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Evolution of the adaptogenic concept from traditional use to medical systems: Pharmacology of stress-and aging-related diseases

  • Saint Petersburg State Chemical Pharmaceutical University


Adaptogens comprise a category of herbal medicinal and nutritional products promoting adaptability, resilience, and survival of living organisms in stress. The aim of this review was to summarize the growing knowledge about common adaptogenic plants used in various traditional medical systems (TMS) and conventional medicine and to provide a modern rationale for their use in the treatment of stress-induced and aging-related disorders. Adapto-gens have pharmacologically pleiotropic effects on the neuroendocrine-immune system, which explain their traditional use for the treatment of a wide range of conditions. They exhibit a biphasic dose-effect response: at low doses they function as mild stress-mimetics, which activate the adaptive stress-response signaling pathways to cope with severe stress. That is in line with their traditional use for preventing premature aging and to maintain good health and vitality. However, the potential Med Res Rev. 2020;1-74. | 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Received: 16 March 2020
Revised: 26 August 2020
Accepted: 11 October 2020
DOI: 10.1002/med.21743
Evolution of the adaptogenic concept from
traditional use to medical systems:
Pharmacology of stressand agingrelated
Alexander G. Panossian
|Thomas Efferth
Alexander N. Shikov
|Olga N. Pozharitskaya
Kenny Kuchta
|Pulok K. Mukherjee
|Subhadip Banerjee
Michael Heinrich
|Wanying Wu
|Dean Guo
Hildebert Wagner
Phytomed AB, Vaxtorp, Sweden
Department of Pharmaceutical Biology,
Institute of Pharmacy and Biochemistry,
Johannes Gutenberg University, Mainz,
Department of technology of dosage forms,
SaintPetersburg State Chemical
Pharmaceutical University, St. Petersburg,
Department of Biotechnology, Murmansk
Marine Biological Institute of the Kola
Science Center of the Russian Academy of
Sciences (MMBI KSC RAS), Murmansk, Russia
Department of Far Eastern Medicine, Clinic
for Gastroenterology and Gastrointestinal
Oncology, University Medical Center
Göttingen, Göttingen, Germany
Department of Pharmaceutical Technology,
School of Natural Product Studies, Jadavpur
University, Kolkata, India
Research Cluster Biodiversity and
Medicines, UCL School of Pharmacy, Centre
for Pharmacognosy and Phytotherapy,
University of London, London, UK
Adaptogens comprise a category of herbal medicinal and
nutritional products promoting adaptability, resilience,
and survival of living organisms in stress. The aim of this
review was to summarize the growing knowledge about
common adaptogenic plants used in various traditional
medical systems (TMS) and conventional medicine and to
provide a modern rationale for their use in the treatment
of stressinduced and agingrelated disorders. Adapto-
gens have pharmacologically pleiotropic effects on the
neuroendocrineimmune system, which explain their
traditional use for the treatment of a wide range of
conditions. They exhibit a biphasic doseeffect response:
at low doses they function as mild stressmimetics, which
activate the adaptive stressresponse signaling pathways
to cope with severe stress. That is in line with their
traditional use for preventing premature aging and to
maintain good health and vitality. However, the potential
Med Res Rev. 2020;174.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited.
© 2020 The Authors. Medicinal Research Reviews published by Wiley Periodicals LLC
Shanghai Research Center for TCM
Modernization, Shanghai Institute of Materia
Medica, Chinese Academy of Sciences,
Shanghai, China
Department of Pharmacy, Center for
Pharma Research, LudwigMaximilians
Universität München, Munich, Germany
Alexander G. Panossian, Phytomed AB,
Bofinkvagen 1, Vaxtorp 31275, Sweden.
of adaptogens remains poorly explored. Treatment of
stress and agingrelated diseases require novel ap-
proaches. Some combinations of adaptogenic plants
tions in organisms not obtainable by any ingredient in-
dependently. Further progress in this field needs to focus
on discovering new combinations of adaptogens based
on traditional medical concepts. Robust and rigorous
approaches including network pharmacology and sys-
tems pharmacology could help in analyzing potential
synergistic effects and, more broadly, future uses of
adaptogens. In conclusion, the evolution of the adapto-
genic concept has led back to basics of TMS and a new
level of understanding of holistic approach. It provides a
rationale for their use in stressinduced and aging
related diseases.
adaptogen, aging, ethnopharmacology, network pharmacology,
Numerous systematic reviews, metaanalyses of preclinical and clinical studies, and comprehensive assessment
on the efficacy and safety of adaptogenic plants have been published in the last several decades. The
aim of this review is to summarize our knowledge about common concept relating to adaptogenic plants used as
officinal medical preparations in the USSR/Russian and in traditional Chinese medicine (TCM), Ayurveda, Kampo,
and other traditional medical systems (TMS) and alternative medical systems, and to analyze how such prepara-
tions have been studied scientifically. This provides a basis for assessing the use of adaptogens in the treatment of
stressinduced and agingrelated disorders.
Adaptogens must be innocuous and cause minimal disorder in the physiological functions of an organism, and
have nonspecific actions, that is, increase resistance to adverse influences of a wide range of factors with physical,
chemical, and biological properties. In addition, they typically possess normalizing actions irrespective of the
direction of the foregoing pathologic changes.
1.1 |Evolution of the adaptogenic concept: From postulates to evidencebased
The term adaptogens is currently widely used in alternative and complementary medicine, as well as in
pharmacognosy, phytomedicine, and phytotherapy research.
It was implemented in scientific lexicon in the
middle of the 20th century in the Soviet Union with the aim of characterizing the physiological mechanisms
of action of compounds and some medicinal plants that presumably increased the nonspecific resilience of
organisms to harmful challenges. The definition of adaptogens is continuously updated (Table 1), in-
corporating the increasing body of scientific evidence related to understanding their pharmacological and
molecular mechanisms of action.
Importantly, the term adaptogen is related to a physiological processadaptation to environmental
challenges, which is a multistep process including diverse mechanisms of extracellular and intracellular
interactions. The renewed definition of adaptogens
is supported by the results of recent studies on the
molecular mechanisms of action of adaptogens in a variety of regulatory systems from the cellular to entire
organism levels.
Similar to antioxidants and vitamins, adaptogens constitute a category of nutritional and herbal medicinal
products essential for good health, adaptability, resilience, survival, and healthy aging. Regardless of the nature of
the stimulus (stressor), an adaptogen increases adaptability, resilience, and survival by activating adaptive signaling
pathways of cellular and organismal defence systems (stress system e.g., neuroendocrineimmune complex). Fur-
thermore, adaptogens trigger the generation of hormones (cortisol, corticotropinreleasing hormone [CRH] and
gonadotropinreleasing hormones, urocortin, neuropeptide Y), playing key roles in metabolic regulation and
TABLE 1 Definitions of adaptogens
Adaptogens are medicinal substances causing the state of nonspecifically increased resistanceof the organism.
Only those preparations that meet the following requirements may be included in the group of adaptogens: (a) An
adaptogen should be innocuous and cause minimal disorders in the physiological functions of an organism; (b) The
action of an adaptogen should be nonspecific, i.e., it should increase resistance to adverse influences of a wide range
of factors of physical, chemical and biological nature, (c) An adaptogen may possess normalizing action irrespective
of the direction of the foregoing pathologic changes.
The adaptogens are nontoxic compounds with polyvalent mechanisms of action and pharmacological effects related
to adaptability and survival.
Adaptogens are substances, which elicit in an organism a state of nonspecifically raised resistance, allowing them to
counteract stressor signals and to adapt to exceptional strain.
Adaptogens are metabolic regulators, which increase the ability of an organism to adapt to environmental factors and
to avoid damage from such factors.
Plant adaptogens are agents, which reduce damaging effects of various stressors due to reduction of the reactivity of
host defense system. They adapt organism to stress and have curative effect in stressinduced disorders.
Adaptogenic substances have the capacity to normalize body functions and strengthen systems compromised by
stress. They have a protective effect on health against a wide variety of environmental assaults and emotional
Adaptogens comprise a pharmacotherapeutic group of herbal preparations used to: increase attention and endurance in
fatigue and prevent/mitigate/reduce stressinduced impairments and disorders related to neuroendocrine and
immune systems.
Botanical adaptogens are plant extracts, or specific constituents of plant extracts, which function to increase survival
in animals and humans by stimulating their adaptability to stress by inducing adaptive responses.
Adaptogens are stressresponse modifiers that increase an organism's nonspecific resistance to stress by increasing its
ability to adapt and survive.
Botanical adaptogens are metabolic regulators that increase survival by increasing adaptability in stress.
Adaptogens are natural compounds or plant extracts that increase adaptability and survival of living organisms to
Adaptogenany of various natural substances used in herbal medicine to normalize and regulate the systems of the
homeostasis. Meanwhile, multitarget mechanisms of action and a wide range of pharmacological effects indicate
their nonspecific pharmacological activity.
Therefore, adaptogens are most likely effective for the prevention and treatment of stressinduced and adult
onset disorders such as chronic fatigue, memory impairment, depression, anxiety, sleep disturbance, diabetes,
heart disease and high blood pressure, chronic inflammation and autoimmune diseases, cold and flu, infections, skin
diseases, liver diseases, and cancer. This can be achieved due to their ability to activate the innate defence system,
increase resistance to stress, adapt organisms to stress, increase recovery of stressinduced damages, provide
energy to fight fatigue, reduce agingassociated decline of the neuroendocrineimmune system. Table 2provides a
summary of the general characteristics of adaptogens, which comprise a category of nutritional and herbal
medicinal products.
2.1 |Origin of the adaptogenic concept and use in officinal medicine of the USSR
The term adaptogen was introduced in 1958 by the Soviet toxicologist Lazarev, who applied it to the
synthetic stimulant dibazol (2phenylimidazol) assuming that adaptogens increase the nonspecific re-
sistance of organisms under conditions of stress resulting in increased endurance, stamina, and perfor-
This assumption was based on the results of intensive studies of Schisandra chinensis in the USSR
during World War II,
with the goal of finding an alternative to stimulants used by the German and U.K.
army to increase the attention and endurance of pilots.
The aim was also to supply the Soviet Armed
Forces and Military Industry (soldiers, pilots, sailors, and civilians engaged in the production of weapons and
war materials) with easily available natural stimulants, presumably extracts from S. chinensis berry or
The interest in S. chinensis (known as limonnik = лимонник in Russian) arose from ethnopharmacological in-
vestigations by. Komarov (1895) and Arsenyev (19031907) in far eastern Siberia and northern Manchuria. The
berries and seeds were determined to have been used by Nanai hunters (natives of far eastern Siberia and Chinese
Manchuria, also known as Goldis or Samagir) as a tonic to reduce thirst, hunger, and exhaustion and to improve
nighttime vision.
TABLE 2 Summary of characteristics of adaptogens
Definition: Adaptogens are natural compounds or plant extracts that increase adaptability, resilience, and survival of
organisms to stress.
Chemical class: Various, predominantly tetracyclic triterpenes, phenethyland phenylpropanoids glycosides, stilbenes,
lignans, etc.
Pharmacological activity/health claims: adaptogenic
Mechanism of action: Multitarget effects on neuroendocrineimmune system including:
(i) Triggering of intracellular and extracellular adaptive signaling pathways that promote cell survival and organismal
resilience in stress
(ii) Regulation of metabolism and homeostasis via effects on expression of stress hormones (corticotropin and
gonadotropinreleasing hormones, urocortin, cortisol, neuropeptide Y, heat shock proteins Hsp70) and their
Indications for use: Stressinduced fatigue, mental and behavioral disorders, agingassociated diseases.
The first studies on the stimulating and tonic effects on S. chinensis were published in World War IIera military
During the 1960s and 1970s, other Soviet scientists extended the research of adaptogens to re-
juvenating and invigoratingmedicinal plants traditionally used in China, Korea, Japan, Siberia, and the far east of
the USSR for a variety of pathological conditions including diseases and their symptoms such as hypodynamia,
asthenia, shortness of breath, palpitation, insomnia, hemorrhage, impotence, and diabetes.
The authors screened many plants assuming that adaptogens must be safe and normalize body functions
irrespective of the nature of stressorsand in 1967, some were incorporated into official medical practice in the
USSR as central nervous system (CNS)stimulating medicinal products and as tonics to fight fatigue and general
weakness during convalescence for infectious diseases, chemotherapy and psychiatric disorders, after surgery,
poisoning, heart attacks, ischemia, chemotherapy, and psychiatric disorders (Table 3). Rhodiola rosea extract
(Rhodiolae roseae rhizomatum et radicum extractum liquidum) is an example of an adaptogenic medicinal product
used since 1975 in officinal medicine in the USSR/Russia. It is indicated for decreased mental and physical
capacities such as weakness, exhaustion, tiredness and loss of concentration, as well as during convalescence.The
extent of adaptogen research conducted in the USSR was enormous with more than 1000 pharmacological and
clinical studies published in Russia until 1982.
Most common extracts or compounds isolated from Siberian Ginseng (Eleutherococcus senticosus), Schisandra
(S. chinensis), Ginseng (Panax ginseng), and Golden Root (R. rosea) have been studied. All adaptogenic plants and
preparations from them have been clinically tested and approved before incorporation into official medical
TABLE 3 Adaptogenic plants used in officinal medicine in the USSR/Russia
Name of plant Products Pharmacopoeia monograph
Aralia elata (Miq.) Seem (A. mandshurica Rupr. et maxim.) Radices FS.2.5.0058.18
Tincture FS 42164793
Dry extract in tablets FS 42175581
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. Radices and rhizomes, FS.2.5.0053.15
Liquid extract FS.3.4.0009.18
Oplopanax elatus (Nakai) Nakai (Echinopanax elatum Nakai) Radices and rhizomes, FS 4231472
Tincture FS 42188782
Panax ginseng C.A. Meyer Radices FS.2.5.0013.15
Tincture FS 42188682
Rhaponticum carthamoides (Willd).Iljin Radices and rhizomes, FS.2.5.0091.18
Liquid extract FS 42199599
Rhodiola rosea L. (a synonym of Sedum roseum (L.) Scop.) Radices and rhizomes, FS.2.5.0036.15
Liquid extract FS.3.4.0008.18
Schisandra chinensis (Turcz.) Bail. Fruits FS.2.5.0081.18
Seeds FS.2.5.0082.18
Tincture from seeds, FS 42182290
Tincture from fruits, VFS 4211772
Oil from seeds in capsules VFS 42342399
The State Pharmacopoeia of the Russian Federation, 2018. (Accessed date: March
15, 2020).
practice. The list of clinically approved true adaptogenic plants with related pharmacopeial monographs is pre-
sented in Table 3.
Regardless of the formal indication for use in officinal medicine as tonics, adaptogens were widely used in:
sports medicine to promote quicker recovery after heavy exercise and overstraining,
occupational medicine for protection against negative environmental factors, and
geriatric medicine with the aim of promoting health by preventing and treating diseases and disabilities in older
These areas of practical use of adaptogens were of socioeconomic importance in the USSR, a superpower
where great achievements in space, military power, and sports have been the subjects of pride and special
attention. Indeed, adaptogens were used in space medicine by Soviet cosmonauts during long missions on the MIR
as well as by sailors aboard ships; on submarines during long Arctic, Antarctic, or tropical expeditions;
and by pilots and sportsmen in multiple stressful conditions such as hypoxia, irradiation, cold, and physical and
mental overload. In addition, adaptogens termed Kremlin Magic Pillsand Elixir of Youththat increase strength,
stamina, and longevity were popular among elite elderly leaders of Communistic Party of the USSR, which gov-
erned the country for many years.
In conclusion, the concept of adaptogens can be traced back to their first definitions provided by the Soviet
scientists Lazarev and Brekhman, and the introduction of herbal medicinal products as official medicaments and in
the State pharmacopoeia of the USSR.
2.2 |Ethnopharmacological background
Key points of the adaptogenic concept defined by Brekhman and Dardymov in 1969 are in line with basic principles
of the TMS of China, Korea, Japan, India (Ayurveda), and Middle Asia (Yunani).
For instance, an assumption is that some adaptogens used in TCM, Kampo, and Ayurveda medicine (e.g.,
Ginseng, Ashwagandha, Andrographis, Bryony) must have normalizing effects, irrespective of the nature of the
disease. Herbalists refer to adaptogens as restoratives, qitonics, rasayanas, or rejuvenating herbs. Tonic herbs are
classified as the highest and most soughtafter herbal remedies in many traditional systems of healing such as TCM
and Ayurveda. Both traditional systems are based on holistic approaches to patients and treatment, suggesting
that the patient is an individual and not a disease. Holistic medicine strives to consider the whole person, sug-
gesting that one can only achieve optimal health by complex treatment of all imbalances (physical, emotional, or
spiritual) induced by environmental factors. Consequently, multitarget therapy by herbal preparations have
polyvalent actions on various mediators, effectors, and regulatory systems, presumably making it the most ef-
fective approach for the treatment of complex diseases.
Both TMS have a similar notion of life vital energyand activating the body and mind: the qi in TCM and the
prana in Ayurveda. Similar notions exist in various cultures including the Greek pneuma, the Armenian zorutyun
(զորություն), the Polynesian mana, the German od, and the Hebrew ruah. Prana is also referred to as life force, subtle,
or bioplasmic energy. Below are brief descriptions of the ethnopharmacological roots of the adaptogenic concept.
2.2.1 |Traditional Chinese, Korean, and Japanese medicines
TCM is about 5000 years old, so billions of people in China (the world's biggest population with ~1.4 billion) have
been treated with these herbal medicines/botanicals for centuries.
The core of the TCM concept is the yinyang theory consisting of two natural, complementary, and contra-
dictory forces of opposite polarity that interact to form a dynamic system in which the entire is dual and better/
superior than the collected parts. According to this philosophy, everything has both yin and yang features (for
instance, shadow cannot exist without light), which are in dynamic equilibrium (balance); yin is negative/passive/
dark/female/water, while yang is positive/active/bright/male/fire. Although yin is stronger, they are always in
We can find many relevant examples of the yinyang balance when this concept is applied to the regulation of
cellular and organismal homeostasis
(e.g., cyclic adenosine monophosphate [cAMP] and cyclic guanosine
monophosphate [cGMP], prostacyclin and thromboxane, sympathetic and parasympathetic nervous systems,
testosterone, cortisol). For example, the testosterone/cortisol ratio is associated with stressrelated disorder
symptoms such as fatigue, decreased performance, and impaired recovery from overtraining syndrome in sports
The major symptoms and signs of overtraining were categorized
physiological (chronic fatigue, decreased performance and muscular strength, muscle soreness, extended re-
covery time, increased oxygen uptake at physical loads, loss of appetite, and decreased body fat).
psychological (difficulty concentrating, emotional instability characterized as restlessness and excitation fol-
lowed by apathy and depression),
immunological (immunosuppression characterized as decreased blood immunoglobulins and lymphocyte count,
decreased chemotaxis of neutrophils, increased susceptibility to infection),
biochemical (decreased free testosterone and raised cortisol levels, elevated lactate, and reduced hemoglobin
levels in blood).
All of these symptoms of overtraining healthy subjects in stress as well as their overall health status are in line
with a subpar health status
known in TCM as shanghuoor reqi(upper fever, pathology fire, internal heat, or
excessive energy associated with energy metabolism), which is characterized by a general decline in health, cut of
energy, weakness, impaired physiological functions and adaptability (presumably XieHuo in TCM), leading to the
onset and progression of diseases.
In other words, shanghuo
is a state of decreased resistance (or increased susceptibility) leading to stress
and progression of diseases. That is similar to lowgrade inflammation,
resulting in and involving wholebody
systems such as the neuroendocrineimmune (stresssystem), cardiovascular, and other systems.
According to TCM, the onset of disease is due to both external (wind, cold, heat, dampness, dryness, fire) and
internal causesexcessive emotional activity induces the yinyang imbalance of the following seven emotions: joy,
anger, anxiety, concentration, grief, fear, and fright. Bacteria, viruses, and chemicals are not considered to be
causes. Most people whose health is not affected by external factors, but in whom excessive emotional activity
causes a severe yinyang imbalance, experience blockage of qi and impairment of vital organ function. According to
TCM theory, shanghuocaused by emotional stress can induce insomnia, depression, increase susceptibility to
infectious diseases, and promote cardiovascular disease and tumor progression. Therefore, unsurprisingly the idea
to prevent and treat stressinduced disorders caused by a yinyang imbalance with prophylactic treatment using
medicinal plants trace back to centuries (e.g, Weibing in China, Mibyeong in Korea,
and Mibyou in Japan.
Subsequently, the concepts underlying preventive treatment for subhealth by adaptogens (presumably fu zheng
in TCM for strengthening body resistance or strengthening vital qi) were implemented in USSR under the names
Medical Fitness, Farmacosanacia, and Valeology.
According to TCM, the treatment of diseases must rectify harmony, and restore qi and the yinyang balance. It
is the quality, quantity, and balance of qi that determine the state of health and lifespan. Food and air affect health;
therefore, diet and breathing exercises are of primary importance. According to The Divine Husbandman's Classic
of the Materia Medica, the earliest existing monograph of TCM prepared 4000 years ago, P. ginseng tonifies the
primal qi and qi of all organs, particularly those of the lungs and spleen. Therefore, it has been indicated for
deficiency of qi in patients with shallow breathing, shortness of breath, coldness of limbs, profuse sweating, or
weakness and has been used to reduce the symptoms of stress and inflammation and delay aging.
Medicinal plants are considered for the treatment of diseases and recovery of vital energy, which is believed to
gradually dissipate throughout life. So, it is important to conserve it using diet, kung fu, breathing exercises, and
herbal medicines. As an example, fatigue is due to qi deficiency, and P. ginseng (tonic herb) activates qi and
therefore has nourishing effects in fatigue.
In TCM, all known medicinal plants are divided into three categories: inferior, middle, and superior. The highest
forms of medicine revered in China are the superior herbs (tonic herbs), which help everything to heal and nurtures
life itself. Superior herbs are thought to possess restorative properties and are used as general tonics for the
treatment of disease and in convalescence. The most wellknown broad action medicinal plant in TCM is
The pharmacological activity of ginseng was first described in the 1st century by an unknown author. Ac-
cording to his records, ginseng improves mental activity and visual acuity, dispels pathogenic factors, enhances
longevity with longterm intake tonifying five vital organs of the body (spleen, lung, heart, kidney, and liver).
According to other ancient regards written by Hongjing Tao (AD 456536), ginseng can be used to enhance
cognitive function; improve blood circulation; relieve thirst and feelings of solidity; and cure internal coldness, pain
in the chest or abdomen, vomiting, and diarrhea. These and other beneficial effects of ginseng have also been
described in other more complete and comprehensive medical textbooks including treatment for general weakness
and fatigue.
Kampo(Traditional Japanese Academic Medicine) developed on the Japanese Islands from ca. 500 AD based
on Ancient Chinese Medicine (ACM)the common ancestor system of Japanese Kampo, Korean Medicine (KM),
and Traditional Chinese Medicine (TCM). Subsequent independent developments and European influence in the
16th century resulted in a divergent cultural evolution establishing Kampo as an independent TMS distinct from
other systems. Over the past centuries, fundamental philosophical differences have developed.
Kampo is mostly
based on the systematic collection of case historiesempirical knowledge of the effect of Kampo preparation. As
Kampo is regulated by the Japanese government, Kampo prescriptions (as finished pharmaceutical products) are
included in the Japanese Pharmacopoeia (JP) and covered by the national health insurance. Every Kampo formula
is indicated for individuals with the same symptom patterns(sho), based on a pathological status of an
A special class of Kampo prescriptions with close similarity to the adaptogenic concept are the socalled
support preparationsor Hozai. The term hozai is used to describe preparations that are applied to stop or
partially reverse the symptoms of physical weakness and degenerative diseases. Hozai can be used in cases of
typically geriatric ailments but also in any other case of physical decay.
The traditionally accepted explanation for the activity of Kampo medicines including Hozai was summarized
in the 18th century CE by the philosopher Yoshimasu Todo (17021773), who stated that curative and toxic
effects are two phases of the same process; since diseases are triggered by uncontrolled poisoning, the patient has
to be healed by a positive, challenging poisoning. This controlled poisoning initiates a regeneration reaction that
removes toxicity from the body, thus restoring the patient's health.
In this context, hozai and adaptogens are
similar since adaptogens are eustressors (i.e., good stressors) acting as mild stress mimetics or stressvaccines that
induce a stressprotective response,
which is in line with the basics of Kampo medicine.
The re-
lationship of the two concepts is illustrated by P. ginseng rootone of the classical USSR Adaptogens.
This is an
essential component drugs of most Hozai preparations (Table 4).
The two major prescriptions of the hozai
category are Juzentaihoto
and Hochuekkito
(Table 4).
Both formulations are mainly used in cases of geriatric ailments and physical decline.
Juzentaihoto is also used for
decubitus ulcers, radiation sickness, rheumatoid arthritis, supportive therapy in cancer, and to reduce adverse effects
from surgical treatment and chemotherapy. The indications given by the Japanese national health insurance for
Hochuekkito are related to general vigor, anorexia, myasthenia gravis, chronic gastritis, and atopic dermatitis.
The Western indications, for which hozai are most often used in Japan, are related to cachexia,
a loss of
skeletal muscle mass that differs from weight loss due to malnutrition, anorexia nervosa, or anorexia due to
depression or sarcopenia (agingrelated muscle loss).
In conclusion, shanghuo, a state of decreased resistance to stress can be treated with whatfirst in the Soviet/
Russian literaturehas been labeled adaptogenic plants. These will and increase the nonspecific resistance to
stress; the yinyang balance, a synonym of homeostasis (see the next section of this chapter); and vital energy or qi,
which has a similar meaning as adaptability or a state of nonspecific resistance. The concept of hozai is very similar
to the adaptogenic concept, particularly in the context of their modes of action as eustressors (i.e., good stressors),
and as mild stress mimetics or stressvaccines that induce a stressprotective response; its systematic use in
gerontology might be very beneficial, as has already been demonstrated in Japan.
The multipurpose use of adaptogens (ginseng) in numerous conditions suggests their nonspecific and nor-
malizing effects in organisms. The traditional use of ginseng in billions of people for centuries is one important
argument in favor of it being nontoxic, innocuous, and not influencing normal bodily functions more than
2.2.2 |Ayurveda
Ayurveda is a conventional medicinal system with varied treatments, which originated over 3 millennia ago in
South Asia.
In Ayurvedic philosophy, the central concept is the Tridosha theory suggesting that good health
TABLE 4 Crude drugs and their respective daily dosages (g) in the two traditional Kampo Hozai prescriptions
Juzentaihoto (Japanese name) Hochuekkito (Japanese name)
ShiQuanDaBuTang (Chinese name) BuZongYiQiTang (Chinese name)
Sipjeondaebotang (Korean name) Bojungikgitang (Korean name)
Tonifying the Middle and Augment the Qi Decoction Tonifying Decoction
Ginseng Radix3 Ginseng Radix4
Astragali Radix3 Astragali Radix4
Glycyrrhizae Radix1.5 Glycyrrhizae Radix1.5
Angelicae sinensis Radix3 Angelicae sinensis Radix3
Atractylodis macrocephalae Rhizoma3 Atractylodis macrocephalae Rhizoma4
Paeoniae Radix3 Bupleuri Radix2
Cinnamomi Cortex3 Jujubae Fructus2
Ligusticum Rhizoma3 Zingiberis Rhizoma0.5
Sclerotium Poriae Cocos3 Cimicifugae Rhizoma1
Rehmanniae Radix preparata3 Citri reticulatae Pericarpium2
Corresponding daily dose is 7.5 g of dried extracts in representative finished pharmaceutical products (JP: The Japanese
Pharmacopoeia). Both formulations are regarded as effective by the Japanese regulatory authorities and are available as
finished pharmaceutical products of equal quality to traditional herbal medicinal products registered in the EU under
coverage of the Japanese National Health Insurance.
occurs when there is a dynamic balance between three fundamental dynamic forces or dosh as called Vata, Pitta,
and Kapha.
o Vata is the combination of air and water, which is associated with the function of the nervous system. An
imbalance leads to pain, sleeplessness, and inability to concentrate and stay on task.
o Pitta is the combination of fire and water, and is associated with bile, digestion, and metabolism.
o Kapha is the combination of water and earth, and is associated with mucous, lubrication, and transporting
nutrients into the arterial system.
According to Ayurvedic theory, the life vital energy, Prana, comes from the air into the brain via respiration.
Prana is settled in the brain and governs emotions, memory, and other functions of the mind. It also rules the
functioning of the heart and enters the bloodstream to control all vital organs.
In Ayurveda, the plants known as rasayana are used as rejuvenating and for improving the overall health of
anyone undergoing this treatment. The word rasayana literally means the path that rasa takes (rasa: the primordial
tissue or plasma; ayana: path). According to Ayurveda, the qualities of rasadhatu influence the health of other
dhatus (tissues) of the body, as it is the most primary in function and works as the basic unit. Hence any medicinal
plant or formulation that improves the quality of rasa (rasayanas), strengthen or promotes the health of all tissues
of the body. Apart from promoting good health, increasing the ability to concentrate, improving memory and mood,
an important effect of rasayana therapy is increasing resistance to diseases.
The rasayana effect is not a specific
pharmacological action, but rather a complex response operating through a comprehensive holistic mechanism of
regulation of homeostasis.
Species most commonly used in Ayurveda as rejuvenating include:
o AshwagandhaWithania somnifera (L.) Dunal
o KalmeghAndrographis paniculata (Burm. F.) Wall. Ex. Nees.
o Yasthimadhu (Licorice)Glycyrrhiza glabra L.
o SatavariAsparagus racemosus Willd
o Tulsi (Holy basil)Ocimum tenuiflorum L. (syn.: Ocimum sanctum L.)
o Pipul (Pepper)Piper longum L.
o GuduchiTinospora cordifolia Miers
o AmlaEmblica officinalis Gaertn
o HaritakiTerminalia chebula Retz.
W. somnifera is used in Ayurveda toward promoting health and longevity, slowing the aging process, revitalizing
the body, reducing anxiety, and creating a general sense of wellbeing. These traditional applications of W. som-
nifera are due to a wide range of pharmacological effects observed in recent preclinical studies in animals and
clinical trials in humans including anxiolytic, sedative, antiinflammatory, analgesic, immunomodulatory, antioxidant
effects, cardiopulmonary, and hypotensive effects.
A. paniculata,the king of bitters,is used in Ayurvedic and other traditional health care systems of India,
China, and other Asian countries for numerous medicinal purposes, for example as an effective antipyretic
treatment against a variety of infectious diseases including bronchitis, tonsillitis, tuberculosis, malarial and inter-
mittent fever, urinary infection with difficult painful urination, dysentery, bacillary dysentery, colitis, dyspepsia,
hepatitis, mouth ulcers, colic, otitis, vaginitis, pelvic inflammatory disease, chickenpox, carbuncles, sores, and
eczema. The plant is effective for venomous snake bites, burns, and traumatic infection. Efficacy for prophylaxis
and symptomatic treatment of upper respiratory infections such as the common cold, bronchitis uncomplicated
sinusitis and pharyngotonsillitis, urinary tract infections, and acute diarrhea has been supported by clinical
The root of the liquorice plant (Glycyrrhiza sp.) is also oa wellknown rasayana drug in Ayurveda mainly due to
antiinflammatory, antiviral, and antimicrobial activities.
In Ayurveda, A. racemosus is used as rasayana medicine and is acknowledged for promoting physical and mental
health. Its wide range of therapeutic effects such as antitussive, antiplasmodial, antileishmanial, antibacterial,
hepatoprotective, diuretic, antiulcer, antidiarrheal, antenatal tonic, cardioprotective, anticancerous, antiepileptic,
and antidepressant are likely associated with its immunomodulatory and adaptogenic activities.
many of these therapeutic claims go well beyond preventive medical concepts.
In Ayurveda, P. longum is used in hepatosplenomegaly, respiratory disorders including asthma, chronic cough,
tuberculosis, skin disorders, piles, diabetes, and anemia. It is also beneficial in fever and infection including typhoid
and has analgesic effects in dyspepsia, worm infestation, and abdominal pain. It is also reported to have aphrodisiac
properties. P. longum, P. nigrum, and Zingiber officinalis are combined in the Ayurvedic formulation Trikatu, which is
effective in several ailments. It increases the action of other drugs by increasing the bioavailability, as piperine is
the main biomarker compound.
In Ayurveda, Guduchi (T. cordifolia) is effective against various infections to boost immunity, especially in the
convalescent period, as it has antipyretic, analgesic, and antiinflammatory properties. It is also useful for dys-
pepsia, anorexia, liver disorders, dysentery, and worms, and is prescribed for anemia, diabetes mellitus, gout, and
rheumatoid arthritis.
In Ayurveda, E. officinalis is used for the treatment of peptic ulcer, dyspepsia, altered gastrointestinal motility
(diarrhea, constipation, vomiting), and symptoms from pancreatitis, piles, liver disorders, diabetes, tuberculosis, and
other lung infections. It has antiinflammatory and antistress effects. Regular intake of E. officinalis fruit has been
advised for the general maintenance of health and preventive healthcare. External application is prescribed for
alopecia or baldness, toothache, and ophthalmic conditions.
T. chebula is considered as digestive and gives strength to tissues, particularly the sense organs. It purifies
blood and has laxative and antipyretic actions. It is prescribed for dyspepsia, piles, hepatosplenomegaly, irritable
bowel syndrome, and cardiac dysfunction. Triphala, a formulation containing equal parts of E. officinalis, T. chebula,
and T. bellerica, is used as a laxative and general wellbeing as it maintains the balance of Vata, Pitta, and Kapha.
Modern practices derived from Ayurveda are now classified as a type of complementary or alternative
medicine, especially in the Global North.
In conclusion, the fundamental philosophy of Ayurvedic medicine, particularly in the context of homeostasis
regulation of the stresssystem (neuroendocrineimmune complex, see below), nonspecific resistance (vital life
energy = prana), pharmacologically pleiotropic or polyvalent effects, and the antiaging effects of adaptogens is very
similar to the concept of adaptogens.
2.2.3 |Impact of ancient Greece, Rome, and medieval TMS of middle Asia
Yunani or Unani is the term for ParsiArabic traditional medicine as practiced in the Indian subcontinent, and in
Muslim culture in central and southern Asia. The term is derived from Arabic Greek and has Hellenistic origin
based on teachings of the Greek physicians Hippocrates, Dioscórides, and Galen Unani. It was further developed
and enriched by AbuAli Ibn Sina (Avicenna), Amirdovlat, and other medieval physicians and philosophers.
For instance, Amirdovlat devoted considerable attention to those medicinal plants, which had antitoxic (la-
vender, marigold, ironwort) and tonic properties (birthwort, bryony). Amirdovlat used bryony, the sacred medicinal
plant, as a panacea for all diseases to prevent premature aging and maintain good health and vitality.
In preChristian times, the root of Bryonia alba L. was an occult object in Armenia (Loshtak in Armenian), where
it was used as a drug for all diseases.
It has been referenced by the scientists of ancient Greece (Dioscórides,
Hippocrates, Theophrastus), Rome (Celsius, Columella, Galen, Plinius), and Asia (Amirdovlat, Avicenna), and was
studied in Jensen's 1914 thesis.
The Bryonia root has been used to treat a wide range of conditions and
disorders including fatigue, gout, arthritis, rheumatism, neuralgia, pain. psoriasis, abscesses, allergies, leprosy,
edema, bronchitis, pleurisy, asthma, tuberculosis, tonsillitis, lung inflammation, cough, influenza, fever, sciatica,
ulcers, gastrointestinal diseases, liver diseases, cancer, hypertension, cardiovascular diseases, epilepsy, lockjaw,
paralysis, hysteria, madness, sleeplessness, and impotence. It has also been used as a laxative, cathartic, lactogenic,
anthelmintic, diuretic, expectorant, and to induce abortion, as well as a cosmetic to remove spots, pimples, warts,
blackheads and bruises; to prevent allergic reactions and for the prevention of hair loss.
Bryonia extract was integrated in official medicine as a tonic and adaptogenic drug in Armenia, Russia, Ukraine,
and Belorussia in the 1990s of the XX century and the first decade of the XXI century.
Preparations from
Bryonia alba L. root extract (Loshtaktablets) were registered as medicines by the Russian Federation in 2002,
Belarus in 2003, Ukraine in 2007, and Armenia in 1992 and 2003 as an adaptogen and tonic in asthenia; agent for
decreased resistance to infections; maintenance of working capacity, coordination, and mental activity; and pre-
vention of stress, radiationand chemotherapyinduced toxicity and disorders, and so forth.
In conclusion, experiences in ancient Greece, Rome, and Medieval TMS of Middle Asia, particularly regarding
the multitasking effects of medicinal plants as a panacea for all diseases can be expressed using the modern
concept of adaptogens, and their benefits at low doses to prevent premature aging and maintain good health and
2.2.4 |European traditions and core rational elements of homeopathy
The basic idea of homeopathy assumes that a substance at a high dose causes the symptom of disease in healthy
subjects, while curing similar symptoms in illness if applied at a low dose.
Homeopathic preparations are made from ingredients which, in undiluted form, cause symptoms similar to the
disease they aim to treat. These ingredients are repeatedly diluted, with shaking at each stage (Table 5). Ho-
meopaths consider that this technique prevents side effects, enhances the ability of preparations to amplify a
response, and generates curative properties, even for ingredients that are chemically inactive or so significantly
diluted that none of the original material remains. While highpotency preparations (i.e., highly diluted ones) clearly
cannot be evaluated using bioscientific concepts and methods, lower potency ones may well exert relevant
pharmacological and toxicological effects.
Homeopathic preparations are generally not tested and regulated under the same laws as conventional drugs.
Usage varies from only 2% of people in Britain and the United States using homeopathy in any 1 year, to 15% in
India, where homeopathy is now considered part of its traditional medicine. Homeopathic medicines are generally
considered safe, with rare exceptions.
TABLE 5 Dilution scales and homeopathic potency
Dilution scales
Mother tincture Homeopathic potency
1 vol of tincture + 9 vol solvent = D1 1X
1 vol of D1 + 9 vol solvent = D2 2X
1 vol of D2 + 9 vol solvent = D3 3X
1 vol of tincture + 99 vol solvent = C1 1H
1 vol of C1 + 99 vol solvent = C1 2H
Note: Preparations obtained by dilution of 1 M solution (6.02 x 1023 molecules per L) in potencies higher of D24 do not
actually contain a single active molecule.
However, homeopaths have been criticized for putting patients at risk by advising them to avoid conventional
medical treatments.
According to homeopathic theory, the efficacy and safety of the same plant significantly depends on when and
where it was collected, and how it was processed. For example, freshly collected summer roots of Bryonia are used
in the homeopathic tincture Acofit and is indicated in lumbago, neuromyelitis, and radiculomyositis, whereas 20% of
ethanolic extract and dried powder of the roots are recognized as a treatment for bronchitis, pleurisy, asthma,
whooping cough, and other inflammatory disorders.
Homeopathic tablets and pellets are used in the United
States, England, France, Germany, and Russia for the treatment of rheumatic pain and headache; acute in-
flammation of the pleura and abdomen; and fever and viral infections (mainly in combination with Aconitum, i.e.
Bryaconel Heel, 1994). Various preparations of Bryonia roots are used to relieve muscle pain and diminish the
symptoms of asthma and epilepsy.
In addition to homeopathy, other traditions also pay close attention to selfhealing and coping with adverse
situations. Anthroposophical medicine is a complementary medical tradition founded in the 1920s by Rudolf
who advocated for the use of Viscum album L. (the European whiteberry mistletoe) in cancer.
It is a
holistic approach to medicine focusing on ensuring that the conditions for health are present in a person.
Anthroposophical therapies are intended to enhance an organism's ability to heal in line with the adaptability
concept and the concept of adaptive homeostasis, as explained below.
V. album L., an obligate hemiparasite plant growing on apple, pear, plum, hawthorn, beech, willow, poplar,
maple, sweetgum, oak, almond, elm, pine, spruce, juniper, and eucalyptus, exhibits immunostimulatory, anti
inflammatory, analgesic, antioxidant, antiglycemic, antihypertensive, and neuroprotective properties.
In allo-
pathic doses, mistletoe preparations (fresh juice, tinctures, and decoctions of various parts) are used in various
countries (Armenia, Russia, Ukraine, Bulgaria, the Czech Republic) to treat cough, broken bones, diarrhea, rheu-
matism, gout, inflammation of lymphatic glands, wounds, and ulcers, as well as hypotensive, antiatherosclerotic,
antiosteoarthritis, analgesic, sedative, and antiepileptic remedies.
It is worth noting that mistletoe growing on
different trees are used for different purposes. Thus, mistletoe growing on the willow is mainly used as a sedative,
whereas mistletoe growing on the pear is used in cardiovascular medicine, and the one growing on the hawthorn is
used as a hypotensive drug.
In homeostatic doses, the mistletoe preparations Iscador, Eurixor, Helixor, Abnobaviscum, and Isorel stan-
dardized for the content of mistletoe lectin 1 (1 ng/kg) are widely used in Europe as alternative adjuvant therapies
against colon, oral, lung, pancreatic, and breast cancers.
The mistletoe extracts boost immunity, delay tumor
progression, improve the quality of life, and increase survival and lifespan of cancer patients by helping with coping,
fatigue, sleep, exhaustion, energy, nausea, vomiting, appetite, depression, anxiety, the ability to work, and emo-
tional and functional wellbeing.
Mistletoe treatment also alleviates the adverse effects from
In conclusion, the same substance can have dosedependent reversal effects.
In small doses, it can activate
defence systems and exhibit beneficial/curative effects, while in high doses, it can inhibit the defence system and
be harmful for the organism. The bell shapedoseeffect relationship is common for adaptogens, which have high
therapeutic indices (effective dose: toxic dose ratio). In addition, toxic medicinal plants in small doses activate the
body's defence systems, particularly the immune system, to cope with cancer and other diseases associated with
suppressed immunity. Adaptogens similarly activate the body's defence systems, but at doses not toxic for humans.
2.3 |Physiological background on the adaptogenic concept
The concept of adaptogens is based on Hans Selye's theory of stress and homeostasis. The word stressis
commonly used in numerous conditions and has quite different meanings in daily life. In this review, we used
commonly accepted definitions of stress, homeostasis, adaptive stress response, and adaptive homeostasis
(Table 6). Repeated mild exposure or low doses of stress induce the increased resistance of cells and organisms to
subsequent stress exposure, resulting in an adaptation favouring survival. This phenomenon of adaptation to
repetitive lowlevel stress was first described by Hans Selye in 1936.
Survival of organisms and resistance to stress depends on adaptability, and adaptive homeostasis is the
threshold that determines an organism's innate tolerance to a given level of stress (Figure 1).
In recent years our understanding of mechanisms underlying the health benefits of natural dietary compounds
has improved considerably. Based on modern concepts, plants synthesize in their most susceptible parts (flowers,
roots, and leaves) special secondary metabolites for selfprotection against microorganisms, insects, and other
pests, as well as to mitigate harmful environmental conditions.
In animals that use plants as their primary
nutrition multiple mechanisms to counteract the potentially poisonous effects of phytotoxins have evolved. These
natural compounds are not noxious in humans at lower doses but are able to induce mild cellular stress re-
The ability of plant secondary metabolites to activate the adaptive cellular stress response pathway in
human body is one of their essential mechanisms of action.
TABLE 6 Definitions of stress, stress system, homeostasis, adaptation, adaptedness, adaptability, resilience,
adaptive homeostasis, adaptive stress response (hormesis), adaptive stress system, and adaptive signaling
Stress is a state of threatened homeostasis,
depending on severity and duration, stress can have quite a different
impact on the organismfrom beneficial to harmful: chronic eustress (too little stress), acute stress (optimum stress)
initiate beneficial adaptive stress response, while when stress increases beyond a certain level acute distress (too
much stress), and chronic stress (burnout)it leads to harmful health effects and can cause numerous diseases. In
this context, adaptogens act like chronic eustress activating adaptive stress response, resilience and overall survival.
Stress system is the neuroendocrineimmune complex, Adaptive stress system includes all physiological systems
involved in the process of adaptation to stress.
Homeostasis is a complex dynamic equilibrium/steady state, maintained by coordinated physiological processes in
the organism.
In other words, homeostasis is the ability of a living organism or cell to maintain the state of
internal balance despite changes in the conditions around it, while stressis temporary inability to maintain this
steady state.
Adaptation as an active process of responding to challenges which includes behavioral, physiological, structural, and
genetic changes upon environmental impacts that are beyond the biologically adequate ranges.
Adaptedness is a result of adaptation process when a positive outcome, that is, survival and reproduction, is achieved
in the face of adversity. Adaptedness is a state that has a capacity for adaptation.
Adaptability is an ability of an organism to alter itself or its responses to the changed circumstances or environment.
Adaptability shows the ability to learn from experience and improves the fitness of the learner as a competitor.
Resilience is the ability to maintain or quickly return to a stable physical and psychological equilibrium despite
experiencing stressful events.
Adaptive homeostasis is defined as the transient reversible adjustments of the homeostatic range in response to
exposure to signaling molecules or events.
Adaptive homeostasis is the cellular or organismal capability to adjust
the homeostatic range in response to herbal adaptogens.
In this context, adaptogens increase homeostatic range to
the level of adaptive homeostasis activating adaptive stress response resulted in increased resilience and overall
survival, Figure 1.
General adaptation syndromethree phase response including nonspecific reactions (thymus atrophy, adrenal,
hyperplasia, stomach ulceration, increased secretion of cortisol and catecholamines, etc.) of organisms evoked to
stress: (i) alarm phase, (ii) phase of nonspecific resistance, following which symptoms disappear, and (iii) phase of
exhaustion, when the same symptoms reappear, followed by death.
Adaptive stress response (hormesis) is the ability of a cell, tissue, or organism to better resist stress damage by prior
exposure to a lesser amount of stress is known as adaptive response. It is observed in all organisms in response to a
number of different cytotoxic agents.
This phenomenon has been categorized as hormesis or as adaptive stress response, preconditioning.
The multiple mediators of the stress signaling system (the neuroendocrineimmune complex) including different
growth factors, antioxidants, and stressresistant proteins such as heat shock proteins (Hsps) are involved in
stressinduced responses of the innate and adaptive defence systems.
We suggest that adaptogens are the
first line of plant secondary metabolites activating adaptive stress response pathways
(Figure 2).
Adaptive stress response is important in cell maturation, with initiation by mild stress of mechanisms of repair
and maintenance to protect cells against subsequent stresses, while chronic stress induce progressive failure of
these mechanisms, leading to cellular senescence, aging, and death.
With cellular maintenance on overdrive, the
organism can continue to protect himself from chronic inflammation, which causes a range of serious illnesses,
particularly agingrelated diseases.
The adaptive stress response is a survival mechanism. All functions of the body systems (e.g., cardiovascular,
immune, nervous, endocrine, gastrointestinal digestive) are regulated by about 30,000 genes and fragments of
FIGURE 1 (A) Adaptive homeostasis was defined as the transient reversible adjustments of the homeostatic
range in response to exposure to signaling molecules or events. Any biological function or measurement oscillate
around a mean or median, within a homeostatic range that is considered a normalor physiological, upgraded
from Reference [131]. (B) Adaptogens and physical exercise adjust the homeostatic range of salivary nitric oxide.
Effects of physical exercise and androgens on the nitric oxide level in saliva of athletes regularly trained for 3 and
7 years
[Color figure can be viewed at]
DNA, which are located in the nucleus of every single cell. The activity of genes depends on the signals/stimuli
received from numerous receptors and various proteins located on the outside surface of the cell membrane. The
receptors specifically trigger signals from extracellular moleculesstressors (Figure 3) and transfer the signals to
genes via many signaling cascades (adaptive signaling pathways), which can interact and influence each other in a
complex molecular network (Figure 4). Collectively, this stimulusresponse system is known as the adaptive stress
response system of the body responding to environmental stress.
In conclusion, the adaptive stress response is a survival mechanism that includes the genetic response to
environmental mild stressors. The mild stressors include exercise, calorie restriction, and adaptogens, which ac-
tivate adaptive signaling pathways of the adaptive stress system to boost the body's cellular maintenance functions
into high gear with cells having a more efficient response. Adaptogens trigger the adaptive stress response to
reduce chronic inflammation (inflammaging) and promote healthy aging.
The principal active constituents of adaptogenic plants (as investigated to date, Table 7) can be divided into three
main chemical groups
o compounds with a tetracyclic skeleton like cortisol and testosteroneterpenoids ginsenosides, sitoindosides,
cucurbitacines, and withanolides,
o structural analogues of catecholamines or tyrosinelignans (schizandrin B from S. chinensis, eleutheroside E
from E. senticosus), phenylpropane derivatives (rosavin from R. rosea and syringin from E. senticosus), pheny-
lethane derivatives (tyrosol and salidroside from R. rosea),
o structural analogues of resolvins
oxylipins (polyhydroxylated polyunsaturated fatty acids
FIGURE 2 Adaptive stress response factors, mediators, and effectors (updated and adapted from
Reference [143] and authorsdrawings.
Adaptive stress response involves activation of intracellular and
extracellular signaling pathways and increased expression of antiapoptotic proteins, neuropeptides, antioxidant
enzymes, and defense response of an organism resulting in increased survival. One basic mechanism of action of
adaptogens, that is, that they activate adaptive cellular stress response pathways in humansbrain cells [Color
figure can be viewed at]
The number of plants reported as being adaptogenic has increased exponentially during the past dec-
ades. However, it should be emphasized that onlyafewcomplywiththemostimportantcriterium
exhibiting multitarget effects on the neuroendocrineimmune system. These effects include triggering in-
tracellular and extracellular adaptive signaling pathways that promote cell survival and organismal resilience
in stress; and regulating metabolism and homeostasis via effects on the expression of stress hormones
(corticotropinand gonadotropinreleasing hormones, urocortin, cortisol,melatonin,Hsp70,andneuro-
peptide Y) and their receptors.
Various adaptogens and their active principlesfor example, salidroside,
schisandrin A,
withaferin A,
Ginsenoside 20(S)Rg3,
Ginsenoside 20(S)Rh2,
compound K,
and 20(S)25
exhibit anticancer effects in various in vitro and in vivo models of breast, col-
orectal, prostate, hepatic, and intestinal cancers, and so forth by interacting with multiple intracellular signaling
pathways, including the inhibition of proinflammatory pathways, such as the ERK/MAPK
and STAT3 signaling
It was found that compound K, an intestinal microbiome metabolite of ginsenoside Rb1,
one of the major
ginsenosides of Panax ginseng, has much stronger cancer chemopreventive activity than its precursor (Rb1 in HCT
FIGURE 3 Effects of adaptogens on adaptive stress response signaling pathways that promote synaptic
plasticity and protect neurons against degeneration. Illustration of a glutamatergic neuron receiving excitatory
signals from neurons activated in response to intellectual tasks, exercise, and dietary energy restriction.
Postsynaptic receptors for glutamate, acetylcholine, and serotonin, are activated to trigger intracellular signaling
pathways and transcription factors that activate the expression of neuroprotective proteins including
antiapoptotic proteins, brainmitochondrial uncoupling proteins (UCPs), and derived neurotrophic factor (BDNF).
BDNF activates neuronal growth by stimulating the mammalian target of rapamycin (mTOR). Mild cellular stress
resulting from dietary energy restriction and oxidative stress (ROS) activates adaptive stress response pathways
including those that upregulate antioxidant enzymes (AOEs) and protein chaperones. CREB, cyclic AMP response
elementbinding protein; CaMKII, calcium/calmodulin kinase II; DAG, diacylglycerol; FOXO3, forkhead box protein
O3; HO1, heme oxygenase 1; HSF1, heat shock factor 1; IP3 PKC, inositol trisphosphate 3 protein kinase C; NFB,
nuclear factor B; NRF2, nuclear regulatory factor 2 NQO1, NAD(P)Hquinone oxidoreductase 1 (updated and
adapted from Reference [59] and from authorsdrawings
[Color figure can be viewed at]
116 and HT19 human colorectal cancer cell lines), suggesting that Rb1 may have potential clinical significance in
the prevention of inflammatoryassociated colorectal cancer
because of the regulation of the microbiome
balance and compound K.
R. rosea extracts and the active compound salidroside decrease the growth of bladder cancer cell lines via the
inhibition of the mTOR pathway and induction of autophagy.
Salidroside was shown to exhibit antioxidant, anti
inflammatory, and anticancer effects in human breast cancer in vitro and in vivo experimental models.
droside treatment significantly inhibits MCF7 breast cancer cell proliferation, colony formation, migration, inva-
sion, apoptosis, and cellcycle arrest at the G0/G1 phase in vitro and significantly suppressed tumor growth in
In vitro and in vivo experiments demonstrated that salidroside enhances the chemotherapeutic effect of
apatinib in gastric cancer.
Ginseng potentiates the effects of chemotherapeutic agents via synergistic
activities, supported by cellcycle evaluations, apoptotic observations, and computerbased docking
Finally, the results of many studies suggest that adaptogens might be useful for the prevention of liver cancer
because of the upregulation of Nrf2 signaling, followed by the induction of the antioxidant and phase II detoxifying
engines, for example, induction of the phase II detoxification enzyme NQO1 in hepatocarcinoma cells by lignans of
S. chinensis, tigloylgomisin H (TGH), and angeloylgomisin H (AGH), which have exhibited a relatively high chemo-
prevention index (10.80 and 4.59, respectively).
FIGURE 4 Effects of adaptogens on adaptive stress response intracellular signaling pathways (updated from
). Activation of the PI3K/AKT/mTOR signaling pathway positively regulates cell cycle,
proliferation, neural longterm potentiation (memory cognitive functions and longevity. AC, adenylate cyclase;
AMPK, 5' AMPactivated protein kinase; AP1, activator protein 1 transcription factor; CREB, cyclic AMP response
elementbinding protein; DAG, diacylglycerol; Fos, Fos protooncogene, AP1 transcription factor subunit; FOXOs,
forkhead box proteins; IP3, inositol 1,4,5trisphosphate; JNK, cJun Nterminal kinases; MaMkinase, Ca
calmodulindependent protein kinase II; MAPKMEK (MAPK/ERK), mitogenactivated protein kinases; NFκB,
nuclear factor kappalightchainenhancer of activated B cells; NRF2, nuclear regulatory factor 2; PDE, 3',5'cyclic
AMP phosphodiesterase; PI3K, phosphoinositide 3kinase; PIP3, phosphatidylinositol (3,4,5)trisphosphate; PIP2,
phosphatidylinositol (4,5)bisphosphate; PKA, cAMPdependent protein kinase; PKBAkt, serine/threoninespecific
protein kinase; PKC, protein kinase C; PLC, phospholipase C [Color figure can be viewed at]
TABLE 7 List of the plants reported to have antistress (adaptogenic) activity and used in traditional medicinal
systems as rejuvenating medicinal plants, qi tonics, rasayanas, or restoratives
Plants reported in Literature as adaptogens (1)* and for
References supporting such use in
specific medical systems
TCMqi tonifying Ayurveda
1Aegle marmelos (L.) Corrêa [153] [154]
2Ajuga turkestanica (Regel) Briq. [155]
3Albizia julibrissin Durazz. [156]
4Alstonia scholaris (L.) R. Br. [157] [158]
5Allium sativum L. [159]
6Andrographis paniculata (Burm.f.) Nees [160,161] [162]
7Annona muricata L. [163]
8Aralia elata (Miq) Seem. [164]
9Aralia elata var. mandshurica (Rupr. &
Maxim.) J.Wen (syn. Aralia mandshurica
Rupr. & Maxim)
10 Aralia cordata var. sachalinensis (Regel) Nakai
(syn.Aralia schmidtiiPojark.)
11 Argyreia nervosa (Burm. f.) Bojer (syn.
Argyreia speciosa (L. f.) Sweet)
[168] [168]
12 Asparagus racemosus Willd. [169] [170,171]
13 Azadirachta indica A. Juss. [172] [173]
14 Bacopa monnieri (L.) Wettst. [174] [175,176]
15 Bergenia crassifolia (L.) Fritsch [177179]
16 Boerhaavia diffusa Brandegee [180] [181]
17 Bryonia alba L. [12,114]
18 Butea monosperma (Lam.) Taub. [182] [183]
19 Caesalpinia bonduc (L.) Roxb. [184] [185]
20 Cannabis sativa L. [186] [187]
21 Carum carvi L. [188] [188]
22 Centella asiatica (L.) Urb. [189] [190]
23 Chlorophytum borivilianum Santapau &
[191,192] [193,194]
24 Chrysactinia mexicana A. Gray [195]
25 Cicer arietinum L. [196] [170]
26 Clematis alpina subsp. sibirica (L.) Kuntze
(syn. Atragene sibirica L.)
27 Cnestis ferruginea Vahl ex DC. [198]
28 Codonopsis pilosula (Franch.) Nannf. [10] [199,200]
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for
References supporting such use in
specific medical systems
TCMqi tonifying Ayurveda
29 Convolvulus pluricaulis Chois [201] [190]
30 Curculigo orchioides Gaertn. [202] [203,204] [204]
31 Curcumin from Turmeric (Curcuma longa)[205] [204]
32 Dioscorea deltoidea Wall. ex Griseb. [206]
33 Diospyros malabarica (Desr.) Kostel. (Syn.
Diospyros peregrina (Gaertn.) Gürke)
34 Elaeagnus rhamnoides (L.) A.Nelson.
(Syn.Hippophae rhamnoides L.)
[208,209] [210]
35 Eleutherococcus senticosus (Rupr. & Maxim.)
36 Eleutherococcus sessiliflorus (Rupr. & Maxim.)
S.Y. Hu (syn Acanthopanax sessiliflorus
(Rupr. & Maxim.) Seem.)
[8,166] [211,212]
37 Emblica officinalis Gaetrn. [170] [213,214]
38 Eucommia ulmoides Oliv. [215] [216,217]
39 Evolvulus alsinoides (L.) L. [218220] [218,219]
40 Fagopyrum esculentum Moench [221]
41 Firmiana simplex (L.) W. Wight (Syn Sterculia
plantanifolia L.)
42 Gentiana pedicellata (D.Don) Wall [223]
43 Ginkgo biloba L. [224]
44 Glycyrrhiza glabra L. [193,225] [226] [193,227]
45 Hebanthe eriantha (Poir.) Pedersen
(Syn.Pfaffia paniculata (Mart.) Kuntze)
46 Heteropterys aphrodisiaca Machado [229]
47 Heteropterys tomentosa A.Juss.[230]
48 Hibiscus cannabinus L. [231]
49 Holoptelea integrifolia Planch [232] [233]
50 Hoppea dichotoma Willd. [234]
51 Hypericum perforatum L. [235]
52 Justicia diffusa Willd. (Syn Rostellularia
diffusa (Willd.) Nees.)
53 Lagenaria siceraria (Molina) Standl. [237]
54 Lepidium meyenii Walp. (Syn. Lepidium
peruvianum G.Chacón)
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for
References supporting such use in
specific medical systems
TCMqi tonifying Ayurveda
55 Marantodes pumilum (Blume) Kuntze.
(Syn.Labisia pumila (Blume) Mez)
56 Melilotus officinalis (L.) Pall. [240]
57 Mitragyna inermis (Willd.) Kuntze (Syn
Mitragyna africana (Willd.) Korth.)
58 Momordica charantia L. [242]
59 Morus alba L. [243]
60 Mucuna pruriens (L.) DC. [244] [190]
61 Murraya koenigii (L.) Spreng. [245]
62 Mussaenda frondosa L. [246]
63 Nelumbo nucifera Gaertn. [247] [248]
64 Nigella sativa L. [249]
65 Ocimum tenuiflorum L. (Syn.Ocimum
sanctum L.)
66 Oplopanax elatus (Nakai) Nakai (Syn.
Echinopanax elatum Nakai)
[165,166,253] [165]
67 Panax ginseng C.A.Mey. [8,165,187,224] [84,85,254]
68 Panax notoginseng (Burk.) FH Chen [107]
69 Panax pseudoginseng Wall. [255] [256]
70 Pandanus odorifer (Forssk.) Kuntze
(Syn.Pandanus odoratissimus L.f.)
71 Paullinia cupana Kunth [258]
72 Putranjiva roxburghii Wall. (Syn. Drypetes
roxburghii (Wall.) Hurus.)
73 Piper longum L. [260,261] [170,261]
74 Polyalthia cerasoides (Roxb.) Bedd. [163,262]
75 Polyscias filicifolia (C.Moore ex E.Fourn.)
76 Potentilla alba L. [264]
77 Prunella vulgaris L. [265]
78 Psidium guajava L. [266]
79 Ptychopetalum olacoides Benth. [267]
80 Pueraria tuberosa (Roxb. ex Willd.) DC. [268]
81 Rhaponticum carthamoides (Willd.)Iljin (Syn.
Leuzea carthamoides (Willd.) DC.)
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for
References supporting such use in
specific medical systems
TCMqi tonifying Ayurveda
82 Rhodiola crenulata (Hook.f. & Thomson)
83 Rhodiola heterodonta (Hook. f. & Thomson)
84 Rhodiola imbricata Edgew. [271,274]
85 Rhodiola rosea L. [today classed as Sedum
roseum (L.) Scop.]
[8,21,66,72,275,276] [277] [278]
86 Rubia cordifolia L. [279] .[280]
87 Salvia miltiorrhiza Bunge [281] [282]
88 Schisandra chinensis (Turcz.) Baill. [18,64,69,165,283] [284,285]
89 Scutellaria baicalensis Georgi [286] [287]
90 Serratula tinctoria L. (Syn.Serratula
inermis Poir.)
91 Sida cordifolia L. [289] [289]
92 Silene italica (L.) Pers.[290]
93 Sinomenium acutum (Thunb.) Rehder &
94 Solanum torvum SW. [292]
95 Serratula coronate L. [293]
96 Sutherlandia frutescens (L.) R.Br. [294]
97 Syzygium aromaticum (L.) Merr. & L.M.Perry.
(Syn. Eugenia caryophyllus (Spreng.)
Bullock & S.G.Harrison)
[295] [185]
98 Terminalia chebula Retz. [296] [297] [170,193]
99 Tinospora sinensis (Lour.) Merr.
(Syn.Tinospora cordifolia (Willd.) Miers,
Syn Tinospora malabarica (Lam.) Hook. f.
& Thomson)
[298,299] [170,300]
100 Tribulus terrestris L. [301] [301]
101 Trichilia catigua A.Juss. [229]
102 Trichopodium zeylanicum (Gaertn.) Thwaites
(Syn.Trichopus zeylanicus Gaertn.)
[302,303] [302,303]
103 Trigonella foenumgraecum L. [304306] [307]
104 Tylophora indica (Burm. f.) Merr. [308]
105 Turnera diffusa Willd. ex Schult. [229]
106 Uncaria tomentosa (Willd. ex Schult.) DC. [309]
107 Vitis vinifera L. [310] [310]
Stressprotective and stimulating effects are characteristic and common pharmacological effects of adapto-
which have been observed in many animals and humansstudies. The effects of adaptogens on
cognitive functions and physical endurance in stress are summarized in several reviews.
The main difference between adaptogens and conventional stimulants such as caffeine and amphetamine is
that after prolonged use, the latter can cause the user to develop both tolerance and addiction (Table 8).
Primarily, adaptogens have potential benefits in cases of behaviorrelated disorders, mental illness, stress
induced fatigue (Figure 5), and cognitive function.
In a number of clinical stu-
dies, the beneficial effects of adaptogens have been demonstrated on healthy subjects in stress condi-
This is especially true of the mental and physical performance of fatigue and
mental strain. Furthermore, the efficacy of adaptogens in mild and moderate depression has been
The prophylactic use of adaptogens seems to be justified in healthy subjects for preventing agingrelated
diseases, and to attenuate stressinduced harmful effects.
Several systematic reviews and assessment reports have been conducted on the clinical efficacy and safety of
and other adaptogens on several indications
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for
References supporting such use in
specific medical systems
TCMqi tonifying Ayurveda
108 Withania somnifera (L.) Dunal [232,311313] [170,314318]
109 Zingiber officinale Roscoe [319]
Updated from References [16,183].
TABLE 8 The differences in properties between adaptogens and other stimulants
Stimulants Adaptogens
Stress protective (neuro, hepato, cardioprotective) No High
Recovery process after exhaustive physical load Low High
Energy depletion Yes No
Performance in stress Increased
Survival in stress Increased
Quality of arousal Poor Good
Addiction potential Yes No
Side effects Yes Rare
DNA/proteins synthesis Decreased Increased
NPY mediated activation of Hsp70 Increased
Note: Updated from References [27,152].
such as cognitive function,
cardiovascular diseases,
chronic pulmonary disease,
prevention of common
and erectile dysfunction.
The clinical evidence of the benefits of W. somnifera in male infertility is also
promising but very limited to provide sufficiently robust evidence because of the small number of eligible studies
and available data.
The results suggest the potential role of W. somnifera in managing diabetes mellitus, but
evidence is not robust because of insufficient available clinical data. Furthermore, welldesigned randomized
controlled trials (RCTs) with a larger sample size and longer duration are warranted to evaluate its effect primarily
on blood glucose, HbA1c, and insulin.
In five studies conducted in patients with anxiety and stress, significant (in
most cases) improvements were observed with Withania intervention as compared with placebo, but cases of
potential bias were identified.
There is some evidence from randomized, placebocontrolled, doubleblind trials
regarding the benefits of W. somnifera on cognitive function, such as improved performance on cognitive tasks,
attention, and reaction time.
However, the study population was heterogeneous, including older adults with
mild cognitive impairment and adults with schizophrenia, schizoaffective disorder, or bipolar disorder.
In most of the early clinical studies on Eleutherococcus preparations conducted in the USSR in the 1960s and
1970s, positive results were commonly reported.
However, most of these trials lacked good methodology (e.g.,
lack of randomization, proper control, blinding, statistical tools, description of inclusion and exclusion criteria,
description of the medication, diagnosis, study design, and small sample size). In 2009, Li et al. assessed the efficacy
and safety of Eleutherococcus in patients with acute ischemic stroke in a Cochrane systematic review. The authors
included 13 RCTs (962 participants). The primary outcome measure in all included trials was the improvement of
the neurological deficit after treatment. Eleutherococcus was found to significantly increase the number of parti-
cipants with improvement in neurological impairment. However, because the risk of bias in all of the included trials
was high, the authors concluded that much larger trials of greater methodological quality are required.
In the
EMEA assessment report dated March 25, 2014, the authors concluded that despite the large number of studies on
the topic, Eleutherococcus root preparations do not reach the level of wellestablished usescientific evidence
sufficient to grant a marketing authorization, although in total, the data available are sufficient to justify further
research on the concept of adaptogens.
FIGURE 5 Chronic stressinduced symptoms and effect of adaptogens, updated from authorsdrawings
[Color figure can be viewed at]
Similar decisions were made in 2011 and 2012 regarding Rhodiola
and ginseng.
The beneficial effects of
ginseng on cognitive function have been demonstrated in several studies, but the evidence was not sufficient to
achieve the designation of wellestablished use in 2012 because of the heterogeneity of the investigated pre-
parations, limited numbers of participants, differences in study design, and methodological quality.
Because the
number of clinical trials on the clinical efficacy of R. rosea was limited, we could not conclude that there was
sufficient evidence for wellestablished use in the treatment of fatigue or mental weakness. However, the data
support the plausibility of the use of the traditional herbal medicinal products of R. rosea as adaptogens.
In Sweden, Norway, and Denmark, Rhodiola traditional herbal medicinal product is indicated as an adaptogen
in situations of decreased performance such as fatigue and sensation of weakness.
In a systematic review and metaanalysis of 11 RCTs of R. rosea, Hung et al.
concluded that the metho-
dological quality of most trials was moderate or good. Five of the 11 RCTs reached more than 3 points on the
Jadad score (i.e., good quality). R. rosea may have beneficial effects on physical performance, mental performance,
and certain mental health conditions. Only a few mild adverse events were reported. There is, however, a lack of
independent replications of the single different studies.
Extracts of Red Korean Ginseng have been tested extensively in mice and isolated cells infected with influenza
virus. The antiviral protective effects were observed regardless of influenza virus strains, including various sub-
types of H1N1, H3N2, H5N1, and H7N9. Mice inoculated with a lethal dose of virus and ginseng preparations were
protected against weight loss with 100% survival rates during primary infection, and they developed immunity
against secondary viral infection.
The use of various ginseng extracts to treat mice infected with influenza
virus decreased the interleukin (IL)6 and IL8 cytokines and increased antiviral cytokine interferon (IFN) upon
influenza virus infection.
It was demonstrated that ginsenosides, particularly Rb1, interact with viral he-
magglutinin proteins, preventing the virus from binding to host cells and viral entry into the cytoplasm.
Meanwhile, ginseng polysaccharide fraction exhibits a strong antiviral effect in mice infected with influenza A virus,
predominantly by reducing the accumulation of tumor necrosis factor α(TNFα)/inducible nitric oxide synthase
(iNOS)producing dendritic cells (tipDCs) in mouse lungs.
Clinical trials suggest that ginseng is an effective
prophylactic agent for respiratory infections, reducing the risk and duration of colds and flu and providing
symptom relief.
The efficacy and safety of Andrographiscontaining preparations were studied in patients with common cold in
Scandinavia, South America, and India.
Evidence from a metaanalysis of the results of 33 RCTs showed that
Andrographis relieves inflammatory symptoms and shortens the duration of cough, sore throat, and sick leave/time
to resolution when compared with usual care.
Several epidemiological studies conducted in the USSR during the 1970s appeared to establish that Eleu-
therococcus root extract, given prophylactically, can reduce morbidity rates during an influenza virus epidemic as
well as typical complications of influenza infection, such as bronchitis, pneumonia, and otitis.
Eleutherococcus is an
effective antiviral agent that induces IFNγproduction
and increases leukocyte, cytotoxic Tcell, Thelper,
and Band Tlymphocyte counts in peripheral blood.
The efficacy of adaptogens in the treatment of
acute respiratory tract diseases is possibly also partially associated with the downregulation of proinflammatory
NFkB signaling in various cells and tissues involved in the acute inflammatory response.
The fixed combination (Kan Jang) of Andrographis and Eleutherococcus has been used since 1979 in Sweden as
an herbal medicine (naturmedel), with wellestablished use (naturläkemedel) in Denmark since 1997 for re-
ducing the severity and duration of symptoms of common cold.
This combination was tested in controlled clinical
trials for the treatment of common cold and influenzaassociated uncomplicated upper respiratory infections as
well as for the prevention of common colds.
The studies confirmed the safety and superior efficacy of this
combination regimen as compared with monodrug therapy,
presumably because of its antiviral effects,
effects on innate and adaptive immunity,
and antiinflammatory, antioxidant, and detoxifying effects
of both adaptogenic plants as well as due to their synery.
It should be noted that the postmarketing pharma-
covigilance assessment of Kan Jang showed a high benefitrisk ratio: one adverse event in about 100,000 patients
was recorded for the 23year period from the adverse event reports (concerning mainly allergic reactions) to the
Swedish and Danish medical product agencies. Further studies are needed to evaluate the efficacy of these plants
in patients with COVID19 and other viral respiratory invidious diseases.
One more possible benefit of adaptogens in respiratory tract infectious diseases might be their beneficial
effect during patient convalescence. Adjuvant therapy with Chisan/ADAPT232, a fixed combination of Eleuther-
ococcus,R. rosea, and S. chinensis, in pneumonia has a positive effect on patient recovery by decreasing the duration
of the acute phase of the illness, increasing patient mental performance during the rehabilitation period, and
improving patient quality of life (QOL).
Both the clinical and laboratory results of the present study suggest that
Chisan (ADAPT232) can be recommended in the standard treatment of patients with acute nonspecific pneu-
monia as an adjuvant to increase patient QOL and to expedite their recovery.
Dietary supplements containing Rhodiola, Withania, Ginseng, Eleutherococcus, Schisandra, and other adaptogenic
plant extracts are widely used all over the world,
while in China, Korea, Japan, Russia,
and some neighbor countries various pharmaceutical forms of adaptogenic plants form a part of official medi-
Overall, it is well documented now that adaptogens act polyvalently with positive effects on aging
related disorders including atherosclerosis and other chronic inflammatory diseases, metabolic diseases, neuro-
degenerative cognitive impairment as well as cancer.
For example, numerous in vivo
and in vitro studies on P. ginseng have shown its beneficial effects in aging, CNS disorders, and neurodegenerative
and cardiovascular diseases, cancer, immune deficiency, and hepatotoxicity. Clinical trials have been conducted on
the effects of ginseng preparations on cognitive function, lipid and glucose metabolism, cardiovascular function,
erectile dysfunction, quality of life, improvement of the immune system, and chronic respiratory diseases.
All of
them are associated with the metabolic regulation of homeostasis and threatened adaptability of the stress system.
Adaptogenic plants possess compounds that exhibit anticancer activity and potentiate the effects of antitumor
drugs, suggesting that they can be used alone or as adjuvants to conventional chemotherapy to improve their
efficacy or reduce radiotherapyor chemotherapyinduced toxicity,
for example, nausea and vomiting.
Supplementation with adaptogens is also considered a promising therapy for cancerrelated fatigue, a debilitating
syndrome that persists for years in many cancer survivors.
More evidence from controlled clinical studies supporting health claims and indications for use in diseases are
5.1 |Mechanisms of adaptogenic and stressprotective actions
The pathogenesis of complex diseases as well as the adaptive stress response, inflammation, and senescence are
multistep processes which involve extracellular and intracellular communications at differing stages of stress
regulation and cannot be limited to the few biochemical interactions that occur in the brain or other tissues.
Clearly, for the description of the mechanism of action of adaptogens the reductionist model that assumes a single
drugsingle receptor interaction is insufficient and not valid. Adaptogens have many molecular targets
volved in the metabolic regulation of homeostasis at both the cellular and systemic levels and play a role of stress
response modifiers.
Network pharmacology with the use of the systems biology offers exciting new opportunities for under-
standing such complex systems.
During the past several decades, many molecules, signaling pathways, and
networks targeted by adaptogens have been identified.
They include stress hormones and some
other important mediators of homeostasis regulation such as the molecular chaperons Hsp70, neuropeptide Y, G
proteincoupled receptors (GPCRs), dopaminecAMPPKACERT, IP3, PLC, DAG, phosphoinositide 3kinase (PI3K),
nuclear factor kappalightchainenhancer of activated B cells (NFκB)mediated signaling pathways,
stressactivated kinase cJun Nterminal kinase (JNK), forkhead box protein O3 (FOXO3), cortisol, estrogens, and
nitric oxide (NO).
The mechanisms of action of adaptogens are mainly associated with metabolic
regulation via extracellular communication of hypothalamicpituitaryadrenal (HPA)axis hormones and activation
of intracellular adaptive stress response signaling pathways.
5.1.1 |Effect of adaptogens on extracellular communications within the
neuroendocrineimmune system
The hypothetical mechanism of adaptogensaction on HPAaxis hormones in stress is presented in Figure 6. The
HPA axis plays a pivotal role in regulating the majority of endocrine hormones associated with the CNS. Stress
hormones regulate growth, appetite, blood pressure, emotion, sexual function, body temperature, sleep, bior-
hythms, and hydration. They are produced by the endocrine system, are secreted into the bloodstream, and target
FIGURE 6 Hypothetical mechanism of action underlying the effects of adaptogens on the adaptive stress
response in the hypothalamicpituitaryadrenal axis: forkhead box O, neuropeptideY (NPY), and Hsp70 signaling.
Persistent chronic stress induces and blockage of negative feedback regulation of cortisol and disruption of ATP
synthesis. During stress, corticotropinreleasing hormone (CRH) is released from the hypothalamus, followed by
the release of adrenocorticotropic hormone (ACTH) from the pituitary, which stimulates the release of adrenal
hormones and NPY. Feedback regulation of overreaction is triggered by cortisol release from the adrenal cortex,
followed by binding to glucocorticoid receptors (GRs) in the brain, which halts the further release of brain
hormones, resulting in decreases of cortisol to normal levels. Although mild stress (eustress) is a vital part of life,
chronic and severe stress can cause depression associated with the production of active oxygencontaining
molecules including nitric oxide, which inhibits ATP formation. The stressinduced signaling protein cJun
Nterminal kinase (JNK) inhibits GRs. Subsequently, this feedback control is inhibited and the cortisol content in
the bloodstream of depressed patients is permanently high, which is associated with impaired memory, decreased
ability to concentrate, fatigue, among others. Adaptogens normalize increased cortisol/corticosterone levels in the
bloodstream and saliva of humans or animals
presumably due to direct interaction with GRs. Adaptogens also
attenuate elevated JNK and cortisol levels during stress and activate the generation of Hsp70, which inhibits JNK.
Therefore, the nitric oxide level no longer rises, and ATP production is not inhibited (adapted from authors
) [Color figure can be viewed at]
other tissues to regulate physiological functions. The main function of stress hormones is to maintain homeostasis
to counteract stress
Ginsenoside Rg1 directly interacts with glucocorticoid receptor (GR) ligandbinding sites and behaves as a
partial agonist of GR. Ginsenoside Rb1 is a functional ligand of the estrogen receptor (ER).
Along with CRH, another primary upstream mediator of extracellular communications stimulated by adap-
togens is the stress hormone neuropeptideY (NPY).
Stimulation and release of NPY into the blood circulatory
system are innate defence responses to mild stressors (adaptogens), which increase resistance to stress. This leads
to stressprotective and adaptive effects via various elements of the endocrine, immune, central nervous, sym-
pathetic, cardiovascular, and gastrointestinal systems. Both Hsp72 and NPY play essential roles in stress, and
pathogenesis of agingrelated diseases. The antinarcotic effects of adaptogens are mediated by NPY, which is an
important intermediate involved in morphine tolerance and opioid dependence.
5.1.2 |Molecular mechanisms of actionEffects on intracellular signaling pathways
Gene expression analysis has helped to gain an improved understanding of the molecular mechanisms of action of
adaptogenic plants and elucidation of adaptive stress response signaling.
One recent study in which
the gene expression profiles of isolated brain cells were exposed to adaptogens, showed that at least 88 of the
3516 genes regulated by adaptogens modulate many signaling pathways involved in the adaptive stress re-
Genes encoding neurohormones, transmembrane channels, and receptors, transcription regulators and
liganddependent nuclear receptors, protein kinases phosphatases, peptidases, metabolic enzymes, chaperones and
other intermediates of intraand extracellular communications (Table 9) are key elements in several canonical
pathways involved in defence response, survival, longevity, and in maintaining of cellular and organismal
Some of these proteins play key roles in regulating numerous processes. As an example, all adaptogens
upregulate TLR9, a member of the PI3K (complex) geneencoding transmembrane receptor that plays key roles in
regulating 152 signaling pathways including glucocorticoid receptor signaling, interleukins IL2, IL3, IL4, IL6, IL7,
IL8, IL9, ILK, IL12, IL15, IL17A, IL17 signaling, Band Tcell receptor signaling, leukocyte extravasation,
extracellular signalregulated protein kinase (ERK)/MAPK, PI3K/AKT signaling in the pathogenesis of influenza,
lipopolysaccharidestimulated MAPK signaling, p53 and JNK signaling, production of NO and reactive oxygen
species (ROS) in macrophages signaling, eNOS signaling NO signaling in the cardiovascular system, leptin signaling
in obesity, type II diabetes mellitus signaling, IGF1 and insulin receptor signaling, prolactin signaling, AMPK
signaling, and so forth.
All adaptogens upregulate protein kinase C (PKC) eta, an enzyme encoded by the PRKCH gene that plays key
roles in the regulation of 72 signaling pathways including CRH signaling, androgen signaling, prolactin signaling,
growth hormone signaling, melatonin signaling, Gαq signaling, feedback in cAMP signaling, Nrf2mediated oxida-
tive stress response, production of NO and ROS in macrophages, mTOR signaling, NFκB activation by viruses,
calciuminduced T lymphocyte apoptosis, protein kinase A signaling, phospholipase C signaling, eNOS signaling,
opioid signaling pathway, neuropathic pain signaling in dorsal horn neurons, axonal guidance signaling, CREB
signaling in neurons, dopamineDARPP32 endothelin1 signaling, αadrenergic signaling, nNOS signaling in neu-
rons, synaptic longterm potentiation and synaptic longterm depression signaling pathways.
All adaptogens upregulate mitogenactivated protein kinases MAPK10 and MAPK13 which correspondingly
involved in the regulation of 77 and 58 signaling pathways, including adaptive stress response signaling survival
and longevity. These findings support the use of adaptogenic plants in TMS as a panacea for the treatment of
numerous diseases.
All adaptogens tested (R. rosea L., E. senticosus, W. somnifera, R. carthamoides, and B. alba) activate the melatonin
signaling pathway by acting through two GPCRs MT1 and MT2, and upregulating the ligandspecific nuclear
TABLE 9 Genes regulated by adaptogens
Number of
regulatedEntrez gene nameSymbolType(s)
Note: Upregulated genes are in red color while downregulated genes are in blue color text.
receptor RORA, which plays a role in different common aging diseases such as neurological disorders, hyperten-
sion, dyslipidemia, intellectual disability, retinopathy, and cancer. Furthermore, melatonin activates adaptive sig-
naling pathways and upregulates the expression of UCN, GNRH1, TLR9, GP1BA, PLXNA4, CHRM4, GPR19, VIPR2,
RORA, STAT5A, ZFPM2, ZNF396, FLT1, MAPK10, MERTK, PRKCH, and TTN, which are commonly regulated by all
adaptogens tested.
The common features of recently tested extracts (B. alba L., Boswellia serrata Roxb. ex Colebr., Curcuma longa L.,
E. senticosus (Rupr. & Maxim.) Maxim, Rhaponticum carthamoides (Willd.) Iljin,R. rosea L., and W. somnifera (L.) Dunal)
are related to the downregulation of ALOX12, which is also associated with the neuroprotective action of these
medicinal plants as well as their potential benefits in neurodegenerative diseases.
R. rosea, W. somnifera, and E. senticosus downregulate the expression of key genes (ALOX5AP, DPEP2, LTC4S)
involved in the biosynthesis of leukotrienes A, B, C, D, and E, resulting in inhibition of the leukotriene signaling
pathway suggesting their potential benefits in Alzheimer's disease (Figure 7).
Adaptogens exhibit multitarget node of action targeting several receptors including receptors for corticos-
teroid, mineralocorticoid, progestin, estrogen, serotonin, NMDA, nicotinic acetylcholine, receptor tyrosine kinases,
and many GPCRs.
Numerous molecular network interactions (including feedback reg-
ulation of the neuroendocrine and immune systems) resulting in agonistdependent antagonism are presumably the
most suitable model for understanding the mechanism of action of adaptogens.
Interactive pathway analysis has demonstrated that adaptogens targets mediators of extracellular commu-
nications, intracellular networks, and signaling pathways, which are involved in stressinduced and agingrelated
disorders such as chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic dis-
orders, and cancer.
Importantly, the effect on every disease is multitargeted. As an example, Robiola
regulates 22 genes, which are deregulated in mood disorders, including 14 genes that are deregulated in de-
NCAM1, and PDE11A.
FIGURE 7 Effect of Rhodiola extract on the eicosanoids signaling pathway. Upregulated genes are shown in red
color, while downregulated genesin green color
[Color figure can be viewed at]
5.1.3 |Mechanisms underlying the cytoprotective, antioxidant, and antitoxic activities
of adaptogens
Cytoprotective, antioxidant, and antitoxic effects of various adaptogenic preparations have been shown in many
isolated cells as experimental models and (in vitro and ex vivo) in animals.
Extensive research on E.
senticosus reveals its antitoxic, neuroprotective, hepatoprotective, cardioprotective, antioxidant, im-
munomodulating, and antiviral activities along with stressprotective, antifatigue, hypoglycaemic, antidepressant
and antiproliferative effects.
As an example, E. senticosus inhibits the cadmiuminduced apoptosis and
mitosis of hepatocytes in mice, and significantly decreased cadmium concentration in their liver and blood.
It has
been shown that hepatoprotective effect of E. senticosus extract is triggered by upregulation of expression Nrf2
and activation of innate antioxidant enzymes that increase the ratio of reduced versus oxidized glutathione in liver
homogenate and serum.
Repeated administration of E. senticosus preparation decreased isoproterenol induced
cardiotoxicity and increased ventricular fibrillation threshold in rats with postinfarction cardio-
Eleutherococcus reduces the toxic effects of cytostatic drugs (cyclophosphane, etimidine, benzotef,
sarcolisyne, ribomicine, 6mercaptopurine, dopane thiophosphamide, trichlortriethylamin) as chemotherapy in-
cluding loss of body weight, increased mortality, decreased life span, reduction of tumor growth, thymic involution,
haematopoiesis, and immunosupression. Adjuvant treatment with Eleutherococcus significantly increases the sur-
vival of rodents following etimidine treatment for carcinoma (100% survival vs. 70% control [etimidine]). Similarly,
adjuvant treatment with Eleutherococcus significantly increases survival following thiophosphamide treatment (85%
survival vs. 47% control [thiophosphamide]).
The antioxidant and hepatoprotective activity of Eleutherococcus and Andrographis paniculate preparations have
been reviewed in EMA assessment report.
The chemopreventive effects of A. paniculata and Andrographolide
against cyclophosphamide (CTX)induced urothelial toxicity were previously demonstrated.
Both substantially
lowered the elevated levels of IL2 and IFNγand reduce CTXinduced toxicity during CTX treatment.
another study, the aqueous extract of A. paniculata was shown to attenuate gentamicininduced nephrotoxicity
decreasing blood levels of urea, creatinine, and urea nitrogen levels in rats.
A. paniculata and andrographolide exhibit an extremely wide array of pharmacological activities
including adaptogenic,
antioxidant, chemopreventive,
and neuroprotective activities.
The cytoprotective effect of several adaptogenic plant extracts on chemotherapeuticsinduced dramatic im-
pact on transcriptomewide RNA microarray profiles of neuroglia cells culture have been recently studied.
The fixed combination 5fluorouracil, epirubicin, and cyclophosphamide (FEC) has been shown to deregulate 67
genes involved in the reduction of neuronal development, 37 genes involved in development of the sensory system,
12 genes involved in axon extension, and 3 genes involved in neuronal migration. Pretreatment of cells with A.
paniculata prevented the FECinduced deregulation of genes involved in regulation of neuronal death, neurogen-
esis, and other vital functions in the nervous system. Similar cytoprotective effects exhibit a fixed combination of A.
paniculate with E. senticosis, which prevented the FECinduced deregulation of gene expression involved in mi-
gration of T98G neuroglia cells, axon extension, conduction of nerves, and other neuronal functions associated
with cognitive impairments. Adaptogens significantly modify FECinduced deregulation of genes involved in the
regulation of cell morphology, synaptic, mitochondrial function, and proteinrelated functions suggesting their
potential neuroprotective and hepatoprotective effects, which are associated with FECinduced adverse events in
cancer chemotherapy. The authors concluded that adjuvant treatment with adaptogens can prevent mild cognitive
impairments and chemobraineffect associated with cancer chemotherapy.
It is noteworthy that adaptogens
potentiate the cytotoxic effects of chemotherapeutics in human T98G glioblastoma cells.
There are several mechanisms underlying the cytoprotective and antitoxic effects of adaptogens.
One of them is the Nrf2/antioxidant response element (ARE) signaling pathway, which a key defense response
signaling pathway regulating the expression of phase II detoxifying enzymes in response to toxic stimuli (Figure 8).
An imbalance between the production of reactive oxygen radicals and their degradation results in
oxidative stress. Reactive intermediates interact with polyunsaturated fatty acids, proteins, and RNA and
DNA fragments, initiating numerous redox reactions that damage many cellular components such as the
membrane, mitochondria, and nucleus, which leads to dysfunction of cellular processes and homeostasis, and
triggers apoptosis and necrosis. Oxidative stress is increased in chronic inflammation and agingrelated
disorders including atherosclerosis, angiogenesis, and neurodegeneration.
The feedback cellular response
is associated with activation of defence mechanisms including induction of antioxidant and detoxifying
enzymes and molecular chaperones. Several adaptive signaling pathways such as p38, PKC, ERK, JNK, and
PI3K signaling may activate Nrf2. Two other adaptive signaling pathways involving NFκBandFOXO
transcription factors are important in neuronal stress adaptation.
FIGURE 8 Adaptogens exhibit antioxidant and detoxifying effects presumably by activation of the Nrf2/ARE
pathway.Nrf2 is a principal regulator of redox homeostasis normally retained in the cytoplasm by association
Kelchlike ECHassociated protein1 (Keap1). Upon exposure of cells to oxidative stress, Nrf2 is phosphorylated in
response to PKC, phosphatidylinositol 3kinase (PI3K), and MAPK pathways. After phosphorylation, this complex
dissociates and Nrf2 translocates to the nucleus where it binds to the ARE and triggers expression of antioxidant
and detoxifying genes including superoxide dismutase, glutathione Stransferase, NAD(P)H quinone
oxidoreductase 1, and heme oxygenase 1. Thus, activation of Nrf2 translocation or upregulation of gene expression
resulting in activation of the Nrf2 signaling pathway is the key mechanism of the cellular defense response
associated with the antioxidant effects of medicinal plants, and particularly of adaptogenic plants, which are useful
in stressand agingrelated diseases [Color figure can be viewed at]
Although adaptogens at high concentrations are potent radical scavengers, in lower amounts, they may ac-
tivate some intracellular adaptive stress response signaling pathways resulting in the expression of cytoprotective
proteins including neurotrophic factors, protein chaperones, antioxidant and phase II enzymes, and antiapoptotic
proteins. One of them is transcription factor Nrf2.
The beneficial effects of adaptogens appear to be related, at least in part, to their ability to activate the Nrf2/
ARE pathway (Figure 8) and regulate the number of genes playing important roles in activation of the production of
antioxidant and detoxifying proteins and genes involved in the reduction of oxidation damage (Figure 9).
Other possible cytoprotecting mechanisms of adaptogens related to drug toxicity, oxidative stress, chronic
inflammation, and agingrelated disorders include their effects on Hsp70 and FOXO expression (Figure 10).
5.1.4 |Agingassociated disorders
Agingassociated disorders arise from declining capabilities to cope with stress, to sustain cellular and system
homeostasis, and to maintain physiological functions. These disorders are associated with neurodegeneration
(common for Alzheimer's disease, Parkinson's disease, and senile dementia), atherosclerosis (cause of cardiovas-
cular and cerebrovascular diseases), immune regulation (dysregulated in cancer, autoimmune, and chronic in-
flammatory diseases), and endocrine/metabolic dysfunction (imbalanced in diabetes and obesity).
Overproduction of ROS in stressinduced condition leads to destruction of proteins, including those triggering
genetic programs of cellular senescence and cell death (apoptosis). Attenuation of functions, increasing damage to
proteins, and toxic protein aggregates initiate agingrelated changes leading to disease, senescence, and reduced
life span. In aging cells, substantially decreased expression of heat shock protein Hsp70 and its precursor, heat
shock transcription factor HSF1, correlates with a decreased ability to cope with stress.
When cells are
exposed to stress resulting in protein damage, HSF1 initiates the production of molecular chaperone Hsp70,
which repairs proteins by folding denatured parts of proteins and promotes the degradation of irreversibly
FIGURE 9 Adaptogens prevents the chemotherapy (FEC)induced downregulation of genes activating
production of antioxidant and detoxifying proteins and upregulates genes involved in reduction of oxidation
damage via Nrf2 signaling. Upregulated genes are shown in red, whereas downregulated genes are shown in blue
[Color figure can be viewed at]
damaged proteins and their aggregates. In addition, Hsp70 directly protects cells against switch to apoptosis.
Decreased expression of HSF1 and Hsp70 in brain cells is observed in Alzheimer's disease.
It is associated
with the accumulation of protein aggregates of βamyloid peptide and cytoskeletal protein.
Agingrelated de-
cline of hepatic Hsp70 expression results in decreased liver detoxification
and protection from toxic sub-
Decrease of Hsp70 is coupled with upregulation of stressactivated protein kinase (JNK) dependent
apoptosis and progression of cancer Stressinduced decline in induction of Hsp70 observed in humans, is asso-
ciated with aging and agingrelated disease.
Amazingly, in some individuals which are more than 100 years old,
Hsp70 does not decrease with age.
In young age, the balance between proand antiaging JNKmediated programs is shifted in favor of Hsp70
(Figure 11). Apparently, oxidative stress does not affect survival and reproduction of young cells because stress
activated Hsp70 blocks JNKstimulated apoptosis. Enhanced levels of Hsp70 correlate with increased life span. In
contrast, with age, when induction of Hsp70 is reduced, the balance shifts in favor of the aging and apoptosis
programs. Consequently, even weak oxidative stress can induce the degeneration of neuronal cells and the pro-
gression of agingrelated diseases. The ability to respond effectively to stress by generating increased Hsp70
correlates with high adaptability and increased life span.
Thus, the onset of neurodegenerative diseases and
other agingrelated illnesses may be delayed by modulating these two pathways.
The adaptogens R. rosea,S. chinensis, and E. senticossus, alone and in combination, upregulate transcription
factor HSF1, and increase generation of molecular chaperon Hsp70 in vitro and in vivo.
togens also inhibit stressactivated protein kinase JNK,
a key mediator of apoptosis and aging (Figure 11).
Furthermore, adaptogens trigger translocation of transcription factor DAF16 (FOXO) from the cytoplasm into the
The protective effect against myocardial ischemiareperfusion injury via increase of Hsp25 and Hsp70
expression in rat hearts was described for schizandrin B, an active constituent of S. chinensis.
Induction of Hsp27
FIGURE 10 Hypothetical mechanism of action of adaptogens in the regulation of the innate antioxidant system
and oxidative stressinduced apoptosis in aging. According to the free radical theory of aging, the organisms are
continuously exposed to reactive oxygen species containing molecules/species (ROS), which are produced as
byproducts of normal cellular metabolism. When the innate antioxidant system (glutathione peroxidase,
superoxide dismutase, and catalase) incompletely deactivates ROS, increasing cellular oxidative damage induces
irreversible functional changes leading to early senescence and to agingassociated diseases. Oxidative stress
triggers many signaling pathways, including FOXO and Hsp70 mediated pathways. Adaptogens upregulate Hsp70,
which directly regulates FOXO signaling and promote translocation of FOXO/DAF16 to nucleus triggering
activation antioxidant systems and antiaging programs. Updated from authorsdrawings
[Color figure can be
viewed at]
and Hsp70 genes and protein expression were observed in a dosedependent manner after oral administration of
schizandrin B to rats.
The prolongation of life span and increased survival under stress after treatment with preparations from R.
rosea, S. chinensis, E. senticossus, W. somnifera, and P. ginseng have been shown. in the fruit fly Drosophila melano-
the nematode Caenorhabditis elegans,
and yeast Saccharomyces cerevisiae.
supplementation with salidroside or extracts of E. senticosus, S. chinensis, and R. rosea significantly decreased stress
induced elevation of pSAPK/pJNK in rabbits subjected to restraint stress.
Based on these observations, it was
suggested that adaptogens acts as mild stressors inducing enhanced stress resistance and an extended life span.
Adaptogens regulate Gprotein signaling phosphatidylinositol and phospholipase C pathways (Figure 4). R.
rosea, S. chinensis, and E. senticossus upregulate the expression of PLCB1 gene, which encodes phosphoinositide
specific phospholipase C (PLC), and the PI3KC2G gene, which encodes PI3Ks.
Gprotein activated, phospholipase
C (PLC) catalyzes the hydrolysis of phosphatidylinositol 4,5bisphosphate (PIP2) into diacylglycerol (DAG) and
inositol1,4,5triphosphate (IP
) that is involved in numerous intracellular signaling pathways associated with
various diseases including depression and cancer. DAG triggers protein kinase C (PKC), which phosphorylates
numerous proteins and plays an important role in tumor progression. PI3K is a key upstream mediator of in-
tracellular signaling related to regulation of NFkBmediated defence responses and apoptosis as well as to long
term potentiation of neurotransmission, which improves memory and learning.
R. rosea, S. chinensis, and E. senticossus downregulate the CETP gene
expression, which regulate the bio-
synthesis of cholesteryl ester transfer protein that facilitates the transport of cholesterol esters and triglycerides
between lowdensity lipoproteins (LDL) and highdensity lipoproteins (HDL).
Inhibiting of expression of CETP
may be helpful in the treatment of atherosclerosis, cardiovascular and metabolic diseases.
Adaptogens downregulate the ESR1 gene.
ESR1 encodes estrogen receptor α(ERα), which is overexpressed
in some cancers.
Downregulation of expression of ESR1 by Rhodiola and other adaptogens may be effective
for preventing and treating some agingrelated cancers such as breast cancer, ovarian, colon, prostate, and en-
dometrial cancers.
The neuroprotective effects of adaptogens
may be also partially associated with the
upregulation of ESR1 in glia cells, as estrogen signaling through ERαdecreases the inflammatory neurodegen-
eration via its effect on astrocytes. Since pretreatment with adaptogens is known to adapt the cell to stress
FIGURE 11 Effects of age and adaptogens on longevity regulatory pathways during oxidative stress. HSF1, heat
shock factor 1; Hsp70, heat shock protein 70; JNK, JN kinase; P53, p53 transcription factor;or ,for activation;
x, for blocking; |, for inhibition; bold text for the prevailing process [Color figure can be viewed at]