk parameters influencing such
lified case reports, and those relying on preliminary, speculative, events. Our conscious intention in assessing data is to tilt
and/or questionable data. Within each interaction pair, the toward safety and emphasize conservative, nontoxic interven-
pharmaceutical agent, and/or drug class, is introduced by gen- tions. The development of this text has also emphasized avoid-
eric name(s) and a summary characterization regarding type(s) ance of unreasonable and poorly founded extrapolations,
of interaction(s) involved, quality of the evidence base, and especially speculative construction of ‘‘backwards interactions’’
estimated probability of clinical relevance, followed by subsec- based on tenuous assumptions. For example, asserting that
tions presenting mechanism(s) of action, evidence and practical because an herb may relieve symptoms assumed to derive
clinical implications, suggestions, and cautions. from estrogen deficiency, the herb inherently will adversely
Presenting the development of evidence chronologically and interact with agents intended to elevate estrogen levels; or
thematically places emphasis on critical factors such as study when a nutrient or herbal preparation demonstrates a beneficial
design, number and characteristics of subjects, study duration, effect on glycemic control, it is somehow interpreted as
form, and dosage. Data from in vitro experiments and animal adversely ‘‘interacting’’ with hypoglycemic medications. In
research are primarily used to examine possible mechanisms of fact, however, such effects often represent a therapeutic synergy
action and to elucidate or qualify evidence from human worth investigating.
research. In general, the standards applied in evaluating the Awareness of narrow therapeutic index, titration in response
strength of evidence are less demanding than those appropriate to gradual introduction or withdrawal of any agent, and indivi-
to evaluation of clinical trial relevance. Furthermore, patient dualized assessment and evolving interventions stand as the
safety is emphasized as the highest value, with a focus on opti- recurrent issues and key operative watchwords in safe and effec-
mizing outcomes while minimizing adverse effects. Overall, tive implementation of interactions in a clinical setting. Overall,
given the emerging state of interactions literature, the threshold developing methods for approaching potential interactions can
of inclusion applied in weighing the available evidence is often help health care professionals avoid inherently dangerous situa-
of a lower standard than ideal, and conclusions are often qua- tions; minimize, neutralize, or counter risks and potential
lified as such, with the oft-repeated recommendation that adverse effects or impaired therapeutic responses; and engineer
‘‘further research through well-designed and adequately pow- increased therapeutic potency through additive, synergistic, or
ered clinical trials is warranted.’’ Specific citations are appended strategic combinations.
to each monograph, and a separate file listing Reference Many of the limitations in the scientific literature relating to
Literature underpinning the overview presentations for each interactions reflect and parallel those in the broader study of
nutrient monograph is available. herbal and nutritional therapies in general. The scientific litera-
The default bias often displayed in the medical literature ture available to those attempting to assess the probability and
assumes that interactions involving herbs and nutrients result clinical significance of interactions among various agents is
in adverse effects. Not only are such outcomes merely one of inherently incomplete and inclined to be reactive. Whether in
several possible effects, but such reports are also often of sub- the area of drug-drug interactions or those involving nutrients
standard quality in the professional literature and are typically or herbs, the instances of purposeful research into adverse inter-
caricatured and misrepresented in the popular press. In asses- actions are rare. Case reports and circumstantial findings tend to
sing the quality of evidence, we have appreciated the taxonomy dominate the literature and are of highly variable quality, with
articulated by Fugh-Berman and Ernst (2001) for the review the clear majority qualifying as incomplete and unreliable.
and assessment of report reliability in the area of herb-drug Further, although the scientific study of combined drug and

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Preface xx

nutrient therapies is emerging, and study of drug-induced of clinical trials focusing on, or at least taking note of, interac-
nutrient depletions is occasionally commanding attention tions will grow as researchers in conventional medicine become
(again, usually in reaction to accumulating reports of adverse more conversant with nutrient and herbal therapies and engage
outcomes), the literature investigating drug-herb interactions is practitioners experienced in such modalities in study design. All
in a highly preliminary, and often woeful, state. Again, unqua- these observations emphasize the need to develop tools to facil-
lified case reports tend to dominate the headlines, and only itate submission of clinical data with complete and pertinent
recently have experienced practitioners of herbal medicine details to high-quality case reports of herb-drug-nutrient inter-
become involved in designing clinical trials or evaluating case actions, with the active cooperation of all parties involved.
reports. Notably, most discussions of herbs in the conventional High-quality case reports can form the basis for meaningful
literature involve single herbs, and if being used for treatment, clinical research and allow the emergence of informed and clini-
then only using a generic, pathology-focused treatment model, cally relevant pharmacovigilance.
when in fact experienced health care professionals almost always Grappling with drug-drug interactions is well known for its
prescribe herbs in formulae that are modified to match peculiar difficulties, and the emerging field of drug-nutrient and drug-
individual patient characteristics and that evolve over time in herb interactions introduces many other complications, as men-
response to changes in the patient’s condition. Similarly, the tioned. Because interactions involving drugs are commonplace
dosages, clinical indications, prescribing methodology, prepara- and can be dangerous, those involving nutrients and herbs need
tion methods, and even plant parts used in most published trials not seem particularly unusual. Most notoriously, as one noted
often reflect little on the professional practice of herbal medi- PharmD commented in conversation: ‘‘We just assume that
cine. In other words, the two groups are usually talking about warfarin interacts with everything.’’ Drug-drug interactions
different things, and the designs of most studies have limited are known for variability based on dose, timing, gender, hepatic
relevance to clinical practice of European, American, or East function, and other drug clearance parameters. Reliably predict-
Asian schools of herbal medicine. Thus, we see a surge in dis- ing interactions involving more than two agents, of any type,
cussion of the use of St. John’s wort for depression, when a poll inherently invokes greater uncertainty, and any declarations
of professional herbal prescribers before such papers would have other than probability are best viewed with skepticism. As a
revealed no consistent use of the plant for that condition as a result, throughout the interactions literature, including that
broad psychiatric diagnostic category; perhaps for melancholy covering drug-drug interactions, there is often an implicit
and head injuries, but not ‘‘depression.’’ Even more disturbing understanding that such interactions are strictly pharmacody-
are studies using parts of plants never used or rarely used by namic or pharmacokinetic and thus completely within the pro-
herbalists or in doses at grossly different levels of potency than vince of pharmacology. On close examination, however, such
typical in clinical practice. Similar issues arise when looking at assumptions often unravel as it becomes apparent that interac-
studies of vitamins, minerals, or other nutrients where single- tions operate at many levels, and that firm distinctions are elu-
agent interventions using forms usually avoided by professional sive and assurances of a complete mechanism of action may be
prescribers, and often at doses considered ineffectual, produce hasty. Interestingly, many combinations described as interac-
insignificant outcomes. ‘‘Well, what would you expect; that’s tions are not really interactions in the narrow technical defini-
why we don’t do it that way,’’ is the usual response from experi- tion. Although some may be ‘‘interactions’’ in some broader
enced botanical/nutritional practitioners. The major conse- definition, a large proportion of adverse events derive from
quences of such ill-conceived research are wasted money and situations more accurately described as ‘‘contraindications’’ or
resources and lost opportunities at evolving scientific knowl- ‘‘inappropriate prescriptions’’ (e.g., excessive additive effects;
edge and collegial collaboration. contrary actions; effective but inappropriately sequenced inter-
The secondary literature discussing interactions involving ventions; patients too young, compromised, or otherwise inap-
herbs and nutrients amplifies and distorts the problems with propriate for a certain agent[s] at the given dose).
the primary source material. Again, ‘‘news’’ tends to be hyper- Within the interactions literature, scant attention has been
bolic and inflammatory and information delayed, reactive, and paid to the methodology by which interactions are analyzed.
overrun with incestuous overuse of poorly qualified and super- Borgert and associates (2005) noted in this connection that
ficially analyzed or incomplete reviews of the primary literature; the ‘‘commonest approach was the no method approach.’’ In
consequently the conclusions are often poorly founded and general, there is insufficient quantitative dose-response data in
hasty, of questionable clinical relevance, and misleading in herb and nutrient interaction studies to meet rigorous criteria
their therapeutic implications. ‘‘The devil is in the details,’’ for the accurate demonstration of supra-additive and subaddi-
and more often than not, no one bothered to look into the tive effects of different dose levels for a given pair of agents.
details. Although not nearly as ‘‘glamorous’’ and headline pro-
ducing as adverse events and dangerous interactions, the areas
of drug-induced nutrient depletions and integrative interven- THE INTERACTIONS UNIVERSE
tions combining drugs, nutrients, and/or herbs represent the The evaluation schema and detailed definitions and standards
bulk of substantive interactions material. Beyond simply cor- used in this text are provided in the following Interactions
recting problematic interactions resulting from ignorance and Evaluation Guide. The primary emphasis of this taxonomy is
lack of communication, these potential avenues of purposeful to establish an operational characterization of each interaction
interactions management also constitute the most promising pair based on clinical priorities. In summary, the type and clin-
opportunities for the development of scientific knowledge cap- ical significance of each known or potential interaction are
able of delivering the clinical interventions most likely to result parsed according to several variables: pharmacokinetic, pharma-
in successful outcomes. Again, we see the necessity of distin- codynamic, or clinical/strategic; adverse, beneficial, or bimodal
guishing between supplemental use of nutrients, especially vita- (bidirectional); prevention or reduction of adverse effects; com-
mins and minerals, on a broad level for undifferentiated pensatory or protective response to probable depletions; negli-
populations and the clinical application of botanical and nutri- gible, cautionary, or avoidance levels of probable effects; and
tional agents as therapeutic interventions in their own right or suitability for self-care or necessity of professional management.
as part of multicomponent strategies. The quantity and quality The levels of probability of clinically significant interaction are

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
xviii Preface

graded as ‘‘1. Certain,’’ ‘‘2. Probable,’’ ‘‘3. Possible,’’ activity. Once again, we see the need to place all substances
‘‘4. Plausible,’’ ‘‘5. Improbable,’’ or ‘‘6. Unknown.’’ In a par- with known or potential pharmacological activity on a level
allel assessment, the available and reviewed evidence is evaluated playing field using objective research design and integrative
according to strength and quality: ‘‘Consensus,’’ ‘‘Emerging,’’ clinical approaches.
‘‘Preliminary,’’ ‘‘Mixed,’’ or ‘‘Inadequate.’’ The overall posi- The complexities of these various influences on drug activity
tion of each interaction pair within this taxonomy is clearly are rarely discussed in the literature with regard to resultant
data dependent, and when the available data suggested ambi- ‘‘interactions’’ and possible clinical implications. For example,
guity or conflict, a final assignation was established by review clinicians of many modalities might recommend exercise, but
and agreement of the entire editorial team. how often do they consider the potential impact of exercise on
In this text, all interactions are considered as potentially drug metabolism? Might not a sudden increase in physical activ-
operating on several levels within the genomic variability and ity significantly change clearance of certain drugs as much as or
physiology of individual patients, their behavior and local envir- more than many common nutrients or herbs? Similarly, in an
onment, the clinical strategy and therapeutic relationship(s), era when every patient (except those on warfarin) is advised to
and among practitioners. These multiple levels may be repre- ‘‘eat more fruits and vegetables,’’ how can we calculate the
sented as a set of concentric circles (see figure). impact of a significant change in dietary habits, especially for
the better? Do we want to discourage patient initiative and
Cultural archetypes of motivation? Here, for example, one might consider the use of
meaning and healing pomegranate juice in the patient with a family history of pros-
Provider collaboration tate cancer, or high intake of vegetables in someone with a
Clinical strategy
Doctor - patient relationship
family history of vascular disease. The recent finding that pome-
Pharmacodynamics/pharmacokinetics granate juice, like grapefruit juice, inhibits the 3A4 isotype of
Pharmacogenomics cytochrome P450 enzymes involved in the metabolism of many
Pharmacogenetics pharmaceuticals, adds another level of complexity to prescribing
and pharmacovigilance. Further, when the recommendation of
dietary fiber and healthy oils is almost universal, doesn’t every
clinician need to advise patients about the known pharma-
Interactions Universe cokinetic effects on drug metabolism of increasing fiber
(which can bind many medications) or of eating more fish
Within this ‘‘interactions universe,’’ multiple interventions or olive oil, with the unknown implications of the effects
are more often the rule than the exception, and interactions of lipids on simultaneously consumed drugs? In considering
may be influenced by several different levels; as always, these these possibilities, we realize the limitations of scientific knowl-
effects may vary based on patient characteristics and the timing edge and clinical experience regarding pharmacokinetics of diet-
relationship between different interventions. Some interactions ary intake, which does not even take into account the wide,
may be significantly affected by pharmacogenomic variability, pharmacogenomically determined variability among patients
with those involving warfarin, statin drugs, or folic acid being in the activity of hepatic enzymes and other systems of
prime examples. In other cases, by shifting the perspective to detoxification.
clinical strategy, what may appear superficially as an interaction
may simply be a clinical contraindication; that is, the therapeutic
intent of one agent is antagonistic to the other agent, and these
would generally be avoided in combination. More subtly, con- The questions raised here and throughout this text challenge
comitant use of two agents may be characterized as ‘‘divergent’’ the attentive reader to reconsider drug activity within the full
or ‘‘distracting,’’ in which the action of a secondary or adjuvant context of therapeutic strategy and patient outcomes. Simply
therapy could theoretically reduce the action of the primary put, is it a higher priority to manage therapies for the sake of
agent and thereby reduce overall therapeutic efficacy. A similar the patients or for the stability of their drug levels? Ultimately,
interaction pattern might be described as ‘‘dissonant’’ when the question arises: when do we counsel patients to avoid
two interventions are potentially appropriate but often can healthy behavior on the basis of the possible risk of disrupting
be incompatible in their action or mode of administration. predictable drug levels? Even with such cautions and qualifica-
Likewise, from a strategic perspective, some agents in pairs or tions, can we be certain this is really obtainable? How does such
in clusters, particularly when applied in a logical sequence, may an approach address interindividual biochemical and metabolic
act in a ‘‘consonant’’ manner. Thus, two agents given simulta- variability? These issues have been discussed in nutrition ther-
neously may provide minimal benefit but administered sequen- apeutics for decades (e.g., Roger Williams, PhD, discoverer of
tially may enhance therapeutic outcomes through strategic pantothenic acid and father of the concept of ‘‘metabolic indi-
synergy. Two examples of such patterns are seen in the relation- viduality’’) and are foundational to the methodology of many of
ship between antibiotics and probiotic flora and, in a more the so-called alternative medical traditions. For example, after
complex form, between chemotherapy and antioxidants. emphasizing to patients the importance of the modern mantra
Further, as recognition of herbs and nutrients as therapeutic of ‘‘eat right and exercise,’’ how do we accept the paradox of
agents, rather than mere supplements, grows, so does the telling ‘‘warfarinized’’ patients with cardiovascular disease to
need for expanding study of interactions between and refrain from eating green vegetables, while also asserting repeat-
among herbs and nutrients. Classical herbal traditions all edly that food sources of nutrients are inherently superior to
have guidelines regarding synergies and contraindications for pharmaceutical supplemental sources?
coadministration; such a methodology is inherent to formula Most experienced health care professionals understand that
building. However, research is only coming into the light in many ‘‘disruptive’’ behaviors (in terms of medication levels) are
regard to such phenomena as the potential adverse effects on not really ‘‘problematic’’ in an absolute sense, and that simply
healthy intestinal bacterial flora from herbs with direct anti- refraining from such behaviors is not the answer. In fact, the
bacterial activity, as opposed to indirect immune-enhancing patient who abruptly stops using a nutrient or herb, drops

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Preface xxii

something from the diet, or radically changes habits out of fear MD, who focused on such phenomena, particularly in geriatric
and ill-informed warnings is actually at greater risk from sudden patients, more than three decades ago. Growing awareness of
changes. Carried to its extreme, might we not recommend to nutrient use by patients and interest in nutritional therapies
patients that they sit on the couch and eat only nonnutritive food within conventional medicine suggest that this body of scientific
so as best to maintain stable drug levels? Do we want our patients literature will expand in coming years.
to imitate the in vitro experiments that we so often caution our- In essence, the issue of interactions presents physicians and
selves not to extrapolate so freely into human physiology? Thus, other health care professionals with the challenge of working as
for example, with patients receiving oral anticoagulants, it would allies, treating all interventions as options to be evaluated as
be more desirable, both from a health perspective and in terms of tactics with a potential to enhance the therapeutic strategy.
building patient rapport, if we could work with them on increas- Thus, we may come to reframe the term ‘‘alternative medicine’’
ing healthy foods in their diet, teaching them to maintain a stable not as ‘‘unconventional’’ or ‘‘competing’’ but rather as a range
intake of dietary vitamin K, while monitoring their INR and of options within a comprehensive repertoire to be considered
titrating it with the appropriate warfarin dosage to maintain in light of the patients’ risks, needs, and history, as well
the desired clinical effect. as their preferences and values, motivation and compliance.
In reviewing the broad literature relevant to interactions Furthermore, effective clinical practice requires more flexible
between drugs and natural products, four key factors seem para- approaches, given the limitations of predictive models, espe-
mount and decisive to safety and efficacy: doctor-patient com- cially when we question whether any model can accurately com-
munication and trust; therapeutic index and rapidity of prehend and predict the outcomes if more than two factors
response; monitoring, feedback, and titration; and the urgent interact in a patient whose natal pharmacogenomic individuality
need for high-quality research and well-documented case has been modified by a lifetime’s layers of stressors, trauma, and
reports together with communication and collaboration. supports. These complexities suggest the need for an evolving
Moreover, the overview of all the findings involving such inter- and customized response in providing medical care, especially
actions strongly suggests that other than a minority of clearly when treating chronic disease, in which some generic elements
dangerous and contraindicated combinations of agents, most of treatment intertwine with some highly individualized aspects,
interactions are therapeutically advantageous when managed and all components shift through phases of the clinical strategy
properly, and some portion are between these two polarities, and are crafted to optimize multiple interventions. The nature
where they pose clinically significant risks only when frank dis- of the therapeutic relationship and its central role in such a
cussion and full disclosure are lacking and corrective measures setting emphasize the primacy of establishing and maintaining
are not implemented. In some cases, nutritional and herbal trust and frank open communication, the ability to be sup-
therapies may impair activity of a drug by promoting healthy portive and challenging, especially regarding diet and other
physiological functions (our primary goal) and thereby increase lifestyle factors, and the need to be nonjudgmental, flexible,
metabolism of stressful or toxic substances, including many and responsive.
drugs. Thus, in these circumstances, the issue is not necessarily These issues point to patient self-care and utilization of mul-
incompatibility, but rather lack of coordination and inappropri- tiple health care professionals from different modalities or spe-
ate timing, such as separation of bile sequestrant intake from the cializations as central but often-ignored factors in the clinical
ingestion of fat-soluble nutrients, which tend to be depleted by reality of drug-herb and drug-nutrient interactions. In discus-
such a drug, or separating intake of an immune-supportive sions of diverse approaches to health care and medicine, two
nutrient such as zinc from antibiotics when the two might che- distinct but often-related issues often become confused and
late when ingested simultaneously. inappropriately intermingled.
Although some observations and recommendations in this First, patients are using a wide range of medical treatments,
text may appear unfamiliar to some medical practitioners, the ingesting unsupervised and untested permutations of substance
material used is inherently conservative, and the clinical sugges- combinations, and experimenting with both ancient and novel
tions are designed to be both pragmatic and clinically oriented, techniques and behaviors for enhancing wellness and treating
with an emphasis on objectivity and evidence, safety and efficacy. disease. Since the early 1990s, conventional medicine has
Apart from research into certain well-known drug-induced nutri- become increasingly aware of the patterns of utilization of
ent depletion patterns, direct clinical trials of adequate power are health care services provided by health care professionals other
nearly absent from literature pertaining to drug-herb and drug- than medical physicians (MDs), as well as use of nonconven-
nutrient interactions. The scant number of reports of well-qua- tional therapies by MDs. Likewise, the emerging educational,
lified and clinically significant adverse events suggests that dan- legal, and professional infrastructures of accredited educa-
gers may be less than some have anticipated or declared, tional institutions, professional associations, and licensing laws
especially given the widespread use of herbs and nutrients and reveal the continued growth of naturopathic physicians, chiro-
the overlap with medication intake. Moreover, research directed practors, acupuncturists, massage therapists, medical herbalists,
at the potential value of the anecdotal evidence available in qua- and others. Providing safe and effective clinical care in this
lified case reports strongly suggests that these could be a resource environment requires knowledge, mutual respect, communica-
of premier value, given the complexities of interactions and the tion, and collaboration among health care providers working
metabolic idiosyncrasies of patients. with individual patients, recognizing, affirming, and utilizing
Drug-induced nutrient depletion patterns constitute a sig- their choices, instincts, experiences, and intuitions. These
nificant proportion of drug-nutrient interactions. In these situa- issues become even more complex when patients have ready
tions, awareness of interference with physiological functions of access to previously unavailable medical information and
key nutrients or simple decline in available nutrient levels con- demand a partnership based on informed decision making.
tributes directly or indirectly to known adverse drug effects and Professionals may have difficulty accepting that each patient,
offers simple and safe interventions for reducing adverse effects, especially patients with chronic disease, holds this final respon-
increasing patient comfort and compliance, and improving ther- sibility and control and that health care providers are simply
apeutic efficacy and clinical outcomes. Research in this area was participants in this critical aspect of the patient’s life and person-
largely established in professional discourse by Daphne A. Roe, al evolution.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

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xx Preface

Demographic data indicate that higher educational and botanical agents prescribed, administered, and supervised by
income levels are associated with the use of natural medicine health care professionals trained and experienced in the
and alternative therapies. Whether acting from healthy initiative respective therapies are virtually nonexistent. The few excep-
or desperation, these patients deserve respect in their health care tions typically represent interventions considered within the
choices and support in obtaining coherent medical care. Self- standards of care but subsequently determined to be inap-
care is a strong tradition within American, English, and other propriate to specific patient populations or in particular
cultures. Whether Culpepper or the Thomsonian and Hygienic dosages or preparations. Thus, MDs, naturopathic physicians,
movements, individuals, families, and communities have long and qualified herbalists have rarely been involved in situations
fought for their right to continue their traditions of care that of adverse reactions or interactions with prescribed nutritional
predate professional medicine. Although potentially challenging or herbal treatments; in fact, they usually are enthusiastic
to our authority as educated health care professionals (and to advocates of scientific research through well-designed trials
the time constraints of daily practice), education and initiative, that might ensure safety, clarify indications, and enhance
informed decision making, and self-empowerment can be our efficacy.
greatest allies in promoting health, preventing illness, and treat- Based on our education, training, and clinical experience
ing disease, with proper timing and strategic coordination. and strongly influenced by the process of compiling and
Here, must we not defer to the obvious necessity and profes- analyzing the material in this text, we offer the following
sional duty to build trust based on honesty and full disclosure? final thoughts. First, the issue of interactions involves not
Enabling frank discussions can provide the most reliable means only avoiding unnecessary risks, but also recognizing unfore-
of respecting patients’ choices and satisfying their needs within a seen opportunities. The greater promise in integrative med-
context of communication and mutual respect, collaboration icine lies not in the use of naturally occurring agents, such as
and coordination among an integrative team of health care an herb, food, or nutrient, to treat standard diagnoses in
professionals. place of pharmaceutical agents, nor in the benefits of
This brings us to the second broad and often-unstated issue expanding the clinical repertoire of conventional medicine,
deeply involved in adverse events and interactions involving but in rendering its medicines more effective, especially in
patients utilizing the services of multiple health care providers. combination with innovations in pharmacogenomics, systems
Short of learning many types of medicine directly, clinicians of physiology, and new research methodologies. More pro-
every type, whether conventional MDs, practitioners of natural foundly, the very movement of engaging with transdisciplin-
medicine traditions, or practitioners from indigenous medical ary approaches and their underlying models offers all
traditions, can benefit from cultivating collegial alliances with practitioners and providers, conventional or otherwise, an
professionals from the diverse health care traditions that their inseparable corollary to the restructuring of their practice,
patients utilize, as a means of developing practical familiarity the potential for transformation and expansion of their
and experience in cross-referrals. Each of these schools of med- own consciousness, and an openness to a greater vision of
icine possesses its own respective models, techniques, and tools, the mysterious and miraculous in medicine.
and each derives from unique circumstances of history, demo-
graphics, and culture. Although simply the result of a lack of Mitchell Bebel Stargrove, ND, LAc
opportunity in some cases, ignorance of other health care sys- Jonathan Treasure MA, MNIMH, RH(AHG)
tems often results from indefensible reliance on ill-founded Dwight L. McKee, MD
rumors and inherited prejudices. Rarely does an MD really
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Interactions Probability, Significance, and Source Strength Guides, xxiii A. Vitamins
Beta-Carotene, 173
Folic Acid, 186
Aloe, 1 Vitamin A (Retinol), 235

Astragalus, 5 Vitamin B1 (Thiamine), 253

Bilberry, 9 Vitamin B2 (Riboflavin), 263
Black Cohosh, 12 Vitamin B3 (Niacin), 281
Cascara, 17 Vitamin B6, 306
Cayenne, 20 Vitamin B12, 338
Dang Gui, 26 Vitamin C (Ascorbic Acid), 356
Devil’s Claw, 30 Vitamin D (Calciferol), 399
Echinacea, 32 Vitamin E, 422
Eleuthero, 39
Vitamin K, 447
Ephedra, 42
Feverfew, 49 B. Minerals
Garlic, 53 Boron, 458
Ginger, 62
Calcium, 464
Ginkgo, 69
Chromium, 499
Ginseng, 80
Copper, 511
Gotu Kola, 88
Iron, 522
Green Tea, 91
Magnesium, 556
Hawthorn, 99
Potassium, 583
Horse Chestnut, 104
Kava, 106 Selenium, 609

Licorice, 113 Zinc, 618

Milk Thistle, 123

C. Amino Acids
Red Clover, 131
Reishi, 133 Arginine, 653

Saw Palmetto, 137 Carnitine, 661

St. John’s Wort, 140 Methionine, 677

Turmeric/Curcumin, 160 Phenylalanine, 682
Valerian, 167 Tryptophan, 690
Vitex, 171 Tyrosine, 698

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
xxviii Contents

D. Nutraceuticals and Physiologics Probiotics, 815

5-Hydroxytryptophan, 706 S-Adenosylmethionine (SAMe), 824
Alpha-Lipoic Acid, 718
Chondroitin Sulfate, 725
DHEA, 746 A. Interactions by Drug Class, 832
B. Interactions by Generic Drug Name, 835
Glucosamine Sulfate, 757
C. Interactions by Drug Trade Name, 855
Inositol, 764
Melatonin, 769
Omega-3 Fatty Acids, 783
INDEX, 891
PABA, 807
Monograph references are located on the CD at the back of the book.
Policosanol, 809

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Aloe Botanical Name: Aloe vera (L.) Burm.
Pharmacopoeial Name: Aloe vera gel.

Herb-Drug Interactions
Synonym: Aloe barbadensis (Mill.).
Common Names: Aloe gel, aloe vera gel.

Drug/Class Interaction Type Mechanism and Significance Management
Chemotherapy and radiotherapy associated with mucositis Aloe gel may ameliorate chemotherapy-induced oral and Use prophylactically and symptomatically during
/ gastrointestinal mucositis. chemotherapy with agents known to induce mucositis.
Wound care, surgery Aloe gel incorporated into conventional dressings improves Commercial hydrogel dressings available.
/ healing in wound care settings.

s0020 HERB DESCRIPTION products are available, including Carrysyn (73% acemannan,
s0030 Family Carrington Laboratories).
p0100 Aloaceae (formerly in Liliaceae).
Note: ‘‘Aloe juice’’ is not a pharmacopoeial term; it describes p0170

varied products sold commercially that contain diluted gel.

s0040 Related Species These products may contain only small amounts of the active
p0110 Aloe ferox Mill., A. africana Mill., A. spicata Baker., A. perryi gel constituents and may incorporate added thickeners such as
Baker.; the Aloe genus has more than 300 species. Aloe vera has pectins and starch. These juice products are usually anthraqui-
been widely hybridized in commerce, and cultivars are the none free.
primary source of the gel.

s0050 Habitat and Cultivation Overview s0090

p0120 Native to Africa, widespread in cultivation throughout Aloe vera gel, the clear, colorless mucilage from the central p0180

subtropical regions in North and South America, West parenchyma of the leaf, is primarily known for promoting
Indies, and East Asia; the cactuslike aloe is also a popular topical healing of burns, wounds, incisions, frostbite, ulcers,
houseplant. and related inflammatory problems. The gel is also widely
incorporated into natural cosmetic and skin care products.
Modern research interest has focused on identifying the
s0060 Parts Used active polysaccharide components of the gel and investigating
p0130 Aloe gel is a mucilaginous, colorless liquid derived from the their potential immunomodulatory properties as biological
central parenchymatous cells of the fresh leaves of aloe. response modifiers.1 Internal applications are also of interest,
such as for inflammatory bowel disease, and a positive trial in
p0140 Note: Aloe gel and aloe latex are completely distinct remedies. active ulcerative colitis patients is available.2,3
The anthraquinone-containing dried juice, a yellow-orange Proprietary aloe extracts based on hydrogel are available p0190

latex, or sap exuded from the outer or pericycle (vascular in professional and consumer markets. These are either
bundles) area of the leaf, is often known as ‘‘Cape aloe’’ or stabilized by means of rapid pasteurization or freeze-dried as a
‘‘Curacao aloe.’’ Some traditional cultures have used the root soluble powder; both forms contain standardized amounts of
as a medicine, but this is not a current Western usage. the main active polysaccharide (acemannan). Professional
Aloe latex can be considered with the Rhamnacae species products are available in a variety of applications for wound
such as cascara (Rhamnus purshiana DC), the buckthorns care, burn treatment, diabetic care, general first-aid dressings,
(R. frangula L. and R. cathartica L.), as well as senna and management of radiation and chemotherapy adverse
leaf and fruits (Cassia senna L.) and rhubarb root (Rheum effects. Limited clinical evidence supports these applications,
palmatum L.). All these species contain closely related although promotion of wound healing appears to be better
anthraquinone glycosides that dominate their pharmacology, supported by the available data than burn treatment.
particularly the pronounced laxative and purgative activity In the United States, popular dietary supplement products p0200

associated with these herbs. combining freeze-dried acemannan with other ingredients
are ‘‘network marketed’’ as ‘‘glyconutritionals.’’ These are
promoted as nonspecific immunostimulants, often with wide-
s0070 Common Forms ranging therapeutic claims, including for the treatment of
p0150 100% Fresh gel and freeze-dried concentrates, typically 4.5:1 cancer and human immunodeficiency virus (HIV). Evidence
concentrate, equivalent to 11.25 mg/mL of acemannan. for such claims is not substantial at this time and is partly
p0160 Standardized Extracts: Preparations based on acemannan extrapolated from non!peer-reviewed data supplied to
(acetylated mannose polysaccharide) obtained by hydroethano- the U.S. Patent Office based on in vitro or uncontrolled
lic extraction from the inner leaf gel. Multiple proprietary animal studies using parenteral routes of administration.4

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
2 Aloe

p0210 Aloe gel and its derivative products are not officially In the setting of externally applied medications, aloe p0290

approved for internal medical use, although some interactions are limited to various combination preparations,
proprietary topical hydrogel products have been approved using the hydrogel as a vehicle with related materials
by the U.S. Food and Drug Administration (FDA). (e.g., algal gums, synthetic hydrogels) or as an ingredient of
Herb-Drug Interactions

The botanical literature emphasizes the anthraquinone creams and ointments in combination with anti-inflammatory
herb rather than the gel. The World Health Organization agents.
(WHO) monograph series includes both remedies The topical effects of the gel are thought to be the result of p0300

separately, but this is the exception.5 Comprehensive literature several mechanisms.11,12 Anti-inflammatory effects have been
reviews relating to recent immunological research on the established experimentally in the treatment of adjuvant arthritis,
gel are unavailable, although there are surveys of the data paw edema, frostbite, and diabetic ulceration in animal
up to the late 1990s.6 The available clinical trial evidence models,11,13-15 as well as in human mucosal CaCO2 cells in
on aloe gel extracts was systematically reviewed in 1999 by vitro.2 The mechanisms involved are probably multifactorial
Vogler and Ernst.7 and include inhibition of prostaglandin synthesis, antioxidant
quenching of free radicals, and bradykinin inhibition, as well
as promotion of connective tissue development, inhibition of
s0100 Historical/Ethnomedicine Precedent collagenase (and metalloproteinase) activity, and stimulation
p0220 Aloe leaf has been in recorded use for centuries, with docu- of cell-mediated immunity.14,16-21 Research at Carrington
mentation by Dioscorides, Pliny, and Galen, as well as in Laboratories has established that the pectins present in aloe
traditional Ayurvedic and Chinese medicine. The gel was vera gel are efficient stabilizers of peptides, which constitute
allegedly used by Cleopatra for cosmetic skin enhancement, a large class of tissue growth factors and immunomodulators,
but Europeans became more familiar with uses of the and may explain some of the observed activities of the plant
gel from African tribes and subsequently planted specimens gel (by increasing the half-life of peptide cytokines and
of Aloe spp. throughout their colonies, which became growth factors).22
rapidly naturalized in subtropical zones. Aloe spread in the Since the 1930s, when aloe gel was first investigated p0310

United States, especially Florida, where it was used by for the topical treatment of ‘‘roentgen dermatitis,’’ there
the Seminole people for healing burns and stings. The gel have been persistent attempts to establish its efficacy for
remains in widespread popular folk use; currently it is often topical treatment of ultraviolet B (UVB) and x-ray radiation
kept as a houseplant, with a leaf cut to obtain fresh gel as burns, although with consistently mixed results.23 Recent
treatment for sunburn, thermal burns, insect bite, and other animal tests have been positive,24 but the only randomized
first-aid needs. controlled clinical trial available failed to show any benefit
of the gel against placebo on chest wall and breast
irradiation in 108 breast cancer patients.25 Another
s0110 Known or Potential Therapeutic Uses oncological use is in chemotherapy-induced mucositis,
p0230 External/Topical: Treatment of abscesses, burns, surgical although only oral (aphthous stomatitis) treatment has
incisions, wounds, ulcers (oral, leg), dermatitis, and psoriasis. received substantial evidential support, and a proprietary aloe
p0240 Internal: Antiviral (HIV/herpes simplex virus [HSV]), hydrogel product has been FDA approved for aphthous ulcer
dysglycemia, inflammatory bowel disease, immunomodulation, treatment.26
peptic ulcer preventive, ulcerative colitis. Internal use of the gel has been examined in relation to p0320

potential antiviral and immunostimulating effects for HIV

patients, as well as for glycemic regulation in diabetic patients.
s0120 Key Constituents Neither of these indications is well supported, nor are they in
p0250 The gel is more than 97% water by weight. The solid matter is current general use clinically by practitioners of natural or bota-
approximately 65% carbohydrate, predominantly in the form of nical medicine. Suggestions of potential synergistic interactions
a long-chained, polydispersed, beta-(1,4)-acetylated mannan with antivirals and antidiabetic agents are discussed later
(acemannan).8,9 Sterols, organic acids (especially oxalate), (see Theoretical, Speculative, and Preliminary Interactions
and various amino acids make up the remainder. Novel Research). A recent United Kingdom trial established positive
dihydrocoumarins have recently been described.10 Naturally support for the use of aloe gel internally for ulcerative colitis.2,3
occurring enzymes are present in the fresh gel, and pasteuriza- Wide variation in commercial and proprietary processing meth-
tion is necessary to stabilize the gel to prevent enzymatic ods, leading to products with differing activities, may underlie
degradation. much of the conflicting results in clinical trials in various appli-
cations of ‘‘stabilized’’ Aloe vera products. The only relatively
uniform activity would be from fresh gel obtained from freshly
s0130 Therapeutic Dosing Range harvested aloe leaves, which are, however, logistically difficult
p0260 Fresh Juice Concentrate: 25 mL up to four times daily. to use in studies.
p0270 Standardized Extracts: 500 to 800 mg-equivalent acemannan One recent, small, crossover-design human trial found p0330

daily. a significant effect of aloe on the pharmacokinetics of

vitamin C and vitamin E absorption. When single doses of
the vitamins were consumed orally with 2 oz of aloe gel
s0140 INTERACTIONS REVIEW or whole-leaf extract, absorption of both the water-soluble
s0150 Strategic Considerations and fat-soluble vitamins were significantly slowed, leading to
p0280 The WHO monograph on aloe gel does not ascribe any inter- longer half-life in plasma. The authors suggested that aloe
actions involving the herb.5 The anthraquinone-containing could be used to complement the absorption of these
Aloe latex is not considered here, but the reader should refer nutrients.27
to the Cascara monograph for some interactions typical of the Data on the effects of aloe gel on drug-metabolizing p0340

anthraquinone-containing botanicals. enzymes and transporters are not available.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Aloe 3

s0160 HERB-DRUG INTERACTIONS mucositis also caused by chemotherapeutic drugs is, to some
extent, a different issue clinically from oral mucositis, the same
s0180 Chemotherapy and Radiotherapy Associated with Mucositis, general approach with aloe gel has been used for prophylaxis of
this GI toxicity. Further data and clinical trials are required to

Herb-Drug Interactions
Including Bleomycin, Fluorouracil/5-FU, and Methotrexate
establish whether the anecdotal combination treatment is
p0350 Including Bleomycin (Blenoxane), cisplatin (cis-diaminedichlor- efficacious.
oplatinum, CDDP; Platinol, Platinol-AQ), cyclophosphamide
Surgery and Other Wound Care s0250
(Cytoxan, Endoxana, Neosar, Procytox), docetaxel (Taxotere),
doxorubicin (Adriamycin, Rubex), etoposide (Eposin, Etophos, Evidence: Polyethylene oxide sheet dressing (Vigilon). p0450

VePesid, VP-16), fluorouracil (5-FU; Adrucil, Efudex, Efudix, Extrapolated, based on similar properties: Hydrogel p0460

Fluoroplex), gemcitabine (Gemzar), irinotecan (camptothecin- dressings.

11, CPT-11; Campto, Camptosar), methotrexate (Folex,
Maxtrex, Rheumatrex), paclitaxel (Paxene, Taxol). Interaction Type and Significance s0260

/ Beneficial or Supportive Interaction, with p0470

s0190 Interaction Type and Significance Professional Management

p0360 Potential or Theoretical Beneficial or Supportive
Interaction, with Professional Management Probability: Evidence Base:
p0370 Prevention or Reduction of Drug Adverse Effect 2. Probable Mixed

Probability: Evidence Base: Effect and Mechanism of Action s0290

4. Plausible ✗ Inadequate Addition of aloe vera gel to polyethylene oxide hydrogel dres- p0500

sings may improve abrasive wound healing in the context of

s0220 Effect and Mechanism of Action professional wound management. The extent and significance
p0400 Inflammation of the oral mucosa (mucositis) induced by of the benefit of combining aloe gel with conventional dres-
chemotherapeutic agents or ionizing radiation may be reduced sings are unknown.
by topical application of aloe vera gel.
p0410 The interaction is unsupported by published direct evidence Research s0300

but is based on established pharmacology and empirical clinical Polyethylene oxide is a cross-linked hydrogel containing 96% p0510

practice. water that is supported on a low-density mesh of polyethylene

sheet for dressing wounds with limited epidermal involvement,
s0230 Research such as dermabrasions, minor burns, and pressure ulcers. One
p0420 Mucositis can be a dose-limiting toxicity of certain che- clinician-researcher reported that the addition of aloe vera gel
motherapies (notably 5-FU) and not only compromises to this dressing format increased dermabrasion wound-healing
normal physiological function, but also can present a portal rates.38,39 Another surgical report from an obstetrical practice,
to systemic infection complications in granulocytopenic however, suggested that application of aloe vera gel actually
patients following secondary infection.28 An acemannan- delayed the healing of surgical wounds, with complications
containing product has been licensed by the FDA for aphthous of healing in 21 women.40 A small trial compared the effects
stomatitis, although clinical trial evidence for the efficacy of of an aloe vera hydrogel to a non!aloe-containing hydrogel
aloe in this setting is equivocal.26,29 There is also some experi- in the healing rates of pressure ulcers and found no significant
mental evidence for the efficacy of aloe gel as a cytoprotective differences between the preparations.41 Oral surgical aloe
agent for gastrointestinal (GI) mucosa, in addition to moderate hydrogel products have shown some efficacy on molar
gastric acid inhibition activity.2,30-32 Radiation oncology has extraction sites.42
also investigated aloe gel as a topical preventive against adverse
effects and one trial tested the effects of aloe gel in head and Integrative Therapeutics, Clinical Concerns, and Adaptations s0310

neck radiotherapy for prevention of oral mucositis; although a Despite the general evidence for promotion of wound healing p0520

positive effect was noted, it was not statistically significant.33 by aloe vera gel, further studies are needed before recommend-
Preclinical and clinical studies on radiation-induced dermatitis ing its use in any situation other than uncomplicated,
and mucositis prevention by aloe gel have been conducted but, superficial wounds. Evidence from specialized wound care
to date, have failed to demonstrate convincing benefits of aloe settings remains inconclusive, and although skilled wound
in symptom reduction.23,34-36 care management is available in these contexts, the use of
p0430 Finally, aloe gel has been shown in vitro to exhibit hema- aloe vera gel for intensive wound care requires professional
topoietic activity, which lends additional, if indirect, support to monitoring.
its use in combination with conventional cancer treatments.37

s0240 Integrative Therapeutics, Clinical Concerns, and Adaptations THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS s0320

p0440 Topical oral wash (‘‘swish and swallow’’) formulations contain-

ing aloe gel, often combined with agents such as glutamine and
licorice extracts, have been employed empirically by practi- Antivirals: Acyclovir and Related Purine Nucleoside Analog s0330

tioners using botanical/nutritional approaches to reduce che- Antivirals; Zidovudine/AZT and Related Reverse-Transcriptase
motherapy-induced mucositis and stomatitis and are associated Inhibitor (Nucleoside Analogs and Nonnucleosides) Antiretroviral
with anecdotal reports of symptom reduction. The antiviral Agents
and antifungal effects of aloe gel, along with its putative immu- Evidence: Acyclovir (Zovirax), zidovudine (azidothymidine, p0530

nostimulatory and hematopoietic effects, lend additional cir- AZT, ZDV, zidothymidine; Retrovir).
cumstantial support to aloe gel as a choice of remedial agent Extrapolated, based on similar properties: Zidovudine combi- p0540

for oral mucositis in this setting. Although the indirect GI nation drugs: abacavir (ziager), zidovudine, and lamivudine

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
4 Aloe

(Combivir); abacavir (ziager), lamivudine, and zidovudine Cortef, Cortifair, Cortizone, Cortone, Cortril, Delacort,
(Trizivir); didanosine (ddI, dideoxyinosine; Videx), dideoxycy- Dermacort, Dermarest, DriCort, DermiCort, Dermtex HC,
tidine (ddC, zalcitabine; Hivid), lamivudine (3TC, Epivir), sta- Epifoam, Gly-Cort, Hi-Cor, Hydro-Tex, Hytone, LactiCare-
vudine (D4T, Zerit), tenofovir (Viread). HC, Lanacort, Lemoderm, Locoid, MyCort, Nutracort,
Herb-Drug Interactions

p0550 A preliminary in vitro study examined the potential syner- Pandel, Penecort, Pentacort, Proctocort, Rederm, S-T Cort,
gistic effects of acemannan with both azidothymidine (AZT) Synacort, Texacort, Westcort).
and acyclovir on human U1 cells infected with HSV-1 and Extrapolated, based on similar properties: Alclometasone p0600

HIV-1. The investigators found a synergistic antiviral effect (Aclovate, Modrasone), amcinonide (Cyclocort), beclometha-
in which suboptimal drug doses, when combined with aceman- sone, betamethasone dipropionate/valerate (betamethasone
nan, produced significant antiviral effects. The authors suggest topical; Alphatrex, Beta-Val, Betaderm, Betanate, Betatrex,
this should be further investigated as a possibly beneficial Diprolene AF, Diprolene, Diprosone, Luxiq, Maxivate,
clinical interaction for HIV/AIDS patients because the Teladar, Uticort, Valisone), clobetasol (clobetasol topical;
mechanisms of the drug and herb were considered to be Cormax, Dermoval, Dermotyl, Dermovate, Dermoxin,
mutually exclusive.43 Only one subsequent trial has investi- Eumosone, Lobate, Olux, Temovate, Temovate E, Topifort),
gated the effect of the combination in HIV patients and clobetasone (Eumovate), clocortolone (clocortolone pivalate
found no effect of acemannan on CD4 count decline compared topical; Cloderm), desonide (DesOwen, Tridesilon), desoxi-
with the control groups, which included coadministration with metasone (Topicort, Topicort LP), desoxymethasone, dexa-
AZT over 48 weeks of treatment.44 methasone (Aeroseb-Dex, Decaderm, Decadron, Decaspray),
diflorasone (Apexicon, Florone, Maxiflor, Psorcon), diflucor-
s0340 Glyburide and Related Sulfonylurea Hypoglycemics tolone (Nerisona, Nerisone), fluocinolone (Derma-Smoothe/
p0560 Evidence: Glyburide (glibenclamide; Diabeta, Glynase, Glynase FS, Fluonid, Synelar, Synemol), fluocinonide (Fluonex,
Prestab, Micronase, Pres Tab). Lidex, Lidex-E, Lonide, Vanos), fludroxycortide (flurandre-
p0570 Extrapolated, based on similar properties: Acetohexamide nolone), fluocortolone (Ultralan), flurandrenolide (Cordran,
(Dymelor), chlorpropamide (Diabinese), glimepiride Drenison), fluticasone (Cutivate), halobetasol (Ultravate),
(Amaryl), glipizide (Glucotrol, Glucotrol XL), tolazamide halcinonide (Halog), mometasone (Elocon, mometasone
(Tolinase), tolbutamide (Orinase, Tol-Tab); combination topical), triamcinolone, (Aristocort, Triderm, Kenalog,
drugs: glipizide and metformin (Metaglip), glyburide and Flutex, Kenonel, triamcinolone topical); triamcinolone and
metformin (Glucovance). nystatin (Mycolog II).
p0580 Aloe has been attributed with mild antidiabetic activity and A single animal study used rodent paw models of inflamma- p0610

is often listed as such in surveys of hypoglycemic medicinal tion to compare the effect of topical hydrocortisone acetate
plants.45,46 Vogler and Ernst’s review7 concluded that aloe alone and in combination with aloe hydrogel. The combination
may be useful as an adjunctive treatment in diabetes, but the was found to be more efficacious than the synthetic steroid alone
studies were limited in number and methodologically poor, at reducing edema and inflammation in this model.53 This
and their conclusion is controversial. The possible use combination is frequently reported as a (beneficial) interaction;
of different plant parts (i.e., latex, gel) further confounds however, the combination does not appear to be used at all in
interpretation. A human trial with glyburide comedication practice and, although theoretically plausible, remains clinically
has not been replicated,47 although its findings have been undemonstrated at present and appears to be overstated.
cited as evidence of an aloe gel!glyburide interaction.48 One
negative human study failed to show hypoglycemic effect Sevoflurane s0360

of the juice, and an animal study demonstrated an actual hyper- Sevoflurane p9010

glycemic action of the gel.49,50 Animal studies suggest that A single perioperative incident of excessive bleeding was p0620

antioxidant activity may exert indirect antidiabetic effects.51,52 attributed to preoperative aloe consumption.54 In fact, the
The use of aloe in any form for glycemic control of type 1 or anesthetic sevoflurane is a potent inhibitor of platelet aggrega-
type 2 human diabetes is not common current clinical practice, tion, and the procedure was biopsy of a hemangioma. In this
at least not in Western botanical medicine. This is therefore a case it seems unlikely that the excessive hemorrhage could be
speculative interaction postulated by reverse extrapolation reliably attributed to aloe consumption. Isoflurane is suggested
from a nonestablished pharmacological effect. as a preferred anesthetic to sevoflurane in situations with high
risk of perioperative bleeds.55 No other reports of aloe and
s0350 Hydrocortisone and Related Topical Corticosteroids bleeding or enhanced anticoagulation have been made.
p0590 Evidence: Hydrocortisone 17-butyrate, acetate, probutate, or
valerate (hydrocortisone topical; Acticort 100, Aeroseb-HC, The 55 citations for this monograph are located under Aloe on the p0630

Ala-Cort, Ala-Scalp HP, Allercort, Alphaderm, Bactine, CD at the back of the book.
Beta-HC, Caldecort Anti-Itch, Cetacort, Cort-Dome, Cortaid,

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Aloe

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2. Langmead L, Feakins RM, Goldthorpe S et al. Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active
ulcerative colitis. Aliment Pharmacol Ther 2004;19:739-747.

3. Langmead L, Rampton DS. Review article: complementary and alternative therapies for inflammatory bowel disease. Aliment
Pharmacol Ther 2006;23:341-349.

4. US Patent 5,308,838. Irving, TX: Carrington Laboratories; May 3, 1994.

5. WHO. Aloe. WHO Monographs on Selected Medicinal Plants. 1 vol. Geneva: World Health Organization; 1999:33-42.

6. Reynolds T, Dweck AC. Aloe vera leaf gel: a review update. J Ethnopharmacol 1999;68:3-37.

7. Vogler BK, Ernst E. Aloe vera: a systematic review of its clinical effectiveness. Br J Gen Pract 1999;49:823-828.

8. Tai-Nin Chow J, Williamson DA, Yates KM, Goux WJ. Chemical characterization of the immunomodulating polysaccharide of Aloe
vera L. Carbohydr Res 2005;340:1131-1142.

9. Im SA, Oh ST, Song S et al. Identification of optimal molecular size of modified Aloe polysaccharides with maximum
immunomodulatory activity. Int Immunopharmacol 2005;5:271-279.

10. Zhang X-f, Wang H-m, Song Y-l et al. Isolation, structure elucidation, antioxidative and immunomodulatory properties of two novel
dihydrocoumarins from Aloe vera. Bioorg Med Chem Lett 2006;16:949-953.

11. Heggers JP, Kucukcelebi A, Listengarten D et al. Beneficial effect of Aloe on wound healing in an excisional wound model. J Altern
Complement Med 1996;2:271-277.

12. Heggers JP, Elzaim H, Garfield R et al. Effect of the combination of Aloe vera, nitroglycerin, and L-NAME on wound healing in the
rat excisional model. J Altern Complement Med 1997;3:149-153.

13. Chithra P, Sajithlal GB, Chandrakasan G. Influence of Aloe vera on the glycosaminoglycans in the matrix of healing dermal wounds
in rats. J Ethnopharmacol 1998;59:179-186.

14. Heggers JP, Robson MC, Manavalen K et al. Experimental and clinical observations on frostbite. Ann Emerg Med

15. Muller MJ, Hollyoak MA, Moaveni Z et al. Retardation of wound healing by silver sulfadiazine is reversed by Aloe vera and
nystatin. Burns 2003;29:834-836.

16. Yagi A, Takeo S. [Anti-inflammatory constituents, aloesin and aloemannan in Aloe species and effects of tanshinon VI in Salvia
miltiorrhiza on heart]. Yakugaku Zasshi 2003;123:517-532.

17. Bautista-Perez R, Segura-Cobos D, Vazquez-Cruz B. In vitro antibradykinin activity of Aloe barbadensis gel. J Ethnopharmacol

18. Barrantes E, Guinea M. Inhibition of collagenase and metalloproteinases by aloins and aloe gel. Life Sci 2003;72:843-850.

19. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. III. Mechanism of cathartic effect. (2). Chem Pharm Bull (Tokyo) 1990;38:197-200.

20. Vazquez B, Avila G, Segura D, Escalante B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol

21. Womble D, Helderman JH. Enhancement of allo-responsiveness of human lymphocytes by acemannan (Carrisyn). Int J
Immunopharmacol 1988;10:967-974.

22. Turner C. Personal communication.

23. Maddocks-Jennings W, Wilkinson JM, Shillington D. Novel approaches to radiotherapy-induced skin reactions: a literature review.
Complement Ther Clin Pract 2005;11:224-231.

24. Roberts DB, Travis EL. Acemannan-containing wound dressing gel reduces radiation-induced skin reactions in C3H mice. Int J
Radiat Oncol Biol Phys 1995;32:1047-1052.

25. Williams MS, Burk M, Loprinzi CL et al. Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-
induced skin toxicity. Int J Radiat Oncol Biol Phys 1996;36:345-349.

26. Editorial. Oral ulcers remedy gets FDA clearance. J Am Dent Assoc 1994;125:1308, 1310.

27. Vinson JA, Al Kharrat H, Andreoli L. Effect of Aloe vera preparations on the human bioavailability of vitamins C and E.
Phytomedicine 2005;12:760-765.

28. Peterson DE, Schubert MM. Oral Toxicity. In: Perry M, ed. The Chemotherapy Source Book. 3rd ed. Philadelphia: Lippincott,
Williams & Wilkins; 2001:406-424.

29. Garnick JJ, Singh B, Winkley G. Effectiveness of a medicament containing silicon dioxide, aloe, and allantoin on aphthous
stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:550-556.

30. Borrelli F, Izzo AA. The plant kingdom as a source of anti-ulcer remedies. Phytother Res 2000;14:581-591.

Citations and Reference Literature: Aloe

31. Suvitayavat W, Sumrongkit C, Thirawarapan SS, Bunyapraphatsara N. Effects of Aloe preparation on the histamine-induced gastric
secretion in rats. J Ethnopharmacol 2004;90:239-247.

32. Yusuf S, Agunu A, Diana M. The effect of Aloe vera A. Berger (Liliaceae) on gastric acid secretion and acute gastric mucosal injury
in rats. J Ethnopharmacol 2004;93:33-37.

33. Can A, Akev N, Ozsoy N et al. Effect of Aloe vera leaf gel and pulp extracts on the liver in type-II diabetic rat models. Biol Pharm
Bull 2004;27:694-698.

34. Dorr W, Schlichting S, Bray MA et al. Effects of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis:
preclinical studies. Int J Radiat Biol 2005;81:243-250.

35. Heggie S, Bryant GP, Tripcony L et al. A Phase III study on the efficacy of topical aloe vera gel on irradiated breast tissue. Cancer
Nurs 2002;25:442-451.

36. Richardson J, Smith JE, McIntyre M et al. Aloe vera for preventing radiation-induced skin reactions: a systematic literature review.
Clin Oncol (R Coll Radiol) 2005;17:478-484.

37. Talmadge J, Chavez J, Jacobs L et al. Fractionation of Aloe vera L. inner gel, purification and molecular profiling of activity. Int
Immunopharmacol 2004;4:1757-1773.

38. Fulton JE, Jr. The stimulation of postdermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dressing. J
Dermatol Surg Oncol 1990;16:460-467.

39. Fulton JE, Jr. Dermabrasion-Loo-punch-excision technique for the treatment of acne-induced osteoma cutis. J Dermatol Surg Oncol

40. Schmidt JM, Greenspoon JS. Aloe vera dermal wound gel is associated with a delay in wound healing. Obstet Gynecol

41. Thomas DR, Goode PS, LaMaster K, Tennyson T. Acemannan hydrogel dressing versus saline dressing for pressure ulcers: a
randomized, controlled trial. Adv Wound Care 1998;11:273-276.

42. Poor MR, Hall JE, Poor AS. Reduction in the incidence of alveolar osteitis in patients treated with the SaliCept patch, containing
acemannan hydrogel. J Oral Maxillofac Surg 2002;60:374-379; discussion 379.

43. Kahlon JB, Kemp MC, Yawei N et al. In vitro evaluation of the synergistic antiviral effects of acemannan in combination with
azidothymidine and acyclovir. Mol Biother 1991;3:214-223.

44. Montaner JS, Gill J, Singer J et al. Double-blind placebo-controlled pilot trial of acemannan in advanced human immunodeficiency
virus disease. J Acquir Immune Defic Syndr Hum Retrovirol 1996;12:153-157.

45. Grover JK, Yadav S, Vats V. Medicinal plants of India with anti-diabetic potential. J Ethnopharmacol 2002;81:81-100.

46. Yeh GY, Eisenberg DM, Kaptchuk TJ, Phillips RS. Systematic review of herbs and dietary supplements for glycemic control in
diabetes. Diabetes Care 2003;26:1277-1294.

47. Brunyapraphatsara N, Yongchaiyuda S, Rungpitarangsi V, Chokechaijaroenporn O. Antidiabetic activity of Aloe vera L juice. II.
Clinical trial in diabetes mellitus patients in combination with glibenclamide. Phytomedicine 1996;3:245-248.

48. Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy, OR: Eclectic Medical Publications; 2001.

49. Chalaprawat M. The hypoglycemic effects of Aloe vera in Thai diabetic patients. J Clin Epidemiol 1997;50:3S.

50. Okyar A, Can A, Akev N et al. Effect of Aloe vera leaves on blood glucose level in type I and type II diabetic rat models. Phytother
Res 2001;15:157-161.

51. Beppu H, Shimpo K, Chihara T et al. Antidiabetic effects of dietary administration of Aloe arborescens Miller components on
multiple low-dose streptozotocin-induced diabetes in mice: investigation on hypoglycemic action and systemic absorption dynamics
of aloe components. J Ethnopharmacol 2006;103:468-477.

52. Rajasekaran S, Sivagnanam K, Subramanian S. Antioxidant effect of Aloe vera gel extract in streptozotocin-induced diabetes in rats.
Pharmacol Rep 2005;57:90-96.

53. Davis RH, Parker WL, Murdoch DP. Aloe vera as a biologically active vehicle for hydrocortisone acetate. J Am Podiatr Med Assoc

54. Lee A, Chui PT, Aun CS et al. Possible interaction between sevoflurane and Aloe vera. Ann Pharmacother 2004;38:1651-1654.

55. Dogan IV, Ovali E, Eti Z et al. The in vitro effects of isoflurane, sevoflurane, and propofol on platelet aggregation. Anesth Analg

Astragalus Botanical Name: Astragalus membranaceus (Fisch.) Bunge.
Pharmacopoeial Name: Radix astragali.

Herb-Drug Interactions
Common Names: Astragalus, milk vetch root, Huang-Qi.

Drug/Class Interaction Type Mechanism and Significance Management
Acyclovir Astragalus promotes T helper cell type 1 (Th1) immunity. Consider coadministration during drug therapy for HSV family viruses.
Purine nucleoside analog antivirals Possible additive antiviral activity, against herpes simplex virus type 1
Experimental support only; interaction not established clinically.
Aldesleukin Astragalus may synergistically increase effects of rIL-2. Theoretically, coadministration may enhance therapeutic outcome of IL-2
Recombinant interleukin-2 Experimental evidence only; interaction not clinically established. treatment.
Cyclophosphamide Astragalus promotes myelopoiesis; may protect white blood cell (WBC) Coadminister and continue after myelosuppressive chemotherapy until
Myelosuppressive chemotherapy counts during chemotherapy with cyclophosphamide, platinum agents, WBC count normalized; used with related herbs in formula.
/ / ✗ or other myelosuppressive chemotherapies.
In nonmalignant disease applications, theoretically an adverse interaction.
Interferon alpha (IFN-a) Astragalus increases endogenous IFN; can be used to support IFN therapy or Consider coadministration in chronic viral conditions treated with IFN.
/ potentiate drug, allowing reduced drug dose and increased tolerability.
Empirical clinical support; no trial evidence.
Thrombolytics Astragalus increases fibrinolytic capacity by promoting tissue-type plasminogen Consider use in hyperviscosity or high-risk thrombotic patients with
activator (tPA). appropriate drugs.
Astragalus may additively support fibrinolytic drug therapies.
Interaction not clinically established.


s0030 Family Overview s0090

p0310 Fabaceae. Astragalus has been used for more than 2000 years in Chinese p0390

medicine and is one of several important materia medica

imports into Western botanical medicine. The herb is
s0040 Related Species primarily used in Western herbalism as an immunomodulating
p0320 Astragalus membranaceus var. mongholicus (Bunge). agent and for cardiovascular disease. Interest in the herb as an
adjunct to chemotherapy in oncological settings is increasing,
but a recent Cochrane review found limited evidence of
s0050 Habitat and Cultivation value for astragalus decoctions in improving adverse effects
p0330 Perennial member of the legume family, native to Northern of chemotherapy in colorectal cancer patients.1 Another, more
China, Mongolia, and Siberia and now under organic cultiva- recent meta-analysis reviewed trials in which astragalus was
tion in the United States. The genus contains more than combined with platinum agents in non!small cell lung
400 species. Wild ‘‘locoweeds’’ (various Astragalus spp.) are cancer; evidence showed that the combination may provide
a common livestock forage food. Gum tragacanth is derived increased effectiveness in terms of tumor response, reduced
from a related species, A. gummifer. toxicity of the chemotherapy, survival time, or performance
Most available scientific literature is published in Chinese p0400
s0060 Parts Used and has not been directly accessed for this survey. Much of
p0340 Radix (root). the experimental data on astragalus are based on isolated
polysaccharide fractions, either in vitro or by intraperitoneal
administration in vivo. Extrapolation from this data to human
s0070 Common Forms oral consumption of powdered crude herb or liquid extracts
p0350 Dried Sliced Root: Often soaked, then pressed or flattened; may not be appropriate, particularly with regard to dosage.
variant preparation may be honey-roasted in Chinese medicine. Chinese clinical trials usually use the herb in combination for-
p0360 Powdered Root: For decoction, liquid extracts and tablets. mulae with other herbs, such as ginseng, dang gui, poria,
p0370 Tincture and Fluid Extracts: 60% to 70% ethanol; usually and rhemannia, because this is the typical manner of clinical
include a water-extraction phase for polysaccharides, then administration. The available data have been used to discuss
preserved in ethanol. the interactions later.
p0380 Standardized Extracts: Several preparations are available. There Astragalus, as with other East Asian herbs incorporated into p0410

is no consensus on marker compounds for standardization at the Western materia medica relatively recently, is not mono-
this time; individual manufacturers’ preparations may vary. graphed by the German Commission E, European Scientific
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
6 Astragalus

Cooperative on Phytotherapy (ESCOP), or World Health interactions are not generally supported by published clinical
Organization (WHO). Astragalus does have an American trials; however, strategic coadministration of the herb in some
Herbal Pharmacopoeia monograph,3 and the literature of the therapeutic contexts described is anecdotally established
has been reviewed by McKenna et al.4 and Wagner et al.5 practice among some practitioners of botanical and integrative
Herb-Drug Interactions

Bensky et al.6 provide an authoritative review, and Chen and medicine.

Chen7 relate traditional Chinese uses to conventional
Effects on Drug Metabolism and Bioavailability s0170

There is currently no evidence of interactions resulting from p0500

s0100 Historical/Ethnomedicine Precedent the effects of astragalus on drug-metabolizing systems.
p0420 Chinese uses include spleen (Pi) qi tonification, lung (Fei) qi A rodent study examining the hepatoprotective effects of astra-
tonification, and ‘‘securing the exterior’’; promoting pus dis- galus saponins against acetaminophen-induced toxicity found a
charge and growth of new tissue and providing immune sup- significant increase in hepatic cytochrome P450 (CYP) levels
port. These features may contribute to a number of different after astragalus administration.11 Although studies are lacking,
biomedical pathological conditions. Astragalus is traditionally clinically significant pharmacokinetic interactions have not
used in Chinese medicine in combination formulae for a wide been reported to date.
range of conditions, from the common cold to chronic renal

s0110 Known or Potential Therapeutic Uses Acyclovir and Related Purine Nucleoside Analog Antivirals s0200

p0430 Cardioprotection (anti-ischemic, fibrinolytic, antioxidant); Evidence: Acyclovir (Zovirax). p0510

immunostimulation (reversal of leukopenia, myelosuppres- Extrapolated, based on similar properties: Purine nucleoside p0520

sion); general prophylaxis of infection, stress, hypertension, analog antivirals; famciclovir (Famvir), ganciclovir (Cytovene),
certain viral infections (coxsackieviruses B2 and B3, parain- valciclovir (Valcivir, Valcyclovir, Valtrex).
fluenza type 1, viral myocarditis, Japanese endocarditis,
HSV-1), nephritis, nephropathy, oxidative stress psoriasis, Interaction Type and Significance s0210

prostatic hypertrophy, and Takayasu arteritis. Potential or Theoretical Beneficial or Supportive p0530

Interaction, with Professional Management

s0120 Key Constituents Probability: Evidence Base:
p0440 Polysaccharides (astragalans or astragologlucans); triterpene 4. Plausible Preliminary
saponins (astragolides I-VII); isoflavones and other flavonoids;
amino acids, minerals, essential oils, and phytosterols. Effect and Mechanism of Action s0240

A synergistic pharmacodynamic interaction increases the anti- p0560

viral efficacy of the drug. Astragalus has established activity

s0130 Therapeutic Dosing Range against a number of viruses in experimental and in vivo envi-
p0450 Dried Root: 10 to 15 g daily; by decoction, maximum 120 g ronments. Mechanisms remain to be clarified, but in general,
in Chinese medicine. T helper cell type 1 (Th1) cytokines and cell-mediated immune
p0460 Hydroethanolic Extracts: 10 to 20 mL daily (based on 1:1 responses are enhanced by astragalus extracts.
Research s0250

Zuo et al.12 demonstrated a potentiation of acyclovir against p0570

s0150 INTERACTIONS REVIEW herpes simplex virus type 1 (HSV-1)!infected mice when com-
s0160 Strategic Considerations bined with astragalus that was greater than the effects of either
p0480 Astragalus is used in Western botanical medicine as a tonic, agent alone, when measured by reduced mortality and
adaptogenic, immunomodulating herb with negligible toxicity. extended survival time.
It is myeloprotective, with added cardioprotective, hepatopro-
tective, and antioxidant properties, which make it a potentially Integrative Therapeutics, Clinical Concerns, and Adaptations s0260

useful adjunct in contexts involving immunosuppression, Coadministration or pretreatment with astragalus may be p0580

whether through disease processes, such as human immunode- useful as a possible adjunct to pharmaceutical antiviral therapies,
ficiency virus (HIV) and chronic fatigue immune dysfunction based on limited available evidence. The interaction remains to
syndrome (CFIDS), or drug induced, such as myelosuppressive be confirmed by clinical studies.
chemotherapies for the treatment of malignancies and
immunosuppression in allograft patients. Recent research on
Aldesleukin (IL-2) s0270

the cardiac properties of the herb may help expand the Interleukin-2 (IL-2), recombinant interleukin-2 (rIL-2); p0590

Western use of astragalus beyond the narrow confines of Proleukin.

p0490 Astragalus use with pharmaceutical immunosuppression Interaction Type and Significance s0280

(i.e., allograft patients) may be theoretically problematic, Potential or Theoretical Beneficial or Supportive p0600

but there are no reports of adverse interactions arising Interaction, with Professional Management
from its use in this context. Combination with immunosup- Prevention or Reduction of Drug Adverse Effect p0610

pressants may be regarded as contraindicated in practice.

Several interactions described later are based on pharmacody- Probability: Evidence Base:
namic effects of the herb on immune parameters. These 3. Possible Preliminary

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Astragalus 7

s0310 Effect and Mechanism of Action adverse, although properly speaking, this is a ‘‘contraindi-
p0640 The coadministration of astragalus and rIL-2 may produce a cated’’ combination.
synergistic pharmacodynamic interaction. Astragalus extracts
enhance several aspects of Th1-mediated immunity. Research s0390

Herb-Drug Interactions
Interleukin-2 immunotherapy is used to enhance cell- Several studies using cells from human cancer and healthy p0750

mediated immunity. Astragalus appears to potentiate IL-2 control patients in graft-versus-host (GVH) reaction models
synergistically, which is one plausible mechanism of its suggest that astragalus polysaccharide extracts promote cell-
ability to increase Th1 (cell-mediated) over Th2 immune mediated immunity and reverse cyclophosphamide-induced
activity. immunosuppression.13,17,18 Water extracts increase phagocy-
tosis in carbon clearance tests, stimulate splenic lymphocyte
s0320 Research proliferation, and increase tumor necrosis factor alpha (TNF-a)
p0650 Co-incubation of lymphokine-activated killer (LAK) cells with and interleukin-6 (IL-6) production by macrophages.19
astragalus F3 (fractionated extract) polysaccharide (55 mg/mL) Proliferative effects on bone marrow stem cells and peripheral
achieved the same ‘‘tumor cell kill’’ when combined with WBCs was observed after intraperitoneal (IP) administration of
100 units/mL of IL-2, as did untreated LAK combined with astragalus in mice.20 Rodent macrophages were activated by
1000 units/mL of IL-2, suggesting a tenfold potentiation.13 astragalus polysaccharide in vitro, partly through nuclear factor
In a related study by the same group using LAK cells from kappa B (NF-kB) activation.21 Clinical trials with intravenous
patients with acquired immunodeficiency syndrome (AIDS), (IV) astragalus polysaccharide coadministered with chemother-
measured activity against melanoma cell lines increased tenfold apy have been reported in the Chinese literature with positive
when IL-2 was combined with astragalus F3, allowing a 50% results on outcome, versus chemotherapy alone, in terms of
reduction in effector/target cell ratio.14,15 Similar results of survival as well as quality-of-life measures.22,23
tenfold potentiation with the F3 fraction and IL-2 with
murine renal cell carcinoma have been reported.16 Clinical Implications and Adaptations s0400

The astragalus-cyclophosphamide interaction has been classified p0760

s0330 Integrative Therapeutics, Clinical Concerns, and Adaptations as adverse by some authorities, presumably in the context of cyclo-
p0660 Patients undergoing low-dose cytokine therapy using IL-2 may phosphamide used in autoimmune disease treatment rather than
benefit from concurrent use of astragalus extracts or cancer therapy.24 Astragalus extracts may be incorporated into
combinations, allowing a lower dose of IL-2 to be used and integrative protocols designed to support patients undergoing
thus reducing potential adverse effects of the immunotherapy. any myelosuppressive chemotherapies. Combination formulae
Astragalus tends to favor Th1 over Th2 through additional are typically used in these applications, and experimental evidence
mechanisms and may be considered a useful synergist in this indicates that such combinations may be more efficacious than the
therapeutic context. Direct clinical evidence for the interaction single herb against cyclophosphamide immunotoxicity.25 Lym-
is not available. phopenia also occurs frequently in cancer patients, before, during,
and after chemotherapeutic interventions, and correlates with
s0340 Cyclophosphamide and Related Myelosuppressive Chemotherapy,
decreased immunocompetence. To the degree that astragalus
Especially Alkylating Agents and other botanicals can support lymphocyte counts in such
p0670 Evidence: Cyclophosphamide (Cytoxan, Endoxana, Neosar, patients, these agents may be of clinical benefit, although con-
Procytox). trolled trials are required to demonstrate efficacy.
p0680 Extrapolated, based on similar properties: Busulfan (Myleran),
carboplatin (Paraplatin), chlorambucil (Leukeran), cisplatin
Interferon Alpha (IFN-a) s0410

(cis-diaminedichloroplatinum, CDDP; Platinol, Platinol- Interferon Alpha (IFN-a): Alferon N, Intron A, Roferon-A.
AQ), dacarbazine (DIC, DTIC, DTIC-Dome, imidazole car-
boxamide), ifosfamide (Ifex, Mitoxana), mechlorethamine Interaction Type and Significance s0420

(Mustargen, nitrogen mustard), melphalan (Alkeran), oxalipla- Prevention or Reduction of Drug Adverse Effect
tin (Eloxatin), phenylalanine mustard (Melphalan), pipobro- Potential or Theoretical Beneficial or Supportive p0780

man (Vercyte), streptozocin (Zanosar), temozolomide Interaction, with Professional Management

(Temodar), thiotepa (Thioplex), uracil mustard (uramustine).
Probability: Evidence Base:
s0350 Interaction Type and Significance 4. Plausible Preliminary
p0690 Prevention or Reduction of Drug Adverse Effect
p0700 Beneficial or Supportive Interaction, with Effect and Mechanism of Action s0450

Professional Management Astragalus increases endogenous interferon (IFN) production p0810

p0710 /✗ Bimodal or Variable Interaction, with Professional by leukocytes and thus may potentiate the effects of therapeutic
Management recombinant interferon (rIFN) administration. It is not
established whether this is an additive or synergistic effect.
Probability: Evidence Base: Preliminary clinical support is available.
2. Probable Emerging
Research s0460

s0380 Effect and Mechanism of Action An experimental study compared administration of a combina- p0820

p0740 Astragalus reduces the effects of cyclophosphamide-induced tion of recombinant IFN-2a with astragalus in a cell culture
suppression of cell-mediated immunity, increasing white model of HSV-1!infected diploid human cells. The combina-
blood cell (WBC) counts in chemotherapy-induced leukopenia tion exhibited greater antiviral activity than the rIFN alone.26
and neutropenia, and is lymphoproliferative at splenic and In a human trial, healthy volunteers were given 8 g/day
bone marrow levels. In the context of cyclophosphamide treat- of astragalus. After 2-week and 2-month periods of administra-
ment of nonmalignant disease, the interaction is theoretically tion, blood levels of IFN were significantly elevated compared

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
8 Astragalus

with controls.27 The effect of IFN in treatment of 235 patients with typical anticoagulant drugs, which generally do not
with chronic viral cervicitis was potentiated by astragalus, the act through tPA. Combination with natural fibrinolytic
combination being more effective as topical treatment than agents such as Wobenzyme, nattokinase, and lumbrokinase
either IFN or astragalus alone. Interferon and astragalus may be appropriate in integrative protocols targeting hypercoa-
Herb-Drug Interactions

combinations were superior to either agent alone against the gulable states.
human cold in a human trial using topical nasal spray
application. Duration of symptoms was reduced significantly.

s0470 Integrative Therapeutics, Clinical Concerns, and Adaptations RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS
p0830 Astragalus is known to have antiviral activity and to increase
cell-mediated immunity. It is not clear to what extent augmen-
Aminoglycoside Antibiotics s0560

tation of IFN levels underlies these effects; coordinated use of Amikacin (Amikin), gentamicin (G-mycin, Garamycin, p0910

astragalus extracts may potentiate or synergize with IFN treat- Jenamicin), kanamycin (Kantrex), neomycin (Mycifradin,
ments (e.g., for viral hepatitis). Myciguent, Neo-Fradin, NeoTab, Nivemycin), netilmicin
(Netromycin), paromomycin (monomycin; Humatin), strepto-
s0480 Thrombolytic Agents
mycin, tobramycin (AKTob, Nebcin, TOBI, TOBI Solution,
p0840 Parenteral alteplase, recombinant (Activase); anistreplase TobraDex, Tobrex).
(Eminase); reteplase, recombinant (Retavase); streptokinase A combination of astragalus and Lu Han Cao (Herba p0920

(Streptase); urokinase (Abbokinase, Abbokinase Open-Cath). Pyrolae) was injected into guinea pigs subsequently adminis-
tered intraperitoneal (IP) aminoglycosides, and the combina-
s0490 Interaction Type and Significance tion was found to prevent toxicity and nephrotoxicity.32 Chen
p0850 Potential or Theoretical Beneficial or Supportive and Chen7 overstate this as an interaction. Because the formula
Interaction, with Professional Management included another herb ingredient and parenteral administration,
it should not be extrapolated to astragalus alone in oral admin-
Probability: Evidence Base: istration without further supporting data.
4. Plausible Preliminary
Oral Hypoglycemic Agents and Insulin s0570

s0520 Effect and Mechanism of Action Buformin (Andromaco Gliporal, Buformina), chlorpropamide p0930

p0880 Astragalus extracts increase fibrinolysis and improve rheologi- (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol;
cal characteristics of whole blood. Coadministration with Glucotrol XL), glyburide (Glibenclamide; Diabeta, Glynase,
various forms of antithrombotic therapy may be supportive, Glynase Prestab, Micronase, Pres Tab), insulin (animal-
although clinical evidence is unavailable. source insulin: Iletin; human analog insulin: Humanlog;
human insulin: Humulin, Novolin, NovoRapid, Oralin),
s0530 Research metformin (Dianben, Glucophage, Glucophage XR); combina-
p0890 Astragaloside IV fractionated extracts increased fibrinolytic tion drugs: glipizide and metformin (Metaglip), glyburide and
potential of human umbilical vein endothelial cells in culture. metformin (Glucovance); tolazamide (Tolinase), phenformin
The effect was mediated by upregulation of tissue-type (Debeone, Fenformin), tolbutamide (Orinase, Tol-Tab).
plasminogen activator (tPA) expression and downregulation A traditional Chinese use of astragalus combinations p0940

of plasminogen activator inhibitor (PA-I).28 Increased PA-I includes effects that would be recognized in modern pharma-
activity relative to tPA and urokinase-type plasminogen activa- cology as lowering blood glucose.7 There is also some experi-
tor (uPA) activity strongly correlates with cardiovascular mental support for this theoretical interaction using
morbidity and mortality. Reduced fibrinolytic capacity is streptozocin-induced rodent models of diabetes. It has been
a major cardiovascular disease risk in younger men. PA-I suggested that this implies a potential adverse interaction with
type 1 (PAI-1) is a risk factor for recurrence of myocardial oral hypoglycemics, a speculation that has no foundation, and
infarction (MI), and high PAI-1 levels predict a first MI in if anything is contrary to the known effects and uses of the herb
middle-aged men and women.29-31 in this context. Data even suggest that insulin sensitivity
may be increased by the herb.33 Astragalus is also potentially
s0540 Integrative Therapeutics, Clinical Concerns, and Adaptations beneficial in preventing diabetic cardiomyopathy.34
p0900 Astragalus extracts may be supportive of strategies aimed
at prophylaxis and treatment of thrombosis in at-risk The 34 citations for this monograph are listed under Astragalus on p0950

populations. There are no reports that astragalus extracts the CD at the back of the book.
adversely interfere with normal hemostasis or interact adversely

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Astragalus

1. Taixiang W, Munro AJ, Guanjian L. Chinese medical herbs for chemotherapy side effects in colorectal cancer patients. Cochrane
Database Syst Rev 2005:CD004540.

2. McCulloch M, See C, Shu XJ et al. Astragalus-based Chinese herbs and platinum-based chemotherapy for advanced non-small-cell
lung cancer: meta-analysis of randomized trials. J Clin Oncol 2006;24:419-430.

3. Upton R. Astragalus root. American Herbal Pharmacopoeia. Santa Cruz, CA; 1999.

4. McKenna DJ, Jones K, Hughes K. Astragalus. Botanical Medicines. 2nd ed. New York: Haworth Press; 2002.

5. Wagner H, Bauer R, Peigen X, Jianming C. Radix Astragali [Huang Qi]. Chinese Drug Monographs and Analysis. Bayer Wald:Verlag
für Ganzheitliche Medizin Dr Eric Wühr GmbH; 1997;1(8):18.

6. Bensky D, Clavey S, Stogër E, Gamble A. Ren Shen. Chinese Herbal Medicine: Materia Medica. 3rd ed. Seattle: Eastland Press;

7. Chen J, Chen T. Huang Qi (Radix Astragali). Chinese Medical Herbology and Pharmacology. City of Industry, CA: Art of Medicine
Press Inc; 2004:847-853.

8. Bruneton J. Toxic Plants Dangerous to Humans and Animals. Hatton CK, Translator. 1st ed. Andover, UK: Intercept Ltd; 1999.

9. Zhang W-D, Chen H, Zhang C et al. Astragaloside IV from Astragalus membranaceus shows cardioprotection during myocardial
ischemia in vivo and in vitro. Planta Med 2006;72:4-8.

10. Shen P, Liu MH, Ng TY et al. Differential effects of isoflavones, from Astragalus membranaceus and Pueraria thomsonii, on the
activation of PPARalpha, PPARgamma, and adipocyte differentiation in vitro. J Nutr 2006;136:899-905.

11. Zhang YD, Shen JP, Zhu SH et al. [Effects of astragalus (ASI, SK) on experimental liver injury]. Yao Xue Xue Bao

12. Zuo L, Dong X, Sun X. The curative effects of Astragalus membranaceous Bunge (A6) in combination with acyclovir on mice
infected with HSV-1. Virol Sin 1995.

13. Chu DT, Lepe-Zuniga J, Wong WL et al. Fractionated extract of Astragalus membranaceus, a Chinese medicinal herb, potentiates
LAK cell cytotoxicity generated by a low dose of recombinant interleukin-2. J Clin Lab Immunol 1988;26:183-187.

14. Chu D, Sun Y, Lin J et al. [F3, a fractionated extract of Astragalus membranaceus, potentiates lymphokine-activated killer cell
cytotoxicity generated by low-dose recombinant interleukin-2]. Zhong Xi Yi Jie He Za Zhi 1990;10:34-36, 35.

15. Chu DT, Lin JR, Wong W. [The in vitro potentiation of LAK cell cytotoxicity in cancer and aids patients induced by F3, a
fractionated extract of Astragalus membranaceus]. Zhonghua Zhong Liu Za Zhi 1994;16:167-171.

16. Wang Y, Qian XJ, Hadley HR, Lau BH. Phytochemicals potentiate interleukin-2 generated lymphokine-activated killer cell
cytotoxicity against murine renal cell carcinoma. Mol Biother 1992;4:143-146.

17. Sun Y, Hersh EM, Talpaz M et al. Immune restoration and/or augmentation of local graft versus host reaction by traditional Chinese
medicinal herbs. Cancer 1983;52:70-73.

18. Wang DC. [Influence of Astragalus membranaceus (AM) polysaccharide FB on immunologic function of human periphery blood
lymphocyte]. Zhonghua Zhong Liu Za Zhi 1989;11:180-183.

19. Yoshida Y, Wang MQ, Liu JN et al. Immunomodulating activity of Chinese medicinal herbs and Oldenlandia diffusa in particular. Int
J Immunopharmacol 1997;19:359-370.

20. Rou M, Renfu X. The effect of Radix Astragali on mouse marrow hemopoiesis. J Tradit Chin Med 1983;3(3):199-204.

21. Lee KY, Jeon YJ. Macrophage activation by polysaccharide isolated from Astragalus membranaceus. Int Immunopharmacol

22. Duan P, Wang Z-m. [Clinical study on effect of Astragalus in efficacy enhancing and toxicity reducing of chemotherapy in patients of
malignant tumor]. Zhongguo Zhong Xi Yi Jie He Za Zhi 2002;22:515-517.

23. Zou Y-h, Liu X-m. [Effect of astragalus injection combined with chemotherapy on quality of life in patients with advanced non–
small cell lung cancer]. Zhongguo Zhong Xi Yi Jie He Za Zhi 2003;23:733-735.

24. Mills S, Bone K. The Essential Guide to Herbal Safety. St Louis: Churchill Livingstone; 2005.

25. Wei X, Zhang J, Li J, Chen S. Astragalus mongholicus and Polygonum multiflorum’s protective function against cyclophosphamide
inhibitory effect on thymus. Am J Chin Med 2004;32:669-680.

26. Zhang L, Liu Y, Yu Z. [Study on the anti–herpes simplex virus activity of a suppository or ointment form of Astragalus
membranaceus combined with interferon alpha 2b in human diploid cell culture]. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za
Zhi 1998;12:269-271.

27. Hou YD, Ma GL, Wu SH et al. Effect of Radix Astragali seu Hedysari on the interferon system. Chin Med J (Engl) 1981;94:35-40.

Citations and Reference Literature: Astragalus

28. Zhang WJ, Wojta J, Binder BR. Regulation of the fibrinolytic potential of cultured human umbilical vein endothelial cells:
astragaloside IV downregulates plasminogen activator inhibitor-1 and upregulates tissue-type plasminogen activator expression. J Vasc
Res 1997;34:273-280.

29. Meade TW, Ruddock V, Stirling Y et al. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in
the Northwick Park Heart Study. Lancet 1993;342:1076-1079.

30. Hamsten A, de Faire U, Walldius G et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction.
Lancet 1987;2:3-9.

31. Thogersen AM, Jansson JH, Boman K et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma
precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary
risk factor. Circulation 1998;98:2241-2247.

32. Xuan W, Dong M. Effects of compound injection of Pyrola rotundifolia L and Astragalus membranaceus Bge on experimental guinea
pigs’ gentamicin ototoxicity. Ann Otol Rhinol Laryngol 1995;104:374-380.

33. Wu Y, Ou-Yang JP, Wu K et al. Hypoglycemic effect of Astragalus polysaccharide and its effect on PTP1B. Acta Pharmacol Sin

34. Li C, Cao L, Zeng Q. Astragalus prevents diabetic rats from developing cardiomyopathy by downregulating angiotensin II type 2
receptors’ expression. J Huazhong Univ Sci Technol Med Sci 2004;24:379-384.

Bilberry Botanical Name: Vaccinium myrtillus L.
Pharmacopoeial Names: Myrtilli folium, Myrtilli fructus.

Herb-Drug Interactions
Common Names: Blueberry, bilberry, whortleberry, huckleberry.

s0020 HERB DESCRIPTION activated receptor (PPAR) and shares some of the chemopre-
s0030 Family ventive and antioxidant characteristics of resveratrol.3,4
p0040 Ericaceae. The German literature describes use of 10% dried bilberry p0110

fruit decoction as a safe supportive treatment of nonspecific

diarrhea, including pediatric cases, and for topical inflamma-
s0040 Related Species tions of the mouth and throat, including oral candidiasis.5-8
p0050 There is considerable bioregional diversity of wild blue-fruited These uses are not widespread in North American clinical prac-
Vaccinium spp., whose berries are very similar nutritionally and tice and are unlikely to invoke interactions with pharmaceutical
medicinally to the official species, V. myrtillus L. (e.g., in the agents.
U.S. Pacific Northwest alone, V. ovatum Pursh., V uliginosum L., The concentrated extracts, enriched in anthocyanins, have a p0120

V. occidentale Gray., V ovalifolium Smith., V deliciosum Smith., range of pharmacological actions, including antioxidant, che-
V. membranaceum, Dougl.). Horticultural cultivars are also moprotective, vasoprotective, antiulcer, anti-inflammatory and
common. antiatherogenic, antiaggregatory, and ophthalmic effects.
Clinical evidence supports their use in peripheral vascular dis-
orders (e.g., venous insufficiency, capillary fragility) and in
s0050 Parts Used ophthalmic disorders. Recent reviews of these data include
p0060 Fruit (berries); the leaf, a separate remedy, has been used in the therapeutic monograph from the European Scientific
traditional herbal medicine but currently is not widely used. Cooperative on Phytotherapy (ESCOP)9 and a survey by
McKenna et al.10 Data relating to berry and fruit polyphenols
and cancer chemoprevention has been reviewed by Prior and
s0060 Common Forms Joseph.11 Experimental data demonstrating direct anticancer
p0070 Leaf: Dried leaf (infusion), dried-leaf hydroethanolic extract. effects of anthocyanins is emerging.12 In clinical practice, con-
p0080 Berry (Fruit): Dried whole fruit; hydroethanolic tincture and centrated bilberry extracts are most likely to be used for dis-
liquid extracts; standardized extract (Myrtocyan, Tegens, orders of microcirculation, and the specific advantage of the
MirtoSelect) in capsule form containing 25% anthocyanidins, anthocyanins is their affinity for ophthalmic neurovasculature;
with 36% anthocyanosides. conditions such as optic neuritis of multiple sclerosis, macular
degeneration, glaucoma, and diabetic retinopathy are often the
key prescribing indications.
s0070 INTERACTIONS REVIEW Interactions between standardized bilberry extracts and p0130
s0080 Strategic Considerations pharmaceutical drugs have received minimal study. A single
p0090 Bilberry is currently best known for the properties of the study reported a reduction in platinum compound toxicity
anthocyanidin (Greek antos, ‘‘flower,’’ and kyanos, ‘‘blue’’) without compromise to antitumor efficacy in an Ehrlich
and proanthocyanidin content of the fruit (berries). tumor rodent model using oral anthocyanins at 300 mg/kg
Anthocyanidins and proanthocyanidins are naturally occurring coadministered with cisplatin.13 No English translation of this
polyphenolic flavonoids widely present in berries and other report has been published, and the platinum interaction has
fruit, also responsible for the blue-red pigmentation in many not been confirmed by other studies or clinical reports and is
flowers and fruits. The chemistry and biological activities of the not reviewed further here.
anthocyanidins and anthocyanins (aglycones and glycosides, Pharmacokinetic data suggest that human intestinal flora p0140

respectively) have been extensively studied; the representative are essential for hydrolysis of the glycoside form to the antho-
compound is cyanidin and its glycosides.1,2 cyanin and proanthocyanin aglycones.14-16 This suggests that
p0100 Although the phytomedical literature on bilberry is domi- iatrogenic reduction in microflora populations induced by anti-
nated by the pharmacology of the anthocyanins and proantho- biotics may reduce the bioavailability of the bilberry polyphe-
cyanins and their glycosides, these are present at a level of only nols, although evidence for this is not available.
0.1% to 0.25% in the fresh fruit. The catechin (tannin) content
of the fruit, however, is actually an order of magnitude higher,
5% to 10%. This implies that standardized extracts that are Effects on Drug Metabolism and Bioavailability s0090

widely used in commerce represent a highly concentrated pro- Effects of bilberry extracts, or anthocyanins and proanthocya- p0150

duct, and the safe therapeutic dose range is wide, from 120 to nins, on drug metabolism have not been well studied.
480 mg standardized extract per day (equivalent to upper dose Chemopreventive effects of fruits and berries have been exam-
of ! 500.0 g fresh, or ! 100.00 g dry, berry/day). At these ined in a few studies examining the mechanism of these effects,
dose levels, bilberry concentrated extracts can be considered as including possible inhibition of cytochrome P450 (CYP) 1A1
a ‘‘phytonutriceutical’’ product, better classified with other and 2E1 xenobiotic (aryl hydrocarbon carcinogen)!metaboliz-
concentrated flavonoid supplements, such as quercitin, rutin, ing enzymes.17-20 The data are inconclusive but suggest low or
and the oligomeric proanthocyanidins (OPCs). Resveratrol minimal effects on these enzymes. Resveratrol, present in small
and the related compound pterostilbene may also be present amounts in bilberries, may inhibit CYP1B1, but this is not a
in significant quantities in the concentrated extracts. significant drug-metabolizing cytochrome in humans although
Pterostilbene appears to have hypocholesterolemic properties it is overexpressed in hormone-dependent tumor tissue.21
mediated by its binding affinity to the peroxisome proliferator Recent experimental evidence suggests that bilberry extracts
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
10 Bilberry

potently inhibit organic anion-transporting polypeptide studied in vitro in relation to ADP- and collagen-induced
B (OATP-B), which is an intestinal transporter responsible for stimulation. The bilberry extract/vitamin C group had a
mediating absorption of several drugs.22 The flavonoid fraction higher level of inhibition of aggregation than either the
of bilberry seems likely to be the active inhibitory component, bilberry or the vitamin C group. Aggregation returned to
Herb-Drug Interactions

but the in vivo significance of this inhibition remains to be baseline 120 days after treatment discontinuation.25
established. Pharmacokinetic interactions between bilberry
extracts or ingredients have not been reported.
Integrative Therapeutics, Clinical Concerns, and Adaptations s0180

If thromboprophylaxis is being affected by use of aspirin, there p0220

s0100 HERB-DRUG INTERACTIONS is at least a theoretical benefit in using bilberry extracts, not
only to enhance the antiplatelet effects, but also because bil-
s0120 Antiplatelet Thromboprophylactics berry anthocyanidins have been shown (in rodent models) to
p0160 Acetylsalicylic acid (acetosal, acetyl salicylic acid, ASA, salicyl- be inhibitory of experimental chemically induced gastric ulcera-
salicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, tion, and to promote ulcer healing.26,27 However, combining
Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, deglycyrrhizinated licorice (DGL) with aspirin in such cases
Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis may be a more cost-effective and reliable way of reducing the
Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, nonsteroidal anti-inflammatory drug (NSAID)!induced
Empirin, Extra Strength Adprin-B, Extra Strength Bayer mucosal irritation and bleeding. Patients taking chronic high
Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, doses of concentrated bilberry extracts in combination with
Heartline, Regular Strength Bayer Enteric 500 Aspirin, pharmaceutical antiplatelet agents should be advised to
St Joseph Adult Chewable Aspirin, ZORprin); combination report any symptoms of peripheral bleeding such as epistaxis
drugs: ASA and caffeine (Anacin), ASA, caffeine, and propox- or susceptibility to bruising, but the effect of dietary intake is
yphene (Darvon Compound), ASA and carisoprodol (Soma likely negligible. This hypothetical interaction is probably of
Compound), ASA, codeine, and carisoprodol (Soma marginal clinical significance.
Compound with Codeine), ASA and codeine (Empirin with
Codeine), ASA, codeine, butalbital, and caffeine (Fiorinal);
cilostazol (Pletal), clopidogrel (Plavix), dipyridamole THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS s0190

(Permole, Persantine), ticlopidine (Ticlid); combination RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS
drug: ASA and extended-release dipyridamole (Aggrenox,
Asasantin) Oral Hypoglycemic Agents and Insulin s0200

Buformin (Andromaco Gliporal, Buformina), chlorpropamide p0230

s0130 Interaction Type and Significance (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol;
p0170 ✗ Potential or Theoretical Adverse Interaction of Glucotrol XL), glyburide (Glibenclamide; Diabeta, Glynase,
Uncertain Severity Glynase Prestab, Micronase, Pres Tab), insulin (animal-
source insulin: Iletin; human analog insulin: Humanlog;
Probability: Evidence Base: human insulin: Humulin, Novolin, NovoRapid, Oralin), met-
5. Improbable Inadequate formin (Dianben, Glucophage, Glucophage XR); combination
drugs: glipizide and metformin (Metaglip), glyburide and met-
s0160 Effect and Mechanism of Action formin (Glucovance); tolazamide (Tolinase), phenformin
p0200 Aspirin (ASA) is a well-documented antiplatelet agent acting (Debeone, Fenformin), tolbutamide (Orinase, Tol-Tab).
through inhibition of cyclooxygenase production of throm- Traditionally, bilberry leaf was used as an antidiabetic tea p0240

boxane A2 (TXA2). Ticlopidine interacts with glycoprotein before the ready availability of insulin for management of
IIb/IIIa to inhibit adenosine diphosphate (ADP)!induced blood sugar levels. This use was emphasized in German phy-
fibrinogen binding to activated platelets and has been used totherapy and is discussed at length by Wichtl.6 However, as
for prevention of thrombosis when aspirin is poorly tolerated. pointed out by Weiss,5 bilberry leaf, in common with other
Because of reports of hematological adverse effects associated herbal infusions touted as antidiabetic teas, does not afford a
with ticlopidine, clopidogrel is currently the preferred anti- clinically significant degree of glycemic control, and bilberry
platelet agent in such cases. As with ticlopidine, clopidogrel leaf infusions are not in general use by diabetic patients.
(Plavix) is an irreversible antiplatelet drug operating via ADP Bilberry leaf is ‘‘unapproved,’’ according to the Commission E
receptor antagonism. The potential interaction is therefore an monograph, because of lack of evidence for the antidiabetic
additive pharmacodynamic increase in antiplatelet activity. function. One study of a rodent model of streptozotocin-
Such an additive effect may theoretically increase the likelihood induced (STZ) diabetes suggested that a short-term drop in
of bleeding disorders related to disturbances of primary blood glucose was seen compared with nondiabetic control ani-
hemostasis. mals after acute oral doses of bilberry leaf at a rate of 3.0 g/kg
for 4 days (equivalent to cumulative human dose of ! 840 g
s0170 Research dried leaf).28 Extrapolations from this study that infer interac-
p0210 Preliminary in vitro evidence suggested that concentrated tions with insulin or hypoglycemic agents are unwarranted, given
anthocyanidins can inhibit platelet aggregation, probably by a the excessive dose used and the lack of clinical use of the leaf in
decrease in cyclic adenosine monophosphate (cAMP) or an modern Western botanical medicine.
inhibition of TXA2 formation at the platelet level.23,24 A later
study examined the effect of standardized bilberry extract in 30
Warfarin and Related Oral Vitamin K Antagonist Anticoagulants s0210

healthy adults for 30 and 60 days, at an oral dose of 160 mg Anisindione (Miradon), dicumarol, ethyl biscoumacetate p0250

three times daily (tid). The subjects were divided into three (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom),
groups: extract alone, extract combined with vitamin C phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar),
(1000 mg tid), or vitamin C alone. Platelet aggregation was warfarin (Coumadin, Marevan, Warfilone).

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Bilberry 11

p0260 Some secondary sources have speculated that, because of in certain individuals, so it remains a theoretical possibility that
the in vitro antiplatelet actions previously discussed, interac- chronic coadministration of very high doses of bilberry extract
tions may occur between concentrated bilberry extracts and with warfarin could result in an increased risk of bleeding.
warfarin or related ‘‘vitamin K antagonist’’ oral anticoagulants, However, this remains a speculative extrapolation, without

Herb-Drug Interactions
as well as antiplatelet drugs.29-31 Although some foods supportive data.
(e.g., avocado) have been reported to interact with warfarin,
without a direct effect on vitamin K, the mechanisms of these The 31 citations for this monograph are located under Bilberry on p0270

interactions remain unclear. Combining antiplatelet and anti- the CD at the back of the book.
coagulant medications can result in increased risk of bleeding

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Bilberry

1. Galvano F, La Fauci L, Lazzarino G et al. Cyanidins: metabolism and biological properties. J Nutr Biochem 2004;15:2-11.

2. Kong J-M, Chia L-S, Goh N-K et al. Analysis and biological activities of anthocyanins. Phytochemistry 2003;64:923-933.

3. Rimando AM, Kalt W, Magee JB et al. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. J Agric Food Chem

4. Rimando AM, Cuendet M, Desmarchelier C et al. Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally
occurring analogue of resveratrol. J Agric Food Chem 2002;50:3453-3457.

5. Weiss R. Herbal Medicine. Meuss A, Translator. 6th ed. Beaconsfield, UK: Beaconsfield Publishers Ltd; 1988.

6. Wichtl M. Myrtilli folium. In: Bisset NG, ed. Herbal Drugs and Phytopharmaceuticals. Boca Raton, FL: CRC Press; 1994.

7. Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical
Council: Integrative Medicine Communications; 1998:685.

8. Schilcher H. Phytotherapy in Paediatrics. Stuttgart: Medpharm Scientific Publishers; 1997.

9. ESCOP. Myrtilli fructus. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK:
European Scientific Cooperative on Phytotherapy and Thieme; 2003:345-350.

10. McKenna D, Jones K, Hughes K, Humphrey S. Bilberry. Botanical Medicines. 2nd ed. Binghamton, NY: Haworth Press;

11. Prior R, Joseph J. Berries and fruits in cancer chemoprevention. In: Bagchi D, Preuss H, eds. Phytopharmaceuticals in Cancer
Chemoprevention. Boca Raton, FL: CRC Press; 2005.

12. Zhang Y, Vareed SK, Nair MG. Human tumor cell growth inhibition by nontoxic anthocyanidins, the pigments in fruits and
vegetables. Life Sci 2005;76:1465-1472.

13. Karaivanova M, Drenska D, Ovcharov R. [A modification of the toxic effects of platinum complexes with antocyans]. Eksp Med
Morfol 1990;29:19-24.

14. Aura A-M, Martin-Lopez P, O’Leary KA et al. In vitro metabolism of anthocyanins by human gut microflora. Eur J Nutr

15. Fleschhut J, Kratzer F, Rechkemmer G, Kulling S. Stability and biotransformation of various dietary anthocyanins in vitro. Eur J
Nutr 2005; 45 (1):7-18.

16. Keppler K, Humpf H. Metabolism of anthocyanins and their phenolic degradation products by the intestinal microflora. Bioorg Med
Chem 2005; 13(17):5195-1205.

17. Bagchi D, Bagchi M, Stohs SJ et al. Cellular protection with proanthocyanidins derived from grape seeds. Ann N Y Acad Sci

18. Carlton PS, Kresty LA, Stoner GD. Failure of dietary lyophilized strawberries to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone- and benzo[a]pyrene-induced lung tumorigenesis in strain A/J mice. Cancer Lett 2000;159:113-117.

19. Carlton PS, Kresty LA, Siglin JC et al. Inhibition of N-nitrosomethylbenzylamine-induced tumorigenesis in the rat esophagus by
dietary freeze-dried strawberries. Carcinogenesis 2001;22:441-446.

20. Singletary KW, Meline B. Effect of grape seed proanthocyanidins on colon aberrant crypts and breast tumors in a rat dual-organ
tumor model. Nutr Cancer 2001;39:252-258.

21. Potter GA, Patterson LH, Wanogho E et al. The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol
by the cytochrome P450 enzyme CYP1B1. Br J Cancer 2002;86:774-778.

22. Fuchikami H, Satoh H, Tsujimoto M et al. Effects of herbal extracts on the function of human organic anion transporting polypeptide,
OATP-B. Drug Metab Dispos 2006;34:577-582.

23. Zaragoza F, Iglesias I, Benedi J. [Comparative study of the anti-aggregation effects of anthocyanosides and other agents]. Arch
Farmacol Toxicol 1985;11:183-188.

24. Bottechia D, Bettini V, Martino R, Camerra G. Preliminary report on the inhibitory effects of Vaccinium myrtillus anthocyanosides
on platelet aggregation and clot reaction. Fitoterapia 1987;58:3-8.

25. Pulliero G, Montin S, Bettini V et al. Ex vivo study of the effects of Vaccinium myrtillus anthocyanosides on human platelet
aggregation. Fitoterapia 1989;60:69-74.

26. Cristoni A, Magistretti MJ. Antiulcer and healing activity of Vaccinium myrtillus anthocyanosides. Farmaco [Prat] 1987;42:29-43.

27. Magistretti MJ, Conti M, Cristoni A. Antiulcer activity of an anthocyanidin from Vaccinium myrtillus. Arzneimittelforschung

28. Cignarella A, Nastasi M, Cavalli E, Puglisi L. Novel lipid-lowering properties of Vaccinium myrtillus L. leaves, a traditional
antidiabetic treatment, in several models of rat dyslipidaemia: a comparison with ciprofibrate. Thromb Res 1996;84:311-322.

29. Bone K. A Clinical Guide to Blending Liquid Herbs. St Louis: Churchill Livingstone; 2003.

Citations and Reference Literature: Bilberry

30. Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.

31. Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy, OR: Eclectic Medical Publications; 2001.

Black Cohosh Botanical Name: Cimicifuga racemosa (L.) Nutt.
Pharmacopoeial Name: Rhizoma cimicifugae racemosae.
Herb-Drug Interactions

Synonym: Actea racemosa L.

Common Names: Black cohosh, black snakeroot, macrotys (historical).

Drug/Class Interaction Type Mechanism and Significance Management
Androgen blockade Black cohosh reduces drug-induced vasomotor adverse effects. Coadminister with professional management and monitoring.
LHRH antagonists Established effect in women, but only anecdotal support for the interaction in men.
Hormone replacement therapy (HRT) Black cohosh supports reduced HRT doses, or tapered withdrawal by reducing Consider adoption, especially for HRT withdrawal.
Estrogens/progestins symptoms associated with climacteric.
Tamoxifen, Raloxifene Black cohosh reduces drug-induced climacteric symptoms, may synergize with SERM Consider coadministering with professional management.
(SERMS) antitumor effects in estrogen receptor!positive cancer.

LHRH, Luteinizing hormone!releasing hormone; SERMs, selective estrogen response modulators.


s0030 Family Overview s0090

p0190 Ranunculaceae. Modern use of black cohosh is dominated by its perception as a p0280

remedy for various symptoms associated with menopause. In

1989 the German Commission E approved its use for dysmen-
s0040 Related Species orrhea, premenstrual discomfort, and neurovegetative ailments
p0200 None; blue cohosh (Caulophyllum thalactroides L.) is a differ- associated with menopause. Increasing concern about the
ent species botanically and medicinally. Asian varieties sold as adverse effects of conventional hormone replacement therapy
sheng ma may be derived from Actea foetida or Actea dahrica (HRT), coupled with clinical trial support for menopausal
and are not interchangeable. applications and promotion of standardized European isopro-
panolic preparations of black cohosh, has led to a narrowing of
focus on the herb as a gynecological remedy, especially for
s0050 Habitat and Cultivation menopausal issues. Therapeutic monographs of the herb
p0210 Native to eastern North America; 95% of black cohosh is wild- include those by the British Herbal Medical Association
crafted, and the impact of annual harvests of 600,000 to (BHMA),1 German Commission E,2 and more recently by
700,000 pounds (1998) on the viability of wild populations the World Health Organization (WHO),3 American Herbal
is a cause for concern. Pharmacopoeia,4 and European Scientific Cooperative on
Phytotherapy (ESCOP).5
Contrary to initial research assumptions of its ‘‘estrogenic’’ p0290
s0060 Parts Used properties, recent studies on black cohosh suggest that it is in
p0220 Rhizome and roots. fact antiestrogenic. Lacking any phytoestrogenic isoflavone
constituents, newer data have demonstrated dopaminergic
and serotonergic receptor binding. Ongoing developments in
s0070 Common Forms estrogen receptor molecular biology continue to add to the
p0230 Dried: Powdered rhizome and root. complex emerging picture. The traditionally known affinities
p0240 Tincture: 1:3 to 1:10 60% alcohol-dried. of black cohosh for the nervous and musculoskeletal systems,
p0250 Fluid Extract: 1:1 60% to 90% alcohol-dried. its cardiovascular effects, and the broad scope of its gynecolo-
p0260 Standardized Extracts: Commercial extracts standardized gical indications (which extend far beyond the specific issue of
to 2.5% triterpene glycosides are available. Clinical trials climacteric symptoms) increasingly appear to have an under-
have largely been based on Remifemin, a proprietary isopropa- lying basis in the neuroendocrine pharmacology of the herb,
nolic formulation available as liquid and tablet form equivalent although this awaits full elucidation.
to a 1:1 g/mL fluid extract, or BNO 1055, an ethanolic extract
sold as Klimadynon/Menafem. (See constituents discussed
later for labeling of 27-deoxyactein marker compound.) Historical/Ethnomedicine Precedent s0100

Black cohosh was used by Native Americans for general p0300

p0270 Note: Herbal practitioners may use fresh herb material, but this malaise, various gynecological conditions, kidney ailments,
is not common in commerce. malaria, rheumatism, sore throat, and snakebite.6 The early
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Black Cohosh 13

colonists also used the herb, reputedly for menorrhea, uterine attributable to the herb. The authors concluded that black
disorders, nervous disorders, lumbago, snakebite, and various cohosh was safe when used for menopausal symptoms and is a
infectious conditions, including malaria.7 Cimicifuga was a safe alternative for women in whom estrogen therapy is contra-
primary remedy for the Eclectic physicians, who termed it indicated.18 However, both this and other safety reviews19

Herb-Drug Interactions
‘‘macrotys.’’ The Eclectics used different forms of the herb, mainly examined isopropanolic extracts as used in clinical
including fresh and dried extracts and a ‘‘resinoid’’ concen- trials, and the data do not necessarily apply to traditional pre-
trate. This was employed for a wide range of neuromuscular, parations, which are often used at higher doses. According to
gynecological, and obstetrical conditions, including neuralgia, the manufacturers of Remifemin, animal tests suggest that
headache, rheumatism, false labor, labor, postpartum pain, higher equivalent doses, up to 500 times the 40-mg oral dose
‘‘partus preparator’’ (to encourage natural contractions of isopropanolic preparations, are well tolerated over 6 months.
during labor), mastitis, atony of the uterus, and amenorrhea, Despite the apparently benign toxicity of the herb according p0410

as well as for a variety of nervous system disorders, including to clinical trial data, there have been persistent anecdotal
chorea, convulsions, delirium tremens, nervous excitability, reports of hepatotoxicity linked to black cohosh consumption.
spasmodic cough, and pertussis. Interestingly, Eclectic use A recent National Institutes of Health (NIH) workshop dis-
included male urogenital conditions such as orchalgia and sper- cussed such reports and concluded that at present, hepatoxicity
matorrhea as well as infections such as smallpox.8-10 Grieve has not been conclusively demonstrated, although vigilance,
includes the indication of St. Vitus’ dance (Sydenham’s including liver function monitoring, may be appropriate
chorea) in children.11 Boericke12 emphasized depression as a when higher doses are used.20,21
key mental indication for Cimicifuga as a homeopathic The absence of published interactions data and reports p0420

medicine. requires integrative practitioners to make the best possible

assessments about potential interactions in light of the
known pharmacology of the herb. Given increasing concerns
s0110 Known or Potential Therapeutic Uses about the risks of breast cancer associated with female HRT,
p0310 Antirheumatic, antispasmodic, uterine tonic; treatment of cli- arguably one of the more common clinical settings for use of
macteric symptoms and ovarian insufficiency, especially asso- the herb is the coadministration of black cohosh with HRT.
ciated with iatrogenically induced menopause; mild depression, Related concerns are potential interactions between black
especially associated with cyclical or climacteric changes; cohosh and drugs used for other aspects of menopause, such
fibromyalgia. as the bisphosphonates for osteoporosis.
Hormone-dependent malignancies are another important p0430

area where drug-herb interactions must be considered.

s0120 Key Constituents Premenopausal patients with reproductive malignancies are
p0320 Triterpene glycosides: More than 20 identified, including 23- likely to experience more severe menopausal symptoms,
epi-26 deoxyactein, which is often incorrectly labeled as especially vasomotor effects, as a result of chemotherapy-
‘‘27-deoxyactein’’ on commercial standardized product induced menopause than are postmenopausal patients.22,23
labels.13 The use of HRT in either population is contraindicated
p0330 Flavonoids: Early reports of the presence of the phytoestrogenic because of the proliferative activity of estrogens and the
isoflavones formononetin and biochanin A have not been increased risk of renewed tumorigenesis.24,25 The possible
substantiated by recent analytical data and are not present in efficacy of black cohosh for symptom relief in these popula-
the standardized isopropanolic extract Remifenin.14,15 tions has not been the subject of systematic long-term
p0340 Aromatic acids: Hydroxycinnamic acid esters of fukiic and studies, although some data are available; nevertheless, anec-
piscidic acid; fukinolic and cimicifugic acids, along with dotally the use of black cohosh is widespread in this
ferulic isoferulic and caffeic acids. setting.26 The potential interaction between adjunctive
p0350 Novel polyphenolics have recently been described.16 tamoxifen and black cohosh in this population has been sub-
p0360 Other components include up to 20% resin (‘‘cimicifugin’’).17 ject of small number of preclinical and clinical investiga-
tions.27-30 (See SERMs later.)
Related adjuvant endocrine pharmacotherapies, such as p0440
s0130 Therapeutic Dosing Range aromatase inhibitors, including the more selective third-
p0370 From 0.2 to 4.0 mL/day (1:1 equivalent) hydroethanolic generation drugs, are restricted in use to postmenopausal
extracts. patients.24 Black cohosh does not contain the isoflavones
p0380 Recent clinical trials using isopropanolic extracts average a with known in vitro aromatase inhibition (e.g., red clover,
modest daily dose of 40 to 80 mg-equivalent dried herb. soy) and has no known aromatase inhibitory activity.
Currently, no data relate coadministration of black cohosh
with aromatase inhibitors.
s0140 INTERACTIONS REVIEW Women for whom estrogen therapy is contraindicated and p0450
s0150 Strategic Considerations those with a history of estrogen-dependent malignancies
p0390 Black cohosh therapeutic monographs typically do not identify should avoid black cohosh, according to some sources.31
any drug interactions.2,3,5 The herb appears to be relatively Recent studies on the pharmacology and clinical effects of
safe and is well tolerated with minimal toxicity at therapeutic black cohosh have been reviewed by Borrelli et al.32,33 The
doses. current consensus is that the herb is primarily antiestrogenic,
p0400 A recent comprehensive safety review by Low Dog et al.18 with receptor-binding tests negative for alpha or beta estrogen
analyzed uncontrolled reports, postmarketing surveillance, and receptor (ER), and that it lacks estrogenic effects on uterine
human clinical trials of more than 2800 patients involving tissue.34-40 Despite the predominant evidence for nonestro-
black cohosh. The trials demonstrated a low incidence (5.4%) genicity, as evidenced by assays on immortal ER-positive
of adverse events, of which 97% were minor, and none lines such as the MCF7 (breast) and Ishihara (endometrial)
resulted in discontinuation of therapy. No severe events were cell lines, data on cell proliferation are conflicting, with a few

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
14 Black Cohosh

studies suggesting proliferation at low doses, although not at with drugs metabolized by cytochrome P450 2D6
higher doses.41-44 In contrast, a recent poster report suggested (CYP2D6), following a probe drug study with desobriquin
that MMT-neu transgenic rats (in which mammary tumors on 12 healthy volunteers by Gurley et al.60 This study failed
develop through spontaneous activation of the HER-2/neu to find any effect of black cohosh extracts on CYP1A2,
Herb-Drug Interactions

oncogene), when treated with equivalent oral doses of isopropa- CYP2E1, and CYP3A4, despite significant inhibition of
nolic black cohosh, show increased metastatic progression to the CYP2D6. The preparation was a commercial black cohosh
lung at necropsy.45 However, the black cohosh!treated animals extract standardized to 0.2% triterpene glycosides administered
did not differ from controls in latency or incidence of mammary at 1090 mg orally twice daily for 28 days. An in vitro
tumor formation. Publicity about this poster report suggesting study tested separate black cohosh triterpene compounds
that black cohosh is unsafe for breast cancer patients would for inhibitory activity against recombinant CYP3A4 oxidation
appear premature given that the weight of emerging evidence of nifedipine. Separate isolated triterpenes demonstrated
is against proliferative effects of the herb.46 Further evidence is moderate IC50 (median inhibitory concentration) effects,
needed to establish safety definitively, and use of black cohosh in but the whole extract demonstrated a notable inhibition,
oncological settings should be restricted to health care profes- with IC50 of 0.027 mg/mL. The authors suggested
sionals with appropriate clinical expertise in the use of botanicals potential for interactions with 3A4-metabolized drugs;
in reproductive malignancies. however, this conflicts with the available clinical evidence
p0460 Evidence that both serotonergic and dopaminergic path- from Gurley’s group, who established that black cohosh
ways may be involved in the mediation of some of the clinical extracts had no effect in vivo on the 3A4 substrate
effects of black cohosh on menopausal symptom reduction is midazolam.61
gathering weight from initial experimental studies on serotonin Drugs metabolized by CYP2D6 include important tricyclic p0510

receptor binding of the extract.47 Borrelli et al.33 hypothesized antidepressants, SSRIs, antipsychotics, stimulants (e.g., risper-
that serotonin may account for the apparent low-dose estro- idone), analgesics, and tamoxifen. CYP2D6 is a narrow-band
genic effects, and this hypothesis has also been adopted by (high-affinity) low-throughput cytochrome, and many of the
experienced researchers in the field such as Jarry et al.48 drugs metabolized by 2D6 can also be oxidized by 3A4.
Significantly, recent clinical evidence exists for the effectiveness Polymorphisms of 2D6 are well known, and ‘‘poor metaboli-
of selective serotonin reuptake inhibitors (SSRIs; e.g., parox- zers’’ have been shown to exhibit higher adverse effect levels
etine, venlafaxine, fluoxetine) in reducing hot flashes in breast with several drugs that are 2D6 substrates. Genotyping of
cancer patients.49-51 Circumstantial support for this theory is patients for whom for prescription of 2D6 substrate drugs is
also found in ER research which suggests possible activation indicated has been proposed as advisable.62 Coadministration
effect of ER transcription by serotonin.52 of black cohosh with drugs that are substrates of 2D6
p0470 The ER itself is an intensive focus of ongoing study, and should be avoided, or related drugs that are not 2D6 substrates
the complexities of coactivation factors and pharmacogenomic should be selected, but interactions with 3A4 substrates
variation within the alpha and beta receptor subtypes continue are unlikely.
to expand the picture.53-55 The complexity of ER biology Modulation of drug transporters by black cohosh has p0520

may account for some of the earlier contradictory research received little study. Gurley et al.63 found no effect of the
findings; for instance, the biphasic nature of dose-response herb (40 mg/day for 14 days) on digoxin pharmacokinetics,
curves exhibited by estrogens and phytoestrogens has been suggesting a negligible action on P-glycoprotein (P-gp). An
studied as an example of the general phenomenon of hormesis experimental model of the human organic anion-transporting
(biphasic or U-shaped dose response curves), adding a further polypeptide B (OATP-B) revealed a moderate inhibitory effect
explanatory dimension to the multifactorial mechanisms on estrone-3-sulfate uptake after black cohosh addition; how-
involved.56,57 ever, the number of known OATP-B substrates in humans is
p0480 In clinical practice, combination prescriptions of herbs are limited at present, although it does include DHEA-S and
often employed, but these are rarely studied in trials. An excep- estrone.64
tion is a recent positive trial of the paired combination of
St. John’s wort (Hypericum perforatum) and black cohosh
for climacteric symptoms.58 The study indirectly lends further HERB-DRUG INTERACTIONS s0170

support to the thesis that menopausal symptoms are caused by

neurotransmitter imbalances, given the known pharmacology
Androgen Blockade Chemotherapies s0190

of St. John’s wort, which is devoid of phytoestogenic effects. Chemotherapy, antiandrogens: Bicalutamide (Casodex), p0530

(See St. John’s Wort monograph.) cyproterone (Androcur, Cyprohexal, Cyprostat, Cyproteron,
p0490 Overall, the pharmacodynamics of black cohosh are Procur, Cyprone, Ciproterona, Cyproteronum, Neoproxil,
complex and not fully understood. The focus on menopause Siterone), flutamide (Chimax, Drogenil, Euflex), nilutamide
may have detracted from wider considerations; for example, (Anandron, Nilandron).
black cohosh compounds are chemoprotective against Chemotherapy, estrogens: Diethylstilbestrol (DES; p0540

menadione-induced deoxyribonucleic acid (DNA) damage.59 Stilphostrol).

The model of black cohosh emerging from current research Chemotherapy, luteinizing hormone!releasing hormone p0550

in many ways is more coincident with the traditional picture (LHRH) agonists: Goserelin (Zoladex), leuprolide (Eligard,
of the remedy as a neuroendocrine rather than a hormonal Lupron, Lupron Depot, Viadur), triptorelin (De-capeptyl
agent. Trelstar, Trelstar LA).
Chemotherapy, gonadotropin-releasing hormone (GnRH) p0560

receptor antagonists/LHRH antagonists: Aberelix, etrorelix

s0160 Effects on Drug Metabolism and Bioavailability (Cetrotide), ganirelix (Antagon).
p0500 Pharmacokinetic interactions between black cohosh and 5a-Reductase inhibitors: Dutasteride (Avidart, Avodart, p0570

prescription drugs have not been recorded to date. Avolve, Duagen, Dutas, Dutagen, Duprost), finasteride
Preliminary clinical data suggest a potential for interactions (Propecia, Proscar).

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Black Cohosh 15

p0580 Steroid/androgen synthesis blockade: Ketoconazole HRT, estrogen/progestin combinations: Conjugated p0680

(Nizoral). equine estrogens and medroxyprogesterone (Premelle cycle

5, Prempro); conjugated equine estrogens and norgestrel
s0200 Interaction Type and Significance (Prempak-C); estradiol and dydrogesterone (Femoston); estra-

Herb-Drug Interactions
p0590 Prevention or Reduction of Drug Adverse Effect diol and norethindrone, patch (CombiPatch); estradiol and
p0600 Potential or Theoretical Beneficial or Supportive norethindrone/norethisterone, oral (Activella, Climagest,
Interaction, with Professional Management Climesse, FemHRT, Trisequens); estradiol valerate and cypro-
terone acetate (Climens); estradiol valerate and norgestrel
Probability: Evidence Base: (Progyluton); estradiol and norgestimate (Ortho-Prefest).
4. Plausible Inadequate HRT, estrogen/testosterone combinations: Esterified estro- p0690

gens and methyltestosterone (Estratest, Estratest HS). (See

s0230 Effect and Mechanism of Action also Estrogen Replacement Therapy [ERT] later.)
p0630 Androgen deprivation combining one or more endocrine
agents (or orchiectomy) in prostate cancer patients leads Interaction Type and Significance s0280

to well-documented adverse effects of hot flashes and loss of Prevention or Reduction of Drug Adverse Effect p0700

libido in more than 50% of patients. Black cohosh extracts may Beneficial or Supportive Interaction, with p0710

reduce vasomotor symptoms in patients with androgen Professional Management

Probability: Evidence Base:
s0240 Research 1. Certain Emerging
p0640 To date, research into the effects of black cohosh on vasomotor
symptoms has been in women undergoing menopause, whether Effect and Mechanism of Action s0310

the natural climacteric or chemically or surgically induced. (See Black cohosh extracts have been demonstrated to reduce sev- p0740

later discussion of interactions with HRT and SERMs.) eral menopausal discomforts, especially vasomotor symptoms
such as hot flashes and night sweats, through nonestrogenic
s0250 Reports mechanisms for which female HRT is also prescribed.
p0650 Currently, there are no published reports on the use of black Coadministration can be used to assist drug withdrawal, to
cohosh for adverse effects of androgen blockade, although a reduce drug dosage or form of drug administration, or to
recent general review of the subject by Moyad65 highlights the decrease exposure to undesirable levels of exogenous estrogen.
pressing need for research on this topic.
Research s0320

s0260 Integrative Therapeutics, Clinical Concerns, and Adaptations There is no research directly analyzing the effects of combining p0750

p0660 Although the clinical efficacy of black cohosh in reducing hot HRT and black cohosh, and the majority of clinical trials pre-
flashes is not always consistent, interest in the use of the herb clude use of HRT as an inclusion criterion, comparing the
remains high among menopausal women and is a focus of effects of black cohosh alone to placebo. Coadministration
ongoing research. On the other hand, information regarding data are generally confined to survey information (see
use of lifestyle and integrative strategies or alternative therapies Reports), although two German open-label trials that included
for andropausal symptoms is scarce. The spectrum of clinical and coadministration groups (Petho 1987, Warnecke 1985) were
laboratory abnormalities associated with androgen deprivation cited in McKenna et al.67 but were unavailable for review;
therapy has been characterized as ‘‘androgen deprivation syn- apparently these trials did not demonstrate significant interac-
drome’’ (ADS) by prostate oncologist Strum, who suggests that tions or adverse effects.
ADS is an accelerated and exaggerated form of male menopause
(andropause) involving a spectrum of possible symptoms, includ- Reports s0330

ing mental and emotional changes and bone and joint pain.66 The Recent survey data on menopausal women in Western coun- p0760

traditional indications of black cohosh for depression and rheu- tries reveal extensive use of dietary, botanical, and nutritional
matic conditions, as well as its effects on vasomotor symptoms, supplements for menopausal complaints.68-71 Significant pro-
suggest that its consideration is appropriate in the context of portions of survey participants admitted to concurrent use of
integrative oncological management of prostate cancer patients HRT with herbal therapies for menopause, ranging from 16%
experiencing ADS, and clinical investigation is warranted. in the San Francisco Bay area survey by Kam et al.69 to 46% in
the Seattle area survey by Newton et al.70 (n = 886). Black
s0270 Hormone Replacement Therapy (HRT): Estrogen-Containing and
cohosh was the third most popular supplement used (after
Synthetic Estrogen and Progesterone Analog Medications
soy extracts and ginkgo). Almost all participants believed the
p0670 HRT, estrogens: chlorotrianisene (Tace); conjugated equine natural therapies used were beneficial.
estrogens (Premarin); conjugated synthetic estrogens
(Cenestin); dienestrol (Ortho Dienestrol); esterified estrogens Integrative Therapeutics, Clinical Concerns, and Adaptations s0340

(Estratab, Menest, Neo-Estrone); estradiol, topical/transder- Changing perceptions of menopause (which is increasingly p0770

mal/ring (Alora Transdermal, Climara Transdermal, Estrace, seen as a normal life cycle transition for which ‘‘natural’’ and
Estradot, Estring FemPatch, Vivelle-Dot, Vivelle Transdermal); folk remedies are more appropriate than mainstream medical
estradiol cypionate (Dep-Gynogen, Depo-Estradiol, Depogen, interventions), coupled with increasing concern about the risks
Dura-Estrin, Estra-D, Estro-Cyp, Estroject-LA, Estronol-LA); of breast cancer associated with female HRT, has led to wide-
estradiol hemihydrate (Estreva, Vagifem); estradiol valerate spread self-prescribed use of black cohosh (among other
(Delestrogen, Estra-L 40, Gynogen L.A. 20, Progynova, agents) as a ‘‘replacement’’ for HRT.72 Practitioners familiar
Valergen 20); estrone (Aquest, Estragyn 5, Estro-A, Estrone ‘5’, with botanical therapies use black cohosh in formulations to
Kestrone-5); estropipate (Ogen, Ortho-Est); ethinyl estradiol assist tapered withdrawal from HRT. It is also used to facilitate
(Estinyl, Gynodiol, Lynoral). transition from combination regimens of conjugated estrogens

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
16 Black Cohosh

and synthetic progestins to lower doses of ‘‘safer’’ bioidentical black cohosh and placebo groups were only significant in
HRT protocols using estriol and natural progesterone, or Bi-est the degree of reduction of sweating. This contrasts with
or Tri-est compounded hormonal formulations (i.e., estrone, a more recent study by Hernadez Munoz and Pluchino,28
estradiol, and estriol compounded formulations). Black who compared the use of tamoxifen alone (20 mg/day) to
Herb-Drug Interactions

cohosh is rarely used alone in this context, but rather is used the same dose combined with 20 mg of ethanolic standardized
as one ingredient of formulae addressing the specific pattern black cohosh extract daily, administered for 12 months in
of the individual case. Use of laboratory test data of urinary 136 breast cancer survivors age 32 to 52 years. Almost half
2a-/16a-hydroxyestrone ratio as a screening test is advisable the intervention group were free from hot flashes, and the
to determine incorporation of related interventions affecting incidence of severe hot flashes was 24% in the intervention
estrogen metabolism in postmenopausal women; the 2a- group and 73.9% in the usual-care (tamoxifen-only) group.
substituted estrogen metabolites have much less tumor- Pockaj et al.74 conducted a survey of black cohosh use
promoting activity than those with 16a-substituted structure. among menopausal women with hot flashes, 13 of whom
Typical associated complementary interventions include the had a history of breast cancer or were taking tamoxifen or
dietary consumption of brassicaceous vegetables, use of soy raloxifene, and found that a significant number had reduced
isoflavones and indole-3-carbinol supplements, and lifestyle symptoms and that no adverse effects of the herb were noted.
factors such as physical exercise and weight reduction, all
of which favor the shift from the 16a-hydroxylation to the Integrative Therapeutics, Clinical Concerns, and Adaptations s0410

2a-hydroxylation pathway. Endocrine therapy with tamoxifen remains a standard adjuvant p0860

approach in ER-positive breast cancer for both premenopausal

s0350 Selective Estrogen Response Modulators (SERMs)
and postmenopausal women, despite issues of tumor flare,
p0780 Raloxifene (Evista), tamoxifen (Nolvadex), toremifene development of drug resistance, and a range of adverse effects.
(Fureston). Adverse effects of tamoxifen include hot flashes, vaginal bleed-
ing and discharge, and a range of central nervous system (CNS)
s0360 Interaction Type and Significance symptoms, such as mood changes, irritability, and depression.
p0790 Prevention or Reduction of Drug Adverse Effect In addition, tamoxifen increases the risk of endometrial cancer
p0800 Beneficial or Supportive Interaction, with and blood clots because of its estrogen-like activity, although it
Professional Management also lowers blood lipid levels and enhances bone density for the
same reason.
Probability: Evidence Base: Practitioners experienced in the use of botanical medicines p0870

4. Plausible Preliminary in integrative cancer care settings may consider black cohosh
(along with the isoflavone and lignan phytoestrogens) as
s0390 Effect and Mechanism of Action potential supportive agents for reduction of hot flashes induced
p0830 Black cohosh extracts reduce vasomotor adverse effects asso- by tamoxifen. Furthermore, the experimental data suggest a
ciated with SERMs and may synergize with the antiproliferative potential improvement in anticancer efficacy for the combina-
effects of these agents in the adjuvant setting for ER-positive tion. Large-scale clinical trials of these agents (vs. placebo) in
breast cancers. combination with endocrine therapies are needed to evaluate
fully the potential effects of such combination therapies. (See
s0400 Research also Androgen Blockade Chemotherapies earlier.)
p0840 The mechanism of this interaction is not currently understood,
although the reduction of hot flashes is unlikely to be directly
mediated through ER effects. Preliminary evidence for THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS s0420

enhancement of the antiproliferative effects of tamoxifen by RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS
black cohosh in MCF-7 (estrogen-dependent breast cancer)
cells was demonstrated by Bodinet and Freudenstein,27 who
Estrogen Replacement Therapy (ERT) s0430

found significant inhibition of proliferation by the extract alone Warnings about black cohosh causing ‘‘estrogen excess’’ with p0880

and a synergistic increase when combined with tamoxifen. ERT have been made by Miller.75 This suggestion is not only
Nisslein and Freudenstein30,73 found similar synergistic effects speculative, but also in conflict with the known pharmacology
with tamoxifen for both mammary and endometrial cancer lines of the herb. (See previous sections on HRT with estrogens and
in rodent models; in the endometrial model the effects did not estrogen/progestin combinations.)
result in increased tumor growth or metastasis, either with black
Iron s0440
cohosh alone or with the black cohosh!tamoxifen combination.
p0850 Two trials have examined the effects of black cohosh on It has been suggested that black cohosh extracts may deplete p0890

tamoxifen-induced hot flashes. Jacobson et al.29 used isopro- iron from supplemental sources because of the tannin content of
panolic black cohosh extracts at 40 mg for 60 days in placebo/ the herb.76 Black cohosh rhizome and roots are not excessively
tamoxifen, black cohosh/tamoxifen, black cohosh/no tamox- tannin rich, and circumstantial evidence for the interaction is
ifen, and placebo/no tamoxifen groups. They studied inci- absent, so this interaction can be regarded as wholly speculative.
dence and severity of hot flashes and sampled changes in
follicle-stimulating hormone (FSH) and luteinizing hormone The 76 citations for this monograph are located under Black Cohosh p0900

(LH) levels before and after treatment. The decline in hot on the CD at the back of the book.
flashes was 27% over baseline, but differences between the

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Black Cohosh

1. BHMA. Black cohosh. In: Bradley P, ed. British Herbal Compendium. 1 vol. Bournemouth, UK: British Herbal Medical Association;

2. Blumenthal M, Busse W, Goldberg A et al. Black cohosh root. The Complete German Commission E Monographs. Austin, TX:
American Botanical Council: Integrative Medicine Communications; 1998:90.

3. WHO. Rhizoma cimicifugae racemosae. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization;

4. Upton R. Black cohosh rhizome. American Herbal Pharmacopoeia. Santa Cruz, CA; 2002.

5. ESCOP. Cimicifugae rhizoma. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK:
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8. Felter H, Lloyd J. Cimicifuga. King’s American Dispensatory. 1 vol. 1983 Reprint ed. Sandy, OR: Eclectic Medical Publications;

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13. Chen SN, Li W, Fabricant DS et al. Isolation, structure elucidation, and absolute configuration of 26-deoxyactein from Cimicifuga
racemosa and clarification of nomenclature associated with 27-deoxyactein. J Nat Prod 2002;65:601-605.

14. Kennelly EJ, Baggett S, Nuntanakorn P et al. Analysis of thirteen populations of black cohosh for formononetin. Phytomedicine

15. Jiang B, Kronenberg F, Balick MJ, Kennelly EJ. Analysis of formononetin from black cohosh (Actaea racemosa). Phytomedicine

16. Nuntanakorn P, Jiang B, Einbond LS et al. Polyphenolic constituents of Actaea racemosa. J Nat Prod 2006;69:314-318.

17. Mills S, Bone K. Black cohosh. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000:303-309.

18. Low Dog T, Powell KL, Weisman SM. Critical evaluation of the safety of Cimicifuga racemosa in menopause symptom relief.
Menopause 2003;10:299-313.

19. Huntley A, Ernst E. A systematic review of the safety of black cohosh. Menopause 2003;10:58-64.

20. Thomsen M, Schmidt M. Hepatotoxicity from Cimicifuga racemosa? Recent Australian case report not sufficiently substantiated. J
Altern Complement Med 2003;9:337-340.

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ODS; 2004.

22. Day R, Ganz PA, Costantino JP et al. Health-related quality of life and tamoxifen in breast cancer prevention: a report from the
National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 1999;17:2659-2669.

23. Fisher B, Costantino JP, Wickerham DL et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant
Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371-1388.

24. Ibrahim NK, Hortobagyi GN. The evolving role of specific estrogen receptor modulators (SERMs). Surg Oncol 1999;8:103-123.

25. Rostom AY. The management of menopausal sequelae in patients with breast cancer. Clin Oncol (R Coll Radiol) 2001;13:174-180.

26. Freudenstein J, Dasenbrock C, Nisslein T. Lack of promotion of estrogen-dependent mammary gland tumors in vivo by an
isopropanolic Cimicifuga racemosa extract. Cancer Res 2002;62:3448-3452.

27. Bodinet C, Freudenstein J. Influence of Cimicifuga racemosa on the proliferation of estrogen receptor–positive human breast cancer
cells. Breast Cancer Res Treat 2002;76:1-10.

28. Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas
2003;44 Suppl 1:S59-65.

29. Jacobson JS, Troxel AB, Evans J et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history
of breast cancer. J Clin Oncol 2001;19:2739-2745.

30. Nisslein T, Freudenstein J. Synergistic effects of black cohosh and tamoxifen in an animal model of mammary carcinoma. Maturitas
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31. Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy, OR: Eclectic Medical Publications; 2001.

32. Borrelli F, Ernst E. Cimicifuga racemosa: a systematic review of its clinical efficacy. Eur J Clin Pharmacol 2002;58:235-241.

33. Borrelli F, Izzo AA, Ernst E. Pharmacological effects of Cimicifuga racemosa. Life Sci 2003;73:1215-1229.

34. Zierau O, Bodinet C, Kolba S et al. Antiestrogenic activities of Cimicifuga racemosa extracts. J Steroid Biochem Mol Biol

35. Mahady GB. Is black cohosh estrogenic? Nutr Rev 2003;61:183-186.

36. Einer-Jensen N, Zhao J, Andersen KP, Kristoffersen K. Cimicifuga and Melbrosia lack oestrogenic effects in mice and rats. Maturitas

37. Seidlova-Wuttke D, Jarry H, Becker T et al. Pharmacology of Cimicifuga racemosa extract BNO 1055 in rats: bone, fat and uterus.
Maturitas 2003;44 Suppl 1:S39-50.

38. Wuttke W, Jarry H, Becker T et al. Phytoestrogens: endocrine disrupters or replacement for hormone replacement therapy? Maturitas
2003;44 Suppl 1:S9-20.

39. Wuttke W, Seidlova-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind
placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas 2003;44 Suppl 1:S67-77.

40. Liske E, Hanggi W, Henneicke-von Zepelin HH et al. Physiological investigation of a unique extract of black cohosh (Cimicifugae
racemosae rhizoma): a 6-month clinical study demonstrates no systemic estrogenic effect. J Womens Health Gend Based Med

41. Liu Z, Yang Z, Zhu M, Huo J. [Estrogenicity of black cohosh (Cimicifuga racemosa) and its effect on estrogen receptor level in
human breast cancer MCF-7 cells]. Wei Sheng Yan Jiu 2001;30:77-80.

42. Kruse SO, Lohning A, Pauli GF et al. Fukiic and piscidic acid esters from the rhizome of Cimicifuga racemosa and the in vitro
estrogenic activity of fukinolic acid. Planta Med 1999;65:763-764.

43. Zava DT, Dollbaum CM, Blen M. Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med

44. Liu J, Burdette JE, Xu H et al. Evaluation of estrogenic activity of plant extracts for the potential treatment of menopausal symptoms.
J Agric Food Chem 2001;49:2472-2479.

45. Davis V, Jayo M, Hardy M et al. Effects of black cohosh on mammary tumor development and progression in MMTV-neu transgenic
mice. Abstract R910. Proceedings of the AACR, Vol 44, 2nd ed, July 2003.

46. Stromeier S, Petereit F, Nahrstedt A. Phenolic esters from the rhizomes of Cimicifuga racemosa do not cause proliferation effects in
MCF-7 cells. Planta Med 2005;71:495-500.

47. Burdette JE, Liu J, Chen SN et al. Black cohosh acts as a mixed competitive ligand and partial agonist of the serotonin receptor. J
Agric Food Chem 2003;51:5661-5670.

48. Jarry H, Metten M, Spengler B et al. In vitro effects of the Cimicifuga racemosa extract BNO 1055. Maturitas 2003;44 Suppl

49. Weitzner MA, Moncello J, Jacobsen PB, Minton S. A pilot trial of paroxetine for the treatment of hot flashes and associated
symptoms in women with breast cancer. J Pain Symptom Manage 2002;23:337-345.

50. Loprinzi CL, Kugler JW, Sloan JA et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised
controlled trial. Lancet 2000;356:2059-2063.

51. Loprinzi CL, Sloan JA, Perez EA et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol

52. O’Malley BW, Schrader WT, Mani S et al. An alternative ligand-independent pathway for activation of steroid receptors. Recent
Prog Horm Res 1995;50:333-347.

53. Yoon K, Pallaroni L, Stoner M et al. Differential activation of wild-type and variant forms of estrogen receptor alpha by synthetic and
natural estrogenic compounds using a promoter containing three estrogen-responsive elements. J Steroid Biochem Mol Biol

54. Bramlett KS, Burris TP. Target specificity of selective estrogen receptor modulators within human endometrial cancer cells. J Steroid
Biochem Mol Biol 2003;86:27-34.

55. Igaz P, Pap E, Patocs A et al. Genomics of steroid hormones: in silico analysis of nucleotide sequence variants (polymorphisms) of
the enzymes involved in the biosynthesis and metabolism of steroid hormones. J Steroid Biochem Mol Biol 2002;82:359-367.

56. Calabrese EJ. Estrogen and related compounds: biphasic dose responses. Crit Rev Toxicol 2001;31:503-515.

57. Almstrup K, Fernandez MF, Petersen JH et al. Dual effects of phytoestrogens result in U-shaped dose-response curves. Environ
Health Perspect 2002;110:743-748.

58. Uebelhack R, Blohmer J-U, Graubaum H-J et al. Black cohosh and St. John’s wort for climacteric complaints: a randomized trial.
Obstet Gynecol 2006;107:247-255.

Citations and Reference Literature: Black Cohosh

59. Burdette JE, Chen SN, Lu ZZ et al. Black cohosh (Cimicifuga racemosa L.) protects against menadione-induced DNA damage
through scavenging of reactive oxygen species: bioassay-directed isolation and characterization of active principles. J Agric Food
Chem 2002;50:7022-7028.

60. Gurley BJ, Gardner SF, Hubbard MA et al. In vivo effects of goldenseal, kava kava, black cohosh, and valerian on human
cytochrome P450 1A2, 2D6, 2E1, and 3A4/5 phenotypes. Clin Pharmacol Ther 2005;77:415-426.

61. Gurley B, Hubbard MA, Williams DK et al. 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

62. Cozza K, Armstrong S, Oesterheld J. Drug Interaction Principles for Medical Practice. 2nd ed. Washington, DC: American
Psychiatric Publishing; 2003.

63. Gurley B, Barone GW, Williams DK et al. Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa)
supplementation on digoxin pharmacokinetics in humans. Drug Metab Dispos 2005;34:69-74.

64. Fuchikami H, Satoh H, Tsujimoto M et al. Effects of herbal extracts on the function of human organic anion transporting polypeptide,
OATP-B. Drug Metab Dispos 2006;34:577-582.

65. Moyad MA. Complementary/alternative therapies for reducing hot flashes in prostate cancer patients: reevaluating the existing
indirect data from studies of breast cancer and postmenopausal women. Urology 2002;59:20-33.

66. Strum S, Pogliano D. A Primer on Prostate Cancer. Hollywood, FL: Life Extension Foundation; 2002:151-153.

67. McKenna DJ, Jones K, Humphrey S, Hughes K. Black cohosh: efficacy, safety, and use in clinical and preclinical applications. Altern
Ther Health Med 2001;7:93-100.

68. Gokhale L, Sturdee DW, Parsons AD. The use of food supplements among women attending menopause clinics in the West
Midlands. J Br Menopause Soc 2003;9:32-35.

69. Kam IW, Dennehy CE, Tsourounis C. Dietary supplement use among menopausal women attending a San Francisco health
conference. Menopause 2002;9:72-78.

70. Newton KM, Buist DS, Keenan NL et al. Use of alternative therapies for menopause symptoms: results of a population-based survey.
Obstet Gynecol 2002;100:18-25.

71. Ma J, Drieling R, Stafford RS. US women desire greater professional guidance on hormone and alternative therapies for menopause
symptom management. Menopause 2006;13:506-516.

72. Ness J, Aronow WS, Beck G. Menopausal symptoms after cessation of hormone replacement therapy. Maturitas 2006;53:356-361.

73. Nisslein T, Freudenstein J. Concomitant administration of an isopropanolic extract of black cohosh and tamoxifen in the in vivo
tumor model of implanted RUCA-I rat endometrial adenocarcinoma cells. Toxicol Lett 2004;150:271-275.

74. Pockaj BA, Loprinzi CL, Sloan JA et al. Pilot evaluation of black cohosh for the treatment of hot flashes in women. Cancer Invest

75. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern
Med 1998;158:2200-2211.

76. Harkness R, Bratman S. Mosby’s Handbook of Drug-Herb and Drug-Supplement Interactions. St Louis: Mosby; 2003.

Cascara Botanical Name: Rhamnus purshiana DC.
Pharmacopoeial Name: Cortex rhamni purshianae.

Herb-Drug Interactions
Synonym: Frangula purshiana (DC) A. Gray ex J.C. Cooper.
Common Names: Cascara, cascara sagrada.

s0020 HERB DESCRIPTION binge eating) and use purgation (and/or vomiting) as a self-
s0030 Family imposed means of eliminating ingested food. Although such
p0050 Rhamnaceae. abuse exists, preoccupation with the purgative aspects of these
herbs and their anthraquinone constituents is only one concern
to integrative practitioners. A broader consideration of the
s0040 Related Species activity of these botanicals in light of recent research suggests
p0060 Alder buckthorn, Rhamnus frangula L. (syn. Frangula alnus, therapeutic applications in other fields, such as cancer
Miller.), buckthorn, Rhamnus catharticus L. chemotherapy.
Recent findings have revealed that the earlier concept of all p0140

stimulant laxatives acting through gut motility mechanisms is

s0050 Parts Used oversimplistic. Multiple mechanisms are involved, including
p0070 Dried bark (aged at least 1 year, stored in dark). almost every aspect of active and passive electrolyte transport,
such as sodium/potassium-adenosinetriphosphatase (Na+,
K+-ATPase), cyclic nucleotides, protein kinase C, calcium
s0060 Common Forms (Ca++) dependence, autocoids or neurotransmitter release,
p0080 Dried bark: Powdered or cut for decoction. increased mucosal permeability, and histological damage.6-11
p0090 Fluid Extract: 1:1 25% alcohol.1 Furthermore, it has become clear that significant differences
p0100 Other liquid and solid preparations. exist between the mechanism of action of the different
agents; for example, senna does not stimulate platelet-
activating factor (PAF) or inducible nitric oxide synthase
s0070 INTERACTIONS REVIEW (iNOS), as occurs with cascara.6,8
s0080 Strategic Considerations In the field of cancer biology, hydroxyanthraquinone agents p0150

p0110 Cascara bark is a major representative of the anthraquinone- such as emodin, once considered to be potentially carcino-
containing herbs that are principally used for short-term relief genic, have more recently been studied for a variety of anti-
of constipation. The anthraquinone-containing laxative group proliferative effects, mediated by inhibition of both nuclear
of botanicals traditionally includes related Rhamnaceae species factor kappa B (NF-kB) and tyrosine kinase.12,13 These results
such as the buckthorns (Rhamnus frangula L. and R. cathar- have particular impact on HER-2/neu overexpression, as
ticus L.), senna leaf and fruits (Cassia senna L.), rhubarb root discussed later in the context of cascara’s possible therapeutic
(Rheum palmatum L.), and aloe latex (Aloe ferox, Miller). The combination with herceptin. Parenthetically, it should be
different crude drugs in this group have a large medical and noted that a significant number of conventional chemothera-
commercial application as stimulant laxatives for the prepara- peutic agents, notably doxorubicin, idarubicin, epirubicin, and
tion of patients for radiological or colonoscopic procedures, mitoxantrone, are all anthraquinone derivatives. Interestingly,
softening of stool before anorectal surgical procedures, and drug resistance to these agents may be reduced by plant-
treatment of constipation linked to drug-induced or lifestyle based polyphenols, including aloe-emodin, probably by inhibi-
causes. In traditional botanical medicine, cascara and its tion of NF-kB.14 Experimental studies with whole-herb
relatives have long been used for short-term treatment of extracts are rare, and most available data derive from studies
constipation, with a more recent history of folk use in herbal using isolated anthraquinone ingredients such as emodin and
cancer treatments (e.g., the Hoxsey formula). aloe-emodin, and extrapolations to whole-plant effects must
p0120 The widespread availability of both over-the-counter be qualified.
(OTC) and dietary supplement preparations containing stimu- Pharmacokinetic interactions involving modification of p0160

lant laxatives has emphasized the problem of adverse effects drug absorption resulting from decreased transit times induced
from laxative abuse, with public education through cautionary by cascara administration should not be overlooked. Stockley15
product labeling suggesting restrictions for duration of use and reports only one such interaction between quinidine and a
contraindications for consumers.2 Most of the professional senna preparation in which quinidine AUC (area under
literature echoes this concern. Cascara bark was approved for curve) levels were reduced to 25% of baseline 12 hours after
constipation by the German Commission E3 and is the subject administration of a dose of Liquedepur. This is in contrast to
of monographs by the British Herbal Medical Association the German Commission E, who proposed potential for inter-
(BHMA),1 World Health Organization (WHO),4 and most actions between all laxative herbs and antiarrhythmic drugs
comprehensively by the European Scientific Cooperative on because of electrolyte disturbances (hypokalemia) rather than
Phytotherapy (ESCOP).5 drug depletion from reduced bioavailability. The onset of
p0130 A distinction should be made between appropriate thera- enhanced bowel motility and the formation of soft or semisolid
peutic use of cascara and related botanicals and the uncon- stool after administration of anthraquinone laxatives are known
trolled, self-prescribed consumption of these agents by to lag 6 to 8 hours after ingestion, a result of the bowel
certain individuals. These latter, for psychological reasons, flora hydrolysis of anthrone conjugates into the active
either consider normal bowel movement frequency to be aglycone drug form.16 The extended delay should be taken
unhealthy or compulsively exhibit behaviors classified in the into account if pharmaceuticals with a therapeutically narrow
eating disorder group of diagnoses (i.e., bulimia, anorexia, range are already being administered to the patient before
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
18 Cascara

cascara administration. As always, clinical context and goals first-generation monoclonal antibody drug that targets the
of coadministration are relevant for evaluating the significance HER-2/neu receptor. Currently, trastuzumab is licensed
of a potential interaction, and the cautions persistently only for treatment of HER-2/neu!overexpressing metastatic
repeated in relation to these drugs in the botanical litera- breast cancer in patients with prior chemotherapy failure.32,33
Herb-Drug Interactions

ture (possible hypokalemia) are only discussed here in the Gefitinib (Iressa, AstraZeneca) has been approved for treat-
section Theoretical, Speculative, and Preliminary Interactions ment of NSCLC in patients who have failed treatment with
Research. traditional chemotherapeutic agents.34 Currently, no studies
have directly examined the interaction of trastuzumab and
emodin. However, emodin has been shown in vitro to reduce
s0090 Effects on Drug Metabolism and Bioavailability drug resistance of HER-2/neu!overexpressing NSCLC cells
p0170 Some evidence suggests that the naturally occurring anthraqui- to cisplatin, doxorubicin, and etoposide, as well as with
nones such as emodin and chrysophanol are substrates that paclitaxel in HER-2/neu!positive breast cancer cells.25,31
may undergo bioactivation into carcinogenic (mutagenic/gen-
otoxic) intermediates through cytochrome P450 1A1 and Integrative Therapeutics, Clinical Concerns, and Adaptations s0180

1A2.17 However, in vitro data suggest that they may inhibit At this time, use of natural tyrosine kinase inhibitors, such as p0250

the same enzymes.18,19 Extrahepatic cytochromes, such as curcumin from turmeric or emodin from cascara and related
CYP1B1 (which is often overexpressed in certain reproductive anthraquinone-containing herbs, is tentatively beginning to be
malignancies), have been experimentally induced by emodin in explored in integrative oncological protocols. In practice, effec-
a human lung cancer cell line.20 Similar experimental models tive daily doses to achieve cytotoxicity from emodin have been
also suggest inhibitory effects on phase 2 enzymes, including calculated to be between 160 and 180 mg.35 An issue with
glutathione-S-transferase P1 and N-acetyltransferase.21,22 these doses is the possibility of mutagenicity from emodin
These effects may be due to inhibition or downregulation of itself. Despite in vitro tests that suggest mutagenicity, however,
transcription factors NF-kB and activating protein 1 this factor has been considered a minimal risk factor in
(AP-1).22,23 At present, the pharmacokinetic effects of anthra- humans.36-38
quinone herbs on drug metabolism are not well characterized, The controversial Hoxsey anticancer formula incorporated p0260

but the possibility of clinically significant effects cannot be several anthraquinone-containing herbs, including those
ruled out. with high levels of emodin. Anecdotally, the strongest
support for Hoxsey formula came from breast and some skin
cancers, several of which are now known to overexpress
In China, other herbs containing emodin have been used in p0270
s0120 Trastuzumab cancer therapy, notably Polygonum cuspidatum.35 Practitioners
p0180 Trastuzumab (Herceptin). of integrative oncology use the herb in this setting in botanical
formulae for prevention of cancer recurrence, following con-
s0130 Interaction Type and Significance ventional treatments. It should also be considered as a remedy
p0190 Potential or Theoretical Beneficial or Supportive for opiate-induced constipation in opiate-dependent cancer
Interaction, with Professional Management patients, in whom it might also synergize with certain chemo-
Probability: Evidence Base:
4. Plausible Inadequate

p0220 Anthraquinone constituents of cascara, especially emodin,
inhibit proliferation of HER-2/neu!overexpressing cancer
Digoxin and Related Cardiac Glycosides and Antiarrhythmic Drugs s0200

cells and may additively interact with the monoclonal Amiodarone (Cordarone, Pacerone), deslanoside (cedilanin- p0280

antibody, which also inhibits proliferation of HER-2/ D), digitoxin (Cystodigin), digoxin (purgoxin; Digitek,
neu!overexpressing malignancy. Lanoxin, Lanoxicaps), disopyramide (Norpace), dofetilide
(Tikosyn), flecainide (Tambocor), ibutilide (Corvert), ouabain
s0170 Research (g-strophanthin), procainamide (Procan-SR, Pronestyl), quini-
p0230 Emodin, an anthraquinone constituent (and metabolite) of dine (Quinaglute, Quinidex, Quinora), sotalol (Betapace,
cascara, has been demonstrated to have antiproliferative Betapace AF, Sorine).
effects, including induction of differentiation and apoptosis, Potential electrolyte and acid-base disturbances resulting p0290

through different mechanisms in several cancer cell lines, from chronic diarrhea caused by inappropriately prolonged
including breast, cervical, non!small cell lung cancer use (or abuse) of cascara extracts was considered by the
(NSCLC), and hepatoma, through a variety of mechan- German Commission E. In their 1984 monograph on cascara,
isms.24-29 As a known inhibitor of the HER-2 tyrosine kinase the Commission included a warning about the possibility of
domain,30 emodin is particularly effective against HER-2/ adverse interactions with cardiac glycosides, as well as other
neu!overexpressing cells, and the continuing work by Zhang antiarrhythmic drugs, caused by hypokalemia. This was extended
et al.12,31 suggests that several beneficial interactions may to a possible additive adverse interaction with known potassium-
occur between emodin and chemotherapy for HER-2/ depleting drugs, such as thiazide diuretics and corticosteroids,
neu!overexpressing malignancies. as well as licorice root.3 Over time, through force of repetition,
p0240 The HER-2 proto-oncogene is structurally related to this has now become a consensus interactions concern associated
the epidermal growth factor receptor. HER-2/neu is a p185 with all the stimulant laxative botanicals.
protein tyrosine kinase receptor and is a major target of anti- There are no actual clinical reports of this specula- p0300

proliferative drugs. Trastuzumab (Herceptin) is a successful tive interaction occurring. Therapeutic context should be

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Cascara 19

acknowledged before general warnings about interactions are compared with controls, which the authors considered a
given. Laxative abuse is a possible context to consider. result of absorption losses caused by the laxative.43
p0310 Estimates of the incidence of laxative abuse are scarce. Beyond the situation of overt or covert laxative abuse, the p0320

A review of 73 published studies suggested an incidence of dangers of a hypokalemia-induced interaction seem remote.

Herb-Drug Interactions
approximately 4.0% in the general population, but 14% Stockley’s Drug Interactions15 does not report drug-induced
among bulimic patients.40 The diagnosis of bulimia predomi- hypokalemia cases from any cause, including stimulant laxatives
nantly affects females and is rare in older populations likely to interacting with cardiac glycosides. As suggested by at least one
be taking antiarrhythmic medication. Also, hypokalemia is a commentator, these adverse effects are overstated and unlikely
rarely reported adverse effect of laxative use, although decades to be the basis of a clinically relevant interaction.44,45 Unless a
ago the issue was sporadically noted.41 A single case report patient is borderline hypokalemic from potassium-wasting
from the psychiatric literature does suggest that two severe diuretic therapy without potassium supplementation, diarrhea-
episodes of torsades de pointes in a mentally ill woman were induced hypokalemia would require at least five voluminous
the result of electrolyte disturbance from the stimulant laxative liquid stools per day for several days, which is an improbable
bisacodyl.42 No antiarrhythmics were being used by this consequence of normal therapeutic administration of cascara.
patient; however, a preclinical study that examined the effect
of coadministered bisacodyl on digoxin serum levels found The 45 citations for this monograph are located under Cascara on the p0330

a significant reduction in serum cardiac glycoside levels CD at the back of the book.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Cascara

1. BHMA. Cascara bark. In: Bradley P, ed. British Herbal Compendium. 1 vol. Bournemouth, UK: British Herbal Medical Association;

2. McGuffin M, Hobbs C, Upton R, Goldberg A. American Herbal Products Association’s Botanical Safety Handbook. Boca Raton, Fla:
CRC Press; 1997.

3. Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical
Council: Integrative Medicine Communications; 1998.

4. WHO. Cortex rhamni purshianae. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization;

5. ESCOP. Rhamni purshiani cortex. ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter,
UK: European Scientific Cooperative on Phytotherapy and Thieme; 2003:413-418.

6. Izzo AA, Gaginella TS, Mascolo N, Capasso F. Recent findings on the mode of action of laxatives: the role of platelet activating factor
and nitric oxide. Trends Pharmacol Sci 1998;19:403-406.

7. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. IV. Mechanism of cathartic effect. (3). Biol Pharm Bull 1994;17:495-497.

8. Izzo AA, Sautebin L, Rombola L, Capasso F. The role of constitutive and inducible nitric oxide synthase in senna- and cascara-
induced diarrhoea in the rat. Eur J Pharmacol 1997;323:93-97.

9. Capasso F, Mascolo N, Autore G, Duraccio MR. Effect of indomethacin on aloin and 1,8 dioxianthraquinone-induced production of
prostaglandins in rat isolated colon. Prostaglandins 1983;26:557-562.

10. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. III. Mechanism of cathartic effect. (2). Chem Pharm Bull (Tokyo) 1990;38:197-200.

11. Ishii Y, Tanizawa H, Takino Y. Studies of aloe. V. Mechanism of cathartic effect. (4). Biol Pharm Bull 1994;17:651-653.

12. Zhang L, Lau YK, Xi L et al. Tyrosine kinase inhibitors, emodin and its derivative repress HER-2/neu-induced cellular
transformation and metastasis-associated properties. Oncogene 1998;16:2855-2863.

13. Kumar A, Dhawan S, Aggarwal BB. Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) inhibits TNF-induced NF-κB activation, IκB
degradation, and expression of cell surface adhesion proteins in human vascular endothelial cells. Oncogene 1998;17:913-918.

14. Garg AK, Buchholz TA, Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox
Signal 2005;7:1630-1647.

15. Stockley I. Stockley’s Drug Interactions. 6th ed. London: Pharmaceutical Press; 2002.

16. Leng-Peschlow E. Senna and its rational use. Pharmacology 1992;44 Suppl 1:1-52.

17. Zhou S, Gao Y, Jiang W et al. Interactions of herbs with cytochrome P450. Drug Metab Rev 2003;35:35-98.

18. Mueller SO, Stopper H, Dekant W. Biotransformation of the anthraquinones emodin and chrysophanol by cytochrome P450
enzymes: bioactivation to genotoxic metabolites. Drug Metab Dispos 1998;26:540-546.

19. Sun M, Sakakibara H, Ashida H et al. Cytochrome P4501A1-inhibitory action of antimutagenic anthraquinones in medicinal plants
and the structure-activity relationship. Biosci Biotechnol Biochem 2000;64:1373-1378.

20. Wang HW, Chen TL, Yang PC, Ueng TH. Induction of cytochromes P450 1A1 and 1B1 by emodin in human lung adenocarcinoma
cell line CL5. Drug Metab Dispos 2001;29:1229-1235.

21. Lin S-Y, Yang J-H, Hsia T-C et al. Effect of inhibition of aloe-emodin on N-acetyltransferase activity and gene expression in human
malignant melanoma cells (A375.S2). Melanoma Res 2005;15:489-494.

22. Duvoix A, Delhalle S, Blasius R et al. Effect of chemopreventive agents on glutathione S-transferase P1-1 gene expression
mechanisms via activating protein 1 and nuclear factor kappa B inhibition. Biochem Pharmacol 2004;68:1101-1111.

23. Li H-L, Chen H-L, Li H et al. Regulatory effects of emodin on NF-κB activation and inflammatory cytokine expression in RAW
264.7 macrophages. Int J Mol Med 2005;16:41-47.

24. Zhang L, Chang CJ, Bacus SS, Hung MC. Suppressed transformation and induced differentiation of HER-2/neu-overexpressing
breast cancer cells by emodin. Cancer Res 1995;55:3890-3896.

25. Zhang L, Hung MC. Sensitization of HER-2/neu-overexpressing non-small cell lung cancer cells to chemotherapeutic drugs by
tyrosine kinase inhibitor emodin. Oncogene 1996;12:571-576.

26. Koyama J, Morita I, Tagahara K et al. Chemopreventive effects of emodin and cassiamin B in mouse skin carcinogenesis. Cancer
Lett 2002;182:135-139.

27. Kuo P-L, Lin T-C, Lin C-C. The antiproliferative activity of aloe-emodin is through p53-dependent and p21-dependent apoptotic
pathway in human hepatoma cell lines. Life Sci 2002;71:1879-1892.

28. Srinivas G, Anto RJ, Srinivas P et al. Emodin induces apoptosis of human cervical cancer cells through poly(ADP-ribose)
polymerase cleavage and activation of caspase-9. Eur J Pharmacol 2003;473:117-125.

Citations and Reference Literature: Cascara

29. Shieh D-E, Chen Y-Y, Yen M-H et al. Emodin-induced apoptosis through p53-dependent pathway in human hepatoma cells. Life Sci

30. Castiglioni F, Tagliabue E, Campiglio M et al. Role of exon-16-deleted HER2 in breast carcinomas. Endocr Relat Cancer

31. Zhang L, Lau YK, Xia W et al. Tyrosine kinase inhibitor emodin suppresses growth of HER-2/neu-overexpressing breast cancer cells
in athymic mice and sensitizes these cells to the inhibitory effect of paclitaxel. Clin Cancer Res 1999;5:343-353.

32. Wang SC, Zhang L, Hortobagyi GN, Hung MC. Targeting HER2: recent developments and future directions for breast cancer
patients. Semin Oncol 2001;28:21-29.

33. Chen J-S, Lan K, Hung M-C. Strategies to target HER2/neu overexpression for cancer therapy. Drug Resist Update 2003;6:129-136.

34. Hamid O. Emerging treatments in oncology: focus on tyrosine kinase (erbB) receptor inhibitors. J Am Pharm Assoc (Wash DC)

35. Boik J. Natural Compounds in Cancer Therapy. Princeton, MN: Oregon Medical Press; 2001.

36. Bosch R, Friederich U, Lutz WK et al. Investigations on DNA binding in rat liver and in Salmonella and on mutagenicity in the
Ames test by emodin, a natural anthraquinone. Mutat Res 1987;188:161-168.

37. Mengs U, Krumbiegel G, Volkner W. Lack of emodin genotoxicity in the mouse micronucleus assay. Mutat Res 1997;393:289-293.

38. Mueller SO, Lutz WK, Stopper H. Factors affecting the genotoxic potency ranking of natural anthraquinones in mammalian cell
culture systems. Mutat Res 1998;414:125-129.

39. Brinker F. The Hoxsey treatment: cancer quackery or effective physiological adjuvant? J Naturopath Med 1996;6:9-23.

40. Neims DM, McNeill J, Giles TR, Todd F. Incidence of laxative abuse in community and bulimic populations: a descriptive review.
Int J Eat Disord 1995;17:211-228.

41. Aitchison JD. Hypokalaemia following chronic diarrhea from overuse of cascara and a deficient diet. Lancet 1958;2:75-76.

42. Krahn LE, Lee J, Richardson JW et al. Hypokalemia leading to torsades de pointes. Munchausen’s disorder or bulimia nervosa? Gen
Hosp Psychiatry 1997;19:370-377.

43. Wang DJ, Chu KM, Chen JD et al. [Drug interaction between digoxin and bisacodyl]. J Formos Med Assoc 1990;89:915-919, 913.

44. Muller-Lissner S. [Side effects of laxatives]. Z Gastroenterol 1992;30:418-427.

45. Muller-Lissner SA. Adverse effects of laxatives: fact and fiction. Pharmacology 1993;47 Suppl 1:138-145.

Cayenne Botanical Name: Capsicum annuum L. var annuum.
Pharmacopoeial Names: Capsici fructus, capsici fructus acer.
Herb-Drug Interactions

Common Names: Cayenne, chili pepper, red pepper, hot pepper.

Note: Conventionally, ‘‘chili’’ or ‘‘cayenne’’ refers to the hottest varieties,
‘‘paprika’’ to intermediate varieties, and ‘‘sweet’’ or ‘‘bell’’ pepper to the mild,
nonpungent types. None are ‘‘true peppers’’ of the Piperaceae, such as black
pepper, Piper nigrum L.

Drug/Class Interaction Type Mechanism and Significance Management
Acetylsalicylic acid, nonsteroidal anti-inflammatory drugs Cayenne is ulceroprotective; interaction little used in practice. Coadministration unnecessary; use more effective agents.
(NSAIDs), and other ulcerogenic agents Superior alternative botanical agents available.
Enalapril Cayenne may exacerbate ACE inhibitor!induced cough during Monitor, avoid, or reduce drug and herb dose, if feasible.
Angiotensin-converting enzyme (ACE) inhibitors early coadministration; isolated report.

NSAIDs, oral corticosteroids, antiarthritic medications Topical administration may improve symptom relief from Consider adopting in chronic arthritis patients with
anti-inflammatories or enable lower drug doses. escalating medication requirements.


s0030 Family be distinguished from isolated capsaicin, which unlike the
oleoresin, has been subject to considerable pharmacological
p0120 Solanaceae. research.
Activity of capsaicin and its congeners is responsible p0210

for several of the traditional therapeutic effects of cayenne,

s0040 Related Species especially the topical treatment of painful peripheral
p0130 Capsicum annuum L. var frutescens, Capsicum annuum disorders. Capsaicin has been used extensively in neuro-
L. var longum, Capsicum annuum L. var glabriusculum, pharmacological research, and its vanillyl moiety lent its
(Dunal) Heiser and Pickersgill Capsicum minimum (Roxb). name to the vanilloid receptor (VR). The VR is a chemically
Typically, pungent varieties are classed as C. annuum and and thermally gated cation channel that is opened by heat
its varieties, whereas the nonpungent peppers are classed as and closed by capsaicin. Capsaicin activation causes the
C. frutescens. release of various neuropeptides at the VR, including
substance P, which mediates pain sensation in afferent periph-
eral nocioceptive pathways, with recent evidence suggesting
s0050 Habitat and Cultivation additional mechanisms of central noradrenergic activation
p0140 Native to Central America; naturalized to tropical and subtro- through the locus coeruleus.1 The VR is distributed widely
pical zones globally; now cultivated worldwide. in sensory afferent innervation of joints, muscles, and the inte-
gumentary, respiratory, digestive, and urogenital systems, as
well as in the mucous membranes of the oral cavity and the
s0060 Parts Used cornea.2
p0150 Dried ripe fruit. Apart from its irritant effects (well known to police p0220

departments), internal use of capsaicin isolate has also been

limited by some controversy over the potential mutagenic
s0070 Common Forms and tumorigenic toxicities of the compound.3 Another
p0160 Dried: Powdered fruit. naturally occurring vanillyl compound, resinferatoxin (RTX),
p0170 Oleoresin: Crude extract. derived from Euphorbia resinefera, has been used as a
p0180 Tincture: Typically, 1:10 to 1:20, 60% to 90% ethanol. more potent capsaicin analog, therapeutically investigated as
p0190 Topical: Cream and ointments containing 0.02% to 0.05% an intravesical treatment for incontinence, and is preferred to
capsaicinoids. capsaicin because of a better adverse effects and toxicity
profile.4 Capsaicin itself has been synthesized, and synthetic
analogs such as nonivamide (pellargonic acid vanillamide) are
s0080 HERB IN CLINICAL PRACTICE also available, sometimes employed as adulterants in capsicum
s0090 Overview samples.
p0200 The widespread use of cayenne as a dietary ingredient contrasts Therapeutic use of isolated capsaicin and the oleoresin for p0230

with a relative lack of information about the clinical pharma- external use is approved in the United States and several
cology of the whole herb. The crude herb extract, capsicum European Union (EU) countries as an ingredient in topical
‘‘oleoresin,’’ contains more than 100 different volatile compo- over-the-counter (OTC) preparations for analgesia in various
nents (many of which are not yet fully characterized) and must neuralgic and myalgic conditions, with strengths typically
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Cayenne 21

0.02% to 0.05% for creams and ointments. The German INTERACTIONS REVIEW s0140
Commission E approved capsicum (‘‘Paprika’’ monograph)
Strategic Considerations s0150
for external use only and suggested limits to duration of
administration (2 days), which appear to be conservative.5 The German Commission E monograph for cayenne lists no p0330

Herb-Drug Interactions
Literature reviews of the herb are sparse, except for a recent known interactions, and interactions reports for cayenne
survey by McKenna et al.6 are rare.5 The reason in part may be the rather narrow main-
stream patterns of use as a topical analgesic. Synergistic inter-
actions with coadministered analgesic and anti-inflammatory
s0100 Historical/Ethnomedicine Precedent drugs are theoretically possible in this context, and some
p0240 Cayenne has been used for thousands of years by Native supportive data on this are available. However, topical
American and Meso-American peoples (chili is the Mayan herb-drug combinations are not widely employed in current
term for cayenne) and was introduced to Europe following clinical practice (see later discussion of antiarthritic medica-
Spanish exploration of the Americas in the fifteenth century CE. tions). The dose of capsaicinoids in OTC topical preparations
Besides its near-universal use as a pungent spice additive varies from 0.02% to 0.05%, applied up to four times daily
to the human diet, cayenne is used in the major systems of to the affected area. Therapeutic context is itself apparently a
traditional medicine, including Ayurveda, Chinese, Kampo, determinant of capsaicin activity; animal experiments suggest
Korean, and African. that the analgesic effects of the compound are heightened
p0250 Generally, cayenne has been used topically as a rubefacient in inflammatory states compared with noninflammatory
and counterirritant for arthritis and myalgias and as an controls.7
analgesic for neuralgias and rheumatic pain. Internally, it has Internal prescription of cayenne by practitioners of botanical p0340

been used as a heating and stimulating remedy for colds medicine usually follows traditional prescribing principles;
and respiratory conditions, colic, and dyspepsia and as a thus cayenne is often incorporated in rather small quantities
digestive and circulatory stimulant. In Western botanical as an adjunctive ingredient of polypharmacy prescriptions
medicine, cayenne was associated with the popular folk to confer qualities of stimulation, warmth, and dispersion
medicine doctrines of Samuel Thomson in the United States to the principal formula ingredients. The British Herbal
in the mid-nineteenth century. ‘‘Thomsonian medicine’’ was Pharmacopoeia recommended dose for internal consumption
based on a primitive energetic system that used cayenne in is 30 to 120 mg, thrice daily. Assuming a ‘‘high’’ capsaicin
life-threatening illness ‘‘to raise vital heat.’’ Thomsonian content of approximately 1% capsaicinoids, this would deliver
medicine later became refined and incorporated into the a daily amount of less than 5.0 mg capsaicinoids daily.8
‘‘Physiomedicalist school’’ of botanical medicine, which This is somewhat less than the typical human chronic dietary
placed less emphasis on ‘‘heroic’’ therapeutic strategies of consumption levels in cultures where cayenne is a principal
high doses of cayenne and other stimulants. In traditional dietary spice, estimated at approximately 0.5 to 1.0 mg/kg.2
Western botanical medicine, cayenne is primarily used intern- In this context, interactions that have been extrapolated on the
ally as a stimulating cardiovascular and digestive tonic and basis of experimental and animal data, involving relatively high
topically as an analgesic. levels of isolated capsaicin administered parenterally, are not
directly applicable to clinical practice. (See Theoretical,
Speculative, and Preliminary Interactions Research.)
s0110 Known or Potential Therapeutic Uses
p0260 External: Arthritis, chilblains, cluster headaches, myalgias,
fibromyalgia and rheumatic pains, neuralgias and neuropathies Effects on Drug Metabolism and Bioavailability s0160

(including diabetic neuropathy, postherpetic neuropathy, The effects of dietary levels of cayenne intake on GI p0350

shingles, postsurgical neuropathic pain), osteoarthritis, motility and secretion theoretically may lead to pharmacoki-
pruritus, psoriasis, rhinopathy. netic effects on drug absorption through direct actions on
p0270 Internal: Atony of gastrointestinal (GI) tract, chemopreven- gut permeability, gastric acid levels, and intestinal transit
tion, diaphoretic and antipyretic in feverish conditions, times. Early reports suggested that cayenne increases gastric
noninflammatory flatulent dyspepsia, peripheral circulatory acid secretion, but recent studies do not confirm this.9 An
insufficiency, peptic ulcer prophylaxis. experimental study with a human ileocarcinoma cell line
demonstrated increased cell permeability (tight junction
gap increase) on administration of cayenne, although the
s0120 Key Constituents opposite effect was observed with other spices (e.g., black
p0280 Pungent ‘‘capsaicinoid’’ principles, 0.5% to 1.5%, consisting pepper).10 Animal evidence is inconclusive, although an
principally of capsaicin (8-methyl-6-noneoyl-vanillylamide) ulceroprotective effect has been demonstrated in several stud-
and related vanillyl derivatives, dihydrocapsaicin, nordihydro- ies, possibly related to increased mucous secretion and anti-
capsaicin, homohydrocapsaicin, and homocapsaicin. inflammatory effects.11-14
p0290 Cayenne also contains several carotenoids, including caro- In humans, hot pepper sauce (e.g., Tabasco) appears to p0360

tene, lutein, and zeaxanthin; high levels of vitamins C and A; slow gastric emptying, but overall orocecal time is unchanged,
flavonoids; and steroidal alkaloid glycosides. indicating increased intestinal transit.15 This corresponds with
the empirical observation that diarrhea can result from hot
spicy food ingested by individuals who do not consume it reg-
s0130 Therapeutic Dosing Range ularly. Other evidence suggests a general metabolic stimulation;
p0300 Powdered Dried Herb (cayenne pepper): 30 to 250 mg, two or resting metabolic rate increases after cayenne spice ingestion in a
three times daily. meal, and the simultaneous increases in oxygen uptake, lipolysis,
p0310 Tincture: 0.25 to 1.0 mL three times daily; 1:1 equivalent. and carbohydrate metabolism may be associated with a
p0320 Topical: 0.025% capsaicinoid cream applied up to four degree of beta-adrenergic stimulation.16,17 Gender differences
times daily. in these effects have also been recorded.18,19 Currently, dietary

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
22 Cayenne

cayenne studies suggest that absorption of drugs ingested HERB-DRUG INTERACTIONS s0170
with cayenne-spiced food may be enhanced, regardless of
the drug’s characteristics. The degree to which this effect may Acetylsalicylic Acid, Nonsteroidal Anti-Inflammatory Drugs s0190
be clinically significant is variable and unpredictable.
Herb-Drug Interactions

(NSAIDs), and Other Ulcerogenic Agents

Furthermore, some experimental data appear to conflict
with this general conclusion; in rats, for example, cayenne coad- Evidence: Acetylsalicylic acid (acetosal, acetyl salicylic acid, p0410

ministration appears to reduce the oral bioavailability of ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever,
aspirin.20 Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer
p0370 Pharmacokinetic effects of capsaicin on drug-metabolizing Buffered Aspirin, Bayer Low Adult Strength, Bufferin,
enzymes have been an area of research interest, partly because Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin,
of apparently conflicting data on carcinogenicity of the com- Ecotrin Low Adult Strength, Empirin, Extra Strength
pound from epidemiological and experimental studies. Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra
Capsaicin itself is a substrate of hepatic CYP450 2E1, a cyto- Strength Bayer Plus, Halfprin 81, Heartline, Regular
chrome that shares with 1A1 and 1A2 the role of metabolism Strength Bayer Enteric 500 Aspirin, St. Joseph Adult
of potentially carcinogenic aromatic hydrocarbons.21 Other Chewable Aspirin, ZORprin); combination drugs: ASA and
pathways for capsaicin metabolism have been investigated, caffeine (Anacin), ASA, caffeine, and propoxyphene (Darvon
including aliphatic hydroxylation.22 Capsaicin has been Compound), ASA and carisoprodol (Soma Compound), ASA,
reported to be a tumor promoter, carcinogen, and potential codeine, and carisoprodol (Soma Compound with Codeine),
mutagen.23 At the same time, it has also been found to have ASA and codeine (Empirin with Codeine), ASA, codeine,
antigenotoxic, antimutagenic, and anticancer effects.24,25 More butalbital, and caffeine (Fiorinal), ASA and extended-release
recently, capsaicin has also been found to inhibit nuclear factor dipyridamole (Aggrenox, Asasantin).
kappa B (NF-kB) and to have proapoptotic effects, which Extrapolated, based on similar properties: Nonsteroidal anti- p0420

support a multimechanism basis for its chemopreventive inflammatory drugs (NSAIDs):

properties.26-28 COX-1 inhibitors: Diclofenac (Cataflam, Voltaren), combi- p0430

p0380 Capsaicin and dihydrocapsaicin directly inhibit CYP2E1, nation drug: diclofenac and misoprostol (Arthrotec), diflunisal
which has been suggested as a mechanism of its anticarcino- (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen
genic effects.25,29-33 The primary drug substrates of 2E1 (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB,
include the halogenated aliphatic anesthetics (enflurane, Nuprin, Pedia Care Fever Drops, Provel, Rufen), combination
halothane, isoflurane, methoxyflurane, sevoflurane), as drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen),
well as acetaminophen and ethanol. Ethanol, smoking, indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen
obesity, and diabetes all induce 2E1, which is unusual (Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol),
among the CYP450 enzymes in being subject to so many meclofenamate (Meclomen), mefenamic acid (Ponstel),
environmental influences. However, capsaicin can also meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve,
undergo bioactivation.23,24 The formation of reactive Anaprox, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene),
intermediates from capsaicin may also be a result of salsalate (salicylic acid; Amigesic, Disalcid, Marthritic,
pan-P450 metabolism of capsaicin, according to a recent Mono Gesic, Salflex, Salsitab), sulindac (Clinoril), tolmetin
study by Reilly et al.,34 who report that this is an essential (Tolectin).
part of detoxification of capsaicin rather than bioactivation COX-2 inhibitors: Celecoxib (Celebrex). p0440

because the intermediates can be ‘‘trapped’’ by addition

of glutathione (GSH), suggesting that they are normally con- Interaction Type and Significance s0200

jugated harmlessly. Overall, current data seem to indicate that Prevention or Reduction of Drug Adverse Effect p0450

capsaicin either can be metabolized as a straightforward detox- ? Interaction Possible but Uncertain Occurrence and p0460

ification or can be bioactivated, generating intermediates Unclear Implications

that may have direct or indirect toxicity through pan-P450
enzyme inhibition or covalent adduct formation with hepatic Probability: Evidence Base:
microsomal deoxyribonucleic acid (DNA), depending on 3. Possible Preliminary
the circumstances. Animal experiments suggesting prolonga-
tion of pentobarbital- and phenobarbital-induced sleeping Effect and Mechanism of Action s0230

times may support the pan-P450 inhibition by reactive Internal administration of cayenne may be protective against p0490

intermediates (these agents are multi-P450 substrates, and drug-induced mucosal ulceration by NSAIDs and related
pharmacokinetic-increased levels would require pan-P450 agents. The interaction is likely, but arguably of minimal clin-
inhibition).35 ical importance.
p0390 Preliminary experimental evidence also suggests that
capsaicin inhibits P-glycoprotein (P-gp). Drug resistance to Research s0240

vinblastine in a P-gp!overexpressing, multidrug-resistant Animal studies have provided inconclusive data on the effect of p0500

carcinoma cell line (KB-C2) was significantly inhibited in capsaicin on gastric mucosa, either alone or in combination
vitro by capsaicin at 50 mmol.36 Further data on the effects with ulcerogenic agents.11,13,14,37,38 Early studies suggested
of capsaicin on drug resistance are needed before clinical extra- that cayenne might increase gastric acid secretion.9 In more
polations can be made. recent human studies, Myers et al.39 found that red pepper
p0400 Knowledge of the impact of chronic capsaicin or cayenne (and black pepper) increased gastric cell exfoliation but had
ingestion combined with pharmaceuticals on this complex no effect on gastric secretion. Meanwhile, one rodent study
system is clearly incomplete. However, obvious pharmacoki- found a protective effect against aspirin-induced ulceration in
netic interactions resulting from CYP2E1 inhibition have not rats.11 This effect was confirmed in humans in a small preclin-
been reported, with the possibly relevant exception of ical study by Yeoh et al.,40 who found that 20 g cayenne
theophylline (see later). per day coadministered with 600 mg aspirin daily led to a

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Cayenne 23

significant protective effect against gastric ulceration assessed (delayed-type hypersensitivity, DTH) testing revealed that ena-
endoscopically.40 A study comparing 103 peptic ulcer patients lapril cough was associated with bradykinin, not substance P,
with matched controls examined chili consumption and found reactivity. The drug-induced cough lessened over 28 days, and
that higher chili consumption was significantly associated with its sensitivity to capsaicin exacerbation also decreased.

Herb-Drug Interactions
lower ulcer incidence.41 Another study of 84 healthy volun- Adjusting the dose of enalapril downward (5 vs. 20 mg/day)
teers found that capsaicin administered in low doses intragas- reduced the frequency and severity of cough, but it did not
trically was protective against ethanol- and indomethacin- appear to alter consistently the effect of capsaicin on the
induced mucosal damage when coadministered, but not cough, leading the authors to conclude that there was a
when the capsaicin was given for 2 weeks before drug wide range of dose-dependent variation in response to
administration.42 capsaicin.50,51

s0250 Integrative Therapeutics, Clinical Concerns, and Adaptations Reports s0320

p0510 Although this interaction appears to be reasonably established An isolated report is available, with poor documentation stan- p0600

by experimental evidence, the clinical significance is arguably dards (i.e., concurrent medications not listed). A 53-year-old
rather low. Internal administration of cayenne at medicinal woman had been taking an (unidentified) ACE inhibitor for
doses daily to counter aspirin adverse effects seems a relatively several years without adverse effects, but experienced cough
unfavorable strategy, given the availability of other herbal symptoms every time she applied a capsaicin-containing
agents that are ulceroprotective, anti-inflammatory, and also cream (0.075% capsaicin).52
lack any irritant properties. (See monographs for Aloe and
Licorice.) Clinical Implications and Adaptations s0330

Differential diagnosis of cough includes possible ACE p0610

s0260 Enalapril and Related Angiotensin-Converting Enzyme (ACE) inhibitor!induced cough. This is reversible on cessation of
the drug and will likely diminish over a 28-day period of
p0520 Evidence: Enalapril (Vasotec) drug administration. Exacerbation by capsaicin is possible in
p0530 Extrapolated, based on similar properties: Benazepril some individuals, but the interaction is probably of minimal
(Lotensin), combination drug: benazepril and amlodipine significance. Management strategies are empirical, with
(Lotrel), captopril (Capoten), combination drug: captopril cessation or reduction of the herb or drug.
and hydrochlorothiazide (Acezide, Capto-Co, Captozide,
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), Analgesics, s0340
Co-Zidocapt), cilazapril (Inhibace), combination drug: enala-
pril and felodipine (Lexxel), combination drug: enalapril and
Oral Corticosteroids, and Other Antiarthritic Medications
hydrochlorothiazide (Vaseretic), fosinopril (Monopril), lisino- Nonsteroidal anti-inflammatory drugs (NSAIDs): p0620

pril (Prinivil, Zestril), combination drug: lisinopril and hydro- COX-1 inhibitors: Diclofenac (Voltaren, Cataflam), combi- p0630

chlorothiazide (Prinzide, Zestoretic), moexipril (Univasc), nation drug: diclofenac and misoprostol (Arthrotec), diflunisal
perindopril (Aceon), quinapril (Accupril), ramipril (Altace), (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen
trandolapril (Mavik). (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB,
Nuprin, Pedia Care Fever Drops, Provel, Rufen), combination
s0270 Interaction Type and Significance drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen),
p0540 ✗ Potential or Theoretical Adverse Interaction of indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen
Uncertain Severity (Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol),
meclofenamate (Meclomen), mefenamic acid (Ponstel),
Probability: Evidence Base: meloxicam (Mobic), nabumetone (Relafen), naproxen (Aleve,
2. Probable Emerging Anaprox, Naprosyn), oxaprozin (Daypro), piroxicam
(Feldene), salsalate (salicylic acid; Amigesic, Disalcid,
s0300 Effect and Mechanism of Action Marthritic, Mono Gesic, Salflex, Salsitab), sulindac (Clinoril),
p0570 Cough is a known adverse effect associated with ACE inhibi- tolmetin (Tolectin).
tors. Coadministration with cayenne can exacerbate cough COX-2 inhibitors: Celecoxib (Celebrex). p0640

symptoms, probably through more than one mechanism. Acetylsalicylic acid: acetosal, acetyl salicylic acid, ASA, salicylsa- p0650

The clinical significance is minimal. licylic acid; Arthritis Foundation Pain Reliever, Ascriptin,
Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin,
s0310 Research Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis
p0580 A form of ‘‘sensory hyperreactivity’’ cough induced by capsai- Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength,
cin alone has been described.43-45 This may be mediated by Empirin, Extra Strength Adprin-B, Extra Strength Bayer Enteric
VRs in the bronchial tree.46 Vagal afferents that also include 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline,
vanilloid pathways (C fibers) can be stimulated by capsaicin; Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult
however, experimentally this does not appear to cause a cough Chewable Aspirin, ZORprin; combination drugs: ASA and caf-
reflex but induces apnea (in primates).47 Capsaicin inhalation feine (Anacin), ASA, caffeine, and propoxyphene (Darvon
has also been used to identify a subset of asthmatic patients Compound), ASA and carisoprodol (Soma Compound), ASA,
with chemical sensitivity to inhaled irritants in a controlled codeine, and carisoprodol (Soma Compound with Codeine),
manner, providing a degree of exposure management control ASA and codeine (Empirin with Codeine), ASA, codeine, butal-
in sensitive individuals.48 bital, and caffeine (Fiorinal), ASA and extended-release dipyrida-
p0590 The mechanism of ACE inhibitor!induced cough is mole (Aggrenox, Asasantin).
believed to be related to elevations in bradykinin (ACE is a Corticosteroids, oral: Betamethasone (Celestone), corti- p0660

kininase).49 Yeo et al.50,51 conducted a series of small investi- sone (Cortone), dexamethasone (Decadron), fludrocortisone
gations into ACE inhibitor!induced cough and capsaicin (Florinef), hydrocortisone (Cortef), methylprednisolone (Me-
with normal and hypertensive patients using enalapril. Skin drol), prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone),

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
24 Cayenne

prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), hydroxide and calcium carbonate (Calcium Rich Rolaids);
triamcinolone (Aristocort). magnesium hydroxide, aluminum hydroxide, calcium carbo-
nate, and simethicone (Tempo Tablets); magnesium trisilicate
s0350 Interaction Type and Significance and aluminum hydroxide (Adcomag trisil, Foamicon); magne-
Herb-Drug Interactions

p0670 Beneficial or Supportive Interaction, Not sium trisilicate, alginic acid, and sodium bicarbonate (Alenic
Requiring Professional Management Alka, Gaviscon Regular Strength Tablets); combination drug:
sodium bicarbonate, aspirin, and citric acid (Alka-Seltzer).
Probability: Evidence Base: Mills and Bone60 suggest a possible adverse interaction p0740

1. Certain Emerging between antacid medications and cayenne resulting from gas-
troirritant and hypersecretory effects of the herb. Reports of
s0380 Effect and Mechanism of Action such interactions are lacking, and most data suggest gastropro-
p0700 Topical capsaicin preparations, when coadministered with anti- tective effects follow internal cayenne consumption, with
arthritic medications, can result in increased symptom relief increased mucus and blood flow rather than hyperacidity at
because of substance P modulation by capsaicin. The interaction the gastric mucosa. Clinically, it is common practice to advise
may be used to reduce the dose of pharmaceuticals to lessen patients with acid-related ulcers to avoid spicy food, and inter-
potential drug adverse effects. The interaction is not widely nal administration of stimulants such as cayenne is unusual in
exploited but may be of considerable significance to chronic GI-sensitive individuals. On balance, this suggested interaction
arthritis patients. appears entirely speculative.
Anticoagulant and Antiplatelet Medications
s0390 Research s0430

p0710 Five controlled clinical trials conducted to date support the use Anticoagulants, oral vitamin K antagonists: Anisindione p0750

of topical capsaicin preparations for symptom relief in both (Miradon), dicumarol, ethyl biscoumacetate (Tromexan),
osteoarthritis (OA) and rheumatoid arthritis (RA). The pre- nicoumalone (acenocoumarol; Acitrom, Sintrom), phenin-
paration used most frequently in the trials was Zostrix dione (Dindevan), phenprocoumon (Jarsin, Marcumar), war-
(GenDerm), containing 0.025% capsaicin administered topi- farin (Coumadin, Marevan, Warfilone).
cally to affected areas four times daily.53-55 The mechanisms Anticoagulants, heparin, unfractionated (UFH): Heparin p0760

of pain reduction lie in the ability of capsaicin to modulate (Calciparine, Hepalean, Heparin Leo, Minihep Calcium,
substance P!mediated nocioceptive pathways (see previous Minihep, Monoparin Calcium, Monoparin, Multiparin,
discussion).53,56,57 The effects are similar to the pain relief Pump-Hep, Unihep, Uniparin Calcium, Uniparin Forte).
mechanisms in other conditions and are not primarily anti- Anticoagulants, heparinoids: Danaparoid (Orgaran), fondapar- p0770

inflammatory.58 The trial conducted by Deal et al.59 involved inux (Arixtra).

both OA (70) and RA (31) patients, who were allowed to Anticoagulants, low-molecular-weight heparins: Ardeparin p0780

continue taking their antiarthritis medications, including (Normiflo), dalteparin (Fragmin), enoxaparin (Lovenox),
NSAIDs, corticosteroids, and analgesics. Analgesic effects of tinzaparin (Innohep).
capsaicin are more pronounced in inflammatory states than in Anticoagulants, thrombin inhibitors, hirudins: desirudin p0790

normal controls, according to one animal study.7 (Iprivask, Revasc), lepirudin (Refludan).
Antiplatelet thromboprophylactics: Acetylsalicylic acid (acet- p0800

s0400 Integrative Therapeutics, Clinical Concerns, and Adaptations osal, acetyl salicylic acid, ASA, salicylsalicylic acid; Arthritis
p0720 This is a straightforward example of an additive (or possibly Foundation Pain Reliever, Ascriptin, Aspergum, Asprimox,
synergistic) and beneficial interaction caused by convergent Bayer Aspirin, Bayer Buffered Aspirin, Bayer Low Adult
clinical effects operating through different mechanisms Strength, Bufferin, Buffex, Cama Arthritis Pain Reliever,
(inflammation and nocioception) for drug and herb, respec- Easprin, Ecotrin, Ecotrin Low Adult Strength, Empirin,
tively. The interaction is apparently benign and noncontrover- Extra Strength Adprin-B, Extra Strength Bayer Enteric 500
sial and could be recommended to patients interested in either Aspirin, Extra Strength Bayer Plus, Halfprin 81, Heartline,
increased levels of symptom relief other than that offered by Regular Strength Bayer Enteric 500 Aspirin, St. Joseph Adult
pharmaceuticals or decreased dose levels of pharmaceuticals to Chewable Aspirin, ZORprin); combination drugs: ASA and
reduce adverse effects. caffeine (Anacin), ASA, caffeine, and propoxyphene (Darvon
Compound), ASA and carisoprodol (Soma Compound), ASA,
codeine, and carisoprodol (Soma Compound with Codeine),
s0410 THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS ASA and codeine (Empirin with Codeine), ASA, codeine,
RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS butalbital, and caffeine (Fiorinal); cilostazol (Pletal), clopido-
grel (Plavix), dipyridamole (Persantine), ticlopidine (Ticlid);
s0420 Antacids combination drug: ASA and extended-release dipyridamole
p0730 Aluminum carbonate gel (Basajel), aluminum hydroxide (Aggrenox, Asasantin).
(Alternagel, Amphojel); combination drugs: aluminum hydro- Blood viscosity reducing agents: Pentoxifylline (Pentoxil, p0810

xide, magnesium carbonate, alginic acid, and sodium bicarbo- Trental).

nate (Gaviscon Extra Strength Tablets, Gaviscon Regular Isolated capsaicin has definitively been demonstrated to p0820

Strength Liquid, Gaviscon Extra Strength Liquid); aluminum have some antiplatelet effects in vitro and in animal experi-
hydroxide, magnesium hydroxide, and simethicone (Advanced ments. The mechanism of these effects is not understood and
Formula Di-Gel Tablets, co-magaldrox, Di-Gel, Gelusil, their relevance to human hemostasis unclear. Some experimen-
Maalox, Maalox Plus, Mylanta, Wingel); aluminum hydroxide, tal evidence suggests antiplatelet activity of capsaicin may be
magnesium trisilicate, alginic acid, and sodium bicarbonate related to cell membrane fluidization.61, 62
(Alenic Alka, Gaviscon Regular Strength Tablets); calcium Another study has demonstrated a nitric oxide (NO)!releasing p0830

carbonate (Titralac, Tums); magnesium hydroxide (Phillips’ effect that is modulated by capsaicin-sensitive afferent neurons,
Milk of Magnesia MOM); combination drugs: magnesium which may implicate the vanilloid pathway.63 Capsaicin has effects

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Cayenne 25

on at least three stimuli of platelet activation: platelet-activating MAO-B inhibitors: Selegiline, deprenyl, L-deprenil, L-deprenyl; p0880

factor (PAF), collagen, and thromboxane.64,65 At present, the (Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); pargy-
levels of capsaicin (IC50 for collagen-induced in vitro effect was line (Eutonyl), rasagiline (Azilect).
87 mg/mL), and prolongation of tail bleed times in mice required Newell et al.71 suggest a potential adverse interaction p0890

Herb-Drug Interactions
a dose of 25 mg/kg capsaicin.66 These levels are more than between MAO inhibitors and capsaicin, presumably based on
an order of magnitude higher than typical human doses from extrapolations of ‘‘sympathomimetic-like’’ effects associated
therapeutic topical or chronic dietary administration. Some epide- with acute cayenne ingestion, such as transient increases in
miological data, however, suggest that dietary use of cayenne may resting metabolic rate. Capsaicin is not an adrenomimetic
be related to lower incidence of thromboses in chronic cayenne agent and lacks any direct sympathetic activity; this extrapola-
consumers. A study comparing 88 Thai subjects to 55 Caucasian tion appears to be an overextension of the known pharmacol-
Americans found higher fibrinolytic parameters in the latter than ogy and is unsupported by clinical reports.
in the Thai (cayenne user) group.67 Finally, traditional herbalist
Dr. Christopher68 recommended cayenne as a hemostatic to stop s0460

external bleeding and promote wound healing, and Felter and Theophylline/aminophylline (Phyllocontin, Slo-Bid, Slo- p0900

Lloyd69 suggest it can also be taken internally as an antihemor- Phyllin, Theo-24, Theo-Bid, Theocron, Theo-Dur, Theolair,
rhagic, especially for postpartum bleeding. At present, clinically Truphylline, Uni-Dur, Uniphyl), combination drug:
significant interactions with antiplatelet, fibrinolytic, or ephedrine, guaifenesin, and theophylline (Primatene Dual
anticoagulant medications are unreported and appear improbable. Action).
Two studies by the same investigator examined the kinetics p0910
s0440 Cisplatin
of theophylline and cayenne (dried fruit orally) coadministra-
p0840 Evidence: Cisplatin (cis-diaminedichloroplatinum, CDDP; tion. Single-dose coadministration demonstrated an increase
Platinol, Platinol-AQ). in clearance of the drug. However, cayenne pretreatment for
p0850 Extrapolated, based on similar properties: Carboplatin 1 week led to decreased levels of the theophylline metabolite
(Paraplatin), oxaliplatin (Eloxatin). 1-methyluric acid (1-MU), suggesting a potential increase
p0860 One study using a rodent model demonstrated some in theophylline levels from inhibition of theophylline metabo-
reduction in cisplatin-induced nephrotoxicity in animals after lism.72,73 Slight increases in theophylline levels are associated
single-dose cisplatin when coadministered with intragastric with increased adverse effects, which could indicate a potential
capsaicin.70 The authors suggested that this was caused by interaction; however, the effects in humans are unknown and
antioxidant mechanisms, because renal glutathione and reports unavailable. The author’s speculation that xanthine
superoxide dismutase levels rose with the capsaicin treatment. oxidase inhibition is affected by cayenne may or may not
High doses of capsaicin (10 mg/kg) were used, and the applic- be correct. Theophylline is primarily metabolized by
ability of these data to human oncology settings is difficult to CYP1A; however, a secondary pathway of theophylline meta-
establish until more studies are performed. bolism by 2E1 exists, and this P450 enzyme is inhibited by
s0450 Monoamine Oxidase (MAO) Inhibitors
p0870 MAO-A inhibitors: Isocarboxazid (Marplan), moclobemide The 74 citations for this monograph are located under Cayenne on p0920

(Aurorix, Manerix), phenelzine (Nardil), procarbazine the CD at the back of the book.
(Matulane), tranylcypromine (Parnate).

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Cayenne

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26. Kang HJ, Soh Y, Kim MS et al. Roles of JNK-1 and p38 in selective induction of apoptosis by capsaicin in ras-transformed human
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27. Surh YJ, Han SS, Keum YS et al. Inhibitory effects of curcumin and capsaicin on phorbol ester–induced activation of eukaryotic
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28. Han SS, Keum YS, Chun KS, Surh YJ. Suppression of phorbol ester–induced NF-κB activation by capsaicin in cultured human
promyelocytic leukemia cells. Arch Pharm Res 2002;25:475-479.

29. Zhang Z, Hamilton SM, Stewart C et al. Inhibition of liver microsomal cytochrome P450 activity and metabolism of the tobacco-
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30. Gannett PM, Iversen P, Lawson T. The mechanism of inhibition of cytochrome P450IIE1 by dihydrocapsaicin. Bioorg Chem

31. Sambaiah K, Srinivasan K. Influence of spices and spice principles on hepatic mixed function oxygenase system in rats. Indian J
Biochem Biophys 1989;26:254-258.

32. Miller MS, Brendel K, Burks TF, Sipes IG. Interaction of capsaicinoids with drug-metabolizing systems: relationship to toxicity.
Biochem Pharmacol 1983;32:547-551.

33. Miller CH, Zhang Z, Hamilton SM, Teel RW. Effects of capsaicin on liver microsomal metabolism of the tobacco-specific
nitrosamine NNK. Cancer Lett 1993;75:45-52.

34. Reilly CA, Ehlhardt WJ, Jackson DA et al. Metabolism of capsaicin by cytochrome P450 produces novel dehydrogenated
metabolites and decreases cytotoxicity to lung and liver cells. Chem Res Toxicol 2003;16:336-349.

35. Jancso-Gabor A. Anaesthesia-like condition and/or potentiation of hexobarbital sleep produced by pungent agents in normal and
capsaicin-desensitized rats. Acta Physiol Acad Sci Hung 1980;55:57-62.

36. Nabekura T, Kamiyama S, Kitagawa S. Effects of dietary chemopreventive phytochemicals on P-glycoprotein function. Biochem
Biophys Res Commun 2005;327:866-870.

37. Abdel Salam OM, Mozsik G, Szolcsanyi J. Studies on the effect of intragastric capsaicin on gastric ulcer and on the prostacyclin-
induced cytoprotection in rats. Pharmacol Res 1995;32:209-215.

38. Lippe IT, Pabst MA, Holzer P. Intragastric capsaicin enhances rat gastric acid elimination and mucosal blood flow by afferent nerve
stimulation. Br J Pharmacol 1989;96:91-100.

39. Myers BM, Smith JL, Graham DY. Effect of red pepper and black pepper on the stomach. Am J Gastroenterol 1987;82:211-214.

40. Yeoh KG, Kang JY, Yap I et al. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci

41. Kang JY, Yeoh KG, Chia HP et al. Chili—protective factor against peptic ulcer? Dig Dis Sci 1995;40:576-579.

42. Mozsik G, Szolcsanyi J, Racz I. Gastroprotection induced by capsaicin in healthy human subjects. World J Gastroenterol

43. Ellison N, Loprinzi CL, Kugler J et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical
neuropathic pain in cancer patients. J Clin Oncol 1997;15:2974-2980.

44. Millqvist E. Cough provocation with capsaicin is an objective way to test sensory hyperreactivity in patients with asthma-like
symptoms. Allergy 2000;55:546-550.

45. Huang HC, Chu SH, Chao PD. Vasorelaxants from Chinese herbs, emodin and scoparone, possess immunosuppressive properties.
Eur J Pharmacol 1991;198:211-213.

46. Morice AH, Geppetti P. Cough. 5. The type 1 vanilloid receptor: a sensory receptor for cough. Thorax 2004;59:257-258.

47. Deep V, Singh M, Ravi K. Role of vagal afferents in the reflex effects of capsaicin and lobeline in monkeys. Respir Physiol

48. Millqvist E, Lowhagen O, Bende M. Quality of life and capsaicin sensitivity in patients with sensory airway hyperreactivity. Allergy

49. Fox AJ, Lalloo UG, Belvisi MG et al. Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor
cough. Nat Med 1996;2:814-817.

50. Yeo WW, Higgins KS, Foster G et al. Effect of dose adjustment on enalapril-induced cough and the response to inhaled capsaicin. Br
J Clin Pharmacol 1995;39:271-276.

51. Yeo WW, Chadwick IG, Kraskiewicz M et al. Resolution of ACE inhibitor cough: changes in subjective cough and responses to
inhaled capsaicin, intradermal bradykinin and substance-P. Br J Clin Pharmacol 1995;40:423-429.

52. Hakas JF Jr. Topical capsaicin induces cough in patient receiving ACE inhibitor. Ann Allergy 1990;65:322-323.

53. Fusco BM, Giacovazzo M. Peppers and pain: the promise of capsaicin. Drugs 1997;53:909-914.

54. McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol

55. Rains C, Bryson HM. Topical capsaicin: a review of its pharmacological properties and therapeutic potential in post-herpetic
neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 1995;7:317-328.

56. Lynn B. Capsaicin: actions on nociceptive C-fibres and therapeutic potential. Pain 1990;41:61-69.

57. Pini A, Baranowski R, Lynn B. Long-term reduction in the number of C-fibre nociceptors following capsaicin treatment of a
cutaneous nerve in adult rats. Eur J Neurosci 1990;2:89-97.

58. Hautkappe M, Roizen MF, Toledano A et al. Review of the effectiveness of capsaicin for painful cutaneous disorders and neural
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59. Deal CL, Schnitzer TJ, Lipstein E et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther 1991;13:383-395.

60. Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.

61. Tsuchiya H. Biphasic membrane effects of capsaicin, an active component in Capsicum species. J Ethnopharmacol 2001;75:295-299.

62. Hogaboam CM, Wallace JL. Inhibition of platelet aggregation by capsaicin: an effect unrelated to actions on sensory afferent
neurons. Eur J Pharmacol 1991;202:129-131.

63. Lippe IT, Sametz W, Sabin K, Holzer P. Inhibitory role of capsaicin-sensitive afferent neurons and nitric oxide in hemostasis. Am J
Physiol 1993;265:H1864-1868.

64. Wang JP, Hsu MF, Teng CM. Antiplatelet effect of capsaicin. Thromb Res 1984;36:497-507.

65. Choi SY, Ha H, Kim KT. Capsaicin inhibits platelet-activating factor–induced cytosolic Ca2+ rise and superoxide production. J
Immunol 2000;165:3992-3998.

66. Wang JP, Hsu MF, Hsu TP, Teng CM. Antihemostatic and antithrombotic effects of capsaicin in comparison with aspirin and
indomethacin. Thromb Res 1985;37:669-679.

67. Visudhiphan S, Poolsuppasit S, Piboonnukarintr O, Tumliang S. The relationship between high fibrinolytic activity and daily
capsicum ingestion in Thais. Am J Clin Nutr 1982;35:1452-1458.

68. Christopher JR. School of Natural Healing. Provo, UT: BiWorld Publishers Inc; 1976.

69. Felter H, Lloyd J. Capsicum. King’s American Dispensatory. 1 vol. 1898 Reprint ed. Sandy, OR: Eclectic Medical Publications;
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70. Shimeda Y, Hirotani Y, Akimoto Y et al. Protective effects of capsaicin against cisplatin-induced nephrotoxicity in rats. Biol Pharm
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71. Newell C, Anderson L, Phillipson J. Capsicum. Herbal Medicines. London: Pharmaceutical Press; 1996:170-172.

72. Bouraoui A, Brazier JL, Zouaghi H, Rousseau M. Theophylline pharmacokinetics and metabolism in rabbits following single and
repeated administration of Capsicum fruit. Eur J Drug Metab Pharmacokinet 1995;20:173-178.

73. Bouraoui A, Toumi A, Ben Mustapha H, Brazier JL. Effects of capsicum fruit on theophylline absorption and bioavailability in
rabbits. Drug Nutr Interact 1988;5:345-350.

74. Rasmussen BB, Jeppesen U, Gaist D, Brosen K. Griseofulvin and fluvoxamine interactions with the metabolism of theophylline.
Ther Drug Monit 1997;19:56-62.

Dang Gui Botanical Name: Angelica sinensis (Oliv.) Diels.
Pharmacopoeial Name: Angelicae radix.
Herb-Drug Interactions

Synonym: Angelica polymorpha Maxim. var sinensis Oliv.

Common Names: Dang gui, dong quai, tang kuei, tang kwei, Chinese angelica.
Note: The phonetic ‘‘dong quai’’ Romanization is not the correct Pinyin
transliteration, which is ‘‘dang gui.’’ ‘‘Tang kuei’’ is the earlier Wade Giles
transliteration, less used today.

s0020 HERB CHARACTERISTICS Pharmacopoeia has produced a Western-oriented monograph,

s0030 Family including a supplement on traditional Chinese usage,4 and
p0060 Apiaceae. McKenna et al.5 have reviewed much of the literature.
Chen and Chen6 have reviewed both the pharmacology and
the traditional uses of the herb.
s0040 Related Species Interactions concerns about dang gui are largely the result p0140

p0070 In East Asian commerce, several species may be traded as sub- of extrapolations from experimental pharmacological data of
stitutes. Levisticum officinale Koch., or lovage, sometimes isolated ingredients, such as ferulic acid, ligustilide, or polysac-
known as ‘‘European dang gui,’’ is a recorded adulterant, charide fractions of the herb, and usually stress the risks
not a substitute. of concomitant use with anticoagulants. The traditional
precautions and contraindications for dang gui, which include
bleeding disorders, hemorrhagic disease, excessive menses, and
s0050 Parts Used first-trimester pregnancy, may be seen as equally appropriate in
p0080 Root; in East Asian traditional medicine, the head, body, and Western contexts.
tail of the root are regarded as having different medicinal
Effects on Drug Metabolism and Bioavailability s0090

Minimal data are available on the effects of dang gui on p0150

s0060 Common Forms the different aspects of drug detoxification. Two Japanese
p0090 Dried: Prepared root, smoke-dried; baked in wine. studies are available. One screened a number of umbelliferous
p0100 Fluid Extract: 1:1 70% ethanol, according to the Pharmacopoeia crude drugs in vitro for general cytochrome P450 (CYP450)
of the People’s Republic of China (PPRC). inhibitory effects and found weak but measurable inhibition
p0110 Standardized Extract: Liquid or dry extracts may be standar- by dang gui, as well as other Angelica spp. After high-
dized to ligustilide content (0.8%-1.0%) and to ferulic acid performance liquid chromatography analysis, the authors
(0.05%-0.01%). attributed this to the activity of a coumarin-derivative consti-
tuent, imperatorin.7 A more specific in vitro study using
rodent hepatic microsomes with various drug substrates found
s0070 INTERACTIONS REVIEW partial inhibition by dang gui extracts of CYP450 3A4, 2C9,
s0080 Strategic Considerations and 2D6.8 A Chinese study examined the effects of
p0120 One of the better known herbs from the materia medica of dang gui polysaccharide administration in normal and liver-
classical Chinese medicine, dang gui (in traditional terms) damaged (by prednisolone) rodents and found that
supplements (nourishes) xue (blood), moves and dispels blood the herb fraction increased hepatic microsomal CYP450,
stasis, and regulates menses. It is also used for moistening dry glutathione-S-transferase, and reduced-glutathione content.9
conditions, dispersing swelling, and promoting the discharge Pharmacokinetic interactions have not been reported, and in
of pus.1 The herb has been incorporated into Western herbal the case of warfarin have been ruled out as a mechanism of
medicine, primarily as a women’s tonic herb for menstrual interaction10 (see following discussion). Nonetheless, such
disorders and infertility. Dang gui use for menopausal issues effects seem theoretically possible, and further research is
is not currently supported by clinical trial data.2 The herb is required to clarify the extent and significance of any potential
also used for its cardioprotective, hepatoprotective, and mild pharmacokinetic interactions.
immunomodulatory effects. In the contemporary practice of
Chinese medicine, it is widely used in many herbal formulae,
as well as in combination with conventional treatments, such as HERB-DRUG INTERACTIONS s0100

myelosuppressive chemotherapy.3
p0130 Much of the literature on dang gui is in Chinese-language Warfarin and Related Oral Vitamin K Antagonist Anticoagulants s0120

journals, and many reports relate to formulae involving several Evidence: Warfarin (Coumadin, Marevan, Warfilone). p0160

ingredients, including dang gui. Few controlled trials are avail- Extrapolated, based on similar properties: Anisindione p0170

able, but there is a large body of traditional-use data, as well as (Miradon), dicumarol, ethyl biscoumacetate (Tromexan),
a considerable number of uncontrolled trials in the East Asian nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione
medical literature. Many of the available studies, animal and (Dindevan), phenprocoumon (Jarsin, Marcumar); other drugs
human, involve parenteral administration, which cannot be affecting hemostasis.
readily extrapolated to oral administration used in the West.
The herb is not referenced in official Western pharmacopoeias Interaction Type and Significance s0130

(although it was briefly in the USD in 1937) but has been ✗✗ Minimal to Mild Adverse Interaction—Vigilance p0180

official in the PPRC since 1977. The American Herbal Necessary

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Dang Gui 27

Probability: Evidence Base: Clinical Implications and Adaptations s0190

4. Plausible Mixed The lack of reports of spontaneous bleeding associated with p0250

dang gui consumption alone, with only one report of the

s0160 Effect and Mechanism of Action warfarin!dang gui interaction to date, suggests that concerns

Herb-Drug Interactions
p0210 Addition of dang gui to previously stabilized warfarin anti- about the incidence and severity of the interaction are exagger-
coagulation regimens may require the dose of oral anticoagu- ated. As always, self-prescription is a separate issue, and many
lant to be adjusted to prevent excessive anticoagulation. Only warfarinized patients are poorly compliant with their monitor-
one report is available, suggesting the interaction is unlikely to ing test schedules. As a guideline, prescribing dang gui to
be clinically significant. Dang gui has multiple effects on hemo- warfarinized patients should generally be avoided unless there
rheological parameters, the mechanisms of which are not fully are compelling reasons for coadministration. In such cases,
elucidated, and whether this is a strict interaction or merely an close monitoring of INR is required.
additive common pharmacodynamic effect has not been However, as is often the case from an integrative p0260

established. perspective, the potential interaction may be beneficial

under specific circumstances. Dang gui has cardioprotective
s0170 Research and thrombolytic effects that may be beneficial depending
p0220 The literature on hemorheological activities of dang gui is domi- on the situation.6,22 For example, patients receiving a
nated by an emphasis on isolated constituents (e.g., ferulate, typical 1 mg/day oral dose of Coumadin after temporary
butylidenephthalide) with parenteral administration at high installation of vascular access ports/catheters for prevention
dose levels in animal and human studies. The trend of the data of thrombosis at the catheter tip may benefit from the
supports a possible antiplatelet effect, probably operating addition of dang gui, combined with natural antiplatelet
through arachidonic acid metabolism.11-17 Other hemorheolo- and fibrinolytic agents, particularly if there are other
gical effects were observed in a study using parenteral dang indications for prescribing the herb. However, checking
gui (200 mL aqueous solution, intravenous administration PT/INR weekly would be appropriate if coadministration
daily for 20 days), in a group of 50 patients after acute is considered, because 1 mg Coumadin could affect PTs if
ischemic stroke, where administration resulted in significant circumstances altered (e.g., vitamin K deficiency).
reductions (p <0.001) in platelet adhesion, red blood cell
Erythropoiesis-Stimulating Agents s0200
(RBC) and platelet electrophoresis times, erythrocyte sedimen-
tation rate (ESR) and serum fibrinogen, and blood and Epoetin alpha (EPO, epoeitin alfa, recombinant erythropoie- p0270

plasma adhesion ratios.18 Oral administration of an aqueous tin; Epogen, Eprex, Procrit), epoetin beta (NeoRecormon),
decoction of dang gui and the related Angelica acutiloba darbepoetin alpha (darbepoetin alfa; Aranesp).
were given to six healthy patients, and whole-blood viscosity
was reduced (p <0.05) after 180 minutes compared with Interaction Type and Significance s0210

controls.19 Potential or Theoretical Beneficial or Supportive p0280

p0230 A study of warfarin and dang gui coadministration in Interaction, with Professional Management
rabbits investigated the effect of adding single-dose warfarin
to animals pretreated with dang gui, as well as addition Probability: Evidence Base:
of dang gui to warfarin-stabilized animals, as measured by 4. Plausible Inadequate
coagulation parameters. In the first case, adding warfarin to a
dang gui pretreated group led to a (p <0.05) lowering Effect and Mechanism of Action s0240

of prothrombin time (PT) compared with warfarin alone. Recombinant analogs of endogenous erythropoietin are used p0310

Pharmacokinetic parameters of warfarin were not changed parenterally to correct anemia in seriously ill patients (cancer
in the presence of dang gui pretreatment. Addition of and chronic renal failure). The interaction is a pharmacody-
dang gui to stable, warfarinized animals led to no significant namic additive effect on hematopoiesis. Dang gui may also
change in PT or warfarin levels. In this study, warfarin help facilitate responsiveness to the drug.
was given at high dose levels subcutaneously, and a 2:1 extract
of dang gui was given at 2 g/kg orally. The implication Research s0250

of this study appears to be that adding dang gui to stabilized Several Chinese experimental studies have examined the effects p0320

warfarin is less problematic than adding drug to stabilized dang of dang gui, particularly the polysaccharide fraction, in stimu-
gui (in rabbits), although pharmacokinetic interactions were lating hematopoiesis and erythropoiesis. Hemoglobin, RBC
not observed.10 count, and progenitor cells were all increased by the adminis-
tration of the herb in normal and anemic mice as well as in cell
s0180 Reports culture systems.23-25 Murine studies have demonstrated mye-
p0240 In a single but much-cited report, a 46-year-old female loprotective effects of dang gui and its polysaccharide fractions
warfarinized patient experienced an unexplained rise in against cyclophosphamide-induced and radiation-induced
international normalized ratio (INR) to 4.05. Investigations leukopenia.26,27
revealed no identifiable cause, and she was advised to
discontinue her 5-mg warfarin dose for 24 hours. The INR Reports s0260

remained elevated on retesting 1 week later. The patient Bradley et al.28 reported a single case of an anemic hemodialysis p0330

admitted taking a herbal preparation (Nature’s Way brand patient who was apparently resistant to the recombinant
of dang gui), 565 mg twice daily. She was advised to drug. The patient started self-prescription of a decoction
stop the herb, and the INR declined to 3.41, then to 2.48 of dang gui and Paeonia lactiflora, and after 1 month
after 1 week. Concomitant medications included digoxin the hematocrit increased from 29.7% to 34.4%, and the
and furosemide.20 Fugh-Berman and Ernst21 evaluated amount of the drug was reduced by more than 90%.
the interaction as ‘‘likely,’’ scoring 8 of 10 on their report The effect of the other component of the formula cannot be
reliability scale. ascertained.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
28 Dang Gui

s0270 Integrative Therapeutics, Clinical Concerns, and Adaptations nifedipine alone.32 Dose of dang gui was high (250 mL 25%
p0340 Published data substantiating this interaction are currently solution/day) and was administered parenterally, which
inadequate. However, the Chinese materia medica for makes extrapolation from this study problematic, although
Supplementing the Xue/Blood is an established part of some clinical evidence suggests that dang gui alone may
Herb-Drug Interactions

protocols for supporting patients undergoing myelosuppressive have a vasodilator effect on the pulmonary circulation.
chemotherapies in Chinese medicine. Dang gui is incorporated More investigation is needed before this is confirmed as a
into many of these formulae, which are based on different clinically consequential interaction, particularly in light of the
patterns of bone marrow suppression according to traditional in vitro evidence suggesting a pharmacokinetic reduction of
diagnostic criteria. Specialist review of these formulae is avail- nifedipine level by inhibition of CYP450 3A4 and 2D6 by
able from clinical texts, including Peiwen.3 The risk/benefit dang gui.8
ratios of this approach are favorable, and the combination
Oral Contraceptives and Related Estrogen-Containing and s0320
requires further investigation by preclinical and controlled
Synthetic Estrogen and Progesterone Analog Medications
clinical studies.
Oral contraceptives: monophasic, biphasic, and triphasic
estrogen preparations:
s0280 THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen). p0410
RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/ p0420

50, Nelulen 1/25, Nelulen 1/50, Zovia).

s0290 Acetaminophen Ethinyl estradiol and levonorgestrel (Alesse, Levlen, p0430

p0350 APAP, paracetamol (Tylenol); combination drugs: acetamino- Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil,
phen and codeine (Capital with Codeine, Phenaphen with Trivora).
Codeine, Tylenol with Codeine); acetaminophen and hydro- Ethinyl estradiol and norethindrone/norethisterone (Brevicon, p0440

codone (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, Estrostep, Genora 1/35, GenCep. 1/35, Jenest-28, Loestrin
DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11,
Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11,
Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho
Zydone); acetaminophen and oxycodone (Endocet, Percocet Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50,
2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet Tri-Norinyl, Trinovum).
10/650, Roxicet 5/500, Roxilox, Tylox); acetaminophen Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral). p0450

and pentazocine (Talacen); acetaminophen and propoxyphene Mestranol and norethindrone (Genora 1/50, Nelova 1/50, p0460

(Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Norethin 1/50, Ortho-Novum 1/50).
Propoxacet-N, Wygesic). Related, internal application: Etonogestrel/ethinyl estradiol p0480

p0360 Dang gui extracts and polysaccharide fractions have been vaginal ring (Nuvaring).
shown to have some moderate hepatoprotective activity. One Hormone replacement therapy, estrogens: Chlorotrianisene p0490

study examined CCl4 and acetaminophen-induced hepatotoxi- (Tace); conjugated equine estrogens (Premarin); conjugated
city and found that hepatoprotective effects for dang gui synthetic estrogens (Cenestin); dienestrol (Ortho Dienestrol);
extracts were more pronounced in the case of acetaminophen, esterified estrogens (Estratab, Menest, Neo-Estrone); estra-
suggesting a glutathione-dependent mechanism for the protec- diol, topical/transdermal/ring (Alora Transdermal, Climara
tive effects.29,30 The ‘‘interaction’’ of acetaminophen with Transdermal, Estrace, Estradot, Estring FemPatch, Vivelle-
dang gui described by Chen and Chen6 is thus more likely Dot, Vivelle Transdermal); estradiol cypionate (Dep-
an effect of general antioxidant hepatoprotective activity Gynogen, Depo-Estradiol, Depogen, Dura-Estrin, Estra-D,
mediated by glutathione. Estro-Cyp, Estroject-LA, Estronol-LA); estradiol hemihydrate
(Estreva, Vagifem); estradiol valerate (Delestrogen, Estra-L 40,
s0300 Cycloheximide, Scopolamine
Gynogen L.A. 20, Progynova, Valergen 20); estrone (Aquest,
p0370 Cycloheximide (Acti-aid, ActiDione, Actispray, actidone, Estragyn 5, Estro-A, Estrone ‘5’, Kestrone-5); estropipate
hizaricin, kaken, naramycin, naramycin A, neocycloheximide), (Ogen, Ortho-Est); ethinyl estradiol (Estinyl, Gynodiol,
scopolamine (Scopace Tablet, Transderm Scop Patch). Lynoral).
p0380 A study with a rodent behavioral model examined the effects Hormone replacement therapy, estrogen/progestin combina- p0500

both hexane and methanol extracts of dang gui on amnesia tions: Conjugated equine estrogens and medroxyprogesterone
induced by scopolamine and cycloheximide and p-chloroam- (Premelle cycle 5, Prempro); conjugated equine estrogens
phetamine. High doses of the hexane extract (1 g/kg) appeared and norgestrel (Prempak-C); estradiol and dydrogesterone
to attenuate the amnesia induced by scopolamine and cyclohex- (Femoston); estradiol and norethindrone, patch (CombiPatch);
imide but not by chloramphetamine in this model. The authors estradiol and norethindrone/norethisterone, oral (Activella,
suggest this implies an effect on memory function, but the Climagest, Climesse, FemHRT, Trisequens); estradiol valerate
significance of this for therapeutic doses of conventional and cyproterone acetate (Climens); estradiol valerate and norges-
extracts of dang gui in humans remains unclear.31 trel (Progyluton); estradiol and norgestimate (Ortho-Prefest).
Hormone replacement therapy, estrogen/testosterone combi- p0510
s0310 Nifedipine
nations: Esterified estrogens and methyltestosterone (Estratest,
p0390 Nifedipine (Adalat, Adalat CC, Nifedical XL, Procardia, Estratest HS).
Procardia XL); combination drug: nifedipine and atenolol Selective estrogen response modulators (SERMs): Raloxi- p0520

(Beta-Adalat, Tenif). fene (Evista), tamoxifen (Nolvadex), toremifene (Fureston).

p0400 Coadministration of nifedipine and dang gui in 40 patients Partly because of its reputation as a ‘‘female tonic’’ herb, p0530

with chronic obstructive pulmonary disease (COPD) led to some sources suggest interaction of dang gui with female
a greater degree of reduction of pulmonary arterial sex hormones (ERT, HRT) or hormone-modulating drugs
pressure than in untreated controls or those treated with (e.g., SERMs, aromatase inhibitors). Known phytoestrogenic

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Dang Gui 29

compounds have not been recorded in the root, and a con- (Cystodigin), digoxin (Digitek, Lanoxin, Lanoxicaps,
trolled clinical trial of postmenopausal women found no purgoxin), disopyramide (Norpace), dofetilide (Tikosyn), flecai-
changes in endometrial thickness or vaginal cell proliferation nide (Tambocor), ibutilide (Corvert), procainamide (Pronestyl,
after 24 weeks’ administration of a standardized extract of dang Procan-SR), quinidine (Quinaglute, Quinidex, Quinora), sota-

Herb-Drug Interactions
gui.33 However, a cell line model found some evidence for lol (Betapace, Betapace AF, Sorine).
both estrogen-dependent and estrogen-independent prolifera- Some experimental evidence exists for an antiarrhythmic effect p0560

tive activity by a water extract of dang gui.34 Recent reviews of of parenteral dang gui extracts, in animal models, including
botanicals for menopause have found no positive evidence of ouabain-induced ventricular fibrillation, as well as in digitalis-
effects of dang gui alone on menopausal symptoms.2,34,35 In and epinephrine-induced arrhythmias.37 Some secondary sources
the absence of estrogenic clinical effects or pharmacological suggest that the herb must interact adversely with antiarrhythmic
estrogen receptor binding, suggestions of female hormone drugs, but logically a beneficial interaction would be suggested,
interactions with dang gui by some authors are unsupported and clinical reports of the adverse interaction are lacking.
at this time.36
The 37 citations for this monograph are located under Dang Gui on p0570
s0330 Ouabain and Related Cardiac Glycosides and Antiarrhythmic Drugs
the CD at the back of the book.
p0540 Evidence: Ouabain (g-strophanthin).
p0550 Extrapolated, based on similar properties: Amiodarone
(Cordarone, Pacerone), deslanoside (cedilanin-D), digitoxin

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Dang Gui

1. Bensky D, Gamble A. Chinese Herbal Medicine: Materia Medica. Revised ed. Seattle: Eastland Press; 1993.

2. Low Dog T. Menopause: a review of botanical dietary supplements. Am J Med 2005;118:98-108.

3. Peiwin L. Management of Cancer with Chinese Medicine. Shuzang M, Liling B, Translators. St Albans, UK: Donica; 2003.

4. Upton R. Dang gui root. American Herbal Pharmacopoeia. Scotts Valley, CA; 2003.

5. McKenna D, Jones K, Hughes K, Humphrey S. Dong Quai. Botanical Medicines. 2nd ed. Binghampton: Haworth Press;

6. Chen J, Chen T. Dang Gui (Radix Angelicae Sinensis). Chinese Medical Herbology and Pharmacology. City of Industry, CA: Art of
Medicine Press Inc; 2004:918-923.

7. Guo LQ, Taniguchi M, Chen QY et al. Inhibitory potential of herbal medicines on human cytochrome P450–mediated oxidation:
properties of umbelliferous or citrus crude drugs and their relative prescriptions. Jpn J Pharmacol 2001;85:399-408.

8. Ishihara K, Kushida H, Yuzurihara M et al. Interaction of drugs and Chinese herbs: pharmacokinetic changes of tolbutamide and
diazepam caused by extract of Angelica dahurica. J Pharm Pharmacol 2000;52:1023-1029.

9. Xia X-Y, Peng R-X, Kong R et al. [Effects of Angelica sinensis polysaccharides on hepatic drug metabolism enzymes activities in
mice]. Zhongguo Zhong Yao Za Zhi 2003;28:149-152.

10. Lo AC, Chan K, Yeung JH, Woo KS. Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of
warfarin in rabbits. Eur J Drug Metab Pharmacokinet 1995;20:55-60.

11. Xu LN, Yu WG, Tian JY. [Effect of sodium ferulate on C14-arachidonic acid metabolism in rabbit platelets]. Zhong Xi Yi Jie He Za
Zhi 1988;8:614-615, 583.

12. Xu LN, Yu WG, Tian JY, Liu QY. [Effect of sodium ferulate on arachidonic acid metabolism]. Yao Xue Xue Bao 1990;25:412-416.

13. Xue JX, Jiang Y, Yan YQ. [Effects of the combination of Astragalus membranaceus (Fisch.) Bge. (AM), tail of Angelica sinensis
(Oliv.) Diels. (TAS), Cyperus rotundus L. (CR), Ligusticum chuanxiong Hort. (LC) and Paeonia veitchii Lynch (PV) on the
hemorrheological changes in normal rats]. Zhongguo Zhong Yao Za Zhi 1993;18:621-623, 640.

14. Xue JX, Yan YQ, Jiang Y. [Effects of the combination of Astragalus membranaceus (Fisch.) Bge. (AM), Angelica sinensis (Oliv.)
Diels (TAS), Cyperus rotundus L. (CR), Ligusticum chuangxiong Hort (LC) and Peaonia veitchii Lynch (PV) on the hemorheological
changes in “blood stagnating” rats]. Zhongguo Zhong Yao Za Zhi 1994;19:108-110, 128.

15. Yin ZZ, Wang JP, Xu LN. [Effect of sodium ferulate on malondialdehyde production from the platelets of rats]. Zhongguo Yao Li
Xue Bao 1986;7:336-339.

16. Teng CM, Chen WY, Ko WC, Ouyang CH. Antiplatelet effect of butylidenephthalide. Biochim Biophys Acta 1987;924:375-382.

17. Li CZ, Yang SC. [The effect of yimucao, chishao, danggui, sanleng, erzhu and zelan on blood coagulation in rats]. Zhong Xi Yi Jie
He Za Zhi 1982;2:69, 111-112.

18. Tu JJ. Effects of radix Angelicae sinensis on hemorrheology in patients with acute ischemic stroke. J Tradit Chin Med

19. Terasawa K, Imadaya A, Tosa H et al. Chemical and clinical evaluation of crude drugs derived from Angelica acutilobae and A.
sinensis. Fitoterapia 1985;56:201-208.

20. Page RL, 2nd, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999;19:870-876.

21. Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br J Clin Pharmacol 2001;52:587-595.

22. Mak DH, Chiu PY, Dong TT et al. Dang-Gui Buxue Tang produces a more potent cardioprotective effect than its component herb
extracts and enhances glutathione status in rat heart mitochondria and erythrocytes. Phytother Res 2006; 20(7):561-567.

23. Ma L, Mao X, Li X, Zhao H. The effect of Angelica sinensis polysaccharides on mouse bone marrow hematopoesis. Zhonghua
Xueyexue Zazhi 1988;9:148-149.

24. Wang Y, Zhu B. Effects of polysaccharide from Angelica sinensis on mice erythropoiesis. Chin J Hematol 1993;14:650-651.

25. Wang S, Wang Y, Dai Q et al. Study on effect of Angelica polysaccharide on modulation of human CFU-GM. Jiepou Xuebao

26. Hui MKC, Wu WKK, Shin VY et al. Polysaccharides from the root of Angelica sinensis protect bone marrow and gastrointestinal
tissues against the cytotoxicity of cyclophosphamide in mice. Int J Med Sci 2006;3:1-6.

27. Sun Y, Tang J, Gu X, Li D. Water-soluble polysaccharides from Angelica sinensis (Oliv.) Diels: preparation, characterization and
bioactivity. Int J Biol Macromol 2005;36:283-289.

28. Bradley RR, Cunniff PJ, Pereira BJ, Jaber BL. Hematopoietic effect of radix Angelicae sinensis in a hemodialysis patient. Am J
Kidney Dis 1999;34:349-354.

29. Wang H, Peng RX. [Effects of paracetamol on glutathione S-transferase activity in mice]. Zhongguo Yao Li Xue Bao 1993;14

Citations and Reference Literature: Dang Gui

30. Wang H, Peng RX. [Sodium ferulate alleviated paracetamol-induced liver toxicity in mice]. Zhongguo Yao Li Xue Bao

31. Hsieh MT, Lin YT, Lin YH, Wu CR. Radix Angelicae sinensis extracts ameliorate scopolamine- and cycloheximide-induced
amnesia, but not p-chloroamphetamine-induced amnesia in rats. Am J Chin Med 2000;28:263-272.

32. Xu JY, Li BX, Cheng SY. [Short-term effects of Angelica sinensis and nifedipine on chronic obstructive pulmonary disease in
patients with pulmonary hypertension]. Zhongguo Zhong Xi Yi Jie He Za Zhi 1992;12:716-718, 707.

33. Hirata JD, Swiersz LM, Zell B et al. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-
controlled trial. Fertil Steril 1997;68:981-986.

34. Lau CBS, Ho TCY, Chan TWL, Kim SCF. Use of dong quai (Angelica sinensis) to treat peri- or postmenopausal symptoms in
women with breast cancer: is it appropriate? Menopause 2005;12:734-740.

35. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized,
controlled trials. Ann Intern Med 2002;137:805-813.

36. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern
Med 1998;158:2200-2211.

37. Cha L. Effects of Angelica sinensis on the experimental arrhythmias. Chin Pharmacol Bull 1981;16:259-260.

Devil’s Claw Botanical Name: Harpagophytum procumbens, DC ex Meissner.
Pharmacopoeial Name: Harpagophyti radix.
Herb-Drug Interactions

Common Names: Devil’s claw, grapple plant, Cape grapple plant.

s0020 HERB DESCRIPTION Mechanism aside, clinical trials on the anti-inflammatory

s0030 Family effects of devil’s claw have revealed useful data relating to coad-
p0040 Pedaliaceae. ministration with several different NSAIDs and in clinical
populations with chronic arthritic complaints using long-term
NSAID therapy for management. This is a primary area for
s0040 Parts Used integrative use of the herb.
p0050 Secondary roots (tuber). The cardiovascular effects of devil’s claw have not been p0110

studied in humans, although studies of ex vivo Langendorff

preparations (rabbit heart) and live rats strongly suggest the
s0050 Common Forms potential for protection against arrhythmias, including those
p0060 Dried: Cut/powdered secondary root, containing not less than induced by digoxin, together with a biphasic dose-response
1.2% harpagoside. on heart rate.19-21 Interestingly, harpagoside did not repro-
p0070 Tincture, Fluid Extract, Hydroethanolic extracts 1:2, 1:3, 1:5 duce the electrophysiological effects of whole-plant extract.
in 25% ethanol. The same researchers noted a hypotensive reaction to the
p0080 Standardized Extract: Tablets or capsules, standardized 6:1 to extract in normotensive rats, but only with intraperitoneal
9:1 on 8.5% harpagoside. (WS 1531, Schwabe GmbH) or administration of high doses. Further studies on this aspect
1.5:1 to 2.5:1 standardized at 2.5% harpagoside (Doloteffin, of the herb’s pharmacology have not been published, and
Ardeypharm GmbH). devil’s claw clearly is a complex remedy that is not fully under-
stood. Traditional South African indications include seizures,
and some scientific corroboration of this has been found in a
s0060 INTERACTIONS REVIEW murine model.22 Meanwhile, monitoring heart rate and blood
s0070 Strategic Considerations pressure in patients with either preexisting hypotension or
p0090 Devil’s claw, a South African native, has been used in Western disturbances of rate or rhythm during early stages of adminis-
Europe for chronic arthritic conditions for several decades. The tration of the herb may be prudent.
root tubers are bitter, containing iridoid glycosides, principally
harpagoside.1 The bitter nature of the remedy, suggested by
Weiss2 as comparable to gentian, led the German Commission Effects on Drug Metabolism and Bioavailability s0080

E to approve its use for dyspepsia and loss of appetite.3 In The bitter tonic aspects of the herb suggest that a potential p0120

practice, however, it is only used for atonic digestion secondary for stimulation of hepatobiliary activity, but studies of the
to or associated with a primary arthritic condition. The generic effect of bitters on drug metabolism and detoxification
European Scientific Cooperative on Phytotherapy (ESCOP) systems are unavailable, and pharmacokinetic interactions with
indications are for low back pain and osteoarthritis.4,5 There devil’s claw have not been reported to date. A single in vitro
is positive clinical trial evidence as well as pharmacological sup- screening study of the effect of the herb on a mixture of
port for the use of the herb in painful, chronic arthritic condi- human recombinant drug!metabolizing enzymes derived
tions. Most of the trials to date have been German or French from baculovirus-infected insect cells suggested a potential
and recently reviewed.6-8 Neither of the European therapeutic inhibition of cytochrome P450 (CYP450) by devil’s claw
monographs notes any interactions between devil’s claw and extracts.23
pharmaceutical drugs.
p0100 Pharmacologically, devil’s claw has three principal areas
of action: anti-inflammatory and analgesic, antiarrhythmic HERB-DRUG INTERACTIONS s0090

and hypotensive, and bitter tonic. Data regarding mechanism

of the anti-inflammatory action has been conflicting, with Nonsteroidal Anti-Inflammatory Drugs and Related Antiarthritic s0110

initial studies suggesting a nonecosanoid mechanism because

animal models of inflammation did not respond to the extract, Nonsteroidal anti-inflammatory drugs (NSAIDs): p0130

although some direct effect on lipoxygenase and cyclooxygen- COX-1 inhibitors: Diclofenac (Cataflam, Voltaren), combi- p0140

ase (COX) pathways was noted.9-11 More recent studies nation drug: diclofenac and misoprostol (Arthrotec), diflunisal
suggest that there may be a downregulation of inducible (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbipro-
COX-2 and inducible nitric oxide synthase (iNOS), as well as fen (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin
a similar effect on tumor necrosis factor alpha (TNF-a) IB, Nuprin, Pedia Care Fever Drops, Provel, Rufen); combina-
transcription, probably resulting from upstream effects on tion drug: hydrocodone and ibuprofen (Reprexain,
activating protein-1 (AP-1).12-15 This is consistent with Vicoprofen), indomethacin (indometacin; Indocin, Indocin-
the efficacy of the herb as a chronic, rather than acute, anti- SR), ketoprofen (Orudis, Oruvail), ketorolac (Acular ophthal-
inflammatory and analgesic agent operating through different mic, Toradol), meclofenamate (Meclomen), mefenamic acid
pathways than the nonsteroidal anti-inflammatory drug (Ponstel), meloxicam (Mobic), nabumetone (Relafen),
(NSAID)!type direct effects on arachidonic acid metabo- naproxen (Aleve, Anaprox, Naprosyn), oxaprozin (Daypro),
lism.16 Parallels with other botanical derivatives exist, and piroxicam (Feldene), salsalate (salicylic acid; Amigesic,
evidence is emerging for modulation of nuclear factor kappa Disalcid, Marthritic, Mono Gesic, Salflex, Salsitab), sulindac
B (NF-kB),17 as well as the metalloproteinase TIMP-2.18 (Clinoril), tolmetin (Tolectin).
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Devil’s Claw 31

p0150 COX-2 inhibitors: Celecoxib (Celebrex). compared diacerhein (an unrelated drug of the slow-acting
p0160 Acetylsalicylic acid: acetosal, acetyl salicylic acid, ASA, salicyl- drug for osteoarthritis![SADOA] class) to devil’s claw in
salicylic acid; Arthritis Foundation Pain Reliever, Ascriptin, 122 osteoarthritis patients. Diacerhein (a prodrug of the
Aspergum, Asprimox, Bayer Aspirin, Bayer Buffered Aspirin, anthraquinone rhein, which is an interleukin-1 [IL-1] inhibi-

Herb-Drug Interactions
Bayer Low Adult Strength, Bufferin, Buffex, Cama Arthritis tor), found fewer adverse effects and less rescue medication
Pain Reliever, Easprin, Ecotrin, Ecotrin Low Adult Strength, needed by the devil’s claw group, although the degree of pain
Empirin, Extra Strength Adprin-B, Extra Strength Bayer reduction was not significantly different.30 Lipopolysaccharide
Enteric 500 Aspirin, Extra Strength Bayer Plus, Halfprin 81, (LPS)!stimulated COX-2 (and iNOS) messenger ribonucleic
Heartline, Regular Strength Bayer Enteric 500 Aspirin, acid (mRNA) increases were inhibited by harpagoside through
St. Joseph Adult Chewable Aspirin, ZORprin; combination blocking of NF-kB activation of LPS in a human hepatoma cell
drugs: ASA and caffeine (Anacin); ASA, caffeine, and propox- line model, although the detailed mechanism of inhibition has
yphene (Darvon Compound); ASA and carisoprodol (Soma not been established.17
Compound); ASA, codeine, and carisoprodol (Soma
Compound with Codeine); ASA and codeine (Empirin with Integrative Therapeutics, Clinical Concerns, and Adaptations s0170

Codeine); ASA, codeine, butalbital, and caffeine (Fiori- The NSAIDs, including selective COX-2 inhibitors, remain p0230

nal); ASA and extended-release dipyridamole (Aggrenox, widely used for management of arthritic pain. The adverse
Asasantin). effect profile of nonselective NSAIDs is a well-known problem,
with gastropathies resulting in considerable expense for
s0120 Interaction Type and Significance hospital care and responsible for about 17,000 deaths per
p0170 Beneficial or Supportive Interaction, Not year in the United States from major gastrointestinal bleeding.
Requiring Professional Management Emerging data also suggest that the COX-2 inhibitors are not
p0180 Prevention or Reduction of Drug Adverse Effect as free from adverse effects as initially believed.31,32 Recently, it
has become clear that if aspirin (including low dose, i.e.,
Probability: Evidence Base: 80 mg/day) or any classic NSAIDs are combined with
1. Certain Emerging COX-2 inhibitors, the risk of bleeding is higher than for classic
NSAIDs alone. On the economic cost side of the equation,
s0150 Effect and Mechanism of Action standardized devil’s claw and COX-2 inhibitors are probably
p0210 Additive pharmacodynamic anti-inflammatory effect enables equal in cost. At this stage, however, the use of devil’s claw as
reduced drug dose and reduction in drug adverse effects for adjunctive, or even where possible as an alternative, medication
a range of NSAIDs. in acute exacerbations of long-standing arthritis should be
actively considered. Given that the adverse effect profile of
s0160 Research the herb is benign, coadministration may not require profes-
p0220 Chrubasik et al.24-29 have conducted several trials with a pro- sional management because symptom relief is the determining
prietary extract of devil’s claw (Doleteffin) in various arthritic factor for the patient.
conditions, comparing both drug versus herb and drug in com-
bination with various NSAIDs, including the COX-2 inhibitor
rofecoxib (Vioxx). The general conclusions of this (ongoing) THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS s0180

series of controlled trials and qualitative investigations are RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS
(1) for acute exacerbations of chronic arthritic conditions,
including low back pain, knee pain, and hip pain, devil’s claw Warfarin and Related Oral Vitamin K Antagonist Anticoagulants s0190

extract is associated with fewer adverse effects than NSAIDs; Anisindione (Miradon), dicumarol, ethyl biscoumacetate p0240

(2) coadministation allows a lower dose of NSAIDs (or of (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom),
opioid rescue medications in trials where these were allowed); phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar),
and (3) for longer periods of administration, devil’s claw was warfarin (Coumadin, Marevan, Warfilone).
associated with almost twice the incidence of pain-free out- A secondary survey of plant toxicology in the United p0250

comes than rofecoxib. This latter result was from a subsequent Kingdom over a 5-year period included reference to a single
pilot study, which, although it lacked the statistical power to case in which there was an alleged adverse interaction between
establish the result as significant due to sample size, was inter- devil’s claw and warfarin.33 However, the details of this case
esting because the trial dropouts were almost all in the NSAID were completely unavailable, rendering it impossible to evalu-
group, resulting from adverse effects of the drug.26 In a quali- ate, a conclusion confirmed by Fugh-Berman and Ernst.34
tative study after coadministration of devil’s claw with NSAIDs, Nonetheless, a persistent repetition of this unsubstantiated
the respondents were using a range of drugs that included interaction occurs in the secondary literature despite the lack
aspirin, celecoxib, diclofenac, ibuprofen, indomethacin, keto- of verifiability of the original source and an absence of precli-
profen, metazoal, naproxen, piroxicam, propyphenazon, and nical or clinical evidence for its existence.
rofecoxib. This suggests that the effects observed in the con-
trolled trials may be reasonably extrapolated to a number of The 34 citations in this monograph are located under Devil’s Claw p0260

anti-inflammatory drugs. In this connection, a 4-month trial on the CD at the back of the book.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Devil's Claw

1. Boje K, Lechtenberg M, Nahrstedt A. New and known iridoid- and phenylethanoid glycosides from Harpagophytum procumbens and
their in vitro inhibition of human leukocyte elastase. Planta Med 2003;69:820-825.

2. Weiss R. Herbal Medicine. Meuss A, Translator. 6th ed. Beaconsfield, UK: Beaconsfield Publishers Ltd; 1988.

3. Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical
Council: Integrative Medicine Communications; 1998.

4. ESCOP. Harpagophyti Radix. ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK:
European Scientific Cooperative on Phytotherapy and Thieme; 2003:233-240.

5. Chrubasik S. Addendum to the ESCOP monograph on Harpagophytum procumbens. Phytomedicine 2004; 11:691-695.

6. Setty AR, Sigal LH. Herbal medications commonly used in the practice of rheumatology: mechanisms of action, efficacy, and side
effects. Semin Arthritis Rheum 2005;34:773-784.

7. Gagnier JJ, Chrubasik S, Manheimer E. Harpgophytum procumbens for osteoarthritis and low back pain: a systematic review. BMC
Complement Altern Med 2004;4:13.

8. Gagnier J, Vantulder M, Berman B, Bombardier C. Herbal medicine for low back pain. Cochrane Database Syst Rev 2006:CD004504.

9. Fontaine J, Elchami AA, Vanhaelen M, Vanhaelen-Fastre R. [Biological analysis of Harpagophytum procumbens DC. II.
Pharmacological analysis of the effects of harpagoside, harpagide and harpagogenine on the isolated guinea-pig ileum (author’s
translation)]. J Pharm Belg 1981;36:321-324.

10. Grahame R, Robinson BV. Devil’s claw (Harpagophytum procumbens): pharmacological and clinical studies. Ann Rheum Dis

11. Whitehouse LW, Znamirowska M, Paul CJ. Devil’s claw (Harpagophytum procumbens): no evidence for anti-inflammatory activity
in the treatment of arthritic disease. Can Med Assoc J 1983;129:249-251.

12. Fiebich BL, Heinrich M, Hiller KO, Kammerer N. Inhibition of TNF-α synthesis in LPS-stimulated primary human monocytes by
Harpagophytum extract SteiHap 69. Phytomedicine 2001;8:28-30.

13. Loew D, Mollerfeld J, Schrodter A et al. Investigations on the pharmacokinetic properties of Harpagophytum extracts and their
effects on eicosanoid biosynthesis in vitro and ex vivo. Clin Pharmacol Ther 2001;69:356-364.

14. Jang MH, Lim S, Han SM et al. Harpagophytum procumbens suppresses lipopolysaccharide-stimulated expressions of
cyclooxygenase-2 and inducible nitric oxide synthase in fibroblast cell line L929. J Pharmacol Sci 2003;93:367-371.

15. Kundu JK, Mossanda KS, Na H-K, Surh Y-J. Inhibitory effects of the extracts of Sutherlandia frutescens (L.) R. Br. and
Harpagophytum procumbens DC on phorbol ester-induced COX-2 expression in mouse skin: AP-1 and CREB as potential upstream
targets. Cancer Lett 2005;218:21-31.

16. Moussard C, Alber D, Toubin MM et al. A drug used in traditional medicine, Harpagophytum procumbens: no evidence for NSAID-
like effect on whole blood eicosanoid production in human. Prostaglandins Leukot Essent Fatty Acids 1992;46:283-286.

17. Huang TH-W, Tran VH, Duke RK et al. Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through
inhibition of NF-κB activation. J Ethnopharmacol 2006;104:149-155.

18. Chrubasik JE, Lindhorst E, Neumann E et al. Potential molecular basis of the chondroprotective effect of Harpagophytum
procumbens. Phytomedicine 2006;13:598-600.

19. Circosta C, Occhiuto F, Ragusa S et al. A drug used in traditional medicine: Harpagophytum procumbens DC. II. Cardiovascular
activity. J Ethnopharmacol 1984;11:259-274.

20. Costa De Pasquale R, Busa G, Circosta C et al. A drug used in traditional medicine: Harpagophytum procumbens DC. III. Effects on
hyperkinetic ventricular arrhythmias by reperfusion. J Ethnopharmacol 1985;13:193-199.

21. Occhiuto F, Circosta C, Ragusa S et al. A drug used in traditional medicine: Harpagophytum procumbens DC. IV. Effects on some
isolated muscle preparations. J Ethnopharmacol 1985;13:201-208.

22. Mahomed IM, Ojewole JAO. Anticonvulsant activity of Harpagophytum procumbens DC [Pedaliaceae] secondary root aqueous
extract in mice. Brain Res Bull 2006;69:57-62.

23. Unger M, Frank A. Simultaneous determination of the inhibitory potency of herbal extracts on the activity of six major cytochrome
P450 enzymes using liquid chromatography/mass spectrometry and automated online extraction. Rapid Commun Mass Spectrom

24. Chrubasik S, Conradt C, Black A. The quality of clinical trials with Harpagophytum procumbens. Phytomedicine 2003;10:613-623.

25. Chrubasik S, Junck H, Breitschwerdt H et al. Effectiveness of Harpagophytum extract WS 1531 in the treatment of exacerbation of
low back pain: a randomized, placebo-controlled, double-blind study. Eur J Anaesthesiol 1999;16:118-129.

26. Chrubasik S, Model A, Black A, Pollak S. A randomized double-blind pilot study comparing Doloteffin and Vioxx in the treatment of
low back pain. Rheumatology (Oxford) 2003;42:141-148.

Citations and Reference Literature: Devil's Claw

27. Chrubasik S, Pollak S, Fiebich B. Harpagophytum extracts. Clin Pharmacol Ther 2002;71:104-105.

28. Chrubasik S, Sporer F, Dillmann-Marschner R et al. Physicochemical properties of harpagoside and its in vitro release from
Harpagophytum procumbens extract tablets. Phytomedicine 2000;6:469-473.

29. Chrubasik S, Thanner J, Kunzel O et al. Comparison of outcome measures during treatment with the proprietary Harpagophytum
extract doloteffin in patients with pain in the lower back, knee or hip. Phytomedicine 2002;9:181-194.

30. Chantre P, Cappelaere A, Leblan D et al. Efficacy and tolerance of Harpagophytum procumbens versus diacerhein in treatment of
osteoarthritis. Phytomedicine 2000;7:177-183.

31. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA

32. Zhao SZ, Reynolds MW, Lejkowith J et al. A comparison of renal-related adverse drug reactions between rofecoxib and celecoxib,
based on the World Health Organization/Uppsala Monitoring Centre safety database. Clin Ther 2001;23:1478-1491.

33. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements: a 5-year toxicological study (1991-1995). Drug
Saf 1997;17:342-356.

34. Fugh-Berman A, Ernst E. Herb-drug interactions: review and assessment of report reliability. Br J Clin Pharmacol 2001;52:587-595.

Echinacea Botanical Names: The three principal species used commercially are Echinacea
angustifolia DC, Echinacea purpurea (L.) Moench, and Echinacea pallida
Herb-Drug Interactions

(Nutt.) Nutt.
Pharmacopoeial Names: Echinaceae radix, Echinaceae herba.
Common Names: Echinacea; E. angustifolia: narrow-leaved coneflower, Western
echinacea; E. purpurea: purple coneflower, purple echinacea; E. pallida: pale
coneflower echinacea, pale echinacea.

Drug/Class Interaction Type Mechanism and Significance Management
Cyclosporine Theoretically, long-term concomitant use might require increased levels of Avoid, except for short-term acute coadministration, with professional
Allograft immunosuppressive agents immunosuppression in allograft patients. monitoring.
✗ Inadvertent use without professional care may cause drug failure.
Cyclophosphamide Immunotherapeutic outcomes of low-dose drug protocols (not cytotoxic Adopt; coadminister only with integrative oncologist supervision.
?/ /✗ schedules) may be enhanced by concomitant administration.
High-dose drug effects on myelosuppression may be reduced.
Myelosuppressive Echinacea may help protect white blood cell (WBC) counts in chemotherapy- Adopt; coadminister with related myeloprotective agents. Continue herb
Antineoplastic induced myelosuppression. after chemotherapy.
Chemotherapies Natural killer (NK) cell number and activity increased by long-term
/ administration.
Interferon, interleukin-2 (IL-2) Possible additive effects of herb and drug allow sparing of drug, reduction of Consider adopting; professional management required.
Immunotherapeutic BRMs drug side effects, and enhanced therapeutic responses.
Tumor necrosis factor-alpha antagonists Echinacea may theoretically be used to enhance cellular immunity during Stop drug; administer herb short-term only, before recommencing drug
Immunosuppressive BRMs temporary drug withdrawal mandated by opportunistic infection. therapy.
?/ /✗
BRM s, Biological response modifiers.

s0020 HERB DESCRIPTION Common Forms s0070

s0030 Family Dried: Root powder and aerial parts. p0310

p0270 Asteraceae. Fluid Extract or Tinctures: Any of the above, 45% ethanol. p0320

Fresh Stabilized Juice: Echinacin is a German preparation p0330

(Madaus AG) that consists of E. purpurea flowering tops’

s0040 Related Species succus stabilized in 22% ethanol.
p0280 The Echinacea genus contains about 12 species, depending Solid Extracts, Tableted, or Encapsulated: Combinations of p0340

on the taxonomic authority consulted, although three major the above in different concentrations are available.
species (E. angustifolia, E. purpurea, E. pallida) are used Standardized Extracts: In the U.S., echinacosides have been p0350

in commerce. The minor taxa are sometimes classed as variants used as a marker; however, agreement on standardization is
of the principal species. The minor species are confined lacking, and manufacturers’ preparations may vary.
to relatively small wild populations and include Echinacea
paradoxa, E. simulata, and E. atrorubens; the Eastern species
E. tenneseensis and E. laevigata are endangered. HERB IN CLINICAL PRACTICE s0080

Overview s0090

The medicinal use of echinacea derived from indigenous Native p0360

s0050 Habitat and Cultivation American medicine. Widely used in the U.S. in the preantibio-
p0290 Echinacea angustifolia is native to the Great Plains and Atlantic tic era for infectious diseases of all types, the modern view of
drainage areas of the United States (U.S.) and Canada. the herb is narrower in focus, corresponding to the influence of
Echinacea purpurea was introduced from the U.S. to European phytotherapy. An influential German clinical litera-
Germany by Dr. Madaus before World War II and became ture primarily employed aerial parts of E. purpurea, usually the
cultivated on a large scale in Western Europe, where it is the stabilized fresh-juice preparation, administered both orally and
dominant species of commerce. parenterally. Historically, this resulted from the widespread
cultivation of E. purpurea in Germany, which lacks native
populations of echinacea. The roots of E. angustifolia are the
s0060 Parts Used preferred medicinal species in North American use. Modern
p0300 Root and aerial flowering herb; commercially, the roots of clinical trials of echinacea focus largely on its use in prophylaxis
Western echinacea (E. angustifolia) are preferred in the U.S.; and treatment of common colds and flu, whereas other ther-
aerial parts of purple echinacea (E. purpurea) are the principal apeutic aspects of the herb remain underinvestigated by clinical
part used in Europe. researchers.
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Echinacea 33

p0370 In popular use, echinacea is usually associated with prophy- Topical: Wound healing and connective tissue repair, p0410

laxis and self-treatment of mild respiratory infections such as venomous bites, including snakebites and spider bites.
the common cold. However, the trial evidence for echinacea’s
efficacy for this indication remains conflicting and is perennially

Herb-Drug Interactions
controversial in part because of the different Echinacea spp., Key Constituents s0120

different plant parts used in preparations, and different dosing Caffeic acid derivatives, alkylamides, flavonoids, polyacetylenes, p0420

regimens, as well as varying study design, methodology, and essential oil, polysaccharides, alkaloids. Echinacea angustifolia
power.1,2 The debate regarding the efficacy of echinacea in root contains isobutylamides; E. pallida lacks these compounds
relation to the common cold has unfortunately become emble- but contains polyacetylenes, which appear to have similar
matic of divisions between advocates of natural medicine and pharmacological effects on immune parameters. Constituent
those of conventional medicine. Arguably, this detracts from profiles also vary according to part used (root vs. herb) and
issues of more practical concern to clinicians, who likely are the method of extraction; for example, immunoactive polysac-
more focused on the general immunomodulating properties charides are not present in most hydroethanolic preparations
of the herb rather than on whether a trial shows ‘‘it works’’ because of their insolubility in ethanol. ‘‘Melanin’’ has recently
for the common cold. been identified in phenolic extractions.4
p0380 The detailed pharmacological mechanisms of action of echi-
nacea remain to be fully characterized. It is well established,
however, that the herb enhances cell-mediated immunity, Therapeutic Dosing Range s0130

particularly phagocytosis, and has moderate anti-inflammatory Suggested therapeutic dose ranges of the herb vary widely. p0430

as well as beneficial wound-healing and connective tissue Western echinacea root preparations are often administered
effects. Different constituent groups are thought to act in at lower doses than E. purpurea aerial parts. Acute and chronic
concert to affect immune parameters. Although there have dose ranges also widely vary, as do posological approaches,
been many studies of the herb, variations in the form of which include the homeopathic through supraphysiological.
preparation, including differing plant parts and plant species The following are composite figures based on several
used, as well as dose ranges and routes of administration, sources.8-13
have contributed to a surprising lack of cohesive understanding
of the pharmacology of echinacea. Novel discoveries about Chronic Dose Range s0140

the immunological properties of echinacea emerge as research Dried Root: 1 to 5 g/day p0440

into this complex herb continues; recent examples include Dried Aerial Parts: 2.5 to 6 g/day p0450

the discovery of a ‘‘melanin’’-like constituent that activates Fluid Extract (1:1) 3 to 5.5 mL/day p0460

nuclear factor kappa B (NF-kB) via a toll-like receptor Fresh Juice: 8 to 9 mL/day p0470

(TLR2) mechanism, as well as a cannabinoid receptor!depen-

dent pathway of immunoactivation unique to the alkylamide Acute Dose s0150

fraction.3,4 The chronic doses may be significantly increased for short-term p0480

administration in acute conditions; 10 to 15 g/day or equiva-

lent in liquid preparations is common.
s0100 Historical/Ethnomedicine Precedent
p0390 Echinacea was used by Native American peoples as a medicinal
agent for a wide variety of ailments, both topically and inter- INTERACTIONS REVIEW s0160

nally, including for snakebites, enlarged glands, and septic con- Strategic Considerations s0170

ditions. It was introduced into mainstream herbal medicine as a Authoritative monographs for Echinacea spp. generally list no p0490

component of ‘‘Meyer’s Blood Purifier’’ in the 1870s, where it known interactions.10,11,13,14 The German Commission
came of the attention of the Eclectics, particularly John Uri E listed certain contraindications ‘‘in principle’’ that have
Lloyd and John King. In the 1880s, Eclectic physicians started been challenged as speculative (see Theoretical, Speculative,
using echinacea, and the herb rapidly became a mainstay of and Preliminary Interactions Research). Because the mech-
their practice. Eclectic indications included carbuncles, furun- anisms of action of different constituents of echinacea are
culosis, abscesses, nasopharyngeal and respiratory catarrh, dys- not fully characterized, extrapolations from the available
entery, syphilis, snakebites, sepsis, and cancer; their empirical data to in vivo interactions involve a degree of specu-
reports constitute detailed, comprehensive, and authoritative lation, although consideration of specific clinical contexts
contributions to the literature on echinacea.5,6 Echinacea was of herb/drug administration can clarify potential interaction
official in the National Formulary from 1916 to 1946. issues.
Brinker7 has systematically detailed the divergent historical, Self-prescribing consumers may administer echinacea for p0500

cultural, and pharmacological aspects of the two major medic- more serious conditions than colds and flu, as shown by a
inal Echinacea species, E. angustifolia and E. purpurea, in the recent survey of nonconventional therapy use by cancer
U.S. and Europe. patients.15 Echinacea is anecdotally used by herbalists as an
immune stimulant for various indications, including immuno-
suppressive or immunosupportive pharmacotherapies, and for
s0110 Known or Potential Therapeutic Uses patients with immunodeficiency or autoimmune conditions
p0400 Internal: Immunomodulation and promotion of cell- and cancer. Possible interactions in these contexts are
mediated immunity, particularly increasing phagocytosis by addressed later, despite lack of published data and inherent
macrophages and monocytes, in a wide range of bacterial and problems of extrapolating from limited experimental data to
viral conditions; chemotherapy-induced immunosuppression; in vivo clinical practice. Echinacea in these settings is estab-
recurrent candidiasis, sinusitis, etc.; upper respiratory tract lished in herbal practice, however, and this implies a wider
infections (URIs); prophylaxis of URIs and infection in concept of the therapeutic value of echinacea than the cold
general. and flu treatment that dominates mainstream perceptions and

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
34 Echinacea

publications among conventional health care professionals and substrate, but marked inhibition of CYP2C9.23 Currently,
the lay public.16,17 minimal data exist on echinacea and drug-transporter proteins.
p0510 As a nonspecific cell-mediated immunomodulator, echina- An experimental model of the human organic anion-
cea has been combined with anti-infective pharmacotherapies, transporting polypeptide-B (OATP-B) revealed a moderate
Herb-Drug Interactions

either to increase net antimicrobial effect or to provide a similar inhibitory effect on estrone-3-sulfate uptake after echinacea
degree of antimicrobial action at a lower drug dose. Few stu- addition. However, the number of known OATP-B substrates
dies support this type of strategic interaction, although a study in humans is limited at present, although it does include
showing that a combination of E. purpurea intravenously with DHEA-S and estrone.24 The in vivo relevance of these data
econazole was more efficacious than econazole alone in pre- remains to be established.
venting recurrent candidal infection over a 6-month period is A clinical study by Gorski et al.25 used in vivo CYP450 p0550

an often-cited example.18 Some secondary sources evaluate this substrate specific probe techniques to examine the effect of
single study as evidence for a specific econazole-echinacea echinacea on several drug-metabolizing enzymes in healthy
interaction. However, it is probably more appropriate to con- volunteers. After a washout period following baseline probe
sider it as a specific instance of a general additive combination administration, using as probe drugs caffeine (1A2), tolbuta-
with converging antimicrobial effects leading to an enhance- mide (2C9), dextromethorphan (2D6), and midazolam
ment of T helper cell type 1 (Th1) immunity; this interaction (hepatic and intestinal 3A4), echinacea was administered at
could arguably be extrapolated to several classes of anti- 400 mg of dried root four times daily for 8 days; the probes
infective drugs for which evidence is not currently available. then were readministered and blood samples taken. The echi-
p0520 The emerging use of pharmaceutical biological response modi- nacea appeared to have no effect on 2D6 but exerted moderate
fiers (BRMs) that target different molecular aspects of the inhibition on 2C9 and 1A2 and a complex effect on 3A4
inflammatory process constitutes a challenging and complex involving a near!self-canceling inhibition of intestinal 3A4
scenario for clinicians considering the use of immunomodulat- with induction of hepatic 3A4 (see Theoretical, Speculative,
ing herbs. Several such agents are approved in a variety of and Preliminary Interactions Research). Notably, the Gorski
chronic inflammatory conditions, including psoriasis, inflam- study used powdered E. purpurea root for 8 days, although
matory bowel disease, and rheumatoid arthritis, as well as aerial herb is the more typical form of purple coneflower
spondylosing arthropathies. Currently, the most frequently preparation, and the healthy volunteers were not phenotyped
used class of these drugs targets tumor necrosis factor alpha for polymorphisms of the P450 enzymes studies, which is
(TNF-a) through a variety of mechanisms. Although necessarily particularly relevant for 2C9. A wide range of intersubject
speculative at this stage, the interactions between echinacea and variability in pharmacokinetic responses was noted, in line
these important emerging agents are considered later. A related with predictable levels of individual variation known to be
consideration that should not be overlooked is that herbs influ- partly associated with genetic, genomic, and metabolomic
ence human physiology differently than drugs, even when the differences.
apparent effects are convergent, as with echinacea and recom- More research with larger populations is required to exam- p0560

binant interleukin-2 (rIL-2).19 ine the in vivo effects of echinacea on drug-metabolizing sys-
p0530 Incorporation of echinacea as an ingredient in Western tems. Inhibition of drugs metabolized by CYP2C9 may be a
botanical formulae for bone marrow recovery after myelosup- potential risk. Principal among these would be the S-warfarin
pressive chemotherapies is consistent with known pharmacol- isomer, phenytoin, and the sulfonylureas. These interactions
ogy of the herb. At this time, coadministration with have not been observed or reported to date.
pharmaceutical colony-stimulating factors such as Neupogen
lacks published support, although adverse event reports from
concomitant administration are lacking. Related botanical stra- HERB-DRUG INTERACTIONS s0190

tegies for protection of white blood cell (WBC) counts during

chemotherapy are found in both Chinese and Western botanical Cyclosporine and Related Immunosuppressants s0210

integrative oncological settings.19,20 Evidence: Cyclosporine (Ciclosporin, cyclosporin A, CsA; p0570

Neoral, Sandimmune, SangCya).

Extrapolated, based on similar properties: Azothioprine p0580
s0180 Effects on Drug Metabolism and Bioavailability (asathioprine; Azamun, Imuran, Thioprine), cyclophospha-
p0540 Until recently, data on the effects of echinacea on drug-meta- mide (Cytoxan, Endoxana, Neosar, Procytox), prednisolone
bolizing systems were unavailable. An in vitro fluorometric oral (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone
screening study by Budzinski et al.21 suggested moderate in oral (Deltasone, Liquid Pred, Meticorten, Orasone), tacroli-
vitro inhibition of cytochrome P450 (CYP450) 3A4 by echi- mus (FK-506, fujimycin; Prograf).
nacea extracts, implying a potential for pharmacokinetic inter-
actions with substrates of this drug-metabolizing enzyme, but Interaction Type and Significance s0220

such interactions have not been reported to date in the clinical ✗ Potential or Theoretical Adverse Interaction of p0590

literature. No other potentially significant pharmacokinetic Uncertain Severity

interactions with drug absorption, distribution, metabolism,
and excretion (ADME) parameters have been reported. An in Probability: Evidence Base:
vitro study using a Ca-co cell membrane model examined dif- 4. Plausible Inadequate
ferential transport of the caffeic acid derivatives and alkyla-
mides, the principal components of hydroethanolic extracts Effect and Mechanism of Action s0250

of echinacea, and found that the apparent intestinal permeabil- Enhancement of cell-mediated immunity by echinacea admin- p0620

ity for the alkyl amides was significantly greater than that istration holds the potential to cause a shift in the level of
for the caffeic acid compounds.22 Another in vitro study immunosuppression required to maintain host-graft adaptation
found no inhibition of CYP2D6 and mild to moderate in transplant recipients. Arguably, this proposed phenomenon
inhibition of CYP3A4 that was, unusually, dependent on the represents a ‘‘contraindication’’ rather than interaction.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Echinacea 35

s0260 Research (IL-1), IL-10, and TNF-a by macrophages, although other

p0630 Studies have shown phagocytic activity of human peripheral mechanisms may be, and likely are, involved in echinacea
blood monocytes can be stimulated by echinacea polysaccharide effects.28,38 Cytokine and chemokine cascades are interrelated,
fractions.26-31 Resistance to systemic infection in immunosup- complex, and difficult to study, in that they occur rapidly and are

Herb-Drug Interactions
pressed animals was enhanced by echinacea.32 Natural killer often confined to a small cellular compartment and not reflected
(NK) cell activity from human peripheral blood monocytes in serum levels of these compounds. At the current level
drawn from immunodeficient patients (AIDS, CFIDS) of scientific knowledge, such interactions are best gauged
compared with normal subjects showed that cell-mediated clinically, although continued research is essential to improving
immune activity was significantly enhanced after echinacea our ability to understand, predict, and utilize the potential value
administration to the immunodeficient groups.33 More of this botanical-pharmaceutical interaction.
controversially, a ‘‘melanin’’-like compound from echinacea Lersch et al.39,40 investigated the effects of combining echi- p0720

has been shown to activate NF-kB through a toll-like receptor nacea in the form of intramuscularly administered Echinacin
(TLR) mechanism (involving TLR2), resulting in increased Th1 and concurrent thymostimulin (a thymic peptide preparation)
cytokine levels.4 At this time the clinical role, if any, of plant with low-dose cyclophosphamide (300 mg/m2 intravenously,
melanins as immunomodulating agents remains to be established. every 28 days) in two small groups of patients, one with
advanced hepatocellular carcinoma and the other with
s0270 Integrative Therapeutics, Clinical Concerns, and Adaptations advanced colorectal carcinoma. Numbers of CD4+ and NK
p0640 Immunosuppressed allograft recipients are more vulnerable to cells as well as lymphokine-activated killer (LAK) cell activity
minor infection than normal individuals. Acute use of echina- increased significantly in the hepatoma patients. In the colo-
cea at the onset of symptoms (e.g., common cold, acute URIs) rectal patients, all of whom had previous surgery and progres-
is preferred by some allograft patients and practitioners to anti- sive disease, partial regression was noted in one patient and
biotic therapies, because preexisting susceptibility to opportu- stabilization in six others, with a decrease in tumor markers
nistic infection (e.g., Candida) is likely to be exacerbated by and tumor volume (by ultrasonography).
antibiotics. Assuming prior stable immunosuppression within Steinmuller et al.32 used a rodent model of cyclophosphamide- p0730

accepted safety margins, as reflected in serum immunosuppres- induced immunosuppression and found that resistance to oppor-
sive drug levels, there seems no reason to oppose the use of tunistic infection by Candida albicans or Listeria monocytogenes
echinacea acutely for prophylaxis or treatment of mild infec- was restored in echinacea polysaccharide!treated animals
tion. However, compelling reasons would be needed to extend compared with controls. They also found an increase in TNF-a
echinacea treatment to chronic use in this patient population. and enhanced cytotoxic activity in macrophages from the
Clinical features of graft rejection must be treated by aggressive echinacea polysaccharide!treated animals.
intensification of immunosuppressive therapy.
Integrative Therapeutics, Clinical Concerns, and Adaptations s0340
s0280 Cyclophosphamide
Although published data are tentative, the possibility of strategic p0740

p0650 Cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox). enhancement of responsiveness to immunotherapeutic agents
(e.g., low-dose Cytoxan) and recombinant agents (e.g., IL-2,
s0290 Interaction Type and Significance interferons) by concurrent echinacea administration will be of
p0660 ? Interaction Likely but Uncertain Occurrence and interest to integrative practitioners attempting to address mod-
Unclear Implication ulation of immunoreactivity.19 Although parenteral preparations
p0670 /✗ Bimodal or Variable Interaction, with Professional were used in the studies, as typical in Germany, most intravenous
Management echinacea effects apply also to oral administration. (See also
Astragalus monograph, as well as following section on myelo-
Probability: Evidence Base: suppressive chemotherapy.) Because the therapeutic objectives
4. Plausible Preliminary of cyclophosphamide treatment vary in different situations and
the effects may vary with different doses (biphasic responses),
s0320 Effect and Mechanism of Action experienced professional management is required for coadminis-
p0700 This complex interaction may depend on the dose of drug and tration of cyclophosphamide with echinacea.
the clinical context. In cancer, low doses of cytotoxic agents
Interferon Alpha (IFN-a), Interleukin-2, and Other s0350
such as cyclophosphamide have been found to have ‘‘para-
Immunotherapeutic Biological Response Modifiers
doxical’’ immunostimulatory effects despite their myeloablative
effects at high dose levels. Echinacea appears to increase the Aldesleukin (IL-2, recombinant interleukin-2 (rIL-2); p0750

immunity-dependent anticancer effects of low-dose cyclophos- Proleukin), GCSF/filgrastim (Neupogen), GMCSF/sargramos-

phamide when given concurrently. In autoimmune disease, tim (Granulocyte-Macrophage Colony-Stimulating Factor),
cyclophosphamide may be used at noncytotoxic doses to interferon alpha (IFN-a; Alferon N, Intron A, Roferon-A), inter-
achieve immunosuppression, in which context echinacea feron gamma-1b levamisole (Ergamisol), oprelevkin (Neumega),
would be theoretically contraindicated. pegfilgrastim (PEG-filgrastim; Neulasta), pegylated interferon
alfa-2b (PEG-Intron).
s0330 Research
p0710 Emerging interest in the anticancer effects of nontoxic doses of Interaction Type and Significance s0360

cyclophosphamide and other agents (e.g., vinca alkaloids) has ? Interaction Likely but Uncertain Occurrence and p0760

established an immunity-dependent mechanism of action. Unclear

Although not fully understood, it is considered that T-regula- Potential or Theoretical Beneficial or Supportive p0770

tory cells are effectively disabled by low doses of the drug. Interaction, with Professional Management
Interleukin-10 (IL-10) and TNF-a have also been implicated
as possibly mediating the effect in animal studies.34-37 Echinacea Probability: Evidence Base:
administration is associated with increases in interleukin-1 4. Plausible Inadequate

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
36 Echinacea

s0390 Effect and Mechanism of Action Research s0470

p0800 Echinacea may increase endogenous interferon production In animal studies, echinacea has proliferative effects at both p0930

by leukocytes and potentiate the effects of therapeutic spleen and bone marrow levels in rodents, although this
recombinant interferon administration. It also increases NK cell study was confined to examining elevations in NK cells.43
Herb-Drug Interactions

number and activity, a target of IL-2 treatment. The same group examined the effects of echinacea on
myeloid progenitor cells in spleen and marrow and found
s0400 Research that echinacea did not significantly increase granulocyte
p0810 Research on the coadministration of echinacea and interferon precursors.44 Weight loss was reduced and recovery from
is lacking, although preliminary positive data exist for astraga- cisplatin administration was increased in rodents pretreated
lus, another interferon-enhancing herb (see also Astragalus with E. pallida extracts intraperitoneally.45 A German
monograph, aldesleukin/IL-2 discussion). However, in vitro, study on 70 breast cancer patients post-chemoradiotherapy
ex vivo, and in vivo evidence indicates that echinacea extracts found that a formula containing extracts of E. angustifolia
increase IFN-a, which is consistent with its antiviral effect.41,42 and E. purpurea root with Thuja occidentalis and Baptisia
Miller19 has used murine models to compare echinacea effects tinctoria exhibited a limited ability to protect peripheral
on NK cells to IL-2. blood counts, although the doses of preparation were low
at 1.25 mL of the formula per day.46 A subsequent study
s0410 Integrative Therapeutics, Clinical Concerns, and Adaptations involving 15 patients with advanced gastric cancer undergoing
p0820 Combining immunomodulating BRMs with echinacea has palliative chemotherapy with 5-FU, leucovorin, and etoposide
not been studied. At this time, extrapolations from echinacea received 2 mg daily of intravenous E. purpurea polysaccharide
pharmacology merely suggest the possibility of an additive extract for 10 days total (3 days before chemotherapy) showed
enhancement (or sparing); data are insufficient to make clear significant increases in leukocyte numbers compared with
recommendations. controls.47
s0420 Myelosuppressive Antineoplastic Chemotherapy Integrative Therapeutics, Clinical Concerns, and Adaptations s0480

p0830 Alkylating agents: Busulfan (Myleran), carboplatin (Paraplatin), Many classes of antineoplastic agents exhibit dose-limiting p0940

chlorambucil (Leukeran), cisplatin (cis-diaminedichloroplatinum, toxicities on myelopoiesis, involving some or all cell lines, to
CDDP; Platinol, Platinol-AQ), cyclophosphamide (Cytoxan, the extent that leukopenia, thrombocytopenia, and anemia
Endoxana, Neosar, Procytox), dacarbazine (DIC, DTIC, may prevent continued administration of chemotherapy.
DTIC-Dome, imidazole carboxamide), ifosfamide (Ifex, Mitox- Nutritional status and general health of patients undergoing
ana), mechlorethamine (Mustargen, nitrogen mustard), melpha- myelosuppressive chemotherapy are recognized as important
lan (Alkeran), oxaliplatin (Eloxatin), phenylalanine mustard factors in successful treatment toleration. A number of
(Melphalan), pipobroman (Vercyte), streptozocin (Zanosar), herbal and nutritional agents have been used as myeloprotec-
temozolomide (Temodar), thiotepa (Thioplex), uracil mustard tive influences during chemotherapy, including echinacea
(uramustine). extracts. These agents are often combined with other herbs
p0840 Cytotoxic antibiotics: Bleomycin (Blenoxane), dactinomycin directed at minimizing related chemotherapy-induced toxici-
(Actinomycin D, Cosmegen, Cosmegen Lyovac), mitomycin ties. Chinese medicine has explored these strategies more
(Mutamycin), plicamycin (Mithracin). fully than Western herbal medicine to date, although
p0850 Antimetabolites: Agalsidase beta (Fabrazyme), capecitabine echinacea can be incorporated into Western formulae for this
(Xeloda), cladribine (Leustatin), cytarabine (ara-C; Cytosar- purpose. Additionally, anecdotal clinical experience suggests
U, DepoCyt, Tarabine PFS), floxuridine (FUDR), fludarabine that use of recombinant agents such as granulocyte colony-
(Fludara), fluorouracil (5-FU, Adrucil, Efudex, Efudix, stimulating factor (G-CSF) would not be compromised
Fluoroplex), gemcitabine (Gemzar), lometrexol (T64), mer- by such approaches, and concomitant administration may
captopurine (6-mercaptopurine, 6-MP, NSC 755; Purinethol), potentially be beneficial. The additional effects of Th1 cytokine
methotrexate (Folex, Maxtrex, Rheumatrex), pentostatin promotion (cell-mediated immunity) further support the
(Nipent), pemetrexed (Alimta), raltitrexed (ZD-1694; Tomu- rationale of using echinacea, particularly in combination
dex), thioguanine (6-thioguanine, 6-TG, 2-amino-6-mercap- formulae, in this context.48
topurine; Lanvis, Tabloid), ZD9331.
Tumor Necrosis Factor-Alpha (TNF-a) Antagonists s0490
p0860 Mitotic inhibitors: Docetaxel (Taxotere), paclitaxel (Paxene,
Taxol), paclitaxel, protein-bound (Abraxane), vinblastine Adalimumab (Humira), infliximab (Remicade), etanercept p0950

(Alkaban-AQ, Velban, Velsar), vincristine (Leurocristine, (Enbrel).

Oncovin, Vincasar PFS), vinorelbine (Navelbine).
p0870 Similar natural compounds. Interaction Type and Significance s0500

? Interaction Likely but Uncertain Occurrence and p0960

s0430 Interaction Type and Significance Unclear

p0880 Potential or Theoretical Beneficial or Supportive /✗ Bimodal or Variable Interaction, with Professional p0970

Interaction, with Professional Management Management

p0890 Prevention or Reduction of Drug Adverse Effect
Probability: Evidence Base:
Probability: Evidence Base: 6. Unknown Preliminary
3. Possible Preliminary
Effect and Mechanism of Action s0530

s0460 Effect and Mechanism of Action At this time, the interaction is a theoretical concern but p1000

p0920 Echinacea may help support and protect bone marrow myelo- with important implications. Approved BRMs targeting the
poiesis during chemotherapy, thereby ameliorating toxic effects cytokine TNF-a reduce chronic inflammatory processes
of these agents on white blood cell counts. but increase susceptibility to infection. Echinacea extracts,

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Echinacea 37

administered short-term in acute doses, upregulate cell- interaction, there would appear to be reasonable grounds,
mediated immunity to enhance drug-induced depression in derived from the known immunostimulating pharmacology
mounting endogenous immune responses to pathogenic of echinacea, for regarding it as one example of how echinacea
agents. may be beneficially combined with antimicrobial agents. Trials

Herb-Drug Interactions
combining nonspecific immunomodulating herbs such as echi-
s0540 Research nacea with different antimicrobials are required for evidential
p1010 Some experimental pharmacological in vitro and in vivo evi- support of such a generic interaction claim. Well-designed and
dence suggests that fresh-pressed juice extracts of echinacea adequately powered clinical trials using combination botanicals
may increase TNF-a.28-30,38,41 These results have not been and drugs methodology are, unfortunately, likely to remain the
replicated with hydroethanolic echinacea root extracts (which exception rather than the rule in the short term because of the
lack in polysaccharides) or with oral administration to healthy limited interest in such integrative strategies. However, this
human subjects.42,49,50 Immunosuppressed animals (with may change with the increasing concerns over issues such as
cyclophosphamide or cyclosporine) given echinacea respond the rise of drug-resistant strains, hospital-acquired infections,
to opportunistic infection more effectively than untreated and high drug development costs.
animals.32 A recent trial on echinacea in the treatment of the common p1060

cold in children failed to account for a substantial proportion of

s0550 Integrative Therapeutics, Clinical Concerns, and Adaptations the children in both the placebo and the echinacea group taking
p1020 Despite their common ability to inhibit cytokine bioactivity, a variety of over-the-counter (OTC) medications, as well as
the molecular structures and mechanisms of action of the var- various dietary supplements, presumably assuming that these
ious anti!TNF-a drugs currently approved for different condi- would not have any effect when combined with the echinacea.53
tions are in turn significantly different. For example, the TNF- The trial has also been criticized on other methodological
binding moiety of etanercept is derived from soluble TNF grounds.54,55 Meanwhile, although integrative practitioners
receptor subunits; infliximab is a chimeric (mouse-human) might find that coadministration has multiple benefits, this
monoclonal antibody to TNF, and adalimumab is a fully sweeping generic interaction is classified here as ‘‘speculative.’’
human anti-TNF monoclonal antibody.51 A significant side
effect of these agents is an increase in susceptibility to oppor-
Cytochrome P450 1A2 Substrates, Including Clozapine and s0580

Related Atypical Antipsychotics, Cyclobenzaprine, Tacrine, and

tunistic infections, including by potentially ominous patho-
genic agents such as tuberculosis.52
Tertiary Tricyclic Antidepressants
p1030 Current manufacturer recommendations suggest the Atypical antipsychotics: Aripiprazole (Abilify, Abilitat), cloza- p1070

cessation of TNF-a antagonists at the onset of self-limiting pine (Clozaril), olanzapine (Symbyax, Zyprexa), quetiapine
infections such as influenza, to allow for resolution of the infec- (Seroquel), risperidone (Risperdal), ziprasidone (Geodon).
tion, before recommencing drug therapy. The shortest half-life Cyclobenzaprine (Flexeril), tacrine (tetrahydroaminoacridine, p1080

among this class of drug is etanercept (5 days). This window THA; Cognex).
would be a time to use echinacea as a short-term immunosti- Tertiary tricyclic antidepressants: Amitriptyline (Elavil), p1090

mulant, in acute doses, to enhance cell-mediated immune combination drug: amitriptyline and perphenazine (Etrafon,
responses to accelerate resolution of infection before resump- Triavil, Triptazine), clomipramine (Anafranil), doxepin
tion of the anti-inflammatory therapy. The kinetics of echina- (Adapin, Sinequan), imipramine (Janimine, Tofranil), trimipra-
cea effects on immune cells is known to be rapid. At this time, mine (Surmontil).
use of echinacea and other herbal immunomodulators in Recent in vivo human pharmacokinetic data suggest that p1100

patients using BRMs as chronic anti-inflammatories remains echinacea may inhibit CYP1A2.25 (See Strategic Considerations
problematic due to lack of data, partly because of the novelty earlier.) Interactions between echinacea and 1A2 substrates have
of the TNF-a antagonist drugs, but is likely to become an not been reported to date. A low-affinity, high-throughput
increasingly important therapeutic concern for integrative prac- CYP450 isoform, 1A2 is subject to induction by a range
titioners with the increasing adoption of such agents. of environmental and dietary factors, including caffeine,
brassicaceous vegetables, charbroiled foods, and tobacco
s0560 THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS smoking. Theoretically, the predominant patterns of echinacea
RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS prescription (i.e., short-term acute dosing for URIs) may miti-
gate any tendency to generate significant interactions caused by
s0570 Antimicrobials Such as Antibiotic, Antifungal, Antimycobacterial, CYP450 effects. Until further data are available, however, a few
and Antiretroviral Agents critical substrates of 1A2 should be noted for potential
interactions with prolonged echinacea use. These include the
p1040 Evidence: Econazole (Ecostatin, Spectazole). cholinesterase inhibitor tacrine (also a 1A2 inhibitor), the
p1050 Because of its ability to stimulate nonspecific immunity, methylxanthines theophylline and caffeine, cyclobenzaprine,
echinacea, when taken alone, can be beneficial in a wide clozapine, and related antipsychotics. Tertiary tricyclics are
range of infectious conditions. Echinacea may also be helpful cosubstrates of 1A2 and 3A4, which may be relevant if 3A4 is
when coadministered with many antimicrobial drugs. Studies also inhibited by echinacea.
specifically examining the possible benefits of coadministration
Cytochrome P450 3A4 Substrates
are rare. Coeugniet and Kuhnast18 compared topical econazole s0590

nitrate in 60 patients with recurrent candidiasis with econazole At present, interactions between narrow-therapeutic-index p1110

and E. purpurea given orally, subcutaneously, or intravenously. CYP3A4 drugs and echinacea have not been reported. Budzinski
Rate of recurrence dropped from 60.5% with econazole alone et al.21 originally reported in vitro evidence for inhibition of 3A4.
to 15% to 16% for the echinacea plus econazole groups (oral Gorski et al.25 found that echinacea inhibited intestinal 3A4 and
and parenteral), and Candida recall antigen sensitivity was induced hepatic 3A4 in a manner that tended to offset the net
increased two to three times for all echinacea groups. effects on availability of 3A4 substrates. Yale and Glurich23
Although some authors describe this as an echinacea-econazole found that in vitro, E. purpurea extracts moderately inhibited

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
38 Echinacea

one 3A4 model substrate but did not affect another. This suggests Given the heterogenous and multifactorial mechanisms of p1180

that predicting the effect of echinacea on 3A4 substrates is likely to autoimmunity and the currently available data, a prudent con-
be complex, and that the actual effects will be variable. Further clusion at this time would be to approach echinacea use with
research is required to clarify whether echinacea administration caution in patients with serious or progressed autoimmune
Herb-Drug Interactions

will in lead to any significant 3A4 substrate drug interactions. disease, especially those who are susceptible to symptom
flare, as in lupus (SLE) and some forms of multiple sclerosis.
s0600 Warfarin
Allergenicity s0630
p1120 Coumadin, Marevan, Warfilone.
p1130 Warfarin is metabolized by both CYP1A2 (the R-enantio- A review by Parnham61 of echinacea adverse event data in p1190

mer) and 2C9 (the S-enantiomer). The Gorski study on echi- Germany from 1989 to 1995 found 13 adverse drug reactions
nacea inhibition of P450 enzymes found a significant (ADRs) possibly related to oral Echanacin use, of which four
inhibition of 1A2 and a moderate inhibition of 2C9.25 Yale were attributed to echinacea exposure. All were allergic reac-
and Glurich23 confirmed 2C9 inhibition in vitro. This suggests tions with skin manifestations. In the study period, an
that warfarin levels may theoretically be increased in susceptible unknown number of doses of echinacea were consumed in
individuals (2C9-poor metabolizers) because of lowered clear- Germany, but Dr. Bauer, an acknowledged echinacea expert,
ance after coadministration with echinacea; however, this inter- estimates that 10 million doses are sold annually in Germany;
action has not been reported clinically. Theoretically, normal allowing for a degree of underreporting of herbal ADRs, fre-
monitoring and adjustment of warfarin levels would preclude quency of allergic response would appear to be low.
the potential for increased risk of bleeding resulting from An Australian report of an atopic female patient who experi- p1200

elevated drug levels. enced allergic symptoms requiring emergency room attention
was followed by a review of Australian safety data by the inves-
tigator.62 The author concluded that 26 patients, of whom
s0610 Related Issues more than half were known to be atopic, had experienced
echinacea-related allergic symptoms, and that IgE-mediated
s0620 Duration of Use, Hepatotoxicity, Autoimmunity, and Interactions ADRs are possible from echinacea exposure among susceptible
with Hepatotoxic Drugs, Including Anabolic Steroids, Amiodarone, individuals.63 The national usage data for echinacea in Australia
Methotrexate, and Ketoconazole were not given, but if the figures are of the same order of
p1140 It has been asserted that echinacea administration exceeding magnitude as in Europe and the U.S., the risk/benefit ratio
8 weeks induces hepatotoxicity, which leads to adverse interac- would appear to be lower rather than higher. This is corrobo-
tions with a variety of hepatotoxic drugs, including anabolic rated by a skin test study of sensitivity to various herbal prepara-
steroids, amiodarone, methotrexate, and ketoconazole.56 This tions involving more than 1000 subjects, in which echinacea
assertion may be based on the presence of trace amounts of caused dermatological reactions in only two subjects.64
pyrrolizidine alkaloids (PAs) (! 0.0006% of tussilagine and iso-
tussilagine) in the roots of E. pallida and E. angustifolia.57 These
Probiotics s0640

PAs in fact lack the necessary necine macrocyclic ring structure of In a 10-day randomized trial involving 15 healthy adults, p1210

the hepatotoxic PAs that are metabolized into intermediate Hill et al.65 observed potentially problematic changes
compounds, which form covalent adducts in hepatocytes, lead- in intestinal microbiota after Echinacea administration.
ing to the characteristic veno-occlusive disease toxicity. Standardized E. purpurea (1000 mg daily) stimulated the
p1150 The issue of limits to duration of use originated from growth of certain Bacteroides spp. of intestinal bacteria, which
Commission E, who stated that oral preparations of E. pur- may act as pathogens, particularly when the gut ecology has
purea herb and E. pallida root should be consumed for no been disrupted. In stool samples, Echinacea use was associated
longer than 8 weeks.13 No evidence exists for imposing restric- with increased counts for three groups of organisms: the total
tions on duration of use, either from adverse effects, suppres- group of aerobic bacteria, the anaerobic Bacteroides in general,
sion of immune function, or tachyphylaxis, and this assertion and Bacteroides fragilis in particular. The authors concluded
has been refuted in recent literature.16,58 Miller19 used a that the ‘‘health consequences associated with this change are
murine model to demonstrate that long-term administration unknown.’’65 Notably, reports of potentially related adverse
actually increases health and longevity, with sustained improve- events associated with Echinacea use are lacking, such as irrita-
ments in immunological parameters. ble bowel syndrome or other pathological responses that might
p1160 Echinacea was also stated by Commission E ‘‘in principle’’ be predicted to result from such unfavorable alterations.
to be contraindicated in ‘‘progressive systemic diseases’’ such Although similar findings for echinacea or other herbs (e.g., p1220

as tuberculosis, ‘‘leucosis’’ (sic), collagenosis, multiple sclero- goldenseal, isatis) often used as antimicrobial or immunostimu-
sis, acquired immunodeficiency syndrome (AIDS), human lant agents are generally absent in the scientific literature, such
immunodeficiency virus (HIV) infection, and other autoim- effects from chronic use at high doses would not necessarily be
mune diseases. In fact, phytotherapists regularly use echinacea unexpected. Further research and judicious pharmacovigilance
in several autoimmune conditions, with studies on its use in are appropriate and necessary as the use of botanical medicine
HIV infection and AIDS, as well as a report of extended grows within the consumer self-care market and professional
administration in chronic lymphocytic leukemia.59,60 therapeutic application.
p1170 Historically, Eclectic physicians used echinacea to treat
thousands of patients with tuberculosis. Among professional The 65 citations for this monograph are located under Echinacea on p1230

herbalists and naturopathic physicians, possible aggravations the CD at the back of the book.
of autoimmune disease have been extensively discussed, and
although the consensus is that a blanket contraindication
is generally unsupported, isolated incidents of symptom
flare-up in patients with systemic lupus erythematosus (SLE)
associated with echinacea use have been informally reported.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Echinacea

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30. Goel V, Chang C, Slama J et al. Echinacea stimulates macrophage function in the lung and spleen of normal rats. J Nutr Biochem

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31. Gan XH, Zhang L, Heber D, Bonavida B. Mechanism of activation of human peripheral blood NK cells at the single cell level by
Echinacea water soluble extracts: recruitment of lymphocyte-target conjugates and killer cells and activation of programming for lysis.
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32. Steinmuller C, Roesler J, Grottrup E et al. Polysaccharides isolated from plant cell cultures of Echinacea purpurea enhance the
resistance of immunosuppressed mice against systemic infections with Candida albicans and Listeria monocytogenes. Int J
Immunopharmacol 1993;15:605-614.

33. See DM, Broumand N, Sahl L, Tilles JG. In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell
cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients.
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34. Matar P, Rozados VR, Gonzalez AD et al. Mechanism of antimetastatic immunopotentiation by low-dose cyclophosphamide. Eur J
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35. Berd D, Mastrangelo MJ, Engstrom PF et al. Augmentation of the human immune response by cyclophosphamide. Cancer Res

36. Mihich E, Ehrke MJ. Anticancer drugs plus cytokines: immunodulation based therapies of mouse tumors. Int J Immunopharmacol

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mice. Mech Ageing Dev 1999;111:1-12.

38. Burger RA, Torres AR, Warren RP et al. Echinacea-induced cytokine production by human macrophages. Int J Immunopharmacol

39. Lersch C, Zeuner M, Bauer A et al. Nonspecific immunostimulation with low doses of cyclophosphamide (LDCY), thymostimulin,
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44. Currier NL, Sicotte M, Miller SC. Deleterious effects of Echinacea purpurea and melatonin on myeloid cells in mouse spleen and
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45. Mustea I, Postescu ID, Tamas M, Rasnita TD. Experimental evaluation of protective activity of Echinacea pallida against cisplatin
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46. Bendel R, Bendel V, Renner K et al. [Additional treatment with Esberitox N in patients with chemo-radiotherapy treatment of
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47. Melchart D, Clemm C, Weber B et al. Polysaccharides isolated from Echinacea purpurea herba cell cultures to counteract undesired
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48. Coeugniet EG, Elek E. Immunomodulation with Viscum album and Echinacea purpurea extracts. Onkologie 1987;10:27-33.

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50. Schwarz E, Metzler J, Diedrich JP et al. Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate
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52. Bresnihan B, Cunnane G. Infection complications associated with the use of biologic agents. Rheum Dis Clin North Am

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58. Bone K. Echinacea: when should it be used? Mod Phytotherapist 1997;3:17-21.

59. McLeod D. Case history of chronic lymphocytic leukemia. Mod Phytotherapist 1996;2:34-35.

60. Berman S, Justis J, Tiles J, Ma C. Dramatic increase in immune mediated HIV killing activity induced by Echinacea angustifolia
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61. Parnham M. Benefit-risk assessment of the squeezed sap of the purple coneflower (Echinacea purpurea) for long term oral
immunostimulation. Phytomedicine 1996;3:95-102.

62. Mullins RJ. Echinacea-associated anaphylaxis. Med J Aust 1998;168:170-171.

63. Mullins RJ, Heddle R. Adverse reactions associated with echinacea: the Australian experience. Ann Allergy Asthma Immunol

64. Bruynzeel DP, van Ketel WG, Young E et al. Contact sensitization by alternative topical medicaments containing plant extracts. The
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65. Hill LL, Foote JC, Erickson BD et al. Echinacea purpurea supplementation stimulates select groups of human gastrointestinal tract
microbiota. J Clin Pharm Ther 2006;31:599-604.

Eleuthero Botanical Name: Eleutherococcus senticosus (Rupr. and Maxim.) Maxim.
Pharmacopoeial Name: Radix Eleutherococci.

Herb-Drug Interactions
Synonym: Acanthopanax senticosus (Rupr. and Maxim.) Maxim.
Common Names: Eleuthero, Siberian ginseng.

Drug/Class Interaction Mechanism and Significance Management
Antineoplastic treatments Eleuthero promotes myelopoiesis, helps protect white blood cell (WBC) Pretreat, coadminister, and continue after chemo/radiotherapy until WBC
Myelosuppressive chemotherapies counts during cyclophosphamide or other myelosuppressive count normalized (use with related adaptogenic herbs).
Radiation chemotherapies.
/ May synergize with radioprotective agents. Laboratory support and limited
clinical evidence; controlled studies lacking, but interaction likely.


and exercise endurance and recovery; and has antitoxic and
s0030 Family antialcohol effects, as well as a range of antineoplastic actions.
p0120 Araliaceae. Western reviews of some of the literature are available p0210

by Wagner and Norr,4 Farnsworth et al.,6 McKenna et al.,7

Davidov and Krikorian,8 and Baranov.9 Therapeutic mono-
s0040 Habitat and Cultivation graphs are available from the European Scientific Cooperative
p0130 Native to northern and eastern Russia, northern China, Korea, on Phytotherapy,10 World Health Organization (WHO),11
and Japan; commercially grown in Siberia, as well as parts of German Commission E,12 and British Herbal Medical
China. Association.13
Confusion over nomenclature for the herb exists both with p0220

the binomial name (it is known as Acanthopanax senticosus in

s0050 Parts Used Chinese medicine) and the common name; the previous name
p0140 Root; the leaf is also used in Russia. ‘‘Siberian ginseng’’ implies similarity with ‘‘true’’ Panax gin-
seng. The current common name ‘‘eleuthero’’ was recently
adopted in commerce to emphasize that although both
s0060 Common Forms plants are adaptogenic, eleuthero is pharmacologically distinct
p0150 Dried: Powdered root. from Panax ginseng in terms of both constituents and activity
p0160 Tincture: 1:5. profile. Medical reports often fail to use the correct binomial
p0170 Fluid Extract: 1:1, 33% to 40% ethanol. designation to identify herbal ingredients, and eleuthero has
p0180 Standardized Preparations: Usually based on eleutheroside E > notoriously been confused with the entirely different species
1.0% and/or eleutheroside B. Panax ginseng (see Ginseng monograph).

s0070 HERB IN CLINICAL PRACTICE Historical/Ethnomedicine Precedent s0090

s0080 Overview Eleuthero root (Ci Wu Jia) has been used in traditional p0230

p0190 Eleuthero is considered one of the defining adaptogen medic- Chinese medicine as a spleen (Pi) and kidney (Shen) qi tonic
inal plants. Adaptogens have no equivalent among conventional and is claimed to calm the Spirit/Mind (Shen). The root bark is
pharmaceutical agents. The term was coined by Soviet considered a separate remedy. Eleuthero was incorporated into
researcher Lazarev in 1947 and subsequently defined by Western medicine in Russia in the early 1960s after two dec-
Brekhman in terms of three salient qualities: nonspecific (in ades of Soviet research to locate more economic adaptogenic
relation to a wide range of stressor stimuli), nontoxic (cause species than the slow-growing Panax ginseng, and it was intro-
minimal disturbance to normal physiological function), and duced to the U.S. market in the 1970s.9 As with many herbs
normalizing (direction of action varies depending on the used in Chinese medicine, Ci Wu Jia is used in complex for-
prior state of response to stressor and always normalizes).1,2 mulae corresponding to specific classical diagnostic patterns
The properties of adaptogens have been reviewed recently by and is prescribed in higher typical dose levels than in Western
Panossian3 and Wagner.4 Panossian and Wagner5 also recently usage.14
published an important paper distinguishing between the adap-
togenic effects of the herb resulting from chronic dosing proto-
cols compared with the stimulating effect of single acute doses. Known or Potential Therapeutic Uses s0100

p0200 With more than 1000 studies, eleuthero was initially the most Stress reduction and neuroendocrine balancing (e.g., dysglyce- p0240

widely studied adaptogenic herb, although Panax ginseng has mia, adrenal deficiency); fatigue, convalescence; enhance-
a more voluminous literature. Eleuthero has established immu- ment of stamina, exercise, athletic, and work capacity and
nomodulating, anabolic, radioprotective, chemoprotective, anti- performance; increasing mental alertness and cognitive
viral, gonadotrophic, antiviral, and insulinotropic/antidiabetic performance (e.g., memory, visual acuity); adjunctive to
effects; enhances learning, memory, visual and auditory acuity, radiation and chemotherapy treatment; various psychological
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
40 Eleuthero

complaints (e.g., insomnia, depression); immunoprotection that the extract is likely to alter disposition of drugs metabo-
and immunomodulation; prophylaxis of infection, especially lized by 3A4 and 2D6.17 From the limited data currently avail-
viral infection; antineoplastic. able, pharmacokinetic interactions caused by eleuthero effects
on phase-one drug-metabolizing enzymes seems unlikely, and
Herb-Drug Interactions

clinical reports of such interactions have not to date been made.

s0110 Key Constituents
p0250 Lignans and other phenylpropanoids.
p0260 A series of ‘‘eleutheroside’’ compounds have been identified HERB-DRUG INTERACTIONS s0160

(eleutherosides A-M), but none of these is unique to eleuthero,

and not all are the eleutheroside homologous compounds. Antineoplastic Chemotherapy, Including 6-Mercaptopurine, s0180

p0270 Oleanic acid derivatives (eleutherosides I-M), senticosides A-F,

and polysaccharides, including glycans (eleutherans A-G); mis- Cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox), p0360

cellaneous sterols, saponins, vitamins, and carbohydrates. mercaptopurine (6-mercaptopurine, 6-MP, NSC 755;
s0120 Therapeutic Dosing Range Interaction Type and Significance s0190

p0280 Dried Root: 2 to 3 g daily (Western); 9 to 30 g daily (Chinese). Potential or Theoretical Beneficial or Supportive p0370

p0290 Tincture: 3.0 to 12.0 mL daily (equivalent 1:1). Interaction, with Professional Management
p0300 Standardized Dry Extract: 150 to 300 mg three times daily; Prevention or Reduction of Drug Adverse Effect p0380

10:1 extracts standardized to eleutherosides B and E.

Probability: Evidence Base:
2. Probable Preliminary
s0140 Strategic Considerations Effect and Mechanism of Action s0220

p0310 Authoritative monographs on eleuthero do not list any known Eleuthero extracts are used to reduce adverse effects of anti- p0410

interactions between eleuthero and pharmaceuticals.10-13 The neoplastic therapies through a variety of mechanisms, including
WHO monograph does refer to a case report that suggested protection against and reversal of leukopenia, reduction of che-
eleuthero extracts interacted with digoxin. This case is consid- mical toxicities, and enhancement of general stress resistance.
ered likely an issue of adulteration or of interference between
certain constituents of the herb and the digoxin assay and is Research s0230

discussed later (see Theoretical, Speculative, and Preliminary In vitro and animal studies confirm that eleuthero extracts can p0420

Interactions Research). modulate the immune system through a variety of mechanisms.

p0320 The general adaptogenic properties of eleuthero (according These include increases in phagocytosis, natural killer (NK),
to the criteria of Lazarev and Breckhman) have been substan- and cytotoxic T-cell activity; modulation of T helper cell
tiated by a number of indexed Western studies, particularly types 1 and 2 (Th1 and Th2) cytokines; and increased endo-
regarding performance enhancement, although the bulk of genous granulocyte colony-stimulating factor (G-CSF) pro-
the supporting literature, both experimental and clinical, is in duction.18-28 Two human studies are available. A flow-
Russian-language journals, much of it dating from the 1950s cytometry study was performed by Bohn et al.21 on healthy
through the 1970s. Authoritative evaluations of the original human volunteers, who consumed 10 mL of eleuthero extract
literature in terms of study design, statistics, methods, three times daily for 4 weeks. Significant increases in Th1 and
and materials are not generally available. In the 1980s, NK cell numbers were observed, with increased activity of
Farnsworth et al.6 and Baranov9 attempted to summarize a T cells. Russian researchers Kupin et al.29,30 reported stimulation
number of eleuthero studies from the earlier Russian literature. of immunological reactivity in breast cancer patients treated with
p0330 From an integrative perspective, the use of eleuthero in eleuthero extracts. Although limited, these studies suggest that
oncological settings is of particular interest because of the puta- eleuthero has immunostimulating and immunomodulating
tive protective effects against chemotherapy- and radiation- activities in humans.
induced toxicity suggested by the Russian research. Coadministration of eleuthero with various antineoplastic p0430

Unfortunately, little corroborative work has been undertaken agents (as well as radiation) has been reported in a number
in the West to support the Soviet-era data. This is discussed of Russian studies. Farnsworth et al.6 report several animal
later as a generic interaction. studies in the Russian literature by Monakhov31,32 and other
p0340 As with other adaptogenic herbs, the nonspecific immuno- researchers that involved a variety of antitumor agents, includ-
modulating properties may bring about beneficial interactions ing 6-mercaptopurine, cyclophosphamide, and ethydimine. An
with antimicrobial agents, although for eleuthero there are in vitro study by Hacker and Mendon33 found that eleuthero
minimal data on this application.15 (See also Ginseng [Panax extracts at 75 mg/mL potentiated the effects of antileukemic
ginseng] monograph.) agents cytarabine and N6-adenosine against murine L1210
leukemia cells. In a controlled study, Brekhman34 reported a
reduction of adverse effects in a controlled study of 80 breast
s0150 Effects on Drug Metabolism and Bioavailability cancer patients undergoing chemotherapy and/or radiation
p0350 An in vitro fluorometric probe study failed to detect any effect treatment when treated concurrently with eleuthero extracts,
of eleutherosides E and B on a battery of recombinant human compared with controls not treated with eleuthero. Radio-
cytochrome P450 (CYP450) isoforms (1A2, 2C9, 2C19, 2D6, protective effects of the herb have also been documented.35,36
and 3A4).16 A ‘‘before and after’’ study on 12 healthy human A rodent study by Minkova and Pantev37 found that a radio-
volunteers failed to establish any effect of standardized protective drug known as ‘‘adenturone’’ was potentiated by
Eleutherococcus extract (485 mg twice daily) with dextro- prophylactic pretreatment with eleuthero, although the dose
methorphan and alprazolam probes. The authors concluded of herb used was very high (5 g/kg orally).

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Eleuthero 41

s0240 Integrative Therapeutics, Clinical Concerns, and Adaptations involved in the case, Awang44 postulated that adulteration with
p0440 The documented evidence supporting benefits of coadminis- Periploca could explain the apparent test elevations.
tration of eleuthero with chemotherapy and/or radiation in An alternative explanation is that the botanical preparation p0490

oncology patients is limited, but sufficient data exist to may have interfered with the digoxin assay, causing falsely ele-

Herb-Drug Interactions
justify the inclusion of eleuthero with other adaptogenic vated readings. A recent investigation by Dasgupta et al.45 sup-
herbs in protective protocols designed to minimize myelosup- ports this possibility, showing in vitro, as well as in vivo with
pressive side effects of cancer treatment. (See also Ginseng human subjects, that eleuthero extracts can interfere with
monograph.) fluorescence polarization, creating false elevations in digoxin
assay readings. The modest ‘‘false’’ elevated digoxin test read-
ings caused by eleuthero may not explain the total apparent
s0250 THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS increase found in the case reported by McRae,41 and combina-
RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS tion factors still may have been involved. Finally, it has not
p0450 The lack of equivalent pharmaceutical agents corresponding to been established that eleuthero is without effect on the P-
herbal adaptogens may confound ‘‘theoretical’’ extrapolated glycoprotein transporter, of which digoxin is a substrate.
interactions based on in vitro pharmacology, if adaptogens In summary, currently available data do not support the p0500

are ‘‘normalizing’’ as claimed.38,39 Such extrapolations have existence of any interaction between eleuthero and cardiac
been attempted, however, as in an adverse interaction with glycosides.
alcohol (from prolonged sleeping time with hexobarbital in a
Antimicrobial Agents, Including Aminoglycoside Antibiotics s0270
rodent model) and with oral hypoglycemics (from a rodent
study suggesting alloxan-induced diabetic rats’ blood glucose Evidence: Kanamycin (Kantrex), paromomycin (monomycin; p0510

is lowered by eleuthero). In fact, eleuthero has been used anec- Humatin).

dotally both for treatment of alcoholic toxicity and withdrawal An uncontrolled study by Vereshchagin et al.15 suggests that p0520

and for ‘‘balancing’’ blood sugar, depending on whether the coadministration of eleuthero with antibiotics (monomycin/
prior state was hypoglycemic or hyperglycemic.40 The herb has paromomycin or kanamycin) in the treatment of children with
more recently been shown to be more stimulating than seda- Shigella- or Proteus-related gastrointestinal infections was more
tive, at least in single doses.5 effective than treatment with antibiotic alone. As discussed by
Brinker,46 this possible interaction is circumstantially supported
s0260 Digoxin and Related Cardiac Glycosides by some experimental data on the effects of eleuthero on increas-
p0460 Digoxin (Digitek, Lanoxin, Lanoxicaps; purgoxin). ing lymphocyte and NK cell activity.21 Full evaluation of the
p0470 Extrapolated, based on similar properties: Deslanoside (cedi- original Russian-language study in unavailable in English, and
lanin-D), digitoxin (Cystodigin), ouabain (g-strophanthin). the absence of corroborative data on antimicrobial-eleuthero
p0480 An isolated case report describes a 74-year-old man with combinations indicates that the potential interaction required
atrial fibrillation, stable on taking digoxin, who was tested for may best be categorized as ‘‘overstated’’ at this time. It is the-
excessively high serum digoxin levels during routine monitor- oretically arguable that such an interaction may be of widespread
ing, although he was asymptomatic. The digoxin was stopped, clinical applicability with a variety of antimicrobial drug classes,
but the elevated level persisted. The patient disclosed self- but this hypothesis remains to be tested. (See also interactions
administration of eleuthero. The product was not specified, between Panax ginseng and beta-lactam antibiotics as discussed
and no analysis was performed to confirm the identity of the in the Ginseng monograph.)
commercial preparation reported as consumed. After cessation
of the supplement, digoxin levels normalized, and the patient
Monoamine Oxidase-B (MAO-B) Inhibitors s0280

resumed digoxin therapy.41 Because eleuthero contains no car- Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), p0530

diac glycosides, two hypotheses have been advanced to explain phenelzine (Nardil), procarbazine (Matulane), tranylcypro-
the apparent interaction. First, variation in eleuthero commer- mine (Parnate).
cial products is well known.42 Second, commercial samples of Reports of a ginseng-phenelzine interaction persist in the p0540

eleuthero, especially those sourced from China, have been literature on Panax ginseng. These reports have been shown to
documented on occasion as being contaminated with the spe- be incorrect, arising from a confusion of Panax ginseng with
cies Periploca sepium Bge., a different Chinese herbal substance eleuthero.47 In any event, the reports contained insufficient or
whose bark resembles that of eleuthero. Periploca is cardiotoxic inadequate data for evaluation.
in the doses that equate to nontherapeutic levels of eleuthero
because of the presence of cardiac glycosides.43 Given the fail- The 47 citations for this monograph are located under Eleuthero on p0550

ure to test the composition of the suspected eleuthero product the CD at the back of the book.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Eleuthero

1. Brekhman II, Maianskii GM. Eleutherococcus—a means of increasing the nonspecific resistance of the organism. Izv Akad Nauk
SSSR Biol (Russian) 1965;5:762-765.

2. Brekhman II, Dardymov IV. New substances of plant origin which increase nonspecific resistance. Annu Rev Pharmacol

3. Panossian A, Wikman G, Wagner H. Plant adaptogens. III. Earlier and more recent aspects and concepts on their mode of action.
Phytomedicine 1999;6:287-300.

4. Wagner H, Norr H. Plant adaptogens. Phytomedicine 1994;1:63-76.

5. Panossian A, Wagner H. Stimulating effect of adaptogens: an overview with particular reference to their efficacy following single dose
administration. Phytother Res 2005;19:819-838.

6. Farnsworth NR, Kinghorn AD, Soejarto DD, Waller DP. Siberian ginseng (Eleutherococcus senticosus): current status as an
adaptogen. In: Wagner H, Hikino HZ, Farnsworth NR, eds. Economic and Medicinal Plant Research. 1 vol. London: Academic Press;

7. McKenna D, Jones K, Hughes K, Humphrey S. Eleuthero. Botanical Medicines. 2nd ed. Binghamton, NY: Haworth Press;

8. Davydov M, Krikorian AD. Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look. J
Ethnopharmacol 2000;72:345-393.

9. Baranov AI. Medicinal uses of ginseng and related plants in the Soviet Union: recent trends in the Soviet literature. J Ethnopharmacol

10. ESCOP. Eleutherococci Radix. ESCOP Monographs: The Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK:
European Scientific Cooperative on Phytotherapy and Thieme; 2003:142-149.

11. WHO. Radix Eleutherococci. WHO Monographs on Selected Medicinal Plants. 2 vol. Geneva: World Health Organization;

12. Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, TX: American Botanical
Council: Integrative Medicine Communications; 1998.

13. BHMA. Eleutherococcus. In: Bradley P, ed. British Herbal Compendium. Bournemouth, UK: British Herbal Medical Association;

14. Bensky D, Clavey S, Stogër E, Gamble A. Ci Wu Jia. Chinese Herbal Medicine: Materia Medica. 3rd ed. Seattle: Eastland Press;

15. Vereshchagin IA, Geskina OD, Bukhteeva ER. [Increased effectiveness of antibiotic therapy with adaptogens in dysentery and
Proteus infection in children]. Antibiotiki 1982;27:65-69.

16. Henderson GL, Harkey MR, Gershwin ME et al. Effects of ginseng components on c-DNA-expressed cytochrome P450 enzyme
catalytic activity. Life Sci 1999;65:PL209-PL214.

17. Donovan JL, DeVane CL, Chavin KD et al. Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in
normal volunteers. Drug Metab Dispos 2003;31:519-522.

18. Stukov AN. Eleutherococcus senticosus and spontaneous leukosis in mice. Vopr Onkol (Russian) 1965;11:64-65.

19. Shen ML, Zhai SK, Chen HL et al. Immunomopharmacological effects of polysaccharides from Acanthopanax senticosus on
experimental animals. Int J Immunopharmacol 1991;13:549-554.

20. Schmolz MW, Sacher F, Aicher B. The synthesis of Rantes, G-CSF, IL-4, IL-5, IL-6, IL-12 and IL-13 in human whole-blood cultures
is modulated by an extract from Eleutherococcus senticosus L. roots. Phytother Res 2001;15:268-270.

21. Bohn B, Nebe CT, Birr C. Flow-cytometric studies with Eleutherococcus senticosus extract as an immunomodulatory agent.
Arzneimittelforschung 1987;37:1193-1196.

22. Wang JZ, Mao XJ, Ito H, Shimura K. Immunomodulatory activity of polysaccharide from Acanthopanax obovatus roots. Planta Med

23. Wang JZ, Tsumura H, Ma N et al. Biochemical and morphological alterations of macrophages and spleen cells produced by
antitumor polysaccharide from Acanthopanax obovatus roots. Planta Med 1993;59:54-58.

24. Wagner H, Proksch A, Riess-Maurer I et al. [Immunostimulating action of polysaccharides (heteroglycans) from higher plants].
Arzneimittelforschung 1985;35:1069-1075.

25. Xie SS. [Immunoregulatory effect of polysaccharide of Acanthopanax senticosus (PAS). I. Immunological mechanism of PAS against
cancer]. Zhonghua Zhong Liu Za Zhi 1989;11:338-340.

26. Rogala E, Skopinska-Rozewska E, Sawicka T et al. The influence of Eleuterococcus senticosus on cellular and humoral
immunological response of mice. Pol J Vet Sci 2003;6:37-39.

Citations and Reference Literature: Eleuthero

27. Glatthaar-Saalmuller B, Sacher F, Esperester A. Antiviral activity of an extract derived from roots of Eleutherococcus senticosus.
Antiviral Res 2001;50:223-228.

28. Jeong HJ, Koo HN, Myung NI et al. Inhibitory effects of mast cell-mediated allergic reactions by cell cultured Siberian ginseng.
Immunopharmacol Immunotoxicol 2001;23:107-117.

29. Kupin V, Polevaya E, Sorokin A. Increased immunologic reactivity of lymphocytes in oncologic patients treated with
Eleutherococcus extract. In: Brekhman I, ed. New Data on Eleutherococcus: Proceedings of the Second International Symposium of
Eleutherococcus. Moscow: Vladivostok: DVNTS AN SSSR, 1986; 1984.

30. Kupin VI, Polevaia EB. Stimulation of the immunological reactivity of cancer patients by Eleutherococcus extract. Vopr Onkol
(Russian) 1986;32:21-26.

31. Monakhov BV. Eleutherococcus senticoccus extract and therapeutic activity of cyclophosphamide, ethymidine or benzo-tepa. Vopr
Onkol (Russian) 1967;13:94-97.

32. Monakhov BV. Reduction of toxicity of some antiblastoma drugs by Eleutherococcus extract. Vopr Onkol (Russian) 1967;13:71-76.

33. Hacker B, Medon PJ. Cytotoxic effects of Eleutherococcus senticosus aqueous extracts in combination with N6-(δ-2-isopentenyl)-
adenosine and 1-β-d-arabinofuranosylcytosine against L1210 leukemia cells. J Pharm Sci 1984;73:270-272.

34. Brekhman II. Report on the use of Eleutherococcus with breast cancer patients. Eleutherococcus: Clinical Data. Institute of
Oncology, Georgia: USSR Foreign Trade Publication, Medexport, USSR; 1970.

35. Yonezawa M, Katoh N, Takeda A. Radiation protection by Shigoka extract on split-dose irradiation in mice. J Radiat Res (Tokyo)

36. Miyanomae T, Frindel E. Radioprotection of hemopoiesis conferred by Acanthopanax senticosus Harms (Shigoka) administered
before or after irradiation. Exp Hematol 1988;16:801-806.

37. Minkova M, Pantev T. Effect of Eleutherococcus extract on the radioprotective action of adeturone. Acta Physiol Pharmacol Bulg

38. Medon PJ, Ferguson PW, Watson CF. Effects of Eleutherococcus senticosus extracts on hexobarbital metabolism in vivo and in vitro.
J Ethnopharmacol 1984;10:235-241.

39. Medon PJ, Thompson EB, Farnsworth NR. Hypoglycemic effect and toxicity of Eleutherococcus senticosus following acute and
chronic administration in mice. Zhongguo Yao Li Xue Bao 1981;2:281-285.

40. Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.

41. McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. C MAJ 1996;155:293-295.

42. Harkey MR, Henderson GL, Gershwin ME et al. Variability in commercial ginseng products: an analysis of 25 preparations. Am J
Clin Nutr 2001;73:1101-1106.

43. Chen J, Chen T. Chinese Medical Herbology and Pharmacology. City of Industry, CA: Art of Medicine Press Inc; 2004.

44. Awang DV. Siberian ginseng toxicity may be case of mistaken identity. CMAJ 1996;155:1237.

45. Dasgupta A, Wu S, Actor J et al. Effect of Asian and Siberian ginseng on serum digoxin measurement by five digoxin immunoassays:
significant variation in digoxin-like immunoreactivity among commercial ginsengs. Am J Clin Pathol 2003;119:298-303.

46. Brinker F. Herb Contraindications and Drug Interactions. 3rd ed. Sandy, OR: Eclectic Medical Publications; 2001.

47. Treasure JE. MEDLINE and the mainstream manufacture of misinformation. J Am Herbalists Guild 2006;6:50-56.

Ephedra Botanical Names: Ephedra sinica Stapf., Ephedra equisetina Bunge., Ephedra
intermedia Shenk and CA Meyer.
Herb-Drug Interactions

Pharmacopoeial Name: Ephedrae herba.

Common Names: Ephedra, Ma-huang, Ma huang, jointfir.

Drug/Class Interaction Type Mechanism and Significance Management
Acetazolamide Probable pharmacokinetic interaction. Avoid.
Urinary pH modifiers Significance not established.
/? Drug may increase herb levels by renal retention.
Caffeine, Theophylline Well-established additive increase in sympathetic adverse events by Coadministration requires professional assessment and monitoring.
Methylxanthines multiple mechanisms.
Dexamethasone Possible pharmacokinetic increase in drug clearance during Avoid.
Corticosteroids, oral glucocorticosteroids coadministration.
? Significance and applicability to other steroidal drugs unknown.
Guanethidine Herb reduces drug action and may greatly increase hypertension when Avoid.
Peripheral adrenergic blockers coadministered.
Phenelzine Potential for increased sympathetic adverse effects by multiple Avoid.
MAO inhibitors mechanisms.
Reserpine, clonidine Herb and drug have directly conflicting pharmacodynamic mechanisms. Avoid.
Sympatholytics Coadministration (unlikely) will impair therapeutic efficacy of drug
✗✗✗ or herb.
MAO, Monoamine oxidase.

s0020 HERB DESCRIPTION and species variations in alkaloid content.4 Ephedra is a com-
s0030 Related Species ponent of several commercially available Chinese standard
p0310 The three main Ephedra spp. (E. sinica, E. equisetina, E. inter- formulae.
media) are official in the Chinese and Japanese pharmaco-
poeias. Commercial sources also include E. distachya L. and
E. geradiana Wall. ex Stapf. The latter is common in medicinal HERB IN CLINICAL PRACTICE s0070

use in India. The North American species known as Mormon Overview s0080

or Brigham Tea (E. nevadensis S. Wats.) contains little or no Ephedra has a long history of use in Chinese medicine, dating p0380

alkaloid and is not used medicinally. from 3100 BCE. Some authorities consider ephedra to be the
mythical soma plant of the Vedas.5,6 Traditionally, ephedra,
or Ma Huang, has been used as a bitter warming herb for
s0040 Habitat and Cultivation feverish and catarrhal conditions of the respiratory tract.
p0320 Widespread perennial shrub native to China, Mongolia, Tibet, Currently, regulatory restrictions permitting, it continues to
Siberia, Japan, India, Pakistan, and Afghanistan; it is also exten- be used clinically for its traditional indications, including
sively cultivated. bronchial asthma, allergic rhinitis, and as a diaphoretic in
colds and influenza in both Western and Chinese medical
s0050 Parts Used The activity of the crude herb is dominated by sympatho- p0390

p0330 Dried aerial parts (stems); the roots and rhizomes, known as mimetic phenethylamine alkaloid constituents, principally
Ma Huang gen, are a separate medicinal agent in Chinese ephedrine and pseudoephedrine. Synthetic (racemic) ephe-
medicine with distinct actions and uses. drine itself was produced by Merck in 1926 and introduced
into clinical medicine as a treatment for pediatric asthma in
1927; thereafter it rapidly replaced epinephrine because it
s0060 Common Forms could be orally administered. Then, as now, the undesirable
p0340 Dried: Powdered stems. central stimulating effects of ephedrine were considered limit-
p0350 Tincture: 1:4, 45% alcohol (BHP). ing factors on its clinical use.
p0360 Standardized Extracts: Unavailable. Ephedra monographs by both the World Health p0400

p0370 Alkaloid content of ephedra-containing dietary supplement Organization (WHO)7 and the German Commission E sup-
combinations in the United States and elsewhere are often not port its traditional use for catarrhal conditions of the respira-
accurately labeled, and significant product variability has been tory tract.8 The clinical literature on ephedra appears extensive
demonstrated.1-3 Crude herb extracts are subject to seasonal but actually is dominated by a persistent confusion of the crude
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Ephedra 43

herb with isolated ephedrine alkaloid. To a limited degree, and intramuscular). Ephedrine has been historically used as
pharmacokinetic and pharmacodynamic data suggest a similar- a mydriatic and also as a pharmacotherapeutic agent for
ity between crude ephedra and ephedrine, and the general Stokes-Adams heart block, for enuresis, and for myasthenia
sympathomimetic activity of ephedra is broadly correlated gravis, in which latter its mechanism of action is unclear.16

Herb-Drug Interactions
with ephedrine content. However, aspects of ephedra pharma- Some herbal texts also mention the latter two indications, but
cology, such as cytotoxicity or phosphodiesterase inhibition, these are not general practice today, although some urologists
cannot be attributed to ephedrine alone.9-11 In answer to the continue to investigate the use of ephedrine for enuresis.17
question of whether there is full equivalence between synthetic
ephedrine and ephedra, eminent German phytotherapist Weiss
replied, ‘‘On the whole yes, but not quite.’’5 Key Constituents s0110

p0410 The problems of literature interpretation and data compar- Phenylethylamine alkaloids, from approximately 0.5% to more p0470

ison are compounded by the variable ingredients and combina- than 2.4% total. (See Note.)
tions of agents contained in dietary supplements marketed as Catechin tannins, including epicatechin and epigallocatechin as p0480

‘‘weight loss’’ products that have been used in clinical trials.2,9 well as catechin and gallocatechin.
Caffeine or caffeine-containing herbs such as guaraná Volatile oil, including terpinol, cineole, and tetramethylpyra- p0490

(Paullinea cupana) may be present, with aspirin or salicylate- zine; biflavonols.

containing herbs such as willow bark (Salix alba) sometimes The roots contain dimeric flavonols and spermine alkaloids not p0500

combined with micronutrients such as trivalent chromium. found in the stems.

Most recent trials have invariably examined these combination
products and often incorrectly describe the results as referring Note: Proportions of the different alkaloids vary. The majority p0510

to ‘‘ephedra.’’ This in turn casts some methodological doubts is 1R,2S-ephedrine (up to 80%), which occurs alongside the
on metastudies such as the Cantox and RAND reports, and optical isomer 1S,2S-pseudoephedrine and their corresponding
although both reviews acknowledged the problem, their con- nor- and methyl- derivatives. The ratio of ephedrine to pseu-
clusions should be critically qualified in this regard.12,13 doephedrine is variable and even reversed in some minor spe-
p0420 In the U.S., ephedra-containing supplements previously cies of Ephedra.4 Alkaloid composition can be used to
permitted under the Dietary Supplement Health and ‘‘fingerprint’’ product samples containing ephedra herb
Education Act (DSHEA) have been banned since 2003, largely because of the four possible optical isomers of ephedrine,
because of inappropriate consumption of ephedrine-containing only 1R,2S-ephedrine and 1S,2S-pseudoephedrine occur
weight loss and ‘‘natural stimulant’’ products resulting in a naturally.18
significant number of adverse events (see Note: Regulation,
Safety, and Ephedra Weight Loss Products).
Therapeutic Dosing Range s0120

Adults s0130
s0090 Historical/Ethnomedicine Precedent Dried prepared herb for traditional decoction: 3 to 9 g daily. p0520

p0430 Chinese traditional uses include acute wind-cold syndromes Typical recommended doses in Chinese and Western herbal
(characterized by chills, mild headaches, fevers without sweat- practice deliver between 60 to 90 mg total alkaloid daily.
ing, runny or stuffy nose, and body or joint aches) as well as Commission E: 15 to 30 mg single dose and maximum of p0530

bronchial asthma and allergic rhinitis. Several millennia-old 300 mg daily total ephedra alkaloid.
classical Chinese formulae contain Ma Huang, including Ma OTC ephedrine: Up to 150 mg alkaloid daily. p0540

Huang Tang (ephedra decoction), She Gan Ma Huang Tang OTC pseudoephedrine: Up to 240 mg alkaloid daily. p0550

(belamcanda and ephedra decoction), Ge Gan Tang (pueraria

decoction), and Xiao Qing Long Tang (minor blue dragon Children s0140

decoction). In these combinations, ephedra comprises 15% to Not to be administered to children under 6 years of age. p0560

25% of the total prescription, delivering 60 to 90 mg total Pediatric dose up to 0.5 mg total alkaloid per kg body weight p0570

alkaloid daily at normal adult dose levels. daily; according to Commission E and WHO figures.7,8
p0440 In Chinese medicine, a further distinction is made between
the stems of the plant, Ma Huang, and the root, Ma Huang
gen. The roots contain dimeric flavonols and macrocyclic alka- INTERACTIONS REVIEW s0150

loids not found in the aerial parts. In Chinese medicine the Strategic Considerations s0160

root is considered antisudorific, used for night sweats and Ephedra alkaloids act as combination direct and indirect sym- p0580

excessive perspiration, whereas the stem is diaphoretic. pathomimetic agents at all alpha and beta adrenoceptor sub-
types and have multiple effects on catecholamine pathways.19
As a result, ephedra may interact with a variety of drugs that
s0100 Known or Potential Therapeutic Uses directly target the sympathetic nervous system. They may also
p0450 Asthma, coryza of common colds, fevers, allergic and vasomo- indirectly interact with other classes of drug, such as antihyper-
tor rhinitis, hives, and topical use for insect bites, stings, and tensives or antiarrhythmics that do not directly affect the adre-
allergic irritations of the skin and enuresis. nergic pathways.
p0460 A recent comprehensive meta-analysis of these trials sup- Within an integrative medical setting, however, the use of p0590

ports a moderate short-term weight loss effect from ephedra ephedra-containing formulae for traditional indications is lim-
alkaloids when combined with stimulants such as caffeine.14,15 ited and largely unproblematic when used by professionals
Ephedrine and pseudoephedrine are approved for use in over- trained in botanical medicine. Using traditional formulation
the-counter (OTC) bronchodilator and nasal decongestant models, ephedra is combined with other herbs that mitigate its
products. Ephedrine has limited use in the hospital setting ‘‘warming’’ energetics and the central nervous system (CNS)
for the management of hypotension during epidural block stimulatory aspects of its actions. The proportion of ephedra in
and inhalational anesthesia in the operating room (intravenous a given formula is rarely more than approximately 15% to 20% of

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
44 Ephedra

the total. Administered at therapeutic doses for traditional indi- Brater et al.23 studied ephedrine and pseudoephedrine excre-
cations, ephedra is generally considered safe. This is supported by tion in normal patients and those with renal acidosis. They
the complete absence of adverse event reports associated with concluded that the rate of flow of urine as well as pH affected
administration of the crude herb or crude herb extracts either the elimination of ephedrines.
Herb-Drug Interactions

alone or in traditional formulations, as opposed to isolated alka-

loid in multi-ingredient commercial preparations. Ephedra alka- Clinical Implications and Adaptations s0260

loids are not degraded by monoamine oxidase, lacking the Although acetazolamide is usually listed as the interacting p0700

necessary hydroxyl configuration, and are excreted almost agent, this is an extrapolation from the studies with inorganic
entirely unchanged renally, with a half-life of 3 to 5 hours.20 alkalizing compounds. The further extension from ephedra
p0600 Adverse effects of the herb result from the CNS stimulatory alkaloids to ephedra herb adds an additional layer of imponder-
actions and sympathomimetic actions and include insomnia, ability to the clinical significance and implications of this
anxiety, tachycardia, tremors, and at higher doses, arrhythmias interaction, which is therefore of unknown or problematic
and increased blood pressure. Prolonged and repetitive use status.
may induce tachyphylaxis, but suggestions of ‘‘dependency’’
Caffeine, Theophylline, and Other Methylxanthines s0270
are not corroborated by clinical reports. Nonclinical toxicolo-
gical data is based on studies of the isolated alkaloids, Caffeine (Cafcit, Caffedrine, Enerjets, NoDoz, Quick Pep, p0710

principally ephedrine. Clinical data on safety are derived Snap Back, Stay Alert, Vivarin); combination drugs: acetylsa-
from adverse drug reactions (ADRs) noted in clinical trials licylic acid and caffeine (Anacin); ASA, caffeine, and propoxy-
on weight loss, and anecdotal reports following initial use phene (Darvon Compound); ASA, codeine, butalbital, and
or with abuse of ephedrine-containing combination weight caffeine (Fiorinal); acetaminophen, butalbital, and caffeine
loss products. (Fioricet).
p0610 Assuming normal clinical practice and basic professional Theophylline/aminophylline (Phyllocontin, Slo-Bid, Slo- p0720

physiology and pharmacology knowledge, ephedra herb and Phyllin, Theo-24, Theo-Bid, Theocron, Theo-Dur, Theolair,
its crude extracts do not present any hazardous interactions Truphylline, Uni-Dur, Uniphyl); combination drug: ephe-
issues, despite the recent increases in adverse reports related drine, guaifenesin, and theophylline (Primatene Dual Action).
to weight loss dietary supplements and isolated alkaloids
(see Note: Regulation, Safety; and Ephedra Weight Loss Interaction Type and Significance s0280

Products). Professional management of ephedrine interactions ✗✗ Minimal to Mild Adverse Interaction—Vigilance p0730

for therapeutic purposes also occurs within the hospital Necessary

setting, typically in relation to management of anesthesia-
induced hypotension. Probability: Evidence Base:
1. Certain Consensus
s0170 HERB-DRUG INTERACTIONS Effect and Mechanism of Action s0310

The effects of ephedrine on weight loss through thermogen- p0760

s0190 Acetazolamide and Other Urinary PH Modifiers esis, lipolysis, and appetite suppression are potentiated by caf-
p0620 Acetazolamide (Diamox, Diamox Sequels), aluminum hydrox- feine. Frequency and severity of sympathomimetic adverse
ide, ammonium chloride, kaolin clay, sodium bicarbonate. events, principally palpitations, tachycardia, agitation, and
insomnia, are also increased when theophylline or caffeine are
s0200 Interaction Type and Significance coadministered with ephedrine.
p0630 Adverse Drug Effect on Herbal Therapeutics—Strategic
Concern Research s0320

p0640 ? Interaction Likely but Uncertain Occurrence and Numerous studies have shown the combination of caffeine p0770

Unclear Implications and ephedrine moderately increases weight loss, whereas the
agents administered separately show little or no effect.15,24-31
Probability: Evidence Base: The mechanism of the interaction is multifactorial.
4. Plausible Emerging Methylxanthines antagonize adenosine receptors and are
phosphodiesterase (PDE) inhibitors. Their action on the
s0230 Effect and Mechanism of Action cardiovascular system is complex, mediated by brainstem vaso-
p0670 This pharmacokinetic interaction causes retention of ephedrine motor and vagal centers as well as by direct effects on the
and pseudoephedrine (and amphetamine) by means of reduced vascular and cardiac tissues, mediated by both catecholamines
urinary elimination under alkaline conditions. As pH rises, the and the renin system. At higher doses, caffeine and theophyl-
pKa of ephedrine favors the nonionic association form, which line definitely induce tachycardia and are proarrhythmic, with
is more lipophilic and reabsorbable at the nephron. This effec- sensitive individuals likely to experience premature ventric-
tively reduces clearance and increases half-life. ular contractions (PVCs). As with the ephedra alkaloids,
caffeine is also centrally stimulating, and in methylxanthine-
s0240 Research naive individuals, administration of caffeine or theophylline
p0680 The mechanism of this interaction has been experimentally can cause elevation of circulating epinephrine and initial
established in animals and humans using ephedrine and ammo- hypertension; however, tolerance rapidly develops.32-35
nium chloride,21 as well as with pseudoephedrine and ammo- Caffeine alone is not associated with increased frequency
nium hydrochloride.22 of arrhythmia in normal subjects or those with history of
ventricular ectopy.36
s0250 Reports In a recent study on a proprietary formulation (Metabolife p0780

p0690 Reports of this ADR in patients are rare. After encountering 356) containing 12 mg ephedra extract and 48 mg caffeine,
the interaction in a patient with persistently alkaline urine, among several other ingredients, single dosing caused

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Ephedra 45

significant prolongation of QTc interval, at levels associated Research s0400

with possible torsades de pointes arrhythmia in conventional The mechanism of this interaction was experimentally estab- p0870

drugs (!30 msec prolongation).37 However, a long-term lished in nine asthmatic patients, comparing the effects of
rodent study showed no effects on metabolic cardiac para- ephedrine, theophylline, and placebo on airway symptoms.

Herb-Drug Interactions
meters after 1 year of ephedrine-caffeine administration at 10 The interaction apparently does not occur between theophyl-
times the normal human dose.38 Interestingly, crude ephedra line and dexamethasone. This finding helped tilt bronchodila-
has been shown to have PDE inhibitory activity that is not tor products for asthmatic patients away from ephedrine and
exhibited by pure ephedrine.11,39 Theophylline is generally toward theophylline.44
more potent than caffeine in its effects; it was often combined
with ephedrine in nasal decongestant products before more Reports s0410

selective adrenergic blockers became available. An early Despite some cautions in the drug interactions literature,45 the p0880

study found the theophylline-ephedrine combination no importance and significance of this interaction remain proble-
more effective than theophylline alone in 23 asthmatic matic, and extension to other glucocorticoids has not been
children, whereas the ADR rate was higher for the combination established.
than for theophylline.40 Another study of asthmatic children,
however, showed no additional adverse effects from the Clinical Implications and Adaptations s0420

combination.41 The implications of this interaction are unclear, other than p0890

monitoring concurrent corticosteroid and ephedra use.

s0330 Reports
Guanethidine and Related Peripheral Adrenergic Blocking Agents
p0790 Shekelle et al.13 reviewed hundreds of ADR reports from the s0430

ephedrine-caffeine combination in the RAND study and con- Evidence: Guanethidine (Apo-Guanethidine, Ismelin). p0900

cluded the quality of data was too poor to draw conclusions Similar properties but evidence lacking for extrapolation: p0910

about a causal association of the ADRs with the combination. Betanidine (Esbatal, Regulin), bretylium, debrisoquine, guana-
At the same time, they noted that clinical data suggest that the drel (Hylorel).
combination is associated with a significant risk of nausea,
vomiting, anxiety, mood changes, autonomic hyperactivity, Interaction Type and Significance s0440

and palpitations. Other researchers, however, have concluded ✗✗✗ Potentially Harmful or Serious Adverse p0920

that adverse effects during trials involving the combination are Interaction—Avoid
not significant.31,42
Probability: Evidence Base:
s0340 Clinical Implications and Adaptations 1. Certain Consensus
p0800 Any synergy of effect on weight loss from the ephedrine-
caffeine combination is largely offset by associated increase in Effect and Mechanism of Action s0470

adverse effects. Professional management, screening of at-risk Guanethidine and related drugs are prevented from enter- p0950

patient groups, and therapeutic monitoring might largely pre- ing, and are displaced from adrenergic neurons by, sym-
clude the development of serious adverse effects from the pathomimetics. This abolishes the hypertensive effect of
combination. However, pharmacotherapy for obesity does the blockading drug and also results in superadditional
not generally favor use of herbal combination products, and hypertensive effects because of the release of norepinephrine
integrative approaches to obesity do not emphasize pharma- from the presynaptic terminal by ephedrine-induced indirect
cotherapy.43 In traditional use, ephedra is not combined with stimulation.
other stimulants, and obesity is not considered an indication
for ephedra herb. Therefore the notoriety attached to the inter- Research s0480

action of these agents is incommensurate with the significance The mechanism of this established interaction has been con- p0960

of the issue in informed clinical practice. firmed experimentally in humans and cats with ampheta-
mine.46 In a clinical study involving 16 hypertensive patients
Dexamethasone and Other Oral Corticosteroids
maintained on 25 to 35 mg guanethidine, Gulati et al.47
p0810 Evidence: Dexamethasone (Decadron). observed abolition of the effects of guanethidine, as well as
p0820 Related but evidence lacking for extrapolation: Betamethasone hypertension in excess of the treatment level, when subjects
(Celestone), cortisone (Cortone), fludrocortisone (Florinef), were treated concurrently with a range of oral sympathomi-
hydrocortisone (Cortef), methylprednisolone (Medrol), metics, including ephedrine.47
prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone),
prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), Reports s0490

triamcinolone (Aristocort). Despite clinical confirmation of the underlying mechanism of the p0970

interaction, recent reports of its occurrence are lacking.48 Also,

s0360 Interaction Type and Significance it is unclear to what extent this is an issue with the combination
p0830 ? Interaction Likely but Uncertain Occurrence and of sympathomimetic alkaloids in ephedra herb or crude
Unclear Implications extracts. The German Commission E suggests that the
interaction may ‘‘enhance the sympathomimetic effect,’’ which
Probability: Evidence Base: presumably refers to the experimentally confirmed fact that
3. Possible Emerging peripheral adrenergic blockade causes a hypersensitization of
the postsynaptic receptors to direct sympathomimetic stimula-
s0390 Effect and Mechanism of Action tion.8 The significance of this in practice with mixed sympatho-
p0860 A pharmacokinetic interaction is possible whereby the clear- mimetics is unknown, although guanethidine and epinephrine
ance of dexamethasone is increased during concurrent are known to result in exaggerated pressor and mydriatic
ephedrine administration. responses.49

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
46 Ephedra

s0500 Clinical Implications and Adaptations interaction caused by the increased use of ephedrine-contain-
p0980 Although this must be viewed as a serious and an established ing weight loss products.56
interaction, the poorly tolerated guanethidine is no longer in
widespread use for hypertension as it was in the 1970s. The Clinical Implications and Adaptations s0580
Herb-Drug Interactions

newer derivatives are restricted to use in cases where other The older, nonselective, irreversible MAOIs, whether pre- p1070

blocking agents (e.g., reserpine, methyldopa) have unaccepta- scribed for hypertension or depression, should never be
ble CNS adverse effects. The clinical significance of the inter- combined with indirect sympathomimetics. Even the newer,
action is therefore limited in practice, although it is usually selective, reversible MAOIs should not be combined with sym-
often cited without qualification as a principal ephedra-drug pathomimetics. This established and serious drug interaction
interaction in the herbal literature. can be plausibly extended to ephedra. After use of irreversible
MAOIs, renewed MAO synthesis takes time, and 2 weeks has
s0510 Phenelzine and Other Monoamine Oxidase Inhibitors (MAOIs)
been suggested as a safe period after which ephedrine can be
p0990 MAO-A inhibitors: Isocarboxazid (Marplan), moclobemide administered.56
(Aurorix, Manerix), phenelzine (Nardil), procarbazine
Sympatholytic Agents, Including Clonidine, Methyldopa, Opioids, s0590
(Matulane), tranylcypromine (Parnate).
p1000 MAO-B inhibitors: Selegiline (deprenyl, L-deprenil, L-depre-
nyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); par- Clonidine (Apo-Clonidine, Catapres Oral, Catapres-TTS p1080

gyline (Eutonyl), rasagiline (Azilect). Transdermal Dixarit, Duraclon, Novo-Clonidine, Nu-

Clonidine); combination drug: clonidine and chlorthalidone
s0520 Interaction Type and Significance (Combipres); methyldopa (Aldomet); combination drugs:
p1010 ✗ ✗ ✗ Potentially Harmful or Serious Adverse methyldopa and chlorothiazide (Aldoclor), methyldopa and
Interaction—Avoid hydrochlorothiazide (Aldoril); reserpine (Harmonyl).

Probability: Evidence Base: Interaction Type and Significance s0600

1. Certain Consensus ✗✗✗ Potentially Harmful or Serious Adverse p1090

s0550 Effect and Mechanism of Action
p1040 As indirect and direct sympathomimetics, ephedra alkaloids Probability: Evidence Base:
have ‘‘double’’ potential to cause rapid elevations of epineph- 3. Possible Emerging
rine at adrenergic and noradrenergic terminals if cytosolic
monoamine oxidase (MAO) is inhibited. Monoamine oxidase Effect and Mechanism of Action s0630

inhibitors (MAOIs) cause presynaptic epinephrine accumula- Although each of these agents has somewhat different p1120

tion. Ephedra will both promote release of the accumulated mechanisms of action, they can be considered as a group
presynaptic epinephrine and simultaneously have a direct because their interaction is theoretically likely to induce the
stimulating effect on the postsynaptic receptors itself. adverse effect of hypertension. The rauwolfia alkaloids exert
Exaggerated pressor responses will result, with possible hyper- their sympatholytic effects through depletion of epinephrine
tensive crisis or hemorrhagic stroke. and norepinephrine at the presynaptic vesicles. This has
the dual effect of sensitizing the postsynaptic receptors to
s0560 Research direct sympathomimetics and rendering indirect (presynaptic)
p1050 The sympathomimetic action of ephedra alkaloids is well sympathomimetics ineffective. Mixed direct and indirect
established.50,51 However, the literature seldom mentions sympathomimetics are likely to have mixed effects in combina-
that ephedrine, pseudoephedrine, and norephedrine are them- tion with reserpine. Clonidine is a central alpha agonist that
selves all unlabeled MAOIs, although weak and reversible in reduces peripheral sympathetic outflow; methyldopa may act in
character.52,53 Thus, they may also affect levels of 5-hydroxy- a similar manner.50
tryptamine (5-HT, serotonin) and dopamine both centrally
and peripherally, as well as interact with tyramine-containing Research s0640

foods such as aged cheese and red wine. The manufacturers of Early experiments in dogs, in vivo and in vitro, suggest that the p1130

serotonin agonists such as sibutramine caution against combin- pressor effects of indirect sympathomimetics are reduced or
ing with ephedra alkaloids. Although a theoretical basis for this abolished by reserpine.57 Human data are sparse, but patients
may exist because of the MAOI-like action of ephedra, the risk undergoing ocular surgery who were already taking reserpine
of serotonin syndrome is apparently low, and reports are lack- were found to have blood pressure elevations of + 30/+ 13 mm
ing. Theoretically the newer, selective MAO-A or MAO-B Hg after administration of phenylephrine eyedrops.58 There
drugs should be less interactive, but reports show that moclo- are no data on the methyldopa-ephedrine combination; how-
bemide increases the pressor action of ephedrine twofold to ever, an 80-patient trial, in which subjects were pretreated with
fourfold in healthy volunteers.54 On the other hand, a recent clonidine, showed a blood pressure augmentation when given
case report describes ephedrine and phenylephrine being used intravenous ephedrine at 0.1 mg/kg in both anesthetic and
uneventfully to control hypotension during epidural anesthesia waking control groups.59
in a patient taking moclobemide.55
Reports s0650

s0570 Reports Clinical reports of ADRs from interactions involving these p1140

p1060 The standard drug interactions literature through the 1960s combinations are unavailable.
and 1970s contains isolated reports of fatal intracranial and
subarachnoid hemorrhage, but these refer to amphetamines Clinical Implications and Adaptations s0660

combined with older MAOI drugs.49 More recently, concerns There are obvious pharmacological implications of combining p1150

have been raised about a renewed increase in occurrence of this sympatholytics with sympathomimetics. Concurrent prescription

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Ephedra 47

would be unusual, which may account for the lack of adverse sevoflurane.60-62 In other words, the interaction is beneficial
effect reports. Reserpine is rarely used in hypertension treat- with appropriate management. Advice to disclose ephedra use,
ment, although rauwolfia herbal extracts are frequently used in along with any other relevant herbs and supplements, before
natural medicine as short-term hypotensives, usually with a surgery is more appropriate to anesthesia management issues

Herb-Drug Interactions
holding strategy while implementing long-term lifestyle and than repeating solemn warnings to the general public about the
dietary changes. The methyldopa interaction remains specula- danger of interactions with an inhalational anesthetic that is no
tive, and the clonidine interaction is of questionable practical longer generally used.63
Oxytocin s0700

Oxytocin (Pitocin, Syntocinon). p1240

s0670 THEORETICAL, SPECULATIVE, AND PRELIMINARY INTERACTIONS Commission E lists the interaction between ephedra and p1250
RESEARCH, INCLUDING OVERSTATED INTERACTIONS CLAIMS oxytocin.8 Oxytocin causes vascular relaxation and hypotension
p1160 The principal scientific and clinical literature base describing with reflex tachycardia. There are no reports of oxytocin and
ephedra interactions is almost entirely synonymous with the ephedrine interactions, and the probability of concurrent
literature on the interactions of ephedrine, pseudoephedrine, administration clinically is remote because induction of labor
and related indirect sympathomimetics, including phenylpro- is an unlikely context for ephedrine use. This interaction may
panolamine. Extrapolations to the herb are plausible and may be regarded as speculative.
provide useful guidance to practice. Although the data could
Oral Hypoglycemic Agents and Insulin s0710
be regarded as theoretical, the advantage is that the pure-
alkaloid safety data will provide a conservative assessment Buformin (Andromaco Gliporal, Buformina), chlorpropamide p1260

when applied to the crude herb. (Diabinese), glimepiride (Amaryl), glipizide (Glucotrol;
p1170 A low frequency of reported ephedrine interactions in the Glucotrol XL), glyburide (glibenclamide; Diabeta, Glynase,
mainstream drug interactions literature may reflect the historic Glynase Prestab, Micronase, Pres Tab), insulin (animal-
decrease in the clinical use of ephedrine in favor of more source insulin: Iletin; human analog insulin: Humanlog;
receptor-selective adrenergic agents. This is in stark contrast human insulin: Humulin, Novolin, NovoRapid, Oralin), met-
to the increase in anecdotal reports of self-prescribed formin (Dianben, Glucophage, Glucophage XR); combination
ephedrine-containing weight loss combinations, most of drugs: glipizide and metformin (Metaglip), glyburide and met-
which are technically caffeine-ephedrine interactions, or multi- formin (Glucovance); phenformin (Debeone, Fenformin),
ple interactions involving the caffeine-ephedra combination tolazamide (Tolinase), tolbutamide (Orinase, Tol-Tab).
with other agents. An antagonistic interaction between ephedra and hypogly- p1270

p1180 Likewise, the herbal and phytotherapeutic literature on cemics such as insulin has been implied by some secondary
ephedra interactions is also controversial. The German sources. There is no evidence for this interaction, and, in
Commission E posits certain interactions, without substantia- fact, ephedra extracts have hypoglycemic activity and pancreatic
tion of mechanism or context, which have been widely islet regenerative effects.64,65
repeated by derivative sources.8
Secale Alkaloids s0720

s0680 Cardiac Glycosides

Commission E suggests an interaction between ephedra p1280

p1190 Deslanoside (cedilanin-D), digitoxin (Cystodigin), digoxin and ‘‘secale alkaloids’’ (i.e., ergotamine derivatives from
(Digitek, Lanoxin, Lanoxicaps; purgoxin), ouabain (g- the rye grass fungus Claviceps spp.), presumably based on
strophanthin). theoretical additive pressor effects.8 Because ergotamine deri-
p1200 Commission E suggests the interaction between ephedra vatives are primarily used in postpartum hemorrhage or
and cardiac glycosides, citing increased risk of arrhythmias.8 as migraine prophylaxis, the interaction is clinically improbable.
Despite the large repertoire of known interactions associated The drug interactions literature lacks any reports of this
with digoxin, there are no reported interactions between interaction, and its repetition by secondary sources is presum-
digoxin (or other cardiac glycosides) and ephedrine (or other ably derived from the original, unsubstantiated claim in
sympathomimetics) in the drug interaction literature. In clin- Commission E.
ical practice the interaction is unlikely.
Note: Regulation, Safety, and Ephedra Weight Loss Products s0730

s0690 Halothane and Other Halogenated Inhalational Anesthetic Agents

Ephedrine-containing dietary supplements sold as weight loss p1290

p1210 Desflurane (Suprane), enflurane (Ethrane), halothane aids have been associated with numerous adverse event reports
(Fluothane), isoflurane (Forane), sevoflurane (Sevorane, Ultane). in the U.S., including hypertension, tremors, myocardial infarc-
p1220 Commission E warns that ephedra interacts with tion and hemorrhagic stroke. After a long controversy, this led
halothane.8 Halothane was a primary inhalational anesthetic the Food and Drug Administration (FDA) to invoke a sweeping
for more than 25 years. It has largely been replaced by related restriction on the public sale of ephedra-containing products in
halogenated derivatives (enflurane, isoflurane, desflurane, sevo- 2003, directed specifically at commercial weight loss supple-
flurane) because of concerns of postoperative hepatic necrosis ments. Subsequent clarification has effectively granted limited
associated with halothane. The ability of these agents to sensi- access to licensed practitioners of Chinese medicine. As of
tize the myocardium to arrhythmia is well known in anesthe- 2007, this regulation remains in force. In the context of
siology and probably underlies Commission E’s position, practitioner-level information, political and regulatory concerns
although this is not stated. over weight loss products containing ephedra alkaloids are of
p1230 The halothane ‘‘interaction’’ is arguably a misleading one, secondary importance; the primary interactions issue is the
especially in the context of consumer-oriented literature. underlying ephedra alkaloids!methylxanthine interaction.
Administration of intramuscular or intravenous ephedrine Two major comprehensive reviews of safety and toxicity p1300

remains the best choice in management of anesthetic-induced data on ephedrine-containing weight loss products are
hypotension, both for epidural block and with propofol and available.12,13 The RAND report of Shekelle et al.13 also

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
48 Ephedra

reviewed efficacy trials for weight loss and athletic performance stroke is 75 mg/day.70 A recent case-control study found no
enhancement. None of these clinical trials or case reports association between ephedrine use and hemorrhagic stroke.71
involved ephedra crude herb alone, but only combinations of Meanwhile, research and trials continue on new pharmaco- p1330

herbal extracts or isolated ephedrine with stimulants such as logical interventions for obesity, with recent emphasis on selec-
Herb-Drug Interactions

caffeine. The RAND report analyzed adverse event data from tive beta-3 AR agonist drugs. Despite the prevalence of
both clinical trial reports and postmarketing pharmacosurveil- overweight and obesity and the alarming rate of increase in
lance sources, including reports to the FDA’s MEDWATCH, obesity-related conditions, the overall understanding of this
and data from the customer files of a major weight loss multifactorial condition and the efficacy of current pharmaco-
product manufacturer (HerbaLife). The reviewers concluded logical treatments remain limited.43
that ephedrine-containing formulations are associated with a The adverse events reviewed by RAND and others can be p1340

significant risk of nausea, vomiting, anxiety, mood changes, extrapolated to ephedra herb with some minor qualifications.
autonomic hyperactivity, and palpitations. Their meta-analysis The crude herb contains tannin constituents that have
of the clinical trials on weight loss confirmed that products angiotensin-converting enzyme (ACE)!inhibiting activity, as
combining ephedrine with caffeine were capable of producing well as multiple constituents that include organic acids, flavo-
short-term weight loss of about 1 kg (2.2 lb) per month com- noids, and volatile oils that will modulate the alkaloid-fraction
pared with placebo.13 effects.72 It is plausible that extrapolations from ephedrine
p1310 The possible role of adrenoceptor (AR) polymorphisms as effects will be overly conservative with respect to the crude
an explanatory factor in the variability of weight loss data has herb.72 Again, these studies used combinations with caffeine
not been considered by these reviewers, despite its known rele- or caffeine-containing herbs.
vance to obesity. The precise contribution of direct receptor Classic pressor responses have been established for the crude p1350

interaction, indirect release of endogenous catecholamines, or herb, but the dose-response kinetics are significantly slower than
reuptake inhibition to the overall action of ephedrine remains for pure ephedrine, and the pressor response is small, with con-
unclear. Recently, ephedrine has been shown to act directly on siderable individual variation.73 Nephrolithiasis has been
the human beta-3 AR, which is involved in lipolysis in human reported recently after crude herb consumption; the urologists’
brown adipose tissue as well as thermogenesis, which may search of the Louis C. Herring and Company kidney stone data-
explain the moderate effects on short-term weight loss, espe- base show that this is an endemic complication of ephedrine,
cially combined with the central anorectic properties of the with hundreds of previous episodes.74 At the same time, one
phenylethylamines.66,67 The emerging pharmacogenomic experimental study has showed a significant reduction of
data on AR polymorphisms may partially explain the variable uremic toxins after administration of aqueous crude herb extract
results with obesity and could theoretically support more effec- in an animal model of renal failure.75
tive drug targeting of ephedrine in obese patient popula- The recent banning of ephedra-containing weight loss p1360

tions.68 However, the ‘‘therapeutic gap’’ between current AR products by the FDA has changed the degree to which undis-
polymorphism data and their implications for clinical practice closed use of ephedra may be a potential danger in most cases.
remains sizable.66,69 The market for weight loss products remains active, and
p1320 Several sympathomimetic agents are licensed as prescription ‘‘ephedra-free’’ formulations are available to the public that
medications for short-term use (< 12 weeks) in weight loss, attempt to circumvent regulatory restrictions, based on extracts
including benzphetamine and phendimetrazine, both of which of Citrus aurantium (bitter orange), which contains the mildly
are FDA Schedule III because of their abuse potential. sympathomimetic alkaloid synephrine. Lipolytic effects in
Phenylpropanolamine (PPA), which is identical to norpseudo- human adipocytes have been demonstrated, but convincing
ephedrine found in ephedra, was recently withdrawn from the evidence for efficacy of the extract as a weight loss aid is not
market because of concerns about hemorrhagic stroke in currently available.76-78
women.70 However, the norpseudoephedrine content in ephe-
dra is generally very low, and although a small proportion of The 78 citations for this monograph are located under Ephedra on p1370

ephedrine may also be metabolized to norephedrine, the thresh- the CD at the back of the book.
old dose of PPA considered to constitute a risk for hemorrhagic

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Ephedra

1. Gurley BJ, Wang P, Gardner SF. Ephedrine-type alkaloid content of nutritional supplements containing Ephedra sinica (Ma-huang) as
determined by high performance liquid chromatography. J Pharm Sci 1998;87:1547-1553.

2. Gurley BJ, Gardner SF, Hubbard MA. Content versus label claims in ephedra-containing dietary supplements. Am J Health Syst
Pharm 2000;57:963-969.

3. Betz JM, Gay ML, Mossoba MM et al. Chiral gas chromatographic determination of ephedrine-type alkaloids in dietary supplements
containing Ma Huang. J AOAC Int 1997;80:303-315.

4. Zhang JS, Tian Z, Lou ZC. [Quality evaluation of twelve species of Chinese Ephedra (ma huang)]. Yao Xue Xue Bao

5. Weiss R. Herbal medicine. Meuss A, Translator. 6th ed. Beaconsfield, UK: Beaconsfield Publishers Ltd; 1988.

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8. Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin: American Botanical Council:
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9. Gurley BJ, Gardner SF, White LM, Wang PL. Ephedrine pharmacokinetics after the ingestion of nutritional supplements containing
Ephedra sinica (ma huang). Ther Drug Monit 1998;20:439-445.

10. Lee MK, Cheng BW, Che CT, Hsieh DP. Cytotoxicity assessment of Ma-huang (Ephedra) under different conditions of preparation.
Toxicol Sci 2000;56:424-430.

11. Nikaido T, Ohmoto T, Kuge T et al. [The study on Chinese herbal medicinal prescription with enzyme inhibitory activity. III. The
study of mao-to with adenosine 3',5'-cyclic monophosphate phosphodiesterase]. Yakugaku Zasshi 1990;110:504-508.

12. Cantox. Safety assessment and determination of a tolerable upper limit for ephedra. Mississauga, ON, Canada: Cantox Health
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efficacy and side effects. Evid Rep Technol Assess (RAND) 2003;76.

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23. Brater DC, Kaojarern S, Benet LZ et al. Renal excretion of pseudoephedrine. Clin Pharmacol Ther 1980;28:690-694.

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25. Astrup A, Breum L, Toubro S et al. Ephedrine and weight loss. Int J Obes Relat Metab Disord 1992;16:715.

26. Astrup A, Buemann B, Christensen NJ et al. The effect of ephedrine/caffeine mixture on energy expenditure and body composition in
obese women. Metabolism 1992;41:686-688.

27. Astrup A, Madsen J, Holst JJ, Christensen NJ. The effect of chronic ephedrine treatment on substrate utilization, the sympathoadrenal
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28. Astrup A, Toubro S. Thermogenic, metabolic, and cardiovascular responses to ephedrine and caffeine in man. Int J Obes Relat Metab
Disord 1993;17 Suppl 1:S41-43.

29. Astrup A, Toubro S, Cannon S et al. Thermogenic synergism between ephedrine and caffeine in healthy volunteers: a double-blind,
placebo-controlled study. Metabolism 1991;40:323-329.

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30. Vukovich MD, Schoorman R, Heilman C et al. Caffeine–herbal ephedra combination increases resting energy expenditure, heart rate
and blood pressure. Clin Exp Pharmacol Physiol 2005;32:47-53.

31. Hackman RM, Havel PJ, Schwartz HJ et al. Multinutrient supplement containing ephedra and caffeine causes weight loss and
improves metabolic risk factors in obese women: a randomized controlled trial. Int J Obes (Lond) 2006;30:1545-1546.

32. Dulloo AG, Miller DS. The thermogenic properties of ephedrine/methylxanthine mixtures: animal studies. Am J Clin Nutr

33. Dulloo AG, Miller DS. The thermogenic properties of ephedrine/methylxanthine mixtures: human studies. Int J Obes

34. Dulloo AG, Seydoux J, Girardier L. Potentiation of the thermogenic antiobesity effects of ephedrine by dietary methylxanthines:
adenosine antagonism or phosphodiesterase inhibition? Metabolism 1992;41:1233-1241.

35. Myers MG. Effects of caffeine on blood pressure. Arch Intern Med 1988;148:1189-1193.

36. Myers MG. Caffeine and cardiac arrhythmias. Ann Intern Med 1991;114:147-150.

37. McBride BF, Karapanos AK, Krudysz A et al. Electrocardiographic and hemodynamic effects of a multicomponent dietary
supplement containing ephedra and caffeine: a randomized controlled trial. JAMA 2004;291:216-221.

38. Ray S, Phadke S, Patel C et al. Short-term and long-term in vivo exposure to an ephedra- and caffeine-containing metabolic nutrition
system does not induce cardiotoxicity in B6C3F1 mice. Arch Toxicol 2005;79:330-340.

39. Nikaido T, Iizuka S, Okada N et al. [The study of Chinese herbal medicinal prescription with enzyme inhibitory activity. VI. The
study of makyo-kanseki-to with adenosine 3',5'-cyclic monophosphate phosphodiesterase]. Yakugaku Zasshi 1992;112:124-128.

40. Weinberger M, Bronsky E, Bensch GW et al. Interaction of ephedrine and theophylline. Clin Pharmacol Ther 1975;17:585-592.

41. Tinkelman DG, Avner SE. Ephedrine therapy in asthmatic children: clinical tolerance and absence of side effects. JAMA

42. Boozer CN, Daly PA, Homel P et al. Herbal ephedra/caffeine for weight loss: a 6-month randomized safety and efficacy trial. Int J
Obes Relat Metab Disord 2002;26:593-604.

43. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med 2002;346:591-602.

44. Brooks SM, Sholiton LJ, Werk EE Jr, Altenau P. The effects of ephedrine and theophylline on dexamethasone metabolism in
bronchial asthma. J Clin Pharmacol 1977;17:308-318.

45. Jubiz W, Meikle AW. Alterations of glucocorticoid actions by other drugs and disease states. Drugs 1979;18:113-121.

46. Flegin OT, Morgan DH, Oates JA, Shand DG. The mechanism of the reversal of the effect of guanethidine by amphetamines in cat
and man. Br J Pharmacol 1970;39:253P-254P.

47. Gulati OD, Dave BT, Gokhale SD, Shah KM. Antagonism of adrenergic neuron blockade in hypertensive subjects. Clin Pharmacol
Ther 1966;7:510-514.

48. Starr KJ, Petrie JC. Drug interactions in patients on long-term oral anticoagulant and antihypertensive adrenergic neuron-blocking
drugs. Br Med J 1972;4:133-135.

49. Stockley I. Stockley’s Drug Interactions. 6th ed. London: Pharmaceutical Press; 2002.

50. Hoffman B, Lefkowitz R. Catecholamines, sympathomimetic drugs and adrenergic receptor antagonists. In: Hardman J, Limbird L,
eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 9th ed. New York: McGraw-Hill; 1995.

51. Kalix P. The pharmacology of psychoactive alkaloids from ephedra and catha. J Ethnopharmacol 1991;32:201-208.

52. Ulus IH, Maher TJ, Wurtman RJ. Characterization of phentermine and related compounds as monoamine oxidase (MAO) inhibitors.
Biochem Pharmacol 2000;59:1611-1621.

53. Scorza MC, Carrau C, Silveira R et al. Monoamine oxidase inhibitory properties of some methoxylated and alkylthio amphetamine
derivatives: structure-activity relationships. Biochem Pharmacol 1997;54:1361-1369.

54. Dingemanse J. An update of recent moclobemide interaction data. Int Clin Psychopharmacol 1993;7:167-180.

55. Martyr JW, Orlikowski CE. Epidural anaesthesia, ephedrine and phenylephrine in a patient taking moclobemide, a new monoamine
oxidase inhibitor. Anaesthesia 1996;51:1150-1152.

56. Dawson JK, Earnshaw SM, Graham CS. Dangerous monoamine oxidase inhibitor interactions are still occurring in the 1990s. J
Accid Emerg Med 1995;12:49-51.

57. Furukawa T, Morishita H. Modifications of responses to adrenergic drugs in arterial strip by treatment in vivo with ephedrine and
reserpine. Jpn J Pharmacol 1975;25:441-451.

58. Kim JM, Stevenson CE, Mathewson HS. Hypertensive reactions to phenylephrine eyedrops in patients with sympathetic denervation.
Am J Ophthalmol 1978;85:862-868.

59. Nishikawa T, Kimura T, Taguchi N, Dohi S. Oral clonidine preanesthetic medication augments the pressor responses to intravenous
ephedrine in awake or anesthetized patients. Anesthesiology 1991;74:705-710.

Citations and Reference Literature: Ephedra

60. Lee A, Ngan Kee WD, Gin T. Prophylactic ephedrine prevents hypotension during spinal anesthesia for cesarean delivery but does
not improve neonatal outcome: a quantitative systematic review. Can J Anaesth 2002;49:588-599.

61. Kanaya N, Satoh H, Seki S et al. Propofol anesthesia enhances the pressor response to intravenous ephedrine. Anesth Analg
2002;94:1207-1211, table of contents.

62. Webb AA, Shipton EA. Re-evaluation of i.m. ephedrine as prophylaxis against hypotension associated with spinal anaesthesia for
caesarean section. Can J Anaesth 1998;45:367-369.

63. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA 2001;286:208-216.

64. Konno C, Mizuno T, Hikino H. Isolation and hypoglycemic activity of ephedrans A, B, C, D and E, glycans of Ephedra distachya
herbs. Planta Med 1985:162-163.

65. Xiu LM, Miura AB, Yamamoto K et al. Pancreatic islet regeneration by ephedrine in mice with streptozotocin-induced diabetes. Am
J Chin Med 2001;29:493-500.

66. Strosberg AD. Association of beta 3-adrenoceptor polymorphism with obesity and diabetes: current status. Trends Pharmacol Sci

67. Vansal SS, Feller DR. Direct effects of ephedrine isomers on human beta-adrenergic receptor subtypes. Biochem Pharmacol

68. Dionne IJ, Turner AN, Tchernof A et al. Identification of an interactive effect of beta3- and alpha2b-adrenoceptor gene
polymorphisms on fat mass in Caucasian women. Diabetes 2001;50:91-95.

69. Buscher R, Herrmann V, Insel PA. Human adrenoceptor polymorphisms: evolving recognition of clinical importance. Trends
Pharmacol Sci 1999;20:94-99.

70. Kernan WN, Viscoli CM, Brass LM et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med

71. Morgenstern LB, Viscoli CM, Kernan WN et al. Use of Ephedra-containing products and risk for hemorrhagic stroke. Neurology

72. Inokuchi J, Okabe H, Yamauchi T et al. Inhibitors of angiotensin-converting enzyme in crude drugs. II. Chem Pharm Bull (Tokyo)

73. White LM, Gardner SF, Gurley BJ et al. Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive
adults. J Clin Pharmacol 1997;37:116-122.

74. Powell T, Hsu FF, Turk J, Hruska K. Ma-huang strikes again: ephedrine nephrolithiasis. Am J Kidney Dis 1998;32:153-159.

75. Yokozawa T, Fujioka K, Oura H et al. Decrease in uremic toxins, a newly found beneficial effect of Ephedrae Herba. Phytother Res

76. Fugh-Berman A, Myers A. Citrus aurantium, an ingredient of dietary supplements marketed for weight loss: current status of clinical
and basic research. Exp Biol Med (Maywood) 2004;229:698-704.

77. Dentali SJ. Comment on Citrus aurantium minireview. Exp Biol Med (Maywood) 2005;230:102; discussion 103.

78. Haaz S, Fontaine KR, Cutter G et al. Citrus aurantium and synephrine alkaloids in the treatment of overweight and obesity: an
update. Obes Rev 2006;7:79-88.

Feverfew Botanical Name: Tanacetum parthenium (L.) Schultz Bip.
Pharmacopoeial Name: Tanaceti partheni herba.

Herb-Drug Interactions
Synonyms: Matricaria parthenium L.; Chrysanthemum parthenium (L.) Bernh.;
Leucanthemum parthenium (L.) Gren. and Godron; Pyrethrum parthenium L. Sm.
Common Name: Feverfew.

s0020 HERB DESCRIPTION potentially valuable strategic interactions; these include mod-
s0030 Family ulation of adhesion molecule expression,16 inhibition of indu-
p0050 Asteraceae. cible nitric oxide synthase (iNOS),17,18 and possible targeting
of antireperfusion injury,19 as well as induction of apoptosis
and modulation of drug resistance.20,21 Parthenolide also
s0040 Parts Used appears to be a thiol depleter, which may be part of the
p0060 Aerial herb. mechanism underlying its antiaggregatory effect.22,23 The
induction of apoptosis by parthenolide also involves thiol anti-
oxidant modulation.21,24 The presence of NF-kB in platelets
s0050 Common Forms also suggest that this factor may have a role in aggregation,
p0070 Fresh leaf. independently of gene regulation.25
p0080 Dried leaf, freeze-dried leaf. Parthenolide has recently been shown to be a selective indu- p0150

p0090 Tincture: 1:5 25% ethanol.1 cer of apoptosis in cells from chronic lymphocytic leukemia
p0100 Standardized Extract: Not less than 0.2% parthenolide content. (CLL) patients at the relatively low median inhibitory concen-
tration (IC50) of 6.2 mmol.26 Increasing research interest in the
anticancer properties of feverfew and parthenolide are expand-
s0060 INTERACTIONS REVIEW ing the ‘‘herb for migraine’’ conception of the botanical that
s0070 Strategic Considerations characterized feverfew in the late twentieth century.
p0110 The modern use of feverfew as a specific for migraines followed The official ESCOP monograph lists no known interactions p0160

its adoption by physicians at the London Migraine Clinic in the between feverfew and pharmaceuticals, and interactions
early 1980s, who investigated anecdotal reports of the effec- reports are absent from the literature, although some second-
tiveness of the fresh leaf as a migraine prophylactic and treat- ary sources persistently assert an interaction between feverfew
ment.2,3 Following initial studies, its use spread rapidly to and warfarin7,27 (see Theoretical, Speculative, and Preliminary
North America, and today the herb hovers in the lower ranks Interactions Research). An interaction with drugs targeting
of the top-20 best-selling botanicals in the United States, hemostasis is theoretically more likely with antiplatelet throm-
partly because of the large number (29 million) of migraine bolytics, but depending on context and intent, such interac-
sufferers seeking effective treatment for the often-refractory tions are as likely to be beneficial as adverse. Protection against
condition. This indication was never prevalent in Germany, gastropathies induced by nonsteroidal anti-inflammatory drugs
and the herb is not mentioned by Weiss,4 Wichtl,5 or the (NSAIDs) is a more than theoretically possible interaction, and
German Commission E.6 The first modern-use therapeutic although evidence for adjunctive interactions in oncological
monograph was in the British Herbal Compendium1; this has therapies (involving NF-kB!mediated activities) is preliminary,
been superseded by a comprehensive monograph from the this may be an area of future interest as research evidence
European Scientific Cooperative on Phytotherapy (ESCOP)7 continues to emerge.
and recent reviews from Mills and Bone8 and McKenna et al.9 Pharmacokinetic data on the herb are meager; a recent p0170

p0120 Despite its current public popularity, recent systematic report suggests that parthenolide and other sesquiterpene lac-
reviews of the available controlled trial data suggest that the tones exhibit a high degree of protein binding in human
effectiveness of feverfew for migraine prophylaxis is not con- plasma.28 The metabolic fate of parthenolide and its possible
clusively established beyond reasonable doubt, although most modulation of the cytochrome P450 (CYP450) system is
trials favor the herb against placebo and suggest it has a good unknown, but to date the herb does not appear to be asso-
safety profile.10,11 ciated with any obvious pharmacokinetic interactions.
p0130 Interpretations of the pharmacodynamics of feverfew
extracts that stress only the sesquiterpene lactone parthenolide
as the active constituent responsible for the anti-inflammatory HERB-DRUG INTERACTIONS s0080

and antimigraine actions of the herb have been described as

controversial, particularly the so-called serotonin-parthenolide
Indomethacin and Related Nonsteroidal Anti-Inflammatory Drugs s0100

hypothesis of migraine prophylaxis.12 The recent ESCOP (NSAIDs)

monograph asserts that connections between the constituents Evidence: Indomethacin (indometacin; Indocin, Indocin-SR). p0180

of the herb and its migraine prophylactic action should be Extrapolated, based on similar properties: Nonsteroidal anti- p0190

considered as complex and not definitively established.7 inflammatory drugs (NSAIDs):

However, a clearer picture may be emerging from recent COX-1 inhibitors: Diclofenac (Cataflam, Voltaren), combi- p0200

studies. nation drug: diclofenac and misoprostol (Arthrotec), diflunisal

p0140 Currently, the pharmacology of feverfew is being intensively (Dolobid), etodolac (Lodine), fenoprofen (Dalfon), furbiprofen
reexamined after the discovery of the anti!nuclear factor kappa (Ansaid), ibuprofen (Advil, Excedrin IB, Motrin, Motrin IB,
B (NF-kB) properties of parthenolide.13-15 From an interac- Nuprin, Pedia Care Fever Drops, Provel, Rufen), combination
tions perspective, given the pluripotent activities governed by drug: hydrocodone and ibuprofen (Reprexain, Vicoprofen),
this transcription factor, inhibition of NF-kB suggests several indomethacin (indometacin; Indocin, Indocin-SR), ketoprofen
Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.
Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
50 Feverfew

(Orudis, Oruvail), ketorolac (Acular ophthalmic, Toradol), groups.32 However, use of anti-inflammatory medications by
meclofenamate (Meclomen), mefenamic acid (Ponstel), melox- patients in the feverfew group showed a decline over the
icam (Mobic), nabumetone (Relafen), naproxen (Aleve, Ana- 9-month trial period.
prox, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene),
Herb-Drug Interactions

salsalate (salicylic acid; Amigesic, Disalcid, Marthritic, Mono

Taxanes: Paclitaxel, Docetaxel s0170

Gesic, Salflex, Salsitab), sulindac (Clinoril), tolmetin (Tolectin). Evidence: Docetaxel (Taxotere), paclitaxel (Paxene, Taxol), p0290

p0210 COX-2 inhibitor: Celecoxib (Celebrex). paclitaxel, protein-bound (Abraxane).

Extrapolated, based on similar properties: Chemotherapeutic p0300

s0110 Interaction Type and Significance agents that activate NF-kB:

p0220 Prevention or Reduction of Drug Adverse Effect Cisplatin (cis-diaminedichloroplatinum, CDDP; Platinol, p0310

Platinol-AQ), daunorubicin (Cerubidine, DaunoXome),

Probability: Evidence Base: doxorubicin (Adriamycin, Rubex), doxorubicin, pegylated
3. Possible Preliminary liposomal (Caelyx, Doxil, Myocet), epirubicin (Ellence, Phar-
morubicin), etoposide (Eposin, Etopophos, Vepesid, VP-16),
s0140 Effect and Mechanism of Action idarubicin (Idamycin, Zavedos), irinotecan (camptothecin-11,
p0250 The anti-inflammatory effects of feverfew may protect against CPT-11; Campto, Camptosar), tamoxifen (Nolvadex), topote-
gastropathic adverse effects of indomethacin and possibly other can (Hycamtin), vinblastine (Alkaban-AQ, Velban, Velsar),
NSAIDs occurring with chronic use of these agents. vincristine (Leurocristine, Oncovin, Vincasar PFS), vinorelbine
s0150 Research
p0260 In a rodent model of experimentally induced gastric ulceration Interaction Type and Significance s0180

by ethanol, oral pretreatment with either feverfew extract or Potential or Theoretical Beneficial or Supportive p0320

parthenolide 24 hours before ethanol administration created Interaction, with Professional Management
protective effects ranging between 34% and 100% for the
extract and 27% and 100% for parthenolide. At doses of Probability: Evidence Base:
40 mg/kg body weight, the mean ulcer index declined from 4. Plausible Preliminary
4.8 (control) to 1.4 for the extract and 0.5 for parthenolide.29
The researchers used Tanacetum larvatum (Grisb. ex Pant), Effect and Mechanism of Action s0210

a related feverfew species with a higher parthenolide content Parthenolide experimentally increases the sensitivity of breast p0350

(1.1%) than T. parthenium, to examine the ulceroprotective cancer cells with constitutively active NF-kB expression to
effects of the herb against indomethacin-induced ulcers in apoptosis-inducing effects of taxanes. This is likely a specific
rodents. They concluded that there was significant reduction case of general chemosensitization by naturally occurring
of the ulcerogenic effect at 50 mg/kg orally, given after indo- NF-kB inhibitors to chemotherapeutic agents known to have
methacin (not pretreatment). The same extract significantly antiapoptotic effects of NF-kB. Clinical support for the inter-
reduced NF-kB activation in two assay methods, at levels of action is not available.
20 mg/mL. They also examined the anti-inflammatory effect
of combining indomethacin and the herbal extract on the Research s0220

rat-paw carrageenan model and concluded that although Parthenolide and feverfew extracts both exhibit NF-kB inhibi- p0360

there was slight synergy of effect for the combination, it was tory actions.13-15 This transcription factor is involved in multiple
not significant.29 effects in cancer biology, including cell survival, adhesion,
p0270 Previous studies on the ulceroprotective effects of dihydro- inflammation, proliferation, and metastasis, as well as chemore-
leucodine, a sesquiterpene lactone from Artemisia douglasi- sistance, and its expression can be modulated by a range of
ana, support the hypothesis that the protective effects are chemopreventive natural compounds.33,34 Paradoxically, a
caused by increased mucus secretion, which is significantly number of cytotoxic chemotherapeutic agents activate NF-kB,
reduced by indomethacin.30 More recently, unrelated investi- leading to chemoresistance.35,36 Cory and Cory37 found that
gations have shown that indomethacin markedly activates parthenolide acted as an augmenter of apoptosis through NF-
mucosal NF-kB 48 hours after administration, lending indirect kB inhibition in a leukemia cell line, and later they studied an
support to the hypothesis that the therapeutic effects of fever- NF-kB!expressing subset of breast cancer cells that were
few are mediated through inhibition of this transcription chemoresistant to paclitaxel. The sensitivity to the chemother-
factor.31 apeutic agent could be increased in the malignant cells both
by I-kB-a superrepressor and parthenolide. The effect was
s0160 Integrative Therapeutics, Clinical Concerns, and Adaptations not replicated in nonmalignant cells. The authors suggest that
p0280 The protective effectiveness of feverfew extracts in ameliorating the active ingredients of herbs may be useful in increasing
NSAID-induced gastropathy is experimentally established, and the chemosensitivity of cancers with constitutively active
positive data are available relating to indomethacin. In practice, NF-kB.20,37
unless feverfew is an agent of choice for therapeutic reasons, An in vivo and in vitro study using three breast cancer lines p0370

primarily migraine or arthritis, other botanical agents, such as found that parthenolide combined with docetaxel increased the
licorice or aloe, may have a superior cost/risk profile to fever- antiapoptotic and antimetastatic effects of the taxane, and that
few for this purpose. Toxicological data on possible mutageni- the effect was accompanied by lower tumor levels of NF-kB.38
city of feverfew is controversial, although otherwise the extract Another NF-kB!related effect has been demonstrated with
has a good safety profile. In addition, additive or synergistic tamoxifen resistance reduction and parthenolide in MCF7
anti-inflammatory effects are therapeutically preferable, and in cells.39 Thiol and redox status may also relate to the important
the case of feverfew and NSAIDs, this synergism has not been differential effects of parthenolide on apoptosis between malig-
clearly demonstrated; a controlled trial of 50 migraine patients nant and normal cells.21,24 Parthenolide acted as an in vitro
found no significant difference between placebo and control sensitizer to the NSAID sulindac in a pancreatic carcinoma

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Feverfew 51

cell line. The effect of the combination was synergistic (greater Research s0290

than either agent alone), suggesting possible preclinical support In vitro investigations have demonstrated antiaggregatory p0450

for combining parthenolide with other NF-kB inhibitors in actions of feverfew extracts and isolated parthenolide. Several
chemotherapy.40 For example, parthenolide combined with aggregatory stimuli are inhibited by parthenolide, including

Herb-Drug Interactions
dehydroepiandrosterone (DHEA) attenuated tumor growth ADP, collagen, and arachidonate.43-46 Platelet secretory activ-
in vivo in a murine model compared to either agent alone.41 ity is also inhibited by parthenolide, reducing 5-hydroxytryp-
Weak synergistic effects of parthenolide with other constituents tamine (5-HT, serotonin) release.44,47,48 Thiol depletion plays
of the whole herb on growth inhibition for two breast and one a significant role in the mechanism.22,49,50 Interestingly, the
endometrial cancer cell lines were found in the case of the antiaggregatory effects of feverfew extracts and isolated parthe-
flavonoids apigenin and luteolin by Wu et al.42 nolide appear to be equivalent in magnitude.51
In a comprehensive review of antiplatelet activity of plant p0460

s0230 Integrative Therapeutics, Clinical Concerns, and Adaptations compounds, Venton et al.52 stressed that because the relevant
p0380 This potential interaction may be of considerable significance, assay technologies are currently quite straightforward, many
although it currently lacks clinical support and must be plant extracts and isolated compounds have been screened in
regarded as preliminary. Incorporation into chemotherapy pro- vitro for platelet-inhibiting properties. Although many poten-
tocols at this time should be considered only by practitioners tially active compounds that inhibit activation by one or more
with solid clinical grounding in integrative oncology and may agonists have been identified, none has yet been transformed
be specifically limited to issues related to chemotherapy- into a clinically effective antithrombotic drug.52 Other than the
induced NF-kB activation. pharmacokinetic modeling studies by Boik,33 there has been
little attempt to create meaningful algorithms to extrapolate in
s0240 Acetylsalicylic Acid, Clopidogrel, Ticlopidine, and Other
vitro IC50 values from the different study methods into mean-
Antiplatelet Thromboprophylactics ingful estimates of likely therapeutic levels of the compounds
p0390 Evidence: Acetylsalicylic acid (acetosal, acetyl salicylic acid, after therapeutic oral doses of herb.
ASA, salicylsalicylic acid; Arthritis Foundation Pain Reliever,
Ascriptin, Aspergum, Asprimox, Bayer Aspirin, Bayer Reports s0300

Buffered Aspirin, Bayer Low Adult Strength, Bufferin, There are no preclinical studies or clinical reports confirming p0470

Buffex, Cama Arthritis Pain Reliever, Easprin, Ecotrin, this interaction. On the contrary, the original clinical investiga-
Ecotrin Low Adult Strength, Empirin, Extra Strength tors of feverfew at the London Migraine Clinic reported to the
Adprin-B, Extra Strength Bayer Enteric 500 Aspirin, Extra Lancet in 1982 that they had tested 10 patients who had taken
Strength Bayer Plus, Halfprin 81, Heartline, Regular feverfew for 3½ to 8 years and assayed dose!aggregatory
Strength Bayer Enteric 500 Aspirin, St. Joseph Adult response curves to several platelet agonists, including ADP,
Chewable Aspirin, ZORprin); combination drugs: ASA and thrombin, serotonin, and a prostaglandin analog (U46619).
caffeine (Anacin); ASA, caffeine, and propoxyphene (Darvon Aggregation responses to ADP and thrombin were identical
Compound); ASA and carisoprodol (Soma Compound); ASA, to controls who had not taken feverfew for 6 months.53 This
codeine, and carisoprodol (Soma Compound with Codeine); was in direct conflict with in vitro findings of Makheja and
ASA and codeine (Empirin with Codeine); ASA, codeine, Bailey43 published earlier in 1982, confirming that extrapola-
butalbital, and caffeine (Fiorinal). tion from in vitro activity to in vivo effects is problematic.
p0400 Extrapolated, based on similar properties: Cilostazol (Pletal),
clopidogrel (Plavix), dipyridamole (Permole, Persantine), ticlo- Clinical Implications and Adaptations s0310

pidine (Ticlid), combination drug: ASA and extended-release At present, this potential interaction can be considered p0480

dipyridamole (Aggrenox, Asasantin). clinically insignificant, if in fact it exists. Monitoring migraine

or arthritis patients who may be combining substantial doses
s0250 Interaction Type and Significance of feverfew chronically with antiplatelet drugs for signs relating
p0410 ✗ Potential or Theoretical Adverse Interaction to disturbances of primary hemostasis may be prudent
of Uncertain Severity (e.g., petechiae, ecchymoses, superficial bleeds at mucous
Probability: Evidence Base:
5. Improbable Inadequate

p0440 Aspirin (acetylsalicylic acid, ASA) is a well-documented anti-
5-Hydroxytryptamine Receptor Agonists (Triptans) s0330
platelet agent acting through inhibition of cyclooxygenase pro-
duction of thromboxane A2 (TXA2). Ticlopidine interacts Almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), p0490

with glycoprotein IIb/IIIa to inhibit fibrinogen binding to naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan
activated platelets and has been used for prevention of throm- (Imitrex), zolmitriptan (Zomig).
bosis when aspirin is poorly tolerated. Because of reports There is no evidence of interaction between feverfew p0500

of hematological adverse effects associated with ticlopidine, and the triptan drugs used for prophylaxis and treatment
clopidogrel (Plavix) is currently the preferred antiplatelet of migraine. Triptans are potent 5-HT agonists, and most trip-
agent in such cases. As with ticlopidine, clopidogrel is another tans undergo metabolism by either monoamine oxidase A or
irreversible antiplatelet drug operating through adenosine CYP450 1A2 or 3A4. The serotonin hypothesis of feverfew
diphosphate (ADP) receptor antagonism. The potential inter- pharmacology is no longer considered credible, and although
action is thus a theoretical additive pharmacodynamic increase direct evidence is lacking, obvious effects of the herb on
in antiplatelet activity. Such an additive effect may theoretically CYP450 enzymes appear unlikely, therefore currently ruling
increase the likelihood of bleeding disorders related to distur- out plausible pharmacokinetic and pharmacodynamic mechan-
bances of primary hemostasis. isms for a feverfew-triptan interaction.

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
52 Feverfew

derivative sources, based on in vitro antiplatelet activity

s0340 Warfarin and Related Oral Vitamin K Antagonist Anticoagulants previously discussed. Clinical evidence for this interaction is
p0510 Anisindione (Miradon), dicumarol, ethyl biscoumacetate currently lacking.
(Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom),
Herb-Drug Interactions

phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar), The 53 citations for this monograph are located under Feverfew on p0530

warfarin (Coumadin, Marevan, Warfilone). the CD at the back of the book.

p0520 Although denied by authoritative secondary sources, a
warfarin-feverfew interaction has been suggested by some

Copyright © 2008 Mitchell Bebel Stargrove and Lori Beth Stargrove.

Distributed in electronic format, under license, by, Health Resources Unlimited, Inc.
Citations and Reference Literature: Feverfew

1. Bradley P. British Herbal Compendium. 1 vol. Bournemouth, UK: British Herbal Medical Association; 1992.

2. Johnson S. Feverfew—a Traditional Herbal Remedy for Migraine and Arthritis. London: Sheldon Press; 1984.

3. Johnson ES, Kadam NP, Hylands DM, Hylands PJ. Efficacy of feverfew as prophylactic treatment of migraine. Br Med J (Clin Res
Ed) 1985;291:569-573.

4. Weiss R. Herbal Medicine. Meuss A, Translator. 6th ed. Beaconsfield, UK: Beaconsfield Publishers Ltd; 1988.

5. Bisset N. Wichtl’s Herbal Drugs and Phytopharmaceuticals. 2nd ed. Stuttgart: Medpharm GmbH; 1994.

6. Blumenthal M, Busse W, Goldberg A et al. The Complete German Commission E Monographs. Austin, Texas: American Botanical
Council: Integrative Medicine Communications; 1998.

7. ESCOP. Tanceti Partheni Herba. ESCOP Monographs: the Scientific Foundation for Herbal Medicinal Products. 2nd ed. Exeter, UK:
European Scientific Cooperative on Phytotherapy and Thieme; 2003:492-498.

8. Mills S, Bone K. Principles and Practice of Phytotherapy. Edinburgh: Churchill Livingstone; 2000.

9. McKenna D, Jones K, Hughes K, Humphrey S. Feverfew. Botanical Medicines. 2nd ed. Binghamton, NY: Haworth Press;

10. Ernst E, Pittler MH. The efficacy and safety of feverfew (Tanacetum parthenium L.): an update of a systematic review. Public Health
Nutr 2000;3:509-514.

11. Pittler M, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev 2004;1:CD002286.

12. Awang DVC. Prescribing therapeutic feverfew (Tanacetum parthenium (L.) Schultz Bip., syn. Chrysanthemum parthenium (L.)
Bernh.). Integr Med 1998;1:11-13.

13. Rungeler P, Castro V, Mora G et al. Inhibition of transcription factor NF-κB by sesquiterpene lactones: a proposed molecular
mechanism of action*1. Bioorg Med Chem 1999;7:2343-2352.

14. Koch E, Klaas CA, Rungeler P et al. Inhibition of inflammatory cytokine production and lymphocyte proliferation by structurally
different sesquiterpene lactones correlates with their effect on activation of NF-κB1. Biochem Pharmacol 2001;62:795-801.

15. Kwok BH, Koh B, Ndubuisi MI et al. The anti-inflammatory natural product parthenolide from the medicinal herb feverfew directly
binds to and inhibits IκB kinase. Chem Biol 2001;8:759-766.

16. Piela-Smith TH, Liu X. F