CHAPTER 4 ADAPTOGENIC STRESS REMEDIES Introduction The effort to explore the phylogenetic relationship between plants with adaptogenic

properties must first start with an overview of the history of traditional plant medicines to treat stress. There are problems in applying an exotic paradigm to conventional medicine, especially given the differences in practices of conventional and traditional herbal medicine. Scientists in other countries have accepted this challenge and indeed most of the chemical constituents and bioactivities of traditional plant remedies have been elucidated in labs outside of the USA. This chapter reviews the source of adaptogen plant remedies and explores 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 developing countries because its remedies are well accepted, accessible and cost effective. Therefore, traditional medicine (also referred to as ethnomedicine or ethnopharmacology) is an excellent source of information for plant species used to treat stress and stress-related conditions. Ethnomedical models are difficult to translate 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 psychosomaticphobic pathology that leads to debilitation, 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 very serious 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 as somatic disorders such as low metabolism, diarrhea, nausea, anorexia, and low fever, and as psychological symptoms such as depression and melancholy (Bastien, 1987). In parts of Africa, chira describes diseases that involve wasting and weakness, and now include AIDS in that classification (Geissler et al., 2002). Chira can be treated in various ways, which commonly involves 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 of years and the traditional medical training of its practitioners. Qi is a complex concept that can be partly described as forming the basis of all life. Qi is expressed in the strength of the body and all its organs and tissues (Huan and Rose, 2001). The fundamental principle of health and healing is dependent on the flow of qi. For a better understanding of qi see Huan and Rose (2001). In particular, wei qi tonics protect against pernicious external influences such as viruses and bacterial pathogens and correlates to some degree with the innate immune system (phagocytes and macrophages) (Bensky and Gamble, 1986). Ayurveda, the indigenous traditional medical system in India, classifies remedies that prevent disease and 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). Pharmacologic investigations have supported antiaging and memory promoting activities of many of these rasayana remedies (Misra, 1998). However, not all herbs in the rasayana category fit the adaptogen definition. For example, Argyreia speciosa (Convolvulaceae) contains lysergic acid compounds closely related to LSD. It is 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 traditional healing 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

products to treat stress and fatigue in the United States since the 1960s. Thus, plant remedies in use by other 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 many cultures 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 States on adaptogenic products. However, open clinical uses of these herbs have been taking place for millennia in the indigenous practice of China and India (Wu et al., 2003). The remedies of these ethnomedical models of medicine can provide leads to further drug research and a comparison to known adaptogens. For example, a preliminary survey using ethnobotanical reports has located 65 potential plant adaptogen species belonging to 44 plant families (See Chapter 5). Adaptogens In 1943, the Peoples Commissars Council of the Union of the Soviet Socialist Republics charged its scientists with the task of finding tonic substances to strengthen the health of workers in the Russian defense industry during World War II (Panossian, 2003). Thus began the effort to find remedial substances that 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 termed adaptogens and three criteria were set to describe their remedial action (Brekhman, 1969). An adaptogen 1) should be innocuous and cause minimal disturbance to the normal physiological function of an organism, 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 pathological changes (i.e., be able to normalize either high and low physiological responses to stressors) (Brekhman and Dardymov, 1969). Russia and many other countries have supported hundreds of clinical studies on adaptogens, most of which have not been translated to English (see Appendix D Human Clinical Studies). Continued research on adaptogenic products from natural sources has resulted in the production of dozens of over the counter remedies. Two of these remedies are Bryonia alba tablets which are now registered in Armenia as an adaptogen 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 kill the insect. The discovery that these compounds produced an adaptogenic response when ingested by mammals has since led to over 200 products made from various plants high in phytoecdysteroids, sold around the world (Kholodova, 2001; Oberdorster et al., 2001; Bthori, 2002). These phytoecdysteroid compounds 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 discussed further 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 to initially sort through the 183 species collected in the beginning, for additional support I also used evidence of prevention or remediation of heightened stress sensitivity and dysregulation of stress-coping mechanisms. For example, Emblica officinalis (Euphorbiaceae) was not included in this investigation though it was labeled as adaptogenic in one research paper (Ganju et al., 2003). The reason was a lack of evidence 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 been shown 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 adaptogen.

The pathologies resulting from a dysfunctional response to stressors can be easily confused with the factors involved in the initial dysregulation of stress mediators (e.g., catecholamines and glucocorticoids). 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 are adaptogenic. To complicate matters, most adaptogens often have other non-adaptogenic properties such as antioxidant, cardioprotective and hepatoprotective actions. Many plant remedies with antioxidant properties can ameliorate deficits in memory or learning. But then why are not all such remedies adaptogens? Because the remedy may not meet the definition of an adaptogen which requires enhanced resistance to a wide variety of stressors, not just oxidative or cognitive stress. The remedy must also normalize both deficient and excessive conditions, and not cause side effects. Adaptogens were described in original Russian research as being a stimulant (Brekhman and Dardymov, 1969). Baranov (1982) describes the use of Oplopanax elatus and Panax ginseng to stimulate the central nervous system in asthenic conditions and depression. To conventional medicine a stimulant refers to amphetamines which have marked actions on the sympathetic nervous system, or to cardioactive agents, or to purgatives (Saeb-Parsy et al., 1999). Use of the term stimulant without clarification can result in false positives in natural product research. Kern et al., (1983) investigated the Native American claim that Clematis hirsutissima was a stimulant to horses. Instead of cardioactive compounds, an irritating blistering agent was found. Thus, serious confusion can arise between conventional and traditional models if adaptogenic properties are not clearly defined or tested. In eclectic medicine (1840-1930), plant remedies 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 the heartbeat but not necessarily augment its power or force. The goal was to increase functional power without 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 adaptogenic remedies. Panossian et al., (1999b) explains that the difference between pharmacologic stimulants and adaptogens can be seen in the recovery process where a period of marked suppression follows a stimulant effect but not seen in an adaptogenic effect. Many adaptogens have been labeled immunostimulant, immunomodulator, biological response modulator, or immunopotentiator most likely in the attempt to give these remedies a more specific mechanism of action or perhaps to fit them into the conventional medical paradigm. Though suppression of the immune system is a crucial component in stress dysfunction, its complexity obscures adaptogenic effects. 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 lead to false assumptions that other plant remedies with such activity are then adaptogenic. The criteria of an adaptogen (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. Inclusion of 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 bioactivities involving the normalization of catecholamines and glucocorticoids. Differentiation between true adaptogens and other plant remedies is crucial. A list of the pharmacological bioactivities of the 33 species selected 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 and loss of lean muscle mass. Others will gain weight very quickly (e.g., abdominal obesity) and still others will develop depression (McEwen, 2002). This is why a remedy that is harmless, non-specific, and can normalize both deficient and excess conditions, without side effects is especially valuable. The initial dysfunction of the HPA axis has been shown to involve the following factors (McEwen, 2002): dysregulation of catecholamines, dysregulation of glucocorticoids, dysregulation of cytokines, receptor desensitization, fatigue, anxiety, anorexia, altered cognitive performance, and decreased sexual behavior. The initial dysregulation of the stress mediators primarily involves cortisol and CRF (corticotrophin releasing factor). Chronic cortisol release has been shown to cause atrophy of nerves in the hippocampus and amygdala as well as adrenal hypertrophy, atrophy of the spleen, abdominal obesity, and suppression of

the immune response. Corticotrophin releasing factor (CRF) has been shown to induce negative effects such as motor activation, anxiety-like behavior, anorexia, decreased sexual behavior and altered cognitive performance (Zorrilla 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 such dysregulation. This might suggest that nerve tonics that reduce epinephrine release or otherwise prevent the initial alarm response that sets off the allostatic load cascade may also have adaptogenic action. The question is whether these nerve tonics also increase resistance and normalize dysregulation of cortisol and catecholamines. Does the remedy increase endurance under allostatic load, prevent weight loss or glucose imbalance resulting from allostatic load? Thus many plant remedies that act in a manner specific to a particular stressor (e.g., detoxification challenge, oxidative tissue stress, and fatigue) may not be truly adaptogenic. Some examples of plant remedies 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), and Centella asiatica and its enhancement of memory and cognition (Kumar and Gupta, 2002). Dysregulation of neurotransmitters and hormones can cause a suppressed or hyperactive immune response. Elevated cortisol has been shown to induce the apoptosis of thymocytes weakening the immune response (Kim et al., 1999). Insufficient cortisol can lead to a hyper-responsive immune system causing allergies and autoimmune conditions (McEwen, 2002). The definition of an adaptogen requires that the remedy normalize both deficient and excessive immune responses. Dysregulation of the immune system in either an excess or deficient fashion may be secondary to the initial dysfunction of catecholamines and glucocorticoids. Adaptogen remedies have been shown to ameliorate immune dysfunction by lowering corticosterone level (Kim et al., 1999), thus reducing the damage caused by excess cortisol. Other adaptogen remedies act directly by stimulating macrophages and lymphocytes (Cai et al., 1998) or otherwise reversing immunosuppression caused by stress (Wagner et al., 1994). Thus, it is not always consistent how a plant remedy is ameliorating immune dysregulation. Some plant remedies are not adaptogenic, yet have immunotonic, immunostimulant, and/or immunomodulator property. Echinacea purpurea, for example, can stimulate macrophages, but does not increase resistance to a wide variety of stressors (e.g., psychological stress). Uncaria tomentosa has been shown 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), and enhance recovery of leukopenia induced by doxorubicin (Sheng et al., 2001). But Uncaria tomentosa also does not increase resistance to a wide variety of stressors. Both Echinacea purpurea and Uncaria tomentosa are immunostimulant or immunomodulant, but not adaptogenic. Neither scientific research, nor the 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 many different analytical techniques and bioassays. These studies show an emphasis on neurotransmitter and hormone mediators, such as the release or lowering of cortisol. The swim test is one of the most common analytical 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 are given 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 decreased cortisol, ACTH, and aldosterone Modulation of noradrenaline activity was found upon administration of an alcoholic extract of Ocimum sanctum to mice Al-Qarawi et al., 2002 Khanna and Bhatia, 2003

The methanol extract of Epimedium sagittatum showed nerve growth of cultured cells Ginsenosides from Panax ginseng injected intraperitoneally in mice attenuated stress-induced increase in corticosterone levels Oral administration of an extract of Tinospora cordifolia given to mice was shown to ameliorate damaging effects of radiation Bacosides from Bacopa monniera were shown to enhance protein kinase activity in the hippocampus, increased serotonin and decreased norepinephrine levels in rats Extracts of Epimedium brevicornu showed a protective effect on the HPA axis, decreased levels of ACTH and corticosterone; lymphocyte proliferative reaction reduced; monoamine transmitters activated in hypothalamus, and relieved neuroendocrine-immunological effect inhibited by exogenous glucocorticoid Human Clinical Studies

Kuroda et al., 2000 Kim et al., 2003b Pahadiya & Sharma, 2003 Singh and Dhawan, 1997

Cai et al. 1998

One factor that limited the placement of plant taxa as adaptogens was the lack of human clinical trials of adaptogens on human physical performance and on stress. This is not to say they didnt exist at all. One of the most heavily researched adaptogens is Panax ginseng. Bucci (2000) lists 34 controlled and uncontrolled human studies on Panax ginseng. See Appendix D for more examples of clinical studies involving the effect of adaptogens on humans. Adaptogens have also been shown to protect other mammals and snails (invertebrates) against heat shock 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 following traditional medicines. Fungi. Medicinal fungi have a long history of use in China. These fungi are cultivated and marketed for 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 (Trametes versicolor), and caterpillar fungi (Cordyceps sinensis) (Hobbs, 1995). The main compounds thought to be active as adaptogens are the polysaccharides and triterpenes.

Shilajit. Known also as mumie, researchers first began to investigate the bioactivity and chemical composition of shilajit in the early 1970s. It is believed that this substance is the result of humification of a combination of resinous plant material, lichen, and fungi. Chemical analysis shows that shilajit is primarily composed of humus, a mixture of decomposed organic matter and soil compounds such as fulvic acid and humic 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 collected the 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 1000 and 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 with other herbs and substances, shilajit is included in various formulas for debility, convalescence and wasting disease, 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 Chinese medicine for centuries (Bensky and Gamble, 1986: Hsu, 1986). These substances are used primarily for neuroendocrine 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 be marketed and sold in the United States as dietary supplements, a separate category than drugs, cosmetics or food additives. The Federal Drug Administration and the Federal Trade Commission are charged with the regulation of dietary supplements and have full authority over them (US Congress, 1994). For more information 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 National Institutes of Health (NIH), particularly the Office of Dietary Supplements (ODS) and the National Center for 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 to reach about 15 million dollars by 2002 (Raskin et al., 2002). The most important issues surrounding botanical products are quality, safety and efficacy. These issues are being addressed by the efforts of industry, academic research groups and government agencies though there is still much work to accomplish (Cardellina, 2002). Except for cases of poor scientific studies and consumer abuse, adaptogen products have shown little, if any, toxicity. Properly prescribed conventional drugs and treatments have been ranked as the 4th to 6th leading cause of death in hospitals in the 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 an adaptogenic remedy be applied appropriately, including use of proper dosage. Overuse of an adaptogen itself has been shown to lead to hypoglycemia and other disruptive effects. For example, cautions against improper 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 in inappropriate cases, such as young persons. Still, such situations are very unusual when adaptogens are used according to proper therapeutic guidelines (Brekhman and Dardymov, 1982). The continued interest in adaptogens by the scientific community, as evidenced in the academic literature, and as dietary supplements regulated by governmental agencies, suggests that that adaptogens and their chemical compounds will remain a much needed focus of investigation. SUMMARY

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 in Russia, Sweden and other countries. These adaptogens have been shown to increase resistance to a wide variety of stressors in a normalizing, safe approach. The history of the research of adaptogens is very instructive in helping to define plants with adaptogenic properties. Another clue to the identity of plant adaptogens 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 both deficient 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 the adaptogen activity. Combining both the recent advances in allostasis theory and ethnomedicine practice has illuminated a novel remedy to treat pathologies resulting from allostatic load. Lazarevs original definition of an adaptogen is quite useful and appropriate to the theory of allostasis and can provide a guiding method for identifying adaptogenic plant species. The characteristic dysregulation of stress hormones and neurotransmitters, and the nonspecific nature of 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 of allostatic mediators such as hypercholesteremia and loss of lean muscle mass. The effects of adaptogen remedies are subtle and biphasica modulation of both excessive and deficient conditions. These therapeutic 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 has not yet been fully 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 University Chapter 4 of 8