phylogenetic and phytochemical characteristics ch4 klein

8/13/2019 Phylogenetic and Phytochemical Characteristics Ch4 KLEIN

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CHAPTER 4

ADAPTOGENIC STRESS REMEDIES

Introduction

The effort to explore the phylogenetic relationship between plants with adaptogenic properties mustfirst start with an overview of the history of traditional plant medicines to treat stress. There are problemsin applying an exotic paradigm to conventional medicine, especially given the differences in practices ofconventional and traditional herbal medicine. Scientists in other countries have accepted this challenge andindeed most of the chemical constituents and bioactivities of traditional plant remedies have beenelucidated in labs outside of the USA. This chapter reviews the source of adaptogen plant remedies andexplores their definition and their 60-year history of research throughout the world.

Traditional Medicine

Traditional medicine (as defined in Chapter 2) is the primary medical model in most developingcountries because its remedies are well accepted, accessible and cost effective. Therefore, traditionalmedicine (also referred to as ethnomedicine or ethnopharmacology) is an excellent source of informationfor plant species used to treat stress and stress-related conditions. Ethnomedical models are difficult totranslate into modern biomedical terms, but recent attempts have shown that it is not an impossible task(Heinrich, 2003). For example, in Central America, the term susto is used to describe a psychosomatic-

phobic pathology that leads to debili tation, a state of general organic debilitation, and a loss of vital focem (De Feo, 2003) or animating fluid (Bastien, 1987). Throughout Latin America, susto is regarded as a veryserious condition. Margarita Artshwageer Kay (1996) describes susto as comparable to biomedicines

post-traumatic stress disorder. The Kallawayan people of the Andes describe symptoms of susto assomatic disorders such as low metabolism, diarrhea, nausea, anorexia, and low fever, and as psychologicalsymptoms such as depression and melancholy (Bastien, 1987).

In parts of Africa, chira describes diseases that involve wasting and weakness, and now include AIDSin that classification (Geissler et al., 2002). Chira can be treated in various ways, which commonlyinvolves the use of a special remedy, manyasi . Manyasi remedies are composed of various mixtures of

plants, which are surrounded by secrecy and only known to the person who prepares it. In contrast to

ordinary illnesses and treatments, chira is not usually discussed openly, and treatment is not sought in a public process, but with a person who is known to possess medicine for it (Geissler et al., 2002).

In China, the understanding of qi has literally shaped the worldview of Asian cultures for thousands ofyears and the traditional medical training of its practitioners. Qi is a complex concept that can be partlydescribed as forming the basis of all life. Qi is expressed in the strength of the body and all its organs andtissues (Huan and Rose, 2001). The fundamental principle of health and healing is dependent on the flowof qi . For a better understanding of qi see Huan and Rose (2001). In particular, wei qi tonics protectagainst pernicious external influences such as viruses and bacterial pathogens and correlates to some degreewith the innate immune system (phagocytes and macrophages) (Bensky and Gamble, 1986).

Ayurveda, the indigenous traditional medical system in India, classifies remedies that prevent diseaseand counteract aging as rasayana or rejuvenation remedies (Misra, 1998; Davydov and Krikorian, 2000;Auddy et al., 2003; Bhattacharya and Muruganandam, 2003; Puri, 2003). Modern herbal supplements have

borrowed rasayana herbs such as Withania somnifera (Solanaceae), Asparagus racemosus (Liliaceae), and

Terminalia chebula (Combretaceae). Plant drugs that promote longevity and antiaging are termed jivaniya and vayahsthapana respectively (Dev, 1999) and rejuvenation, kaya kalp (Puri, 2003). Pharmacologicinvestigations have supported antiaging and memory promoting activities of many of these rasayanaremedies (Misra, 1998). However, not all herbs in the rasayana category fit the adaptogen definition. Forexample, Argyreia speciosa (Convolvulaceae) contains lysergic acid compounds closely related to LSD. Itis often combined with other adaptogenic herbs such as Withania somnifera and Centella asiatica (Apiaceae) as an aphrodisiac and to deter old age (Puri, 2003).

The concept of treating stress-related conditions with medicinal plants is familiar to most traditionalhealing models throughout the world (WHO, 2002). Though conventional medicine does not use these

plant remedies, primarily citing lack of research, the popular health market has been selling botanical


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products to treat stress and fatigue in the United States since the 1960s. Thus, plant remedies in use byother countries in the world have not been thoroughly explored by scientists in the United States. Thus,despite the difficult conceptual grasp required, a literary history of the treatment for stress exists in manycultures and can be explored for the development of novel drugs or therapeutics. Few well-designed,randomized, placebo-controlled, double-blinded clinical studies have been conducted in the United Stateson adaptogenic products. However, open clinical uses of these herbs have been taking place for millenniain the indigenous practice of China and India (Wu et al., 2003). The remedies of these ethnomedicalmodels of medicine can provide leads to further drug research and a comparison to known adaptogens. Forexample, a preliminary survey using ethnobotanical reports has located 65 potential plant adaptogenspecies belonging to 44 plant families (See Chapter 5).

Adaptogens

In 1943, the Peoples Commissars Council of the Union of the Soviet Socialist Republics charged itsscientists with the task of finding tonic substances to strengthen the health of workers in the Russiandefense industry during World War II (Panossian, 2003). Thus began the effort to find remedial substancesthat would increase the protective state of resistance during conditions of stress. N.V. Lazarev (1946;1962) showed that ingestion of certain plant extracts could improve stress markers in laboratory animals,such as cognitive function or oxidative damage. Between 1950 and 1960 these plant remedies were termedadaptogens and three criteria were set to describe their remedial action (Brekhman, 1969). An adaptogen1) should be innocuous and cause minimal disturbance to the normal physiological function of anorganism, 2) its action should be nonspecific (i.e., should increase resistance to a wide range of stressors),and 3) it should have a normalizing action irrespective of the direction of the preceding pathologicalchanges (i.e., be able to normalize either high and low physiological responses to stressors) (Brekhman andDardymov, 1969).

Russia and many other countries have supported hundreds of clinical studies on adaptogens, most ofwhich have not been translated to English (see Appendix D Human Clinical Studies). Continued researchon adaptogenic products from natural sources has resulted in the production of dozens of over the counterremedies. Two of these remedies are Bryonia alba tablets which are now registered in Armenia as anadaptogen medicine (Panossian et al., 1997), and the standardized extract of Rhodiola rosea (SHR-5),registered as an herbal medicinal product in Sweden (Swedish Herbal Institute, 2003).

Further investigation of adaptogenic compounds in other Slavic countries, including Czechoslovakia,

led to the discovery that plants synthesize steroidal compounds for plant defense, called phytoecdysteroids.These compounds mimic insect steroids, which in some cases, can inhibit developmental molting and killthe insect. The discovery that these compounds produced an adaptogenic response when ingested bymammals has since led to over 200 products made from various plants high in phytoecdysteroids, soldaround the world (Kholodova, 2001; Oberdorster et al., 2001; Bthori, 2002). These phytoecdysteroidcompounds meet the three criteria of an adaptogen: innocuous, nonspecific and normalizing in action.Adaptogenic activity has also been described for the plant sterol, ! -sitosterol (Park et al., 2001; Bouic,2002; Villasenor et al., 2002; Chattopadhyay et al., 2003). These chemical compounds will be discussedfurther in Chapter 5.

Clarification of Definition

The identification of plant adaptogens for this investigation did not just rely on the three criteria proposed by Lazarev (e.g., innocuous, non-specific, and normalizing). Although these criteria helped toinitially sort through the 183 species collected in the beginning, for additional support I also used evidenceof prevention or remediation of heightened stress sensitivity and dysregulation of stress-copingmechanisms. For example, Emblica officinalis (Euphorbiaceae) was not included in this investigationthough it was labeled as adaptogenic in one research paper (Ganju et al., 2003). The reason was a lack ofevidence of regulation of dysfunctional mediators of stress (e.g. catecholamines and glucocorticoids).Similarly, Ajuga turkestanica was not included because, though high in ecdysteroids which have beenshown to lower blood glucose (Kutepova et al., 2001), increase protein synthesis (Syrov et al., 1978), and

protect the liver (Syrov and Khushbactova, 2001), there is no evidence of use or testing as an adap togen.


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The pathologies resulting from a dysfunctional response to stressors can be easily confused withthe factors involved in the initial dysregulation of stress mediators (e.g., catecholamines andglucocorticoids). To explain further, one must remember that pathologies such as diabetes, memory loss,and cachexia (loss of lean muscle mass) develop long after the initial dysregulation of stress mediators.Many plant remedies are used to treat diabetes, memory loss, and cachexia. Yet not all these remedies areadaptogenic. To complicate matters, most adaptogens often have other non-adaptogenic properties such asantioxidant, cardioprotective and hepatoprotective actions. Many plant remedies with antioxidant

properties can ameliorate deficits in memory or learning. But then why are not all such remediesadaptogens? Because the remedy may not meet the definition of an adaptogen which requires enhancedresistance to a wide variety of stressors, not just oxidative or cognitive stress. The remedy must alsonormalize both deficient and excessive conditions, and not cause side effects.

Adaptogens were described in original Russian research as being a stimulant (Brekhman andDardymov, 1969). Baranov (1982) describes the use of Oplopanax elatus and Panax g inseng to stimulatethe central nervous system in asthenic conditions and depression. To conventional medicine a stimulantrefers to amphetamines which have marked actions on the sympathetic nervous system, or to cardioactiveagents, or to purgatives (Saeb-Parsy et al., 1999). Use of the term stimulant without clarification can resultin false positives in natural product research. Kern et al., (1983) investigated the Native American claimthat Clematis hirsutissima was a stimulant to horses. Instead of cardioactive compounds, an irritating

blistering agent was found. Thus, serious confusion can ar ise between conventional and traditional modelsif adaptogenic properties are not clearly defined or tested. In eclectic medicine (1840-1930), plantremedies with stimulant properties were not used for their forceful properties but for their restorative

properties (Felter, 1922). Eclectic physicians considered a heart stimulant to increase the rate of theheartbeat but not necessarily augment its power or force. The goal was to increase functional powerwithout causing deleterious effects from over-stimulation or to remedy congestion of tissues (Felter, 1922).It is this latter restorative definition that is the true description of the stimulant activity of adaptogenicremedies. Panossian et al., (1999b) explains that the difference between pharmacologic stimulants andadaptogens can be seen in the recovery process where a period of marked suppression follows a stimulanteffect but not seen in an adaptogenic effect.

Many adaptogens have been labeled immunostimulant, immunomodulator, biological responsemodulator, or immunopotentiator most likely in the attempt to give these remedies a more specificmechanism of action or perhaps to fit them into the conventional medical paradigm. Though suppressionof the immune system is a crucial component in stress dysfunction, its complexity obscures adaptogeniceffects. It is unclear whether a single biomarker of the immune system can distinguish a primary role in

increased resistance to stress. These pharmacological descriptions are problematic because they may leadto false assumptions that other plant remedies with such activity are then adaptogenic. The criteria of anadaptogen (i.e., innocuous, nonspecific and normalizing) can help to clarify the application of these

pharmacologic properties.It is the attenuation of the initial dysregulation of stress mediators that defines an increased resistance

to a wide variety of stress , and thus, adaptogenic activity. That is, remedying the downstream effects and pathological conditions of the stress response also include herbs lacking an adaptogen property. Inclusionof such non-adaptogens can easily distort the identity of true plant adaptogens and lead to inclusion of false

positive species. To guard against this possibility , I endeavored to especially attend to bioactivitiesinvolving the normalization of catecholamines and glucocorticoids. Differentiation between trueadaptogens and other plant remedies is crucial. A list of the pharmacological bioactivities of the 33 speciesselected for this investigation as having adaptogenic properties is found in Appendix C.

The dysregulation of stress-coping mechanism is very individual and does not always result in the

same pathologies. Some individuals will have cognitive deficit while others will experience fatigue andloss of lean muscle mass. Others will gain weight very quickly (e.g., abdominal obesity) and still otherswill develop depression (McEwen, 2002). This is why a remedy that is harmless, non-specific, and cannormalize both deficient and excess conditions, without side effects is especially valuable. The initialdysfunction of the HPA axis has been shown to involve the following factors (McEwen, 2002):dysregulation of catecholamines, dysregulation of glucocorticoids, dysregulation of cytokines, receptordesensitization, fatigue, anxiety, anorexia, a ltered cognitive performance, and decreased sexual behavior.

The initial dysregulation of the stress mediators primarily involves cortisol and CRF (corticotrophinreleasing factor). Chronic cortisol release has been shown to cause atrophy of nerves in the hippocampusand amygdala as well as adrenal hypertrophy, atrophy of the spleen, abdominal obesity, and suppression of


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the immune response. Corticotrophin releasing factor (CRF) has been shown to induce negative effectssuch as motor activation, anxiety-like behavior, anorexia, decreased sexual behavior and altered cognitive

performance (Zorril la et al., 2002).Many adaptogenic remedies can be shown to ameliorate or modulate dysregulation of CRH,

epinephrine and/or cortisol in such a way as to limit or reduce pathologies resulting from suchdysregulation. This might suggest that nerve tonics that reduce epinephrine release or otherwise preventthe initial alarm response that sets off the allostatic load cascade may also have adaptogenic action. Thequestion is whether these nerve tonics also increase resistance and normalize dysregulation of cortisol andcatecholamines. Does the remedy increase endurance under allostatic load, prevent weight loss or glucoseimbalance resulting from allostatic load?

Thus many plant remedies that act in a manner specific to a particular stressor (e.g., detoxificationchallenge, oxidative tissue stress, and fatigue) may not be truly adaptogenic. Some examples of plantremedies I did not accept as adaptogens yet having specific stress ameliorating properties are Andrographis

paniculata and its ability to protect the liver from damage (Trevedi and Rawal, 2000), Camellia sinensis (green tea) and its antioxidant properties (Dewick, 2002), Ephedra sinensis and its action on fatigue(Dewick, 2002), Ginkgo biloba and its neuro- and cardioprotective properties (van Beek et al., 1998), andCentella asiatica and its enhancement of memory and cognition (Kumar and Gupta, 2002).

Dysregulation of neurotransmitters and hormones can cause a suppressed or hyperactive immuneresponse. Elevated cortisol has been shown to induce the apoptosis of thymocytes weakening the immuneresponse (Kim et al., 1999). Insufficient cortisol can lead to a hyper-responsive immune system causingallergies and autoimmune conditions (McEwen, 2002). The definition of an adaptogen requires that theremedy normalize both deficient and excessive immune responses. Dysregulation of the immune system ineither an excess or deficient fashion may be secondary to the initial dysfunction of catecholamines andglucocorticoids.

Adaptogen remedies have been shown to ameliorate immune dysfunction by lowering corticosteronelevel (Kim et al., 1999), thus reducing the damage caused by excess cortisol. Other adaptogen remedies actdirectly by stimulating macrophages and lymphocytes (Cai et al., 1998) or otherwise reversingimmunosuppression caused by stress (Wagner et al., 1994). Thus, it is not always consistent how a plantremedy is ameliorating immune dysregulation.

Some plant remedies are not adaptogenic, yet have immunotonic, immunostimulant, and/orimmunomodulator property. Echinacea purpurea , for example, can stimulate macrophages, but does notincrease resistance to a wide variety of stressors (e.g., psychological stress). Uncaria tomentosa has beenshown to stimulate interleukin-1 and interleukin6 in macrophages (Lemaire et al., 1999), stimulate

endothelial cells to produce a lymphocyte proliferating regulating factor (Keplinger et al., 1999), andenhance recovery of leukopenia induced by doxorubicin (Sheng et al., 2001). But Uncaria tomentosa alsodoes not increase resistance to a wide variety of stressors. Both Echinacea purpurea and Uncariatomentosa are immunostimulant or immunomodulant, but not adaptogenic. Neither scientific research, northe ethnobotanical literature indicates that either of these herbs meets the definition of an adaptogen.

Analytical Methods

Scientific studies elucidating the mechanism of action of adaptogen compounds involves manydifferent analytical techniques and bioassays. These studies show an emphasis on neurotransmitter andhormone mediators, such as the release or lowering of cortisol. The swim test is one of the most commonanalytical techniques used to indicate surrender or resistance to fatigue and depression (Sakina et al., 1990;

Zhang et al., 2002). Some examples of in vitro and in vivo studies on adaptogens and their compounds aregiven in Table 2. below.

Table 2. Examples of in vitro and in vivo experiments involving plant adaptogens.

A freeze-dried extract of Glycyrrhiza glabra administered to rats showed Al-Qarawi et al., 2002decreased cortisol, ACTH, and aldosterone

Modulation of noradrenaline activity was found upon administration of Khanna and Bhatia, 2003an alcoholic extract of Ocimum sanctum to mice


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The methanol extract of Epimedium sagittatum showed nerve growth Kuroda et al., 2000of cultured cells

Ginsenosides from Panax ginseng injected intraperitoneally in mice Kim et al., 2003battenuated stress-induced increase in corticosterone levels

Oral administration of an extract of Tinospora cordifolia given to mice Pahadiya & Sharma, 2003was shown to ameliorate damaging effects of radiation

Bacosides from Bacopa monniera were shown to enhance protein Singh and Dhawan, 1997kinase activity in the hippocampus, increased serotonin and decreasednorepinephrine levels in rats

Extracts of Epimedium brevicornu showed a protective effect on the Cai et al. 1998HPA axis, decreased levels of ACTH and corticosterone;lymphocyte proliferative reaction reduced; monoamine transmittersactivated in hypothalamus, and relieved neuroendocrine-immunologicaleffect inhibited by exogenous glucocorticoidHuman Clinical Studies

One factor that limited the placement of plant taxa as adaptogens was the lack of human clinical trialsof adaptogens on human physical performance and on stress. This is not to say they didnt exist at all. Oneof the most heavily researched adaptogens is Panax ginseng . Bucci (2000) lists 34 controlled anduncontrolled human studies on Panax ginseng . See Appendix D for more examples of clinical studiesinvolving the effect of adaptogens on humans.

Adaptogens have also been shown to protect o ther mammals and snails (invertebrates) against heatshock and toxic metals (Koudela et al., 1995; Slma et al., 1996; Boon-Niermeijer et al., 2000).

Appendix C lists the myriad of pharmacological effects of adaptogens on humans and other mammals.

Non-Plant Adaptogens

It is beyond the purpose of this project to explore other substances with adaptogenic properties.However, it should be mentioned that there is an active interest in the research community in the followingtraditional medicines.

Fungi. Medicinal fungi have a long history of use in China. These fungi are cultivated and marketedfor their adaptogenic properties. Some of the more well-known species are shiitake ( Lentinula edodes ),reishi ( Ganoderma lucidum ), maitake ( Grifola frondosa ), chaga ( Inonotus obliquus ), turkey tail ( Trametesversicolor ), and caterpillar fungi ( Cordyceps sinensis ) (Hobbs, 1995). The main compounds thought to beactive as adaptogens are the polysaccharides and triterpenes.


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Shilajit. Known also as mumie, researchers first began to investigate the bioactivity and chemicalcomposition of shilajit in the early 1970s. It is believed that this substance is the result of humification of acombination of resinous plant material, lichen, and fungi. Chemical analysis shows that shilajit is primarilycomposed of humus, a mixture of decomposed organic matter and soil compounds such as fulvic acid andhumic acid. These latter substances contain compounds such as uronic acids, phenolic glycosides,triterpenes, phenolic lipids, and amino acids (Schepetkin et al., 2003). Indigenous peoples have collectedthe blackish-brown substance for centuries from the high mountains of Nepal, Tibet, Bhutan, China,Pakistan, Afghanistan, the Urals, and Norway. It is found on steep rock faces at altitudes between 1000and 5000 meters. In Indian folk medicine, shilajit is a legendary rejuvenator and immunomodulator,termed rasayana . It is primarily used for longevity and to arrest the process of aging. Combined withother herbs and substances, shilajit is included in various formulas for debility, convalescence and wastingdisease, to enhance the libido and to treat stress and immune system deficiency (Schliebs et al., 1997;Bhattacharya et al., 2000; Puri, 2003).

Deer Antler. Deer horn (cervi cornu parvum), deer antler velvet (cervus lu rong), mature deer antler(cervus lu jiao jiao ), and deer antler gelatin ( cervi colla cornus ) have been in use in traditional Chinesemedicine for centuries (Bensky and Gamble, 1986: Hsu, 1986). These substances are used primarily forneuroendocrine deficiency ( qi deficiency) and believed to be adaptogenic and a metabolic restorative(Holmes, 1996). Deer antler contains many amino acids, polyamines, androgens, estrogens,sphingomyelin, cholesterol, ectosaponins, calcium phosphate/carbonate, magnesium, phosphous,sphingmyelin, ganglioside, chondroitin and choline analogues (Holmes, 1996).

Safety of Dietary Supplements

In spite of the fact that few clinical trials have been conducted, adaptogen products continue to bemarketed and sold in the United States as dietary supplements, a separate category than drugs, cosmetics orfood additives. The Federal Drug Administration and the Federal Trade Commission are charged with theregulation of dietary supplements and have full authority over them (US Congress, 1994). For moreinformation on the regulatory role of these agencies see the website for the Council on Responsible

Nutrition (http://crnusa.org). The lead federal agency for dietary supplement research is the NationalInstitutes of Health (NIH), particularly the Office of Dietary Supplements (ODS) and the National Centerfor Complementary and Alternative Medicine (NCCAM) (Cardellina, 2002). In 2002, these two agencies

had a budget of $17 million and $104.6 million, respectively. The familiarity of the public with these products can be documented by the sale of botanical dietary supplements in the U.S., which is expected toreach about 15 million dollars by 2002 (Raskin et al., 2002).

The most important issues surrounding botanical products are quality, safety and efficacy. Theseissues are being addressed by the efforts of industry, academic research groups and government agenciesthough there is still much work to accomplish (Cardellina, 2002). Except for cases of poor scientificstudies and consumer abuse, adaptogen products have shown little, if any, toxicity. Properly prescribedconventional drugs and treatments have been ranked as the 4 th to 6 th leading cause of death in hospitals inthe United States (Lazarou et al., 1998), a perspective that should always be kept in mind.

The classic definition of an adaptogen requires the lack of side effects. This criteria suggests that anadaptogenic remedy be applied appropriately, including use of proper dosage. Overuse of an adaptogenitself has been shown to lead to hypoglycemia and other disruptive effects. For example, cautions againstimproper application of Panax ginseng have been suggested in Russian and Chinese research (Brekhman

and Dardymov, 1982; Bensky and Gamble, 1986). These cautions involve using large doses and ininappropriate cases, such as young persons. Still, such situations are very unusual when adaptogens areused according to proper therapeutic guidelines (Brekhman and Dardymov, 1982).

The continued interest in adaptogens by the scientific community, as evidenced in the academicliterature, and as dietary supplements regulated by governmental agencies, suggests that that adaptogensand their chemical compounds will remain a much needed focus of investigation.

SUMMARY


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It can be shown that many indigenous cultures have used plant remedies to treat stress. From these practices a class of new drugs called adaptogens has been investigated and developed into official drugs inRussia, Sweden and other countries. These adaptogens have been shown to increase resistance to a widevariety of stressors in a normalizing, safe approach. The history of the research of adaptogens is veryinstructive in helping to define plants with adaptogenic properties. Another clue to the identity of plantadaptogens are the chemical compounds found in them that may be responsible for the adaptogenic

properties.There are surely many adaptogenic species not yet recognized. Likewise, many species were not

included in this investigation due to the lack of sufficient indication from laboratory research. Most often,such species cannot be shown to ameliorate dysregulation of catecholamines and glucocorticoids in bothdeficient and excess conditions or have not been shown to increase endurance despite allostatic load.While these may not be the only factors involved in adaptogenic activity, they help differentiate theadaptogen activity. Combining both the recent advances in allostasis theory and ethnomedicine practicehas illuminated a novel remedy to treat pathologies resulting from allostatic load. Lazarevs originaldefinition of an adaptogen is quite useful and appropriate to the theory of allostasis and can provide aguiding method for identifying adaptogenic plant species.

The characteristic dysregulation of stress hormones and neurotransmitters, and the nonspecific natureof the allostatic response both correspond to the distinctive affectations of botanical adaptogenic remedies(Singh et al., 2001). Adaptogens ameliorate the very pathologies that are caused by the dysregulation ofallostatic mediators such as hypercholesteremia and loss of lean muscle mass. The effects of adaptogenremedies are subtle and biphasica modulation of both excessive and deficient conditions. Thesetherapeutic medicines have been missed by conventional medicine most likely because of their esoteric use

by traditional herbal medicine practitioners and because the therapeutic strategy of traditional medicine hasnot yet been ful ly appreciated (Bhattacharya and Muruganandam, 2003).

Robyn Klein 2006 www.rrreading.com Phylogenetic and phytochemical characteristics of plant species with adaptogenic properties

MS Thesis, 2004, Montana State UniversityChapter 4 of 8

phylogenetic and phytochemical characteristics ch4 klein

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