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

Abstract

Abstract Modern studies have shown that adaptogens can non-specifically enhance the resistance of human body under a wide range of external stress conditions with a multi-targeted and multi-channel network-like manner, especially by affect the immune-neuro-endocrine system and the hypothalamic–pituitary–adrenal axis. This review article draws the attention to the relationships of adaptogens, tonics from traditional Chinese medicine (TCM) and ginseng-like herbs worldwide, which all have similar plant sources and clinical applications. To clarify the sources and pharmacological mechanisms of these plant-originated adaptogens, which will provide useful information for the utilization of adaptogens to improve the human health. Meanwhile, the TCMs and the world-wide ginseng-like herbs from each region’s ethnopharmacology will be beneficial modernization and globalization.

Full text

Liaoetal. Chin Med (2018) 13:57
https://doi.org/10.1186/s13020-018-0214-9
REVIEW
A preliminary review ofstudies
onadaptogens: comparison oftheir bioactivity
inTCM withthatof ginseng-like herbs used
worldwide
Lian‑ying Liao1,2, Yi‑fan He1,2, Li Li1,2, Hong Meng1,2, Yin‑mao Dong1,2, Fan Yi1,2* and Pei‑gen Xiao3
Abstract
Modern studies have shown that adaptogens can non‑specifically enhance the resistance of human body under a
wide range of external stress conditions with a multi‑targeted and multi‑channel network‑like manner, especially by
affect the immune‑neuro‑endocrine system and the hypothalamic–pituitary–adrenal axis. This review article draws
the attention to the relationships of adaptogens, tonics from traditional Chinese medicine (TCM) and ginseng‑like
herbs worldwide, which all have similar plant sources and clinical applications. To clarify the sources and pharmaco‑
logical mechanisms of these plant‑originated adaptogens, which will provide useful information for the utilization of
adaptogens to improve the human health. Meanwhile, the TCMs and the world‑wide ginseng‑like herbs from each
region’s ethnopharmacology will be beneficial modernization and globalization.
Keywords: Adaptogen, Immune‑neuro‑endocrine system, HPA axis, Tonics, Ginseng‑like herbs worldwide
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Introduction
e 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 adapto-
gens, 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 condi-
tions, such as physical, chemical or biological stress.
ese may include environmental pollution, climate
change, radiation, infectious diseases, and interpersonal
disharmony. Second, adaptogens must maintain homeo-
stasis in humans, that is, these substances can offset or
resist physical disorders caused by external stress. ird,
adaptogens must not harm the normal functions of the
human body.
en I.Brekhman, a Soviet scientist, studied ginseng in
approximately 1950, he extended the concept of adapto-
gens 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 defi-
nition, 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 Hilde-
bert Wagner, George Wikman and Alexander Panossian,
performed many studies on adaptogens and proposed the
Open Access
Chinese Medicine
*Correspondence: fantasyee@btbu.edu.cn
2 Beijing Key Laboratory of Plant Resources Research and Development,
Beijing Technology and Business University, No. 11/33, Fucheng Road,
Haidian District, Beijing 100048, People’s Republic of China
Full list of author information is available at the end of the article

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Liaoetal. Chin Med (2018) 13:57
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 cen-
tury, 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 exter-
nal harms. Adaptogen has been generally used as a func-
tional 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 com-
panions, based on his clinical experience [4]. Primary
adaptogens are consistent with the traditional definition
of adaptogens and satisfy specific criterias. e 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 resist-
ance 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 homeosta-
sis and allostasis but can also promote anabolic recovery.
Primary adaptogens can produce positive stress response
and the associated hormone expression. Primary adap-
togens strengthen the functioning of each systems, pro-
mote 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 adapto-
gens, which are consistent with most traditional defini-
tions 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 adap-
togens, 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 anabo-
lism 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.
us, these plants are classified as adaptogens compan-
ions 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 crenu-
lata (Hook. f. et oms) 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, biochem-
istry molecular biology, plant sciences and agriculture.
It is still worthy to show its historical development and
find out the relationships among adaptogen and ton-
ics 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.
e mechanism may multi-targets and multi-channel
network to the neuroendocrine system. e adaptogens
with tonics from TCM and the world-wide ginseng-like
herbs have similar phytochemical and pharmacological
properties.
The functions ofadaptogens
Adaptogens can affect different tissues and organs, and
adjust each of these parts to attain homeostasis.

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Liaoetal. Chin Med (2018) 13:57
Adaptogens andadrenal fatigue
Adrenals, the glands of stress, mobilize various stress
responses to each stress, including physical, biochemi-
cal, hormonal, thermal, internal, external, emotional and
mental. Stress rather than pathological damage is the
primary cause of adrenal fatigue. Excessive stress may
be caused by a single strong stimulatory event or by the
accumulation of chronic or repeated stress. When the
capacity of the adrenals to secrete enough hormones
that can make the necessary physiological, and bio-
chemical compensations for that level of stress cannot
meet the requirements of continually excessive pressure,
adrenal fatigue occurs. e adrenal gland continues to
work under adrenal fatigue but cannot maintain normal
homeostasis. On the one hand, if the adrenals can deal
well with this circumstance and cortisol levels remain
adequately elevated to handle the various stresses, over
time, the signs and symptoms of metabolic syndrome,
such as muscle wastage, hyperglycemia, and suppresses
immune or inflammatory responses [6], begin to appear.
On the other hand, if the adrenals are not able to meet
the demands, adrenal fatigue appears, usually developing
more quickly than metabolic syndrome, and which can
become so severe as to disable them [7].
e amount of stress hormone produced by the human
body increases under external pressure. Adaptogens can
increase the effectiveness of adrenal gland secretion,
thereby abolishing excess hormone production [8]. Other
studies can prove this statement: In 2001, B.T.Gaffney
found that the suggested that Panax ginseng inhibits
11-beta hydroxysteroid dehydrogenase one and Eleuthe-
rococcus senticosus inhibits catechol-O-methyl trans-
ferase, both of which reside in close proximity to stress
hormone receptors and catalyze the degradation of stress
hormones into inactive compounds [9]. In the absence of
stress, adaptogens can accelerate the closure of the adre-
nal gland. Furthermore, adaptogens can increase cellular
energy levels and prevent oxidative damages, leading to
the maintenance of normal adrenal function. e follow-
ing plant-originated adaptogens support adrenal func-
tion: Panax quinquefolius L. [10], Withania somnifera
[11], Panax ginseng C.A.Mey. [9], Codonopsis pilosula
(Franch.)Nannf. [12], Eleutherococcus senticosus (Rupr.
& Maxim.) Maxim. [13], Gynostemma pentaphyllum
(unb.) Makino, Glycyrrhiza uralensis Fisch.ex DC.
[14], Ganoderma Lucidum Karst [15], and Sedum rosea
(L.) Scop [16].
Adaptogens andarthritis
Arthritis is caused by tissue damages and joint diseases,
which is typically accompanied by pain and swelling. e
most common types of arthritis are osteoarthritis and
rheumatoid arthritis. Fibromyalgia maybe an accompa-
nying condition of arthritis; however, it is not considered
a form of arthritis because it does not cause inflamma-
tion or joint damage.
Adaptogens can reduce arthritis-associated inflamma-
tion and pain effectively [17, 18]. e anti-inflammatory
effects of the following plant-originated adaptogens can
be used to provide relief rheumatoid arthritis: Witha-
nia somnifera [8, 19], Panax ginseng C.A.Mey [20],
Gynostemma pentaphyllum (unb.) Makino [21], Gano-
derma Lucidum Karst [22], Sedum rosea (L.) Scop. [23],
and Glycyrhiza uralensis Fisch. ex DC. [24].
Adaptogens andsleep
Many people suffer from insomnia and other sleep-
related problems. External stress perturbs the normal
secretion of circadian cortisol, which is the main cause
of sleep-related problems. e secretion of cortisol fol-
lows the biological clock and external circadian rhythms.
e secretion of cortisol peaks in the morning and then
decreases, reaching a minimum value at night. Proper
exercise, diet and sleep can help maintain stable cortisol
levels in the human body.
Adaptogens help produce cortisol and relieve stress [7,
25]. Studies by Steven Maimes and N. V. Provalova sug-
gest that the following plant-originated adaptogens can
act as sleep aids: Panax quniquefolius L. [26], Withania
somnifera (L.) Dunal. [27], Schisandra chinensis (Turcz.)
Baill. [28], Gynostemma pentaphyllum (unb.) Makino
[29], and Sedum rosea (L.) Scop [30].
e following plant-originated adaptogens can allevi-
ate the effects of the time difference syndrome, caused
by disruption of physiological rhythm of the human
body: Panax quniquefolius L., Panax ginseng C.A.Mey,
Gynostemma pentaphyllum (unb.) Makino, Schisandra
chinensis (Turcz.) Baill., and Sedum rosea (L.) [31, 32].
Adaptogens andtheneuroendocrine system
One of the most important functions of adaptogens is
their ability to help stabilize the internal environment of
the human body by affecting the neuroendocrine system.
e chemicals in plant-originated adaptogens enhance
the ability to adapt to external environments and avoid
damage [33–35]. A unique feature of adaptogens is that
these substances affect the neuroendocrine system and
the cellular energy system. Aaptogens can increase the
rates of oxygen, protein, fat and sugar utilization. In addi-
tion to plant-originated adaptogens, other plants may
have some of the functions mentioned above, but plant-
originated adaptogens have a broad range of functions
and systematically strengthen the stability of the internal
environment of the human body [34, 36].

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Anti‑tumor application ofplant‑originated adaptogens
Researchers have found that plant-originated adaptogens
have a positive influence on all aspects of the health of
animals and humans [37]. Cancers studies have shown
that plant-originated adaptogen can reduce the risks of
cancers [38].
Plant-originated adaptogens play key roles in anti-
tumor and multifaceted anticancer mechanisms, such as
inhibition of cancer cells production, stabilization of the
functions of human body, and promotion of cell repair
[39, 40]. e anti-tumor effect of adaptogens is often
closely linked to immune mechanisms. In other words,
adaptogens can activate macrophages, T-lymphocytes,
NK cells and so on to inhibit the growth of tumors and
enhance cell-selective apoptosis and intercellular connec-
tion [16, 41–43].
e most common chemical anti-tumor medicines
currently on the market have side effects such as cyto-
toxicity and immune suppression. Plant-based immune
regulators, for example, plant-originated adaptogens, are
generally used as auxiliary treatments to reduce the side
effects of these chemical medicines and regain health
[44, 45]. Notably, the application of adaptogens improves
the tolerance of humans to drug cytotoxicity [46]. Adap-
togens can improve the physical conditions of cancer
patients in the following ways: first, as modulators of bio-
logical responses, adaptogens can the remodel immune
mechanism and non-specifically enhance the resistance
of the human body [46]; second, adaptogens can pro-
mote the production of marrow, increase the amount
of blood cells and reduce infection [47]; third, adapto-
gens affect the entire body, from cells to organs includ-
ing the liver, kidney, heart and gastrointestinal tract [7];
fourth, adaptogens can strengthen the lethal effects of
chemotherapy and radiotherapy on cancer cells [48];
fifth, adaptogens can inhibit the development of multid-
rug resistance [49]; sixth, adaptogens can inhibit tumor
metastasis and cancer cell aggregation [50]; seven, adap-
togens can reduce stress hormone levels during immune
dysfunction, which is associated with tumor growth [51].
When cancer cells adapt to chemotherapy, the main
consequence is the development of multidrug resistance.
e most simple mechanism of the development of mul-
tidrug resistance is as follows: anti-tumor drug molecules
flow out from cancer cells through membrane chan-
nel proteins driven by ATP, especially by adjustment of
P-glycoprotein pump (Pgp-pump) and due to the effects
of breast cancer resistance protein-1 (BCRP/ABCG-2)
and multidrug-resistance-associated protein-1 (MRP-1)
from thymic cancer cells [52]. Among plant-originated
adaptogens, Panax ginseng C.A.Mey can substantially
reduce multidrug resistance by inhibiting Pgp, and it has
been shown that Panax ginseng C.A.Mey can prolong the
life of the cancer-bearing mice in animal experiments
[24, 53]. In addition, epigallocatechin-gallate (EGCG) in
Eurycoma longifolia can inhibit the expression of Bcl-2 to
prevent the development multidrug resistance [54].
Exploration ofthemechanism ofaction
ofadaptogens
In the case of various stress modes, adaptogens can acti-
vate the adjustment of different responses to cope with
different forms of stress. Adaptogens are the material
basis of the bodily response to the external environ-
ment and can act on the immune system and the stress
response system, showing in Fig. 1. e non-specific
External stress
Homeostasis
and allostasis
ADAPTOGEN
Adrenal Fague
Arthris
Sleep
Neuroendocrine System
An-tumor
Ginseng-like Herbs
Tonics from TCM
PHYTOCHEMISTRY
PHARMACOLOGY
Fig. 1 The mechanism of action of plant‑originated adaptogens on human body

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Liaoetal. Chin Med (2018) 13:57
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]. e human stress response system consists of the
central nervous system (CNS), which includes neurons of
the hypothalamic paraventricular nucleus, and is associ-
ated 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]. e central coordi-
nation 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. e SNS
and HPA system interact in terms of functions and sys-
tematic anatomy. When responding to the external envi-
ronment, 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 glucocorti-
coids cause stimulatory effects that are adjusted by SNS
under stress. e secretion of CRH and AVP increases,
which is stimulated by external pressure, thereby pro-
moting the secretion of cortisol and adrenocortico-
tropic 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 neuropep-
tides, ATP and nitric oxide (NO) [59]. e following
effects are observed upon adjustment the HPA axis: an
increase in and regulation of energy circulation; reduc-
tion in the feeling of external pressure; enhancement of
resistance; improvement of mental concentration; facili-
tation of deep sleep period after sleep. ese 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. us, 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 informa-
tion at the biochemical level and identify analogues adre-
nal cortex hormone analogue, catecholamine analogue
and so indicating that the active ingredients have similar
structures.
Adaptogens andChinese tonics
ere is much overlap between these medicines and
many tonics are internationally recognized as plant-origi-
nated adaptogens [2].
In traditional Chinese medicine, it is believed that har-
mony and balance are indispensable for health and the
concepts of yin and yang are used to diagnose and cure
disease [62]. Medicines that can supplement deficiency
and weakness, correct the pathological bias caused by
deficiency in both qi and blood, and treat the syndrome
of qi deficiency are called tonics in traditional Chinese
medicine (Qì, in the context of Chinese medicine, can
be defined as the physiological processes of the body.).
According to the differences in the properties, functions
and indications of tonics, these medicines can be divided
into qi-supplementing medicines, yang-supplementing
medicines, blood-supplementing medicines, and yin-
supplementing medicines. e common species of tonics
and their functions are listed in Table1.
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-origi-
nated adaptogens [78]. Tonics typically are adaptogens,
but not always. ey 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. e 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 simi-
lar [2]. Chinese herbs considered to be both adaptogens

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Liaoetal. Chin Med (2018) 13:57
Table 1 Various tonics andtheir features
Classication Scientic name Immunity Neuroendocrine Anti‑stress Anti‑
inammatory Anti‑age Hypolipidemic Hypoglycemic Anti‑tumor References
Qi‑supplementing medicines Panax ginseng C.A.Mey √ √ √ √ √ √ √ √ [42]
Codonopsis pilosula (Franch.)
Nannf.
√ √ √ √ √ √ √ [63]
Pannax quinquefolius L. √ √ √ √ [42]
Rhodiola crenulata (Hook.f. et
Thoms) S.H.Fu
√ √ √ √ √ [48]
Astragalus membranaceus
(Fisch.) Bunge.
√ √ √ √ √ [64]
Glycyrrhiza uralensis Fisch. √ √ √ √ [65]
Acanthopan‑ax senticosus
(Rupr. et Maxim.) Harms
√ √ √ √ √ √ [13]
Atractylodes macrocephala
Koidz.
√ √ √ √ [64]
Blood‑supplementing medi‑
cines Angelica sinensis (Oliv.) Diels √ √ √ √ [64]
Fallopia multiflora (Thunb.)
Harald.
√ √ √ [66]
Cynanchum otophyllum
Schneid.
√ √ √ [67]
Yang‑supplementing medi‑
cines Cuscuta chinensis Lam. √ √ [68]
Epimedium brevicornu Maxim. √ √ √ √ [69]
Psoralea corylifolia Linn. √ √ √ [70]
Stachys geobombycis C.Y.Wu √ √ √ √ √ [68]
Cynomorium songaricum
Rupr.
√ √ [71]
Yin‑supplementing medicines Asparagus cochinchinensis
(Lour.) Merr.
√ √ √ √ [72]
Ophiopogon japonicus (Linn. f.)
Ker‑Gawl
√ √ √ √ √ [73]
Polygonatum odoratum √ √ √ [74]
Fructus Ligustri Lucidi. √ √ [75]
Cornus officinalis Sieb.et Zucc. √ √ [76]
Lycium chinense Mill. √ √ √ √ √ √ [77]

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Liaoetal. Chin Med (2018) 13:57
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 tra-
ditional Chinese medicine, the mechanism of action of
plant-originated adaptogens is to achieve equilibrium in
both yin and yang, showing great vitality [80].
Based on the chemical composition, common ton-
ics can be divided into following several categories in
Table2.
According to Panossian’s conclusion, the main active
chemical components can be divided into the follow-
ing two categories. e first category includes terpe-
noids with four-ring skeletons that are similar to cortisol:
sitoindosides (Withania somnifera), cucurbitacin-R-sap-
onin (Bryonia dioica). e second category includes
aromatic compounds with structures similar to that of
catecholamine: (a) lignans: eleuteroside E (Acantho-
panax 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 oms) S.H.Fu); (c) phenylethane derivatives:
salidroside.
Tonics have the following functions: enriching and
activating blood (promoting the secretion of erythropoi-
etin and inducing the production of stimulatory factors,
for example, macrophage colonies, to activate blood),
regulating cellular and humoral immunity, and affecting
cytokine activity. ese 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, ton-
ics are considered the highest grade of medicine [81]. In
traditional Chinese medicine theory, tonics are also con-
sidered to be top grades in traditional Chinese medicine.
It is helpful to expand the range of plant-originated adap-
togen species and to have an in-depth analysis about the
mechanism of tonic traditional Chinese medicine.
Adaptogens andginseng species worldwide
Many regions, ethnic groups and countries, they have
their own medical histories and habits. Continuous
development and transfer of knowledge through gen-
erations leads to the formation of unique medicinal sys-
tems 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. ere is much overlap between
plant-originated adaptogens and ginseng species world-
wide. Furthermore, most ginseng species worldwide are
internationally recognized as plant-originated adapto-
gens. Both ginseng-like herbs worldwide and plant-orig-
inated adaptogens have very similar clinical applications.
Ginseng species are widely used by local communities
world-wide because these plants can enhance the resist-
ance 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. Fur-
thermore, ginseng species may improve the circulatory
system and immune system [34], which correlates pre-
cisely to the function of adaptogens.
Most medicinal plants called ginseng belong to Arali-
aceous, but there are also other medicinal plants that
belong to other families. For example, Withania somnif-
era, which belongs to Slanaceae, is called Indian ginseng;
this plant has nourishing and strengthening effects and
can delay ageing [47]. Panax japonicus, which belongs
to Solanaceae is called Japanese ginseng; this plants have
tonifying, strengthening and anti-fatigue effects [82].
Eurycoma longifolia, which belongs to Simaroubaceae
is called Malaysian ginseng; this plant can be used as a
postpartum tonic or aphrodisiac [83]. Lepidium meyerii,
which belongs to Brassicaceae, is called Peruvian ginseng;
this plant can be used for natural nutrient, can enhance
fertility effectively, and has anti-fatigue effects. e com-
mon ginsengs species from different countries and their
functions are listed in e results of modern pharmaco-
logical studies show that these medicinal plants called
ginseng have effects on the neuroendocrine and immune
systems, which is similar to the mechanism of action of
plant-originated adaptogens, the elite of herbs. However,
there have been few studies on the chemical composi-
tions, mechanisms of action, traditional curative effects
and similarities of these types of medicinal plants. Com-
parisons with ginseng species from around the world are
helpful for widening the spectrum of plant-originated
adaptogen species and for in-depth analysis of the mech-
anism of action of ginseng species worldwide. e func-
tions and the main functional ingredients of common
ginseng-like herbs worldwide were showed inTable3.
Current diculties andprospects ofadaptogens
Plant-originated adaptogens have been demonstrated to
regulate stress-related changes, at least in animal experi-
ments. However, even after more than 40-years of herbal
research, there are very few drugs that have been suc-
cessfully introduced as adaptogens in modern medicine.
Most of these kinds of plant-based medicines are consid-
ered to be plant-originated adaptogens and the remaining
few are immune enhancers, anabolic agents and anti-
oxidants, which are the same as plant-originated adap-
togens. erefore, there are many difficulties associated

Page 8 of 12
Liaoetal. Chin Med (2018) 13:57
with judging whether a plant is a plant-originated adap-
togen or not [94].
Adaptogens are stress response modifiers that non-spe-
cifically increase resistance to various stressors, thereby
promoting adaptation and survival. Adapting to environ-
mental challenges are multistep processes that involve
diverse mechanisms and interactions. Multiple molecular
networks are involved that coordinate both intracellular
and extracellular stress signaling. e metabolic regula-
tion 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 ani-
mal models. e stress responses system can be divided
into three parts: stressor, stress response and stress per-
formance [96]. e stressor is the object that induces
physical strain; therefore, a stressor may be biological
(infection), physical (external force, extreme environ-
ment), 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].
erefore, stress is known to lead to high blood pres-
sure, myocardial ischemia, depression and even cancer.
Briefly, stress performance is the manifestation of the
final effect of the stress response on the target organ.
Table 2 Based on the chemical composition, common
tonics can be divided intofollowingseveral categories
Category Specic tonics
Saponin Panax ginseng C.A.Mey.
Panax japonicus C.A.Mey.
Codonopsis pilosula (Franch.) Nannf.
Codonopsis lanceolata (Siebold & Zucc.) Benth. &
Hook.f. ex Trautv.
Glycyrrhiza uralensis Fisch. ex DC.
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.
Ophiopogon japonicus (Thunb.) Ker Gawl.
Asparagus cochinchinensis (Lour.) Merr.
Cornus officinalis Siebold & Zucc.
Trigonella foenum‑graecum L.
Ipomoea batatas (L.) Lam.
Ziziphus jujuba Mill.
Broussonetia papyrifera (L.) L’Hér. ex Vent.
Cynomorium songaricum Rupr.
Ligustrum lucidum W.T.Aiton
Coumarin Psoralea corylifolia L.
Clinopodium megalanthum (Diels) C.Y.Wu & S.J.Hsuan
ex H.W.Li
Lycium chinense Mill.
Glycyrrhiza uralensis Fisch. ex DC.
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.
Panax ginseng C.A.Mey.
Astragalus membranaceus Fisch. ex Bunge
Flavonoids Epimedium brevicornu Maxim.
Astragalus membranaceus Fisch. ex Bunge
Panax ginseng C.A.Mey.
Eucommia ulmoides Oliver
Psoralea corylifolia L.
Glycyrrhiza uralensis Fisch. ex DC.
Cuscuta chinensis Lam.
Trigonella foenum‑graecum L.
Taxillus sutchuenensis (Lecomte) Danser
Dendrobium nobile Lindl.
Alkaloids Trigonella foenum‑graecum L.
Epimedium brevicornu Maxim.
Cistanche deserticola Ma
Polygonatum odoratum (Mill.) Druce
Phlomis umbrosa Turczaninow
Ilex cornuta Lindl. & Paxton
Allium tuberosum Rottler ex Spreng.
Cuscuta chinensis Lam.
Dendrobium nobile Lindl.
Aconitum carmichaeli Debeaux
Lilium brownii var.viridulum Baker
Volatile oils Atractylodes macrocephala Koidz.
Alpinia oxyphylla Miq.
Angelica sinensis (Oliv.) Diels
Table 2 (continued)
Category Specic tonics
Clinopodium megalanthum (Diels) C.Y. Wu & Hsuan
ex H.W.
Psoralea corylifolia L.
Epimedium brevicornu Maxim.
Trigonella foenum‑graecum L.
Amino acids Rehmannia glutinosa (Gaertn.) DC.
Stachys geobombycis C.Y.Wu
Asparagus cochinchinensis (Lour.) Merr.
Glycyrrhiza uralensis Fisch. ex DC.
Panax ginseng C.A.Mey
Trigonella foenum‑graecum L.
Lycium chinense Mill.
Polysaccharides Astragalus membranaceus Fisch. ex Bunge
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.
Polygonatum sibiricum Redouté
Panax ginseng C.A.Mey.
Other Fallopia multiflora (Thunb.) Haraldson
Cynanchum otophyllum C.K.Schneid.
Rehmannia glutinosa (Gaertn.) DC.
Epimedium brevicornu Maxim.
Eucommia ulmoides Oliver

Page 9 of 12
Liaoetal. Chin Med (2018) 13:57
Table 3 Ginseng-like herbs worldwide withsimilar functions asthose ofplant-originated adaptogens
Scientic name Common name Family Common function Main functional ingredient
Panax ginseng C.A.Mey Asian ginseng Araliaceae Used for strengthening, nourishing, adjusting blood pres‑
sure and restoring heart function, neurasthenia and physi‑
cal weakness [42]
Ginsenoside [84]
Pannax quinquefolius L. American ginseng Araliaceae Used to treat qi and yin deficiency, endogenous heat,
kechuan, sputum, asthenic fever, dysphoria, thirst, and dry
mouth and throat [42]
Ginsenoside, etc. [84]
Panax notoginseng (Burk.) F.H.Chen Notoginseng Araliaceae Used for dispersing blood stasis and haemostasis and reliev‑
ing swelling and pain [85]Notoginseng saponins, Dencichine, etc. [84]
Panax japonicus Japanese ginseng Araliaceae Used for dispersing blood stasis and haemostasis, relieving
swelling and pain, eliminating phlegm and arresting
coughing and for tonifying deficiency and strengthening
[86]
Chikusetsusaponin, pseudo ginsenoside F11, Panax japonicus
polysaccharide, etc. [86]
Panax pseudoginseng Wall.
var. major (Burkill) H. L. Li Himalayan ginseng Araliaceae Used to treat qi and yin deficiency, dysphoria, thirst, asthenia
coughing, injuries from falling down, joint pain, haemop‑
tysis, haematemesis and bleeding wounds [86]
Majoroside, etc. [86]
Eleutherococcus senticosus Siberian ginseng Araliaceae Used for regulating body disorders, improving the circula‑
tory system, to treat fatigue, for promoting blood circula‑
tion for removing blood stasis, invigorating the stomach
and for diuresis and so on [13, 87]
Eleutheroside, acanthopanax senticosus polysaccharide, etc.
[13, 87]
Withania somnifera Indian ginseng Solanaceae Used for strengthening; nourishing;its anti‑ageing, anti‑
stress, antioxidation, anti‑tumor, anti‑anxiety, anti‑inflam‑
matory, anti‑depression properties; immune regulation;
improving cognitive function and so on [19]
Withanolides and other steroid esters and withanine and
other alkaloids [88]
Pfaffia paniculata Brazilian ginseng Amaranthaceae Often used as a tonic, to relieve fatigue effectively, improve
sexual function, and lower blood pressure, blood sugar
and blood lipid levels [89]
Pfaffic acid and its glycoside, for example, pfaffosides A–F, and
nortiperpene and its glycoside, etc. [86]
Eurycoma longifolia Malaysian ginseng Simaroubaceae Used for its anticancer, anti‑malaria properties, improving
male sexual dysfunction, sterilizing, lowering blood pres‑
sure and treating diabetes [54]
Diterpenes with quassinoid skeletons and alkaloids such as
canthin‑6‑one, mainly, biphenyl lignin and squalene deriva‑
tives [54]
Lepidium meyerii Peruvian ginseng Brassicaceae Used as s natural nutrient, for enhancing fertility effectively
and for its anti‑fatigue properties [90]Marca amide, marca alkaloids, etc. [91]
Talinum paniculatum Folk ginseng Talinaceae Used as a medicinal tonic and for strengthening, nourish‑
ing, improving qi, replenishing blood, aiding digestion,
promoting fluid production, quenching thirst and treating
cough and phlegm containing blood [92]
Terpenoids, coumarins, volatile oils, and polysaccharides, etc.
[93]

Page 10 of 12
Liaoetal. Chin Med (2018) 13:57
However, it remains challenging to study various steps
of this stress response [98]. First, this difficulty is associ-
ated 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. e spe-
cific response of mechanisms induced by stressors affect
broad-spectrum stress response. Second, this difficulty is
associated with the stress response. In the terms of devel-
opment, hormones, neurotransmitters, neuro-regulators
and cytokines, which are involved in the response have
been identified, but the specific functions of these pro-
teins divisions remain unknown. e identity of the first
substance to regulate the stress response remains unclear,
and it has not been determined whether there are dif-
ferent mechanisms for different stressors. ere 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]. erefore, scientists use “pre-
vention of stress manifestation” as a guideline to evaluate
the anti-stress properties of a drug [99]. ird, the diffi-
culty 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. e difficulties mentioned above will appear
in the process of the mechanism of action of adaptogens;
therefore, it is necessary to further discuss the mecha-
nisms, 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 vari-
ous stress factors. However, the clinical application of
plant-originated adaptogens and their use in health care
products remains in the preliminary stage. Categoriza-
tion 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 utili-
zation of plant-originated adaptogens, and provide a new
way to guarantee human health.
Authors’ contributions
Conceptualization, P‑GX and FY; Methodology, LL, HM, and Y‑MD; Writing—
original draft preparation, L‑YY; Writing—review and editing, Y‑FH. All authors
read and approved the final manuscript.
Author details
1 Key Laboratory of Cosmetics, China National Light Industry, Beijing Tech‑
nology and Business University, No. 11/33, Fucheng Road, Haidian District,
Beijing 100048, People’s Republic of China. 2 Beijing Key Laboratory of Plant
Resources Research and Development, Beijing Technology and Business
University, No. 11/33, Fucheng Road, Haidian District, Beijing 100048, People’s
Republic of China. 3 Institute of Medicinal Plant Development, Chinese Acad‑
emy of Medical Sciences, Peking Union Medical College, Beijing, 151 Malianwa
North Road, Haidian District, Beijing 100193, People’s Republic of China.
Acknowledgements
We are very grateful to Pr. Yong PENG (Institute of Medicinal Plant Develop‑
ment, Chinese Academy of Medical Sciences, Peking Union Medical College,
Beijing) for his valuable suggestions.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
The datasets used or analyzed during the current study are available from the
corresponding author on reasonable request.
Consent for publication
I, the corresponding author give my consent for my article to be publish in
Chinese Medicine.
Ethics approval and consent to participate
Not applicable.
Funding
This study was supported by the Beijing Technology and Business University
Youth Scholars Fund (PXM2018_014213_000033) and the Key Laboratory of
Cosmetics, China National Light Industry, Beijing Technology and Business
University Innovation Fund (KLC‑2017‑YB2).
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Received: 23 August 2018 Accepted: 12 November 2018
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