A preliminary review of studies on adaptogens: comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide

The term of adaptogen was first proposed in 1940 by a scientist from the USSR, namely, N. Lazarev, when he described Schisandra chinensis (Turcz.) Bail. and other herbs with the following definition: plant-originated adaptogens that can non-specifically the enhance human body. According to the primary definition of adaptogens, these substances must meet three criteria: first, adaptogens must to be non-specific and must assist the human body in resisting a wide range of adverse conditions, such as physical, chemical or biological stress. These may include environmental pollution, climate change, radiation, infectious diseases, and interpersonal disharmony. Second, adaptogens must maintain homeostasis in humans, that is, these substances can offset or resist physical disorders caused by external stress. Third, adaptogens must not harm the normal functions of the human body.

Then I.Brekhman, a Soviet scientist, studied ginseng in approximately 1950, he extended the concept of adaptogens as follows: medicines that have similar functions as adaptogens can help the body maintain ideal homeostasis under adverse or stressful conditions.

Again, Brekhman and Dardymov further defined plant-originated adaptogens in 1969 [1]. According to this definition, plant-originated adaptogens meet four criteria: first, plant-originated adaptogens must reduce the harm caused by stressed states, such as fatigue, infection, and depression; second, plant-originated adaptogens must have positive excitatory effects on the human body; third, in contrast to traditional stimulants, the excitatory effects produced by plant-originated adaptogens must not cause side effects such as insomnia, low protein synthesis, or excessive energy consumption; fourth, plant-originated adaptogens must not harm the human body.

In the 1990s, a group of scientists, comprised of Hildebert Wagner, George Wikman and Alexander Panossian, performed many studies on adaptogens and proposed the following definition: adaptogens are natural bioregulators that increase the ability to adapt environmental factors and avoid the damage caused by those factors. In fact, the advantage of adaptogens are they minimized the bodily response to stress, reducing the negative reactions during the alarm phase and eliminating, or at least decreasing, the onset of the exhaustion phase that is part of the so-called general adaptation syndrome [2].

With continuous research for more than half a century, the concept of adaptogens has been continuously modified and perfected. In 1998, the American Food and Drug Administration (FDA) [3] defined an adaptogen as a new kind of metabolic regulator that has been proved to help in environmental adaptation and to prevent external harms. Adaptogen has been generally used as a functional term.

Yance, an American herbal doctor, held a view that adaptogens can improve our ability to recognize, respond, recover, and restore or regenerate. He divided adaptogens into three categories, including primary adaptogens, secondary adaptogens, and adaptogen companions, based on his clinical experience [4]. Primary adaptogens are consistent with the traditional definition of adaptogens and satisfy specific criterias. The criterias contains: abundant scientific research confirmed their adaptogenic characters, guarantee of general resistance and non-specific action in the human body, maintenance or restoration for homeostasis, and adverse- or toxic-effects after prolonged use [5].

Furthermore, some precise scientific experiments demonstrated that adaptogens can enhance the resistance of human body against various external stimuli as non-specific regulators. Adaptogen function mainly by affecting the hypothalamic–pituitary–adrenal (HPA axis) in response to stimulation by external stress. Primary adaptogens can not only maintain or recover homeostasis and allostasis but can also promote anabolic recovery. Primary adaptogens can produce positive stress response and the associated hormone expression. Primary adaptogens strengthen the functioning of each systems, promote optimal response, promote recovery of function, and help regulate energy use by improving the function of neuroendocrine system and enhancing cellular energy transfer, which can make body utilize oxygen, glucose, lipids and proteins very effectively, thus providing us with a steady supply of energy [4].

Another category of adaptogens is secondary adaptogens, which are consistent with most traditional definitions of adaptogens but not all of the criteria of primary adaptogens. Secondary adaptogens cannot influence the HPA axis directly; however, these adaptogens can affect the immune, nervous and endocrine systems. Secondary adaptogens share several common features: first, these adaptogens typically exert influence on the immune, nervous and endocrine systems; second, these adaptogens do not influence the HPA axis, directly; third, these plant-originated adaptogens include fatty acids, sterols and phenols; fourth, these substances can enhance anabolism. While the secondary adaptogens may meet most of the qualifications of primary adaptogens, but they have yet to be studied extensively [5].

Another category is adaptogen companions, which may not satisfy all the traditional standards but can have beneficial effects on the HPA axis and on anabolism to support the functions of adaptogens. Although these kinds of medicinal plants have similar functions as the other two kinds of adaptogens mentioned above, these plants can not formally be called adaptogen. Thus, these plants are classified as adaptogens companions because they can act synergistically with the other two kinds of adaptogens mentioned above, thereby improving the effects of the adaptogens [5].

Currently, studies have confirmed that the following plants are true adaptogens: Panax ginseng C.A.Mey, Schisandra chinensis (Turcz.) Baill., Acanthopanax senticosus (Rupr. et Maxim.) Harms, Rhodiola crenulata (Hook. f. et Thoms) S.H.Fu, and Lepidium meyenii Walp.

According to web of science database, we searched the key word, adaptogen. Based on the analysis of results, we got a conclusion that more and more researches focus on this field over past 10 years and it showed an increasing tendency from 1999 to 2018, which profiles that it is still a worthwhile direction to explore. Furthermore, we also found out that the many published articles concentrated on the direction of pharmacology pharmacy, biochemistry molecular biology, plant sciences and agriculture. It is still worthy to show its historical development and find out the relationships among adaptogen and tonics and ginseng-like herbs worldwide, which can give a hint to further research in plant-originated adaptogen. Summarized the results of previous studies and our own researches focused on tonics from TCM, we launched out our understanding of adaptogen: Herbs which can non-specific and non-toxicity help human body resist the environmental stress to maintain a homeostasis. The mechanism may multi-targets and multi-channel network to the neuroendocrine system. The adaptogens with tonics from TCM and the world-wide ginseng-like herbs have similar phytochemical and pharmacological properties.

Adaptogens can affect different tissues and organs, and adjust each of these parts to attain homeostasis.

In the case of various stress modes, adaptogens can activate the adjustment of different responses to cope with different forms of stress. Adaptogens are the material basis of the bodily response to the external environment and can act on the immune system and the stress response system, showing in Fig. 1. The non-specific response mode, especially the hormone response mode, occurs when homeostasis is not the driving force. When hormone levels exceed the critical level, the complex neurosecretory reactions may have harmful effects [55, 56]. The human stress response system consists of the central nervous system (CNS), which includes neurons of the hypothalamic paraventricular nucleus, and is associated with to corticotropin releasing hormone (CRH), and arginine vasopressin (AVP), and the adrenalin nucleus as well as its distal ends of the brainstem, the HPA axis and the peripheral nervous system [57]. The central coordination system to respond to external pressure consists of CRH neurons, AVP neurons, catecholamine neurons and other cell tissues, and the HPA axis and sympathetic nervous system (SNS) represent the limbs [58]. CRH and catecholamine neurons interact with each other. The SNS and HPA system interact in terms of functions and systematic anatomy. When responding to the external environment, these systems can interact on different levels, for example, catecholamine can stimulate the HPA axis by releasing of CRH, and the hormone produced by the HPA axis can act on the SNS system [33].

Recent studies have shown that the inhibitory effects and long-term overexpression of endogenous glucocorticoids cause stimulatory effects that are adjusted by SNS under stress. The secretion of CRH and AVP increases, which is stimulated by external pressure, thereby promoting the secretion of cortisol and adrenocorticotropic hormone. Furthermore, angiotensin, cytokines and arachidonic acid metabolites participate in the stress response. SNS provides the human body with a fast response mechanism to external stress. In addition to catecholamine, the sympathetic and parasympathetic nervous systems can also secrete a variety of neuropeptides, ATP and nitric oxide (NO) [59]. The following effects are observed upon adjustment the HPA axis: an increase in and regulation of energy circulation; reduction in the feeling of external pressure; enhancement of resistance; improvement of mental concentration; facilitation of deep sleep period after sleep. These functions are all considered the primary function of adaptogens [55, 56, 60].

Adaptogens do not increase the levels of cortisol and NO in the human body under acute physiological loads [6, 31, 61]. Plant-originated adaptogens, for example, Schisandra chinensis (Turcz.) Baill, can prevent and resist stress because these substances can activate the secretion of cortisol and NO in the plasms and saliva, allowing the body to adapt to heavier loads. After the consumption of plant-originated adaptogens, physical exercises do not increase the level of cortisol and NO in the human body; in fact, the levels decrease, comparing to those present prior to physical exercise. Thus, adaptogens can increase the level of messenger substances that activate stress (NO) and suppress stress (cortisol).

Adaptogens can improve the stress response system to respond to high levels of external signals in the normal or abnormal states. We should determine the similarities or differences between adaptogens and known classical metabolic regulators. According to the above description, the main difference may be that adaptogen can stimulate the CNS. It is now possible to obtain additional information at the biochemical level and identify analogues adrenal cortex hormone analogue, catecholamine analogue and so indicating that the active ingredients have similar structures.

There is much overlap between these medicines and many tonics are internationally recognized as plant-originated adaptogens [2].

Tonics have wide range of applications in traditional Chinese medicine and can be used under the conditions of low body resistance and weak constitution or when the human body is finding it difficult to fight severe diseases, this function of tonics is similar to that of plant-originated adaptogens [78]. Tonics typically are adaptogens, but not always. They are similar in the following aspects: First, the clinical application and mechanisms of action of these substances are similar. Based on their current applications, tonics and plant-originated adaptogens can be described as substances that regulate human bodily functions in order to attain homeostasis. The primary effects exhibited by these substances are regulation of the immune system, improving the disorders of the nervous system, anti-fatigue effects and overall nourishment. In terms of specific mechanisms, both medicines can affect the HPA axis in the immune-neuro-endocrine system, thereby achieving the above pharmacological effects [79]. Second, the plants of origin of these substances are similar [2]. Chinese herbs considered to be both adaptogens and tonics include the following: Panax ginseng C.A.Mey, Panax quniquefolius L., Panax notoginseng (Burkill) F.H.Chen, Eleutherococcus senticosus (Rupr. & Maxim.) Maxim, Sedum rosea (L.) Scop., and Schisandra chinensis (Turcz.) Baill. According to the terminology used in traditional Chinese medicine, the mechanism of action of plant-originated adaptogens is to achieve equilibrium in both yin and yang, showing great vitality [80].

According to Panossian’s conclusion, the main active chemical components can be divided into the following two categories. The first category includes terpenoids with four-ring skeletons that are similar to cortisol: sitoindosides (Withania somnifera), cucurbitacin-R-saponin (Bryonia dioica). The second category includes aromatic compounds with structures similar to that of catecholamine: (a) lignans: eleuteroside E (Acanthopanax senticosus (Rupr. et Maxim) Harms), schisandrin b (Schisandra chinensis (Turcz.)); (b) phenylpropane derivatives: syringin (Acanthopanax senticosus (Rupr. et Maxim) Harms), cinnamyl glycoside (Rhodiola crenulata (Hook.f. et Thoms) S.H.Fu); (c) phenylethane derivatives: salidroside.

Tonics have the following functions: enriching and activating blood (promoting the secretion of erythropoietin and inducing the production of stimulatory factors, for example, macrophage colonies, to activate blood), regulating cellular and humoral immunity, and affecting cytokine activity. These functions are similar with those of the plant-originated adaptogens mentioned above. Plant-originated adaptogens are generally considered to be the “elite of herbs” [5], and in Chinese medicine, tonics are considered the highest grade of medicine [81]. In traditional Chinese medicine theory, tonics are also considered to be top grades in traditional Chinese medicine. It is helpful to expand the range of plant-originated adaptogen species and to have an in-depth analysis about the mechanism of tonic traditional Chinese medicine.

Many regions, ethnic groups and countries, they have their own medical histories and habits. Continuous development and transfer of knowledge through generations leads to the formation of unique medicinal systems such as traditional Chinese medicine and Indian ayurvedic medicine. Coincidentally, in different regions and medical systems, there are several medicinal plants that are considered to be national treasures or that are called ginseng locally. There is much overlap between plant-originated adaptogens and ginseng species worldwide. Furthermore, most ginseng species worldwide are internationally recognized as plant-originated adaptogens. Both ginseng-like herbs worldwide and plant-originated adaptogens have very similar clinical applications. Ginseng species are widely used by local communities world-wide because these plants can enhance the resistance of the human body and can have various beneficial effects, such as anti-fatigue, anti-ageing, anti-stress, anti-anxiety, anti-inflammatory, and anti-depression. Furthermore, ginseng species may improve the circulatory system and immune system [34], which correlates precisely to the function of adaptogens.

Plant-originated adaptogens have been demonstrated to regulate stress-related changes, at least in animal experiments. However, even after more than 40-years of herbal research, there are very few drugs that have been successfully introduced as adaptogens in modern medicine. Most of these kinds of plant-based medicines are considered to be plant-originated adaptogens and the remaining few are immune enhancers, anabolic agents and antioxidants, which are the same as plant-originated adaptogens. Therefore, there are many difficulties associated with judging whether a plant is a plant-originated adaptogen or not [94].

Adaptogens are stress response modifiers that non-specifically increase resistance to various stressors, thereby promoting adaptation and survival. Adapting to environmental challenges are multistep processes that involve diverse mechanisms and interactions. Multiple molecular networks are involved that coordinate both intracellular and extracellular stress signaling. The metabolic regulation of homeostasis by adaptogens at the cellular and systems levels is associated with multiple targets [95]. To date, the main problem in the research of mechanism of adaptogens, is the lack of suitable stress-response animal models. The stress responses system can be divided into three parts: stressor, stress response and stress performance [96]. The stressor is the object that induces physical strain; therefore, a stressor may be biological (infection), physical (external force, extreme environment), chemical (medicine, ethanol), or psychological (sadness, argument). When an organism is exposed to a stressor, the neuroendocrine system of the body changes. It is easy to study stress performances because these effects are visible [97].

Therefore, stress is known to lead to high blood pressure, myocardial ischemia, depression and even cancer. Briefly, stress performance is the manifestation of the final effect of the stress response on the target organ. However, it remains challenging to study various steps of this stress response [98]. First, this difficulty is associated with the stressor because it is difficult to quantify external stressors, especially psychological stressors, for example, sadness. In addition, we know little about the interactions between stressors and the body. The specific response of mechanisms induced by stressors affect broad-spectrum stress response. Second, this difficulty is associated with the stress response. In the terms of development, hormones, neurotransmitters, neuro-regulators and cytokines, which are involved in the response have been identified, but the specific functions of these proteins divisions remain unknown. The identity of the first substance to regulate the stress response remains unclear, and it has not been determined whether there are different mechanisms for different stressors. There are no definitive results regarding the specific mechanisms and pathway changes of that lead to conversion of the status from unsuitable to suitable. As a result, it is impossible to differentiate and characterize the different stages of stress response (including adaptation), making the response difficult to quantify [97]. Therefore, scientists use “prevention of stress manifestation” as a guideline to evaluate the anti-stress properties of a drug [99]. Third, the difficulty is associated with stress expression. According to the strength and severity of the stressor, different changes are observed. Genetic or other external factors (species, day–night cycles, gender, age and physiological state of tissues or organs) also affect the extent of overall stress expression. The difficulties mentioned above will appear in the process of the mechanism of action of adaptogens; therefore, it is necessary to further discuss the mechanisms, targets, similarities and differences associated with the pharmacological functions.

To date, various studies and practical applications have shown that plant-originated adaptogens are a kind of elite herbal medicine, playing an important role in human health and helping the human body resist various stress factors. However, the clinical application of plant-originated adaptogens and their use in health care products remains in the preliminary stage. Categorization of plant-originated adaptogens, clarification of their pharmacological functions, and the determination of the similarities and differences between adaptogens, tonics and ginseng species worldwide, will help in effective utilization of plant-originated adaptogens, and provide a new way to guarantee human health.