By Vince Giuliano
This and the Part 2 blog entry are pursuant to one of the key themes of this blog – the use of phyto substances to promote health and longevity. Specifically, they are about adaptogens – certain plant substances used in traditional and modern herbal medicine. The two entries treat adaptogens from two viewpoints. First, the viewpoint of a practicing herbalist Madelon Hope is conveyed via a video presentation. Second, the viewpoint of current scientific research is covered in my usual manner: I cite a number of recent research citations relating to adaptogens involving their mechanisms of action and their therapeutic potential. This blog discusses adaptogens in general. The following blog entry Adaptogens Part2 – focus on rhodiola is concerned with one adaptogen of particular interest and power. Most of my personal commentary is in that blog entry.
Madelon Hope is Director of the Boston School of Herbal Studies and a long-time practicing herbalist. I asked her for an informal interview which I recorded on a tiny video camera. The first part of the interview is on adaptogens in general and is included here. The second part of the interview is included in the Adaptogens Part 2 entry.
From Wikipedia: “An adaptogen is a metabolic regulator which increases the ability of an organism to adapt to environmental factors, and to avoid damage from such factors. Environmental factors can be either physiological (external), such as injury or aging, or psychological (internal), such as anxiety. — An adaptogen must have a normalizing effect, i.e. counteracting or preventing disturbances to homeostasis brought about by stressors. Moreover, it must be innocuous with a broad range of therapeutic effects without causing any major side effects. The adaptogen concept does not fit easily into the Western model of medicine. — According to the original definition adaptogens are non-specific remedies that increase resistance to a broad spectrum of harmful factors – “stressors” – of different physical, chemical and biological natures. — This definition has been updated and today adaptogens are defined as a “new class of metabolic regulators which increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors.” — Despite an extensive amount of research in the USSR, (by 1984, more than 1,500 pharmacological and clinical published studies), the concept is not generally recognized in Western countries as it seemed to be in contrast to some of the key concepts of modern pharmacology: potency, selectivity and with efficacy balanced by an accepted level of toxicity. In 1998, however, the term adaptogen was allowed as a functional claim for certain products by US Food and Drug Administration and it is now a generally accepted concept, also by the European Medicines Agency and EFSA.[7(ref)”
Most of the research literature relating to adaptogens originates in Asia or Europe; relatively little comes from the US or Canada. Among the topics treated in the literature are actions of adaptogens in the cases of immune system response, energy metabolism, endurance exercise performance, acute lung injury, ischemia-reperfusion injury, early left ventricular regional systolic dysfunction, asthma, metabolic syndrome, type 2 diabetes, Parkinson’s disease, mental and physical fatigue, hypoxia and acute mountain sickness, hypoglycemia, toxicity-induced apoptosis, inflammatory cytokinesm DNA repair, heat shock protein interactions, particular bacteria including propionibacterium, and multiple types of cells including those of the liver and heart, cortical neurons, neuroglia and certain cancer cells. Most of the studies reported recently are on the molecular biology, cell, and small-animal levels. Although I have seen many mentions of clinical trials these appear to be mostlyolder, specialized and conducted on a small scale. The concept of adaptogens appears to be unique to herbal medicine and mainly not recognized from the viewpoint of Western allopathic medicine.
I cite a few citations applicable to adaptogens in general here. Since a great deal of the research on adaptogens is focused on rhodiola, the following blog entry cites a more interesting and extensive collection of publications.
Chinese Medicine and Ayurvedic medicine, the two most comprehensive schools of traditional medicine going back thousands of years, each recognizes a number of what are now called adaptogens.
The 2010 review publication Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: ashwagandha is interesting in that it discusses an important adaptogenic herb in the historical context of Ayurvedic medicine. “Scientific basis for the use of Indian ayurvedic medicinal plants in the treatment of neurodegenerative disorders: ashwagandha. “Ayurveda is a Sanskrit word, which means “the scripture for longevity”. It represents an ancient system of traditional medicine prevalent in India and in several other south Asian countries. It is based on a holistic view of treatment which is believed to cure human diseases through establishment of equilibrium in the different elements of human life, the body, the mind, the intellect and the soul . Ayurveda dates back to the period of the Indus Valley civilization (about 3000 B.C) and has been passed on through generations of oral tradition, like the other four sacred texts (Rigveda, Yajurveda, Samaveda and Atharvanaveda) which were composed between 12(th) and 7(th) century B.C [2, 3]. References to the herbal medicines of Ayurveda are found in all of the other four Vedas, suggesting that Ayurveda predates the other Vedas by at least several centuries. It was already in full practice at the time of Buddha (6(th) century B.C) and had produced two of the greatest physicians of ancient India, Charaka and Shushrutha who composed the basic texts of their trade, the Samhitas. By this time, ayurveda had already developed eight different subspecialties of medical treatment, named Ashtanga, which included surgery, internal medicine, ENT, pediatrics, toxicology, health and longevity, and spiritual healing . Ayurvedic medicine was mainly composed of herbal preparations which were occasionally combined with different levels of other compounds, as supplements . In the Ayurvedic system, the herbs used for medicinal purposes are classed as brain tonics or rejuvenators. Among the plants most often used in Ayurveda are, in the descending order of importance: (a) Ashwagandha, (b) Brahmi, (c) Jatamansi, (d) Jyotishmati, (e) Mandukparni, (f) Shankhapushpi, and (g) Vacha. The general appearance of these seven plants is shown in Fig.1. Their corresponding Latin names, as employed in current scientific literature, the botanical families that each of them belongs to, their normal habitats in different areas of the world, as well as the common synonyms by which they are known, are shown in the Table 1. The scientific investigations concerning the best known and most scientifically investigated of these herbs, Ashwagandha will be discussed in detail in this review. Ashwagandha (Withania somnifera, WS), also commonly known, in different parts of the world, as Indian ginseng, Winter cherry, Ajagandha, Kanaje Hindi and Samm Al Ferakh, is a plant belonging to the Solanaceae family. It is also known in different linguistic areas in India by its local vernacular names . It grows prolifically in dry regions of South Asia, Central Asia and Africa, particularly in India, Pakistan, Bangladesh, Sri Lanka, Afghanistan, South Africa, Egypt, Morocco, Congo and Jordon . In India, it is cultivated, on a commercial scale, in the states of Madhya Pradesh, Uttar Pradesh, Punjab, Gujarat and Rajasthan . In Sanskrit, ashwagandha, the Indian name for WS, means “odor of the horse”, probably originating from the odor of its root which resembles that of a sweaty horse. The name”somnifera” in Latin means “sleep-inducer” which probably refers to its extensive use as a remedy against stress from a variety of daily chores. Some herbalists refer to ashwagandha as Indian ginseng, since it is used in India, in a way similar to how ginseng is used in traditional Chinese medicine to treat a large variety of human diseases . Ashwagandha is a shrub whose various parts (berries, leaves and roots) have been used by Ayurvedic practitioners as folk remedies, or as aphrodisiacs and diuretics. The fresh roots are sometimes boiled in milk, in order to leach out undesirable constituents. The berries are sometimes used as a substitute to coagulate milk in cheese making. In Ayurveda, the herbal preparation is referred to as a “rasayana”, an elixir that works, in a nonspecific, global fashion, to increase human health and longevity. It is also considered an adaptogen, a nontoxic medication that normalizes physiological functions, disturbed by chronic stress, through correction of imbalances in the neuroendocrine and immune systems [9, 10]. The scientific research that has been carried out on Ashwagandha and other ayurvedic herbal medicines may be classified into three major categories, taking into consideration the endogenous or exogenous phenomena that are known to cause physiological disequilibrium leading to the pathological state; (A) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on specific non-neurological diseases; (B) pharmacological and therapeutic effects of extracts, purified compounds or multi-herbal mixtures on neurodegenerative disorders; and (C) biochemical, physiological and genetic studies on the herbal plants themselves, in order to distinguish between those originating from different habitats, or to improve the known medicinal quality of the indigenous plant. Some of the major points on its use in the treatment of neurodegenerative disorders are described below.” Followers of this blog may know that I have long incorporated Ashwagandha as part of the suggested anti-aging supplement firewall in my online treatise ANTI-AGING FIREWALLS – THE SCIENCE AND TECHNOLOGY OF LONGEVITY.
From the Chinese/Japanese point of view related to the adaptogens ginseng for example, we have the publication [Medicinal history and ginsenosides composition of Panax ginseng rhizome, “Rozu”] . “Ginseng is prepared from Panax ginseng C.A. Meyer root. The root of wild P. ginseng has long tortuous rhizome called traditionally “Rozu” in Japanese. In the present historical studies on ginseng, it has been proven that ginseng has sometimes been used after removing “Rozu” due to its emetic effects. However, ginseng with “Rozu” is prescribed in almost all the present Kampo formulations used clinically in China and Japan. Possible reasons for this are (1) some formulations including “Rozu” have been used for vomiting resulting from the retention of fluid in the intestine and stomach, “tan-in” in Japanese, and (2) the present cultivated ginseng has shorter “Rozu” than wild ginseng. Furthermore, it is proved that “Rozu”, rich in ginsenoside Ro with oleanane-type aglycone, is distinguished from ginseng roots rich in ginsenosides Rb1 and Rg1 with dammarane-type aglycone. This is the first report to declare the distribution of ginsenosides in underground parts of wild P. ginseng. Ginsenoside Ro is a minor ginsenoside in ginseng whereas it is the major ginsenoside in P. japonicus rhizome (chikusetsu-ninjin in Japanese). Ginsenoside Ro is characterized by antiinflammatory effects which differ from ginsenosides Rb1 and Rg1 responsible for adaptogenic effects of ginseng. These results suggest that “Rozu” containing both oleanane- and dammarane-type ginsenosides might be a promising raw material distinct from ginseng root or P. japonicus rhizome.”
Upstream targets of adaptogens in response to stress appear to include the neuropeptide NPY and the heat shock protein HSP72.
The June 2012 publication Adaptogens stimulate neuropeptide y and hsp72 expression and release in neuroglia cells reports: “The beneficial stress-protective effect of adaptogens is related to the regulation of homeostasis via mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of the stress response, such as molecular chaperones, stress-activated c-Jun N-terminal protein kinase, forkhead box O transcription factor, cortisol, and nitric oxide (NO). However, it still remains unclear what the primary upstream targets are in response to stimulation by adaptogens. The present study addresses this gap in our knowledge and suggests that an important target for adaptogen mediated stress-protective effector functions is the stress hormone neuropeptide Y (NPY). We demonstrated that ADAPT-232, a fixed combination of adaptogens Eleutherococcus senticosus root extract, Schisandra chinensis berry extract, Rhodiola rosea root extract SHR-5, and its active constituent salidroside, stimulated the expression of NPY and 72 kDa heat shock protein (Hsp72) in isolated human neuroglia cells. The central role of NPY was validated in experiments in which pre-treatment of human neuroglia cells with NPY-siRNA and HSF1-siRNA resulted in the significant suppression of ADAPT-232-induced NPY and Hsp72 release. Taken together our studies suggest that the stimulation and release of the stress hormones, NPY and Hsp72, into systemic circulation is an innate defense response against mild stressors (ADAPT-232), which increase tolerance and adaptation to stress.”
Note that “Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway(ref).” “Neuropeptide Y (NPY) is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system. It regulates energy usage, and is involved in learning, memory processing, and epilepsy. The main effect of its level/activity elevation is increased food intake and decreased physical activity. NPY is secreted by the hypothalamus, and, in addition to increasing food intake, it increases the proportion of energy stored as fat and blocks nociceptive signals to the brain. NPY also augments the vasoconstrictor effects of noradrenergic neurons(ref).”
Multiple studies of adaptogens on humans appear consistently to show beneficial effects. However the studies have generally been small and administered under differing conditions making it difficult to draw rigorous general conclusions. So, the evidence favoring their use appears to be qualitatively different than that for Western pharmacological substances which have been subject to large-scale clinical trials.
An example is described in the 2010 publication Double-blind, placebo-controlled, randomised study of single dose effects of ADAPT-232 on cognitive functions. “The aim of this study was to assess the effect of a single dose of ADAPT-232 (a standardised fixed combination of Rhodiola rosea L., Schisandra chinensis (Turcz.) Baill., and Eleutherococcus senticosus Maxim) extracts on mental performance, such as attention, speed and accuracy, in tired individuals performing stressful cognitive tasks. The pilot study (phase IIa) clinical trial took the form of a double-blind, placebo-controlled, randomised, with two parallel groups. Forty healthy females aged between 20-68 years, who claimed to have felt stressed over a long period of time due to living under psychologically stressful conditions were selected to participate in the pilot study. In addition, a Stroop Colour-Word test (Stroop CW) was used to exhaust/prepare the volunteers prior to the d2 test used for assessment of cognitive function of patients. The participants were randomised into two groups, one (n=20) of which received a single tablet of ADAPT-232 (270mg), while a second (n=20) received a single tablet of placebo. The effects of the extract were measured prior to treatment and two hours after treatment using the d2 Test of Attention (d2). The results of the d2 test showed a significant difference (p<0.05) in attention, speed, and accuracy (TN-E scores) between the two treatment groups. The subjects in the ADAPT-232 group quickly (two hours after verum was taken) gained improved attention and increased speed and accuracy during stressful cognitive tasks, in comparison to placebo. There was also a tendency of ADAPT-232 to reduce percentage of errors, which means better accuracy, quality of the work, and degree of care in the volunteers under stressful conditions. No serious side effects were reported, although a few minor adverse events, such as sleepiness and cold extremities, were observed in both treatment groups.”Although the study was controlled in several important respects, it only measured a single outcome: attention, speed and accuracy of pursuing cognitive tasks two hours after administration of a single dose of an adaptogens cocktail.
Another example human study related to stress is the study reported in the 2010 publication Adaptogenic potential of a polyherbal natural health product: report on a longitudinal clinical trial. “Stress is a risk factor for a number of diseases and is an important predictor of health in general. Herbal medicines have been used as adaptogens to regulate and improve the stress response and there is evidence to support the use of herbal medicines for this purpose. We conducted an open-label longitudinal study on the natural health product, OCTA(c), a compound mixture of eight herbs, to determine its effects on perceptions of stress. Eighteen participants were enrolled in the study and were followed over a period of 3 months. Primary endpoints included scores from four validated questionnaires (SF-36v2, PSS, STAI and BDI-II), serum DHEA, ALT, AST and creatinine all measured at 12 weeks. Seventeen patients completed the study. Except for the physical summary score of the SF36 questionnaire, all the subjective scores indicated a highly significant (P < 0.0001) improvement in the participants’ ability to cope with stress. No adverse effects were reported and there was no evidence of damage to the liver or kidney based on serum markers. Initial evidence for this polyherbal compound supports its potential as an effective ‘adaptogenic’ aid in dealing with stress. Further research using a randomized controlled design is necessary to confirm the findings from this pilot study.”
Yet another controlled human study is reported for the adaptogens Bacopa monnieri in the 2008 publication Effects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly: a randomized, double-blind, placebo-controlled trial. “OBJECTIVES: Study aims were to evaluate effects of Bacopa monnieri whole plant standardized dry extract on cognitive function and affect and its safety and tolerability in healthy elderly study participants. DESIGN: The study was a randomized, double-blind, placebo-controlled clinical trial with a placebo run-in of 6 weeks and a treatment period of 12 weeks. Setting/location: Volunteers were recruited from the community to a clinic in Portland, Oregon by public notification. SUBJECTS: Fifty-four (54) participants, 65 or older (mean 73.5 years), without clinical signs of dementia, were recruited and randomized to Bacopa or placebo. Forty-eight (48) completed the study with 24 in each group. INTERVENTIONS: Standardized B. monnieri extract 300 mg/day or a similar placebo tablet orally for 12 weeks. OUTCOME MEASURES: The primary outcome variable was the delayed recall score from the Rey Auditory Verbal Learning Test (AVLT). Other cognitive measures were the Stroop Task assessing the ability to ignore irrelevant information, the Divided Attention Task (DAT), and the Wechsler Adult Intelligence Scale (WAIS) letter-digit test of immediate working memory. Affective measures were the State-Trait Anxiety Inventory, Center for Epidemiologic Studies Depression scale (CESD)-10 depression scale, and the Profile of Mood States. Vital signs were also monitored. RESULTS: Controlling for baseline cognitive deficit using the Blessed Orientation-Memory-Concentration test, Bacopa participants had enhanced AVLT delayed word recall memory scores relative to placebo. Stroop results were similarly significant, with the Bacopa group improving and the placebo group unchanged. CESD-10 depression scores, combined state plus trait anxiety scores, and heart rate decreased over time for the Bacopa group but increased for the placebo group. No effects were found on the DAT, WAIS digit task, mood, or blood pressure. The dose was well tolerated with few adverse events (Bacopa n = 9, placebo n = 10), primarily stomach upset. CONCLUSIONS: This study provides further evidence that B. monnieri has potential for safely enhancing cognitive performance in the aging.”
Numerous small-animal studies of various adaptogens over the years appear to indicate that they are generally safe and efficacious, particularly for relieving stress.
An example is discussed in the 2011 publication related to curcumin Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostasis. [J Nat Med. 2011] “The present study was designed to investigate the role of curcumin in chronic stress and chronic unpredictable stress-induced memory deficits and alteration of functional homeostasis in mice. Chronic stress was induced by immobilizing the animal for 2 h daily for 10 days, whereas chronic unpredictable stress was induced by employing a battery of stressors of variable magnitude and time for 10 days. Curcumin was administered to drug-treated mice prior to induction of stress. Body weight, adrenal gland weight, ulcer index and biochemical levels of glucose, creatine kinase, cholesterol, corticosterone, thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) were evaluated to assess stress-induced functional changes. Memory deficits were evaluated using the elevated plus maze (EPM) model. Chronic stress and chronic unpredictable stress significantly increased the levels of corticosterone, glucose and creatine kinase and decreased cholesterol levels. Moreover, chronic stress and chronic unpredictable stress resulted in severe memory deficits along with adrenal hypertrophy, weight loss and gastric ulceration. Chronic stress and chronic unpredictable stress also increased oxidative stress assessed in terms of increase in TBARS and decrease in GSH levels. Pretreatment with curcumin (25 and 50 mg/kg p.o.) attenuated chronic stress and chronic unpredictable stress-associated memory deficits, biochemical alterations, pathological outcomes and oxidative stress. It may be concluded that curcumin-mediated antioxidant actions and decrease in corticosterone secretion are responsible for its adaptogenic and memory restorative actions in chronic and chronic unpredictable stress.”
There is a significant collection of earlier studies related to adaptogens, many based on mouse and rat models, including:
- Adaptogenic activity of Siotone, a polyherbal formulation of Ayurvedic rasayanas.[Indian J Exp Biol. 2000]
Adaptogenic activity of Siotone, a polyherbal formulation of Ayurvedic rasayanas.
Bhattacharya SK, Bhattacharya A, Chakrabarti A. Indian J Exp Biol. 2000 Feb; 38(2):119-28.
- Effect of poly herbal formulation, EuMil, on neurochemical perturbations induced by chronic stress.[Indian J Exp Biol. 2002]
Effect of poly herbal formulation, EuMil, on neurochemical perturbations induced by chronic stress.
Bhattacharya A, Muruganandam AV, Kumar V, Bhattacharya SK. Indian J Exp Biol. 2002 Oct; 40(10):1161-3.
- Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress.[Pharmacol Biochem Behav. 2003]
Adaptogenic activity of Withania somnifera: an experimental study using a rat model of chronic stress.
Bhattacharya SK, Muruganandam AV. Pharmacol Biochem Behav. 2003 Jun; 75(3):547-55.
- Review Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine.[Phytother Res. 1999]
Review Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine.
Rege NN, Thatte UM, Dahanukar SA. Phytother Res. 1999 Jun; 13(4):275-91.
- Review [Mechanisms of homeostatic disorders induced by stress vibration injury (literature review)].[Med Tr Prom Ekol. 2000]
- Anti-stress activity of Indian Hypericum perforatum L. Indian J Exp Biol. 2001
- Behavioural and neurochemical evaluation of Perment an herbal formulation in chronic unpredictable mild stress induced depressive model. Indian J Exp Biol. 2011.
- Adaptogenic and anti-amnesic properties of Evolvulus alsinoides in rodents. Pharmacol Biochem Behav. 2005
- Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine.. Phytother Res. 1999 Review.
- Anxiolytic-antidepressant activity of Withania somnifera glycowithanolides: an experimental study. Phytomedicine. 2000
- Adaptogenic effect of Bacopa monniera (Brahmi). Pharmacol Biochem Behav. 2003
- Behavioural studies on BR-16A (Mentat), a herbal psychotropic formulation. Indian J Exp Biol. 1994 Jan;32(1):37-43.
- Effect of Bacopa monniera on stress induced changes in plasma corticosterone and brain monoamines in rats. J Ethnopharmacol. 2007
- Nutritional and botanical interventions to assist with the adaptation to stress. Altern Med Rev. 1999
- Evaluation of Geriforte, an herbal geriatric tonic, on antioxidant defense system in Wistar rats. Ann N Y Acad Sci. 1994
- Evaluation of adaptogenic activity profile of herbal preparation. Indian J Exp Biol. 2006
- Adaptogenic and nootropic activities of aqueous extract of Vitis vinifera (grape seed): an experimental study in rat model. BMC Complement Altern Med. 2005
- Attenuation of acute and chronic restraint stress-induced perturbations in experimental animals by Zingiber officinale Roscoe. Food Chem Toxicol. 2010
- Systemic administration of defined extracts from Withania somnifera (Indian Ginseng) and Shilajit differentially affects cholinergic but not glutamatergic and GABAergic markers in rat brain. Neurochem Int. 1997
Again, these publications all suggest that the adaptogens discussed indeed have health-producing properties.
Except for one important comment which I don’t want to hold back, my impression of adaptogens is discussed at the end of the following blog entry. Adaptogens Part 2 – focus on rhodiola. The comment is that virtually all of the research literature on adaptogens misses a crucial new point of view – that the stress-relieving, antioxidant and other important health-producing properties of adaptogens are almost certainly due to their being activators of Nrf2, and that they act via hormesis. See the blog entries The pivotal role of Nrf2. Part 1 – a new view on the control of oxidative damage and generation of hormetic effects, The pivotal role of Nrf2. Part 2 – foods, phyto-substances and other substances that turn on Nrf2, and The pivotal role of Nrf2. Part 3 – Part 3 – Is promotion of Nrf2 expression a viable strategy for human human healthspan and lifespan extension? The Nrf2 viewpoint is a new way for looking at the actions of many phytosubstances that did not exist when much of the research literature on adaptogens was generated. But even the current publications on adaptogens I have seen do not mention Nrf2.