PHYLOGENETIC AND PHYTOCHEMICAL CHARACTERISTICS

OF PLANT SPECIES WITH ADAPTOGENIC PROPERTIES

by
Roberta Ann Klein

A thesis submitted in partial fulfillment

of the requirements for the degree
of
Masters of Science
in
Plant Sciences and Plant Pathology

MONTANA STATE UNIVERSITY

Bozeman, Montana
May 2004

IMPORTANT NOTE: This thesis document is not the original thesis. It has been reformatted for 10pt and
single spacing and does not include some of the extraneous front matter required by thesis publication. The
purpose is to shorten it and make it easier to download and more accessible.

OM A RA PA TSA NA DHI
vis medicatrix naturae

VITA
Roberta (Robyn) Ann Klein was born in Detroit, Michigan on May 15, 1954, the daughter of
Evangeline Marie (Rioux) Klein and Robert Francis Klein.
After completing a Bachelors Degree in Psychology at Central Michigan University in 1975, Robyn
worked as a drug abuse counselor in a community mental health clinic. She then traveled throughout the
United States becoming interested in medicinal plants and embarking on a twenty-year endeavor in the
study of plants for healing. She completed a course in herbalism at the Dominion Herbal College in
Burnaby, British Columbia in April 1982. In the ensuing years, Robyn taught throughout the United States
at conferences and schools of herbalism, and published many articles for both popular and peer-reviewed
herbal publications. In 1995, she continued her herbal studies with the well-known Rocky Mountain
herbalist, Michael Moore, at the Southwest School of Botanical Medicine in Albuquerque, New Mexico.
Robyn later served as faculty at the Southwest School of Botanical Medicine (Bisbee, AZ); the Dominion
Herbal College (Burnaby, BC); the National School of Phytotherapy (Albuquerque, NM); and the Rocky
Mountain School of Botanical Studies (Boulder, CO). She was accepted as a professional member of the
American Herbalists Guild in 1991, the highest possible recognition of clinical herbalism skills in the
United States at that time. In 1999, Robyn served as chair of the Montana Governors Task Force on Wild
Medicinal Plants to study commercial harvesting activities of native plants in the state.
Thus, at the time of her acceptance into the Graduate Program at Montana State University in 2002,
Robyn was well versed in the discipline of herbal medicine and the bioactivity of plant compounds.

Acknowledgments
I am very grateful for the support and vision of my thesis advisor, Dr. Matt Lavin.
Humble gratitude is also offered to the invaluable members of my thesis committee, Dr. Florence V.
Dunkel, Dr. Cathy Cripps, and Dr. Rich Stout, for their assistance and for their faith in my somewhat avantgarde project.
I must also acknowledge the behind the scenes, unflagging support of the staff and librarians of the
Renne Library. This thesis required access to hundreds of academic papers and a few somewhat obscure
interlibrary loans to which the staff was flawless in obtaining.
The nature of this project required some distant expertise. These professionals were both kind and
generous in their assistance. Of particular mention are Dr. Kelly Kindscher, University of Kansas; Dr.
Alexander G. Panossian, C. Guelbenkian Research and Drug Quality Control Laboratories, Armenia; Dr.
Karel Slama, Czech Academy of Sciences, Republic of Czechoslovakia; and my herbalist colleagues,
Richo Cech, Horizon Herbs, OR; Kevin Spelman, Tia Sophia Institute, MD; Terry Willard, Ph.D., Wild
Rose College of Natural Healing, Calgary, BC; David Winston, Herbalist & Alchemist, NJ; and Donnie
Yance, Center for Natural Healing, OR.

TABLE OF CONTENTS
LIST OF TABLES ..................................................................................................................................x
LIST OF FIGURES ...............................................................................................................................xi
ABSTRACT ..........................................................................................................................................xii
1.

INVESTIGATION AND PROJECT OVERVIEW ......................................................................1

INTRODUCTION...........................................................................................................................1
GOALS OF INVESTIGATION.....................................................................................................3
Methods and Materials.............................................................................................................4
SUMMARY.....................................................................................................................................5

2.

DESCRIPTIVE SURVEY OF THE LITERATURE ...................................................................7

METHODS ......................................................................................................................................7
Complementary and Alternative Medicine...........................................................................11
Conventional Medicine ..........................................................................................................11
Natural Products Research.....................................................................................................12
Plant Science...........................................................................................................................13
Plant Systematics....................................................................................................................13
Human Nutrition.....................................................................................................................14
Pharmacology .........................................................................................................................14
Human Pathophysiology........................................................................................................14
Biochemistry and Molecular Biology ...................................................................................15
Entomology.............................................................................................................................16
Phytotherapy ...........................................................................................................................16
Traditional Medicine and Ethnopharmacology ....................................................................16
Toxicology ..............................................................................................................................18
SUMMARY...................................................................................................................................18

3.

STRESS PHYSIOLOGY AND PATHOLOGY .........................................................................20

THE STRESS RESPONSE ..........................................................................................................20
Homeostasis and Allostasis ...................................................................................................22
Regulation of Stress ...............................................................................................................24
Allostatic Overload and Pathogenesis...................................................................................27
SUMMARY...................................................................................................................................30

4.

ADAPTOGENIC STRESS REMEDIES.....................................................................................32

INTRODUCTION.........................................................................................................................32
TRADITIONAL MEDICINE ......................................................................................................32
ADAPTOGENS ............................................................................................................................35
Clarification of Definition .....................................................................................................37
Analytical Methods ................................................................................................................42
Human Clinical Studies .........................................................................................................43
Non-Plant Adaptogens ...........................................................................................................44
Fungi.................................................................................................................................44
Shilajit ..............................................................................................................................45
Deer Antler ......................................................................................................................45
Safety of Dietary Supplements..............................................................................................46
SUMMARY...................................................................................................................................47

5.

PRELIMINARY SURVEY OF ETHNOBOTANICAL LITERATURE..................................50

INTRODUCTION.........................................................................................................................50
Methods...................................................................................................................................51
RESULTS ......................................................................................................................................52
North American Ethnobotany Aspects .................................................................................56
SUMMARY...................................................................................................................................60

6.

CHEMICAL COMPOUNDS OF ADAPTOGENIC SPECIES.................................................61

INTRODUCTION.........................................................................................................................61
TERPENOIDS...............................................................................................................................66
Triterpene Saponins ...............................................................................................................66
Phytosterols.............................................................................................................................70
Phytoecdysteroids...................................................................................................................74
PHENYLPROPANOIDS .............................................................................................................76
Flavonoids...............................................................................................................................77
Petal Color ......................................................................................................................79
Lignans....................................................................................................................................81
OXYLIPINS AND FATTY ACIDS ............................................................................................82
POLYSACCHARIDES ................................................................................................................85
CHEMOTAXONOMY.................................................................................................................86
SUMMARY...................................................................................................................................89

7.

MECHANISM OF ACTIONS OF ADAPTOGENS ..................................................................91

INTRODUCTION.........................................................................................................................91
NEUROENDOCRINE ACTIVITY .............................................................................................92
Antioxidant Activity...............................................................................................................96
Nootropic Activity..................................................................................................................99
Nitric Oxide Activity............................................................................................................100
Aphrodisiac Activity ............................................................................................................103
HYDROXYLATION..................................................................................................................105
CELL MEMBRANE ACTIVITY ..............................................................................................106
HORMESIS .................................................................................................................................108
SYNERGISM ..............................................................................................................................111
SUMMARY.................................................................................................................................112

8.

PHYLOGENETIC ANALYSIS.................................................................................................115
ADAPTOGENIC TRAIT OF PLANT SPECIES .....................................................................115
Methods.................................................................................................................................117
MONOPHYLETIC CLADES ....................................................................................................129
Trichopus in the Dioscoraceae ............................................................................................130
Trichopus sempervirens ...............................................................................................131
Trichopus zeylanicus....................................................................................................131
Epimedium in the Berberidaceae .........................................................................................132
Epimedium brevicornu .................................................................................................134
Epimedium koreanum ..................................................................................................135
Epimedium saggitattum ...............................................................................................135
Rhodiola in the Crassulaceae...............................................................................................135
Rhodiola rosea..............................................................................................................136
Rhodiola sacra..............................................................................................................137
Rhodiola sachalinensis ................................................................................................137
Astragalus and Glycyrrhiza in the Fabaceae ......................................................................137
Astragalus membranaceus and A. membranaceus var mongholicus ........................139

Glycyrrhiza glabra .......................................................................................................140

Glycyrrhiza uralensis ...................................................................................................141
Hoppea in the Gentianaceae ................................................................................................141
Hoppea dichotoma and H. fastigiata ..........................................................................142
Panax in the Araliaceae .......................................................................................................142
Panax ginseng...............................................................................................................144
Panax quinquefolium ...................................................................................................144
Codonopsis in the Campanulaceae......................................................................................144
Codonopsis lanceolata .................................................................................................145
Codonopsis pilosula .....................................................................................................146
Cardueae in the Asteraceae .................................................................................................146
Leuzea carthamoides....................................................................................................147
Rhaponticum uniflorum ...............................................................................................148
Serratula coronata .......................................................................................................148
Discussion .............................................................................................................................148
PHYTOGEOGRAPHY ..............................................................................................................149
SUMMARY ................................................................................................................................154
LITERATURE CITED .......................................................................................................................156
APPENDICES .....................................................................................................................................184
APPENDIX A: LIST OF 183 SPECIES OF INTEREST ...............................................................185
APPENDIX B: LITERATURE SURVEYED .................................................................................188
APPENDIX C: PHARMACOLOGICAL EFFECTS OF ADAPTOGENS ON HUMANS AND
OTHER ANIMALS ............................................................................................................................195
APPENDIX D: HUMAN CLINICAL STUDIES............................................................................205
APPENDIX E: PLANT COMPOUNDS FOUND IN 33 ADAPTOGENIC SPECIES ................210

LIST OF TABLES
Table

Page
1.

A listing of terms used to search for adaptogenic activity ........................................................... 8

2.

Examples of in vitro and in vivo experiments involving plant adaptogens

........................................................................................................................................................ 43

3.

Potential adaptogens identified in ethnobotanical literature ...................................................... 53

4.

Three classes of compounds associated with adaptogens and the biosynthetic pathways in plants
........................................................................................................................................................ 62

5.

Plant compounds believed to be responsible for adaptogenic effects and the plants containing
them................................................................................................................................................ 65

6.

Petal color of adaptogen species from this investigation ........................................................... 80

7.

Adaptogenic plant species and main chemical classes of compounds...................................... 87

8.

The essential methods employed to build a phylogenetic tree of angiosperm

species with and without the adaptogenic trait ......................................................................... 116

9.

List of taxa applied to Phylomatic in formatted style............................................................... 118

10. Monophyletic groups resulting from the phylogenetic tree (Figure 8) in which shared similarity
of adaptogenic traits is due to inheritance from the most recent common ancestor .............. 127
11. Major angiosperm orders with adaptogenic species ................................................................. 129
LIST OF FIGURES
Figure Page
1.

Structure of plant oxylipins compared to human compounds ................................................... 83

2.

Classes of compounds found in adaptogenic plants ................................................................... 93

3.

Comparison of triterpenoids and cortisol .................................................................................... 93

4.

Comparison of phenylpropanoids and catecholamines .............................................................. 94

5.

Comparison of plant oxylipins and human leukotrienes ............................................................ 94

6.

U-shaped dose-response curve................................................................................................... 109

7.

The Nexus file resulting from Phylomatic List of taxa and presence or absence of adaptogenic
trait with 0/1 codes added........................................................................................................... 120

8.

Tree resulting from TreeView with adaptogenic species bolded ............................................ 126

ABSTRACT
The contribution of plants to pharmacology has been estimated in the billions of dollars over the past
twenty years. In particular, the development of pathological disorders related to heightened stress
sensitivity and dysregulation of stress-coping mechanisms is of great concern today. Modern medicine is
in need of novel remedies that can treat conditions resulting from dysfunctional stress response. An
obscure pharmacological class of medicinal plants called adaptogens suggests novel strategies for treating
stress-related disorders. Adaptogens have been shown to increase resistance to a wide variety of stressors
and are further defined by three criteria. They must: cause minimal disturbance to the normal physiological
function of an organism, increase resistance to a wide range of stressors, and have a normalizing action
irrespective of the direction of the preceding pathological changes.
The recent phylogenetic restructuring of angiosperm plant families due to modern DNA techniques
affords the opportunity to place plant species with similar pharmacological properties on the tree of life. I
hypothesize that by determining the phylogenetic relationships of plant species with adaptogenic activity,
we can begin to search for other potentially adaptogenic plant species that are presently unknown. This
study involves the phylogenetic placement of adaptogenic angiosperm species on the Angiosperm
Phylogeny Group megatree which was derived from national data sources.
A thorough search of the literature resulted in a list of 183 candidate species representing all major
subgroups of angiosperms. From this list 33 species were identified with potential adaptogenic properties.
The resulting phylogenetic tree shows both independent evolution and clustering at the species level, and in
one case, a subtribe. This erratic distribution may be due to the highly variable nature of secondary
metabolites responsible for the adaptogenic response. The systematic value of the adaptogenic trait is open
to interpretation in that absence of the trait could be due to loss or to switched off gene expression. Despite
the seemingly high degree of independent evolution of adaptogenic properties at higher taxonomic levels,
targeting closely related species should prove very worthwhile for increasing the sources of adaptogenic
plant species.
Robyn Klein 2006 www.rrreading.com
Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties
MS Thesis, 2004, Montana State University
Table of Contents