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CHAPTER 2 DESCRIPTIVE SURVEY OF THE LITERATURE Methods In order to identify a list of taxa with adaptogenic activity (adaptogens) it was first necessary to define an adaptogen, then find physiologic factors and possibly chemical constituents to validate the definition of an adaptogen. It appears there has not been an organized attempt to define adaptogenic plant species (adaptogens) according to any set rules, except for the initial definition given by Lazarev in 1958 (Brekhman and Dardymov, 1969). That is, there is no authority that defines an adaptogen. It has apparently been left up to ones judgment whether a plant has adaptogenic properties, that is, increases resistance to stress in a widespread, innocuous and normalizing fashion (see Chapter 4 for elaboration of adaptogenic criteria). Therefore, it appears that there may be plant species that are not really adaptogenic, which are labeled as such in the popular literature and possibly in the scientific literature. Searching the PubMed database (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) using the term adaptogen resulted in limited success with only 48 hits. However, it was possible that plant species with adaptogenic activity would be found using other terms than adaptogen. Very few researchers seemed to use this description, perhaps because it is not an accepted pharmacological term in conventional science. To uncover plant species with potential adaptogenic properties not labeled as such I searched the scientific literature using related descriptive terms associated with stress pathogenesis and amelioration such as those listed in Table 1. Some terms too often resulted in false positives such as tonic, antiinflammatory, nootropic, and antioxidant. Though many adaptogenic plants have these activities as well, they are ubiquitous among medicinal plants. Table 1. A listing of terms used to search for adaptogenic activity. Symptomatic terms: Stress, anorexia, fatigue, asthenia, aging, rejuvenation, longevity, restorative, memory deficit, cognitive performance, insomnia, anxiety, depression, metabolic syndrome, diabetes, impotence, and panic disorder. Pathophysiological clues: Dysregulation of catecholamines (epinephrine/adrenaline) Dysregulation of glucocorticoids (cortisol) Dysregulation of cytokines (interleukins, tumor necrosis factor, Th2 dominance) Motor activation problems (suppressed systems) Anorexia/cachexia and loss of lean muscle mass (loss of anabolic activity) Atrophy of nerve cells in the amygdala and hippocampus (neurodegeneration) Terms not as useful due to confusion with later effects of stress dysfunction: Anxiety and depression (antidepressant) Cognition and memory (nootropic) Tissue damage (antioxidant, antiinflammatory, protection of lipid oxidation) Hypofunctioning or suppression of immune system (immunomodulation) Hyperimmune response and autoimmune conditions Bone mineral loss (phytoestrogenic) Hypercholesteremia (hypoglycemic, hypocholesteremic) Abdominal obesity (hypoglycemic, hypocholesteremic) Cardiovascular disease (cardioprotective)

Liver damage and detoxication dysfunction (hepatoprotective) Oxidation and free radicals (radioprotective) Loss of libido (aphrodisiac) I continued to add plant species that could possibly have adaptogenic properties to a list that included their bioactivity, chemical constituents, and citations. In the final steps I reduced this list to 183 species that had some evidence of adaptogenic activity. These 183 species are shown in Appendix A. Over 1500 papers from a broad array of scientific disciplines were synthesized in this study (Appendix B). Although many adaptogen remedies have been extensively studied, their properties remain largely unknown in the West. Most of the research on adaptogens is found in the scientific literature of Armenia, Russia, Czechoslovakia, Scandinavia, China, and India. Despite this, I was able to attain review papers published in English that synthesized the history of adaptogen research. Some authors assumed an adaptogenic property for a plant based only on ethnomedical use for stress-related conditions. That is, not all published papers validate the plant species using the original Russian definition of adaptogen (e.g., innocuous, nonspecific and normalizing; see Chapter 4). Conversely, many papers should have, but did not suggest an adaptogenic property for the plant species despite studies elsewhere indicating such activity. The adaptogen term was perhaps not familiar to these researchers, or the term was possibly not a comfortable one for researchers to employ because it is not one that is widely accepted by the scientific community in the United States. The majority of scientific and ethnobotanical literature involving adaptogenic species, cited tests of these species using good scientific methods, primarily with laboratory animals or in vitro cell culture, such as induction of growth hormone (Kim et al., 2003a). Few human clinical studies exist (See Chapter 4 for an in-depth look at the human clinical studies on adaptogens). This is a significant problem for most medicinal plant species and is not unusual, especially in North America where the use of medicinal plants in conventional medicine and in pharmacological research is uncommon. Despite these problems, I identified and read a sufficiently thorough and wide representation of the literature involving plant species used to treat stress-related conditions, including the adaptogen research. A prior familiarization with medicinal plant species was extremely useful as a basis for understanding the complex issues surrounding adaptogens as botanical dietary supplement products (see Vita). The candidate list of 183 potential species was subjected to more rigorous scrutiny. Whether a particular plant species had enough weight of evidence to be labeled as an adaptogen in this investigation depended on several factors. Weight of evidence included primarily, a long history of use by a culture and scientific in vitro and in vivo research on the chemistry and mechanism of action of the plant species. These were the main factors in selecting the final 33 species for phylogenetic analysis. The remaining species were dismissed as not having enough support. It is still possible the discarded species have adaptogenic properties, however, more scientific study is needed. In Chapter 4, I will discuss the definition of an adaptogen and how it is possible to differentiate an adaptogen from false positives. Throughout the decision process, the established definition of adaptogen was employed, however a critical view of this definition was maintained, in case a revision of the term was needed. It is beyond this thesis to attempt such a modification, although others may use this investigation to provide a basis for finetuning the definition. Overall, I found the original Russian adaptogen definition quite applicable and useful (see Chapter 4). Terminology used to search the literature is given in Table 1 and includes terms from a wide variety of disciplines involving medicinal plants and stress pathology (see Appendix B for a listing of the references cited). Thus, this project required the investigation of many related disciplines such as plant and human physiology, pathology, biochemistry, phytochemistry, toxicology, and a new discipline specifically related to stress, psychoneuroendocrinology. Complementary and Alternative Medicine (CAM) The literature of CAM is very limited and difficult to access because it is such a specialized field and is not included in the MSU-Bozeman Library subscription of on-line journal packages such as SpringerScience Server! or Kluwer Online Journals!. The few papers I did locate in the CAM literature were primarily focused on the adaptogenic activities of Rhodiola rosea (Kelly, 1999; Kelly, 2001).

Conventional Medicine The conventional medicine literature was not as thoroughly searched as other disciplines. The two primary journals investigated were The Journal of the American Medical Association and The New England Journal of Medicine. This literature did contribute some information concerning regulation of dietary supplements (Marcus, 2002), trends in alternative medicine (Eisenberg et al., 1998), safety concerns of botanical dietary supplements (Straus, 2002), and the adverse events of conventional medicine (FremontSmith, 1998; Lazarou et al., 1998). However, no references to adaptogens were found. Natural Products Research Despite the rare use of botanical products in conventional medicine and the belief that interest in natural products has waned (Newman et al., 2003), the natural products research literature is robust on the pharmacological properties of plants. The particular journals that were most helpful were Phytochemistry and the Journal of Ethnopharmacology. Other specific journals involving the bioactivity of plant compounds were Phytomedicine, Planta Medica, and the Journal of Agricultural and Food Chemistry. A renewed effort is emerging towards natural products as biologically validated starting points for drug design (Breinbauer et al., 2002, Newman et al., 2003, Rouhi, 2003). Advances in genetics and automated nucleotide sequencing have led to new knowledge of genes and their function (functional genomics) along with new discoveries in systems biology, whereby biological processes are studied as an integrated system (Sumner et al., 2003). Regardless of the emphasis on genomics and proteonomics, the investigation of plant compounds in traditional plant remedies, foods, and dietary supplements continues to be an important focus of research. Plant Science The plant science discipline indicated an interest in the comparison of growth and development strategies between plants and mammals such as hormone biosynthesis (Clouse, 2002), and metabolism (Rosati et al., 2003), defense strategies (Grassman et al., 2002), and free radicals in pathogenesis (Hippeli et al., 1999). Key journals were Current Opinion in Plant Biology, Trends in Plant Science, and Plant Physiology. Plant Systematics The literature on plant systematics for this project was primarily found in the journals, Biochemical Systematics and Ecology and the American Journal of Botany. However, Plant Systematics and Evolution, Molecular Phylogenetics and Evolution, Systematic Botany, and the Annual Review of Ecology and Systematics were somewhat helpful. A review of the chemotaxonomic work by Hegnauer (Grayer et al., 1999) suggested a close relationship between the Asteraceae and the Apiaceae because of shared chemical traits, which is reflected in the database of the Angiosperm Phylogeny Group. Apiaceae phylogenetic systematics was also detailed by Plunkett and Lowry (2001) and Downie et al. (2001). The following papers were instrumental in this project: the taxonomic distribution of phytoecdysteroids (Dinan et al., 1998), flavonoid glycosides of Ocimum (Grayer et al., 2002), reclassification of the Dioscoreaceae (Caddick et al., 2002), phylogeny of the Berberidaceae (Kim and Jansen, 1998), and the phylogeny and biogeography of Lepidium (Mummenhoff et al., 2001). Human Nutrition The interest in secondary compounds of plants is quite active in the field of nutrition. The focus tends to be on the antioxidant properties of flavonoids (Murota and Terao, 2003). I was able to find a few papers

on the antioxidant activity of adaptogenic plants such as Rhodiola sacra (Ohsugi et al., 1999), Serratula strangulata (Cai et al., 2002), and Schisandra chinensis (Chiu et al., 2002). The journals Food Chemistry and Nutrition were particularly useful. Pharmacology In general, the journals in the pharmacology discipline did not evidence much interest in the medicinal properties of plants. The journal, Trends in Pharmacological Sciences, clarified the research bias toward the damaging rather than beneficial role of nitric oxide (Cirino et al., 2003). Biochemical Pharmacology evidenced interest in the adaptogen, Panax ginseng and nitric oxide (Gillis, 1997), as did Bioorganic & Medicinal Chemistry (Wang et al., 2000). Ferrari and Torres (2003) reviewed the pharmacology of dietary nutrients and aging in Biomedicine and Pharmacotherapy. Human Pathophysiology Connections have been suggested between phytochemicals and stress hormones such as the effect of flavonoids on cortisol production in humans (Ohno et al., 2002), plants and the central nervous system (Houghton, 2003), and plants used for memory and cognition (Howes and Houghton, 2003). Adaptogenic properties of Withania somnifera (Bhattacharya and Muruganandam, 2003) have been described in the context of pathophysiology, and a comparison has been made between the cognitive enhancing properties of Bacopa monniera and Gingko biloba (Das et al., 2002). Some of the more useful journals were Psychoneuroendocrinology, Neuroendocrinology, and Pharmacology, Biochemistry and Behavior. Biochemistry and Molecular Biology Leaders in this area include Michael E. Baker (Baker 1992; 1995; 1998a; 1998b; 2001a; 2001b; 2003) who has studied the evolution of nuclear receptors and the hormonal properties of plant flavonoid compounds. Ohno et al. (2002) and Tanahashi et al. (2002) studied the hydroxysteroid dehydrogenase enzymes that are involved in the biosynthetic pathway of flavonoids, neurosteroids and hormones. Li et al. (2003b) studied the ability of plant compounds to stimulate nerve growth factor. Similarly, Ohara and Ohira (2003) determined the effect of plant compounds on plant growth regulation. Dietary plant compounds have been suggested to be involved in signaling transduction via interaction with kinase enzymes (Cock et al., 2002; Owuor and Kong, 2002). The following journals were most useful Biochemical Pharmacology, Bioorganic and Medicinal Chemistry, and Life Sciences. Entomology The investigation of three plant species, in particular, Leuzea carthamoides, Rhaponticum uniflorum , and Serratula coronata, led to the investigation of the adaptogenic effects of insect steroids synthesized in plants (see Chapter 6) on mammals and humans (Slma, 1993; Lafont, 1997; Dinan et al., 2001a; Kholodova, 2001). Chemotaxonomic studies of taxa in eight angiosperm families revealed that the Asteraceae adaptogens are most commonly associated with presence of ecdysteroids (Dinan et al., 1998; Whiting et al., 1998; Zibareva et al., 2002). Phytotherapy The recently developed academic discipline of phytotherapy is represented primarily by the journals, Phytomedicine and Phytotherapy Research. Of the two, Phytomedicine contained the majority of published adaptogen research, of which there were eleven papers. Of these, Panossian et al. (1981; 1983; 1997; 1999a; 1999b; 1999c; 2003), authored the most informative papers on the bioactivity, chemistry, and potential mechanisms of actions of adaptogens.

Traditional Medicine and Ethnopharmacology Medicinal plants from traditional healing practices is a very active area of research. The World Health Organization has documented the importance of traditional medicine as a source of primary health care throughout the world (WHO Traditional Medicine Strategy 2002-2005). WHO has defined traditional medicine as The sum total of the knowledge, skills, and practices based on the theories, beliefs and experiences, indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement and treatment of physical and mental illnesses. The terms complementary/alternative/non-conventional medicine are used interchangeably with traditional medicine in some countries. WHO is actively developing a strategy for the training of indigenous practitioners in herbal medicine and the interaction of these practitioners with conventional medicine in countries throughout the world. Ethnobotany reports are best found in the Journal of Ethnopharmacology, which produced a substantial review of the adaptogen, Eleutherococcus senticosus (Davydov and Krikorian, 2000). Fitoterapia, Phytochemistry, and the Journal of Agricultural and Food Chemistry were also rich sources of ethnobotanical uses of plants. Traditional medicine, which included adaptogenic species are reflected best in the Asian and Indian scientific journals, in particular, Zhong Yao Cai, Zhongguo Zhong Yao Za Zhi, Yao Xue Xue Bao, Indian Journal of Pharmacology, and the Indian Journal of Experimental Biology. Toxicology The safety of herbs is of great concern, especially regarding regulation of botanical supplements and adverse event reporting (Bast et al., 2002). Phytoestrogens are of some concern (Adlercreutz, 1999). Adaptogens are intrinsically innocuous by definition (see Chapter 4), but there is some apprehension surrounding the use of botanical supplements to enhance athletic performance (Bucci, 2000). An in vitro study on Bryonia alba root extract showed no genotoxicity (DNA damage) and in fact decreased clastogenicity (chromosome abnormality) in bone marrow cells of rats and mice (Nersesyan and Collins, 2002). The toxicology literature revealed a concern not for dietary supplements and herbal remedies but for mutation and free radical damage surrounding deficiencies in dietary nutrients (Ames, 2001; 2003; Fenech, 2002; Steinkellner et al., 2001). Calabrese and Baldwin (2002a; 2002b; 2003) and Welsons et al. (2003) indicate a renewed interest in hormesis (U-shaped dose responses) as an explanation for the mechanism of action of small doses of natural and synthetic substances. Summary A list of taxa with adaptogenic activity was identified through a search of journals and publications from a wide variety of related disciplines of both plant science and human science. Access to the scientific literature has never been better at this time in history. Direct information on adaptogens was not common. Nonetheless, sufficient information was gathered on the characteristics of adaptogens, their chemical compounds and potential mechanisms of action. Though there is a dearth of human clinical studies on adaptogens, a vast indirect body of literature suggests that adaptogenic plant species are a valid subject of investigation. Robyn Klein 2006 www.rrreading.com Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties MS Thesis, 2004, Montana State University Chapter 2 of 8