Adaptógenos
Adaptógenos
DOI: 10.1002/med.21743
REVIEW ARTICLE
1
Phytomed AB, Vaxtorp, Sweden
2
Department of Pharmaceutical Biology,
Abstract
Institute of Pharmacy and Biochemistry, Adaptogens comprise a category of herbal medicinal and
Johannes Gutenberg University, Mainz,
Germany
nutritional products promoting adaptability, resilience,
3
Department of technology of dosage forms, and survival of living organisms in stress. The aim of this
Saint‐Petersburg State Chemical‐ review was to summarize the growing knowledge about
Pharmaceutical University, St. Petersburg,
Russia common adaptogenic plants used in various traditional
4
Department of Biotechnology, Murmansk medical systems (TMS) and conventional medicine and to
Marine Biological Institute of the Kola provide a modern rationale for their use in the treatment
Science Center of the Russian Academy of
Sciences (MMBI KSC RAS), Murmansk, Russia of stress‐induced and aging‐related disorders. Adapto-
5
Department of Far Eastern Medicine, Clinic gens have pharmacologically pleiotropic effects on the
for Gastroenterology and Gastrointestinal
neuroendocrine‐immune system, which explain their
Oncology, University Medical Center
Göttingen, Göttingen, Germany traditional use for the treatment of a wide range of
6
Department of Pharmaceutical Technology, conditions. They exhibit a biphasic dose‐effect response:
School of Natural Product Studies, Jadavpur
at low doses they function as mild stress‐mimetics, which
University, Kolkata, India
7
Research Cluster Biodiversity and
activate the adaptive stress‐response signaling pathways
Medicines, UCL School of Pharmacy, Centre to cope with severe stress. That is in line with their
for Pharmacognosy and Phytotherapy,
University of London, London, UK
traditional use for preventing premature aging and to
maintain good health and vitality. However, the potential
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
8
Shanghai Research Center for TCM
Modernization, Shanghai Institute of Materia of adaptogens remains poorly explored. Treatment of
Medica, Chinese Academy of Sciences,
stress and aging‐related diseases require novel ap-
Shanghai, China
9
Department of Pharmacy, Center for
proaches. Some combinations of adaptogenic plants
Pharma Research, Ludwig‐Maximilians‐ provide unique effects due to their synergistic interac-
Universität München, Munich, Germany
tions in organisms not obtainable by any ingredient in-
Correspondence dependently. Further progress in this field needs to focus
Alexander G. Panossian, Phytomed AB,
on discovering new combinations of adaptogens based
Bofinkvagen 1, Vaxtorp 31275, Sweden.
Email: [email protected] 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 stress‐induced and aging‐
related diseases.
KEYWORDS
adaptogen, aging, ethnopharmacology, network pharmacology,
stress
1 | INTRODUCTION
Numerous systematic reviews, meta‐analyses of preclinical and clinical studies, and comprehensive assessment
reports1–17 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
stress‐induced and aging‐related 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.
The term adaptogens is currently widely used in alternative and complementary medicine, as well as in
pharmacognosy, phytomedicine, and phytotherapy research. 5 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
632 | PANOSSIAN ET AL.
• Adaptogens are medicinal substances causing the “state of nonspecifically increased resistance” of the organism.6,7
• 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.8
• The adaptogens are nontoxic compounds with polyvalent mechanisms of action and pharmacological effects related
to adaptability and survival.9
• 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.10
• Adaptogens are metabolic regulators, which increase the ability of an organism to adapt to environmental factors and
to avoid damage from such factors.11
• 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 stress‐induced disorders.12
• 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
conditions.13
• Adaptogens comprise a pharmacotherapeutic group of herbal preparations used to: increase attention and endurance in
fatigue and prevent/mitigate/reduce stress‐induced impairments and disorders related to neuro‐endocrine and
immune systems.14
• 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.15
• Adaptogens are stress‐response modifiers that increase an organism's nonspecific resistance to stress by increasing its
ability to adapt and survive.16
• Botanical adaptogens are metabolic regulators that increase survival by increasing adaptability in stress.16
• Adaptogens are natural compounds or plant extracts that increase adaptability and survival of living organisms to
stress.17
• Adaptogen—any of various natural substances used in herbal medicine to normalize and regulate the systems of the
body. https://www.dictionary.com/browse/adaptogen
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 process—adaptation to environmental
challenges, which is a multistep process including diverse mechanisms of extracellular and intracellular
interactions. The renewed definition of adaptogens 16,17 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.11,16–63
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., neuroendocrine‐immune complex). Fur-
thermore, adaptogens trigger the generation of hormones (cortisol, corticotropin‐releasing hormone [CRH] and
gonadotropin‐releasing hormones, urocortin, neuropeptide Y), playing key roles in metabolic regulation and
PANOSSIAN ET AL. | 633
Definition: Adaptogens are natural compounds or plant extracts that increase adaptability, resilience, and survival of
organisms to stress.
Chemical class: Various, predominantly tetracyclic triterpenes, phenethyl‐and phenylpropanoids glycosides, stilbenes,
lignans, etc.
(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
gonadotropin‐releasing hormones, urocortin, cortisol, neuropeptide Y, heat shock proteins Hsp70) and their
receptors.
Indications for use: Stress‐induced fatigue, mental and behavioral disorders, aging‐associated diseases.
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 stress‐induced 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 stress‐induced damages, provide
energy to fight fatigue, reduce aging‐associated decline of the neuroendocrine‐immune system. Table 2 provides a
summary of the general characteristics of adaptogens, which comprise a category of nutritional and herbal
medicinal products.
2 | B AC K G R O U N D O F T H E A D A P T O G E N I C C O N C E P T
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 (2‐phenyl‐imidazol) assuming that adaptogens increase the nonspecific re-
sistance of organisms under conditions of stress resulting in increased endurance, stamina, and perfor-
mance. 6 This assumption was based on the results of intensive studies of Schisandra chinensis in the USSR
during World War II,64–66 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.67 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
seeds. 68
The interest in S. chinensis (known as limonnik = лимонник in Russian) arose from ethnopharmacological in-
vestigations by. Komarov (1895) and Arsenyev (1903–1907) 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
night‐time vision.69
634 | PANOSSIAN ET AL.
Aralia elata (Miq.) Seem (A. mandshurica Rupr. et maxim.) Radices FS.2.5.0058.18
Tincture FS 42‐1647‐93
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. Radices and rhizomes, FS.2.5.0053.15
Oplopanax elatus (Nakai) Nakai (Echinopanax elatum Nakai) Radices and rhizomes, FS 42‐314‐72
Tincture FS 42‐1887‐82
Tincture FS 42‐1886‐82
Rhodiola rosea L. (a synonym of Sedum roseum (L.) Scop.) Radices and rhizomes, FS.2.5.0036.15
Seeds FS.2.5.0082.18
The first studies on the stimulating and tonic effects on S. chinensis were published in World War II‐era military
journals.64–66 During the 1960s and 1970s, other Soviet scientists extended the research of adaptogens to “re-
juvenating and invigorating” medicinal 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.70–72
The authors screened many plants assuming that “adaptogens must be safe and normalize body functions
irrespective of the nature of stressors” and 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
PANOSSIAN ET AL. | 635
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
adults.
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
station,73,74 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 Pills” and “Elixir of Youth” that 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.
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, qi‐tonics, rasayanas, or rejuvenating herbs. Tonic herbs are
classified as the highest and most sought‐after 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 energy” and 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.
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.
636 | PANOSSIAN ET AL.
The core of the TCM concept is the yin‐yang 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
balance.
We can find many relevant examples of the yin‐yang balance when this concept is applied to the regulation of
cellular and organismal homeostasis75 (e.g., cyclic adenosine monophosphate [cAMP] and cyclic guanosine
monophosphate [c‐GMP], prostacyclin and thromboxane, sympathetic and parasympathetic nervous systems,
testosterone, cortisol). For example, the testosterone/cortisol ratio is associated with stress‐related disorder
symptoms such as fatigue, decreased performance, and impaired recovery from overtraining syndrome in sports
medicine.76 The major symptoms and signs of overtraining were categorized77 as:
• 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 status78 known in TCM as “shanghuo” or “re‐qi” (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 Xie‐Huo in TCM), leading to the
onset and progression of diseases.79
In other words, “shanghuo”79 is a state of decreased resistance (or increased susceptibility) leading to stress
and progression of diseases. That is similar to low‐grade inflammation,80 resulting in and involving whole‐body
systems such as the neuroendocrine‐immune (stress‐system), cardiovascular, and other systems.
According to TCM, the onset of disease is due to both external (wind, cold, heat, dampness, dryness, fire) and
internal causes—excessive emotional activity induces the yin‐yang 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 yin‐yang imbalance, experience blockage of qi and impairment of vital organ function. According to
TCM theory, “shanghuo” caused 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 stress‐induced disorders caused by a yin‐yang imbalance with prophylactic treatment using
medicinal plants trace back to centuries (e.g, Weibing in China, Mibyeong in Korea,81 and Mibyou in Japan.82
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.83
According to TCM, the treatment of diseases must rectify harmony, and restore qi and the yin‐yang 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
PANOSSIAN ET AL. | 637
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.84
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.47,85–88
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 well‐known broad action medicinal plant in TCM is
ginseng.89,90
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 long‐term intake tonifying five vital organs of the body (spleen, lung, heart, kidney, and liver).
According to other ancient regards written by Hongjing Tao (AD 456–536), 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.91 Kampo is mostly
based on the systematic collection of case histories—empirical 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
individual.91
A special class of Kampo prescriptions with close similarity to the adaptogenic concept are the so‐called
“support preparations” or 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.92,93
The traditionally accepted explanation for the activity of Kampo medicines ‐ including Hozai —was summarized
in the 18th century CE by the philosopher Yoshimasu Todo (1702–1773), 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.94 In this context, hozai and adaptogens are
similar since adaptogens are eustressors (i.e., good stressors) acting as mild stress mimetics or stress‐vaccines that
induce a stress‐protective response,12,14,27,60,95 which is in line with the basics of Kampo medicine.91 The re-
lationship of the two concepts is illustrated by P. ginseng root—one of the classical USSR Adaptogens.8 This is an
essential component drugs of most Hozai preparations (Table 4).96 The two major prescriptions of the hozai
category are Juzentaihoto97 and Hochuekkito98 (Table 4).
Both formulations are mainly used in cases of geriatric ailments and physical decline.93Juzentaihoto 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.99,100
638 | PANOSSIAN ET AL.
TABLE 4 Crude drugs and their respective daily dosages (g) in the two traditional Kampo Hozai prescriptionsa
https://kampo.ca/herbs‐formulas/formulas/juzentaihoto/ https://kampo.ca/herbs‐formulas/formulas/hochuekkito/
The Western indications, for which hozai are most often used in Japan, are related to cachexia,101,102 a loss of
skeletal muscle mass that differs from weight loss due to malnutrition, anorexia nervosa, or anorexia due to
depression or sarcopenia (aging‐related muscle loss).
In conclusion, shanghuo, a state of decreased resistance to stress can be treated with what—first in the Soviet/
Russian literature—has been labeled adaptogenic plants. These will and increase the nonspecific resistance to
stress; the yin‐yang 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 stress‐vaccines that induce a stress‐protective 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
necessary.
2.2.2 | Ayurveda
Ayurveda is a conventional medicinal system with varied treatments, which originated over 3 millennia ago in
South Asia.103 In Ayurvedic philosophy, the central concept is the Tridosha theory suggesting that good health
PANOSSIAN ET AL. | 639
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 rasa‐dhatu 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.104 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:
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 well‐being. 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, anti‐inflammatory, analgesic, immunomodulatory, antioxidant
effects, cardiopulmonary, and hypotensive effects.105
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
studies.4
640 | PANOSSIAN ET AL.
The root of the liquorice plant (Glycyrrhiza sp.) is also oa well‐known rasayana drug in Ayurveda mainly due to
anti‐inflammatory, 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, anti‐leishmanial, antibacterial,
hepatoprotective, diuretic, antiulcer, antidiarrheal, antenatal tonic, cardioprotective, anticancerous, antiepileptic,
and antidepressant are likely associated with its immunomodulatory and adaptogenic activities.106,107 However,
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.108
In Ayurveda, Guduchi (T. cordifolia) is effective against various infections to boost immunity, especially in the
convalescent period, as it has antipyretic, analgesic, and anti‐inflammatory 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 anti‐inflammatory 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.109
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 well‐being 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 stress‐system (neuroendocrine‐immune 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 Parsi‐Arabic 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 Abu‐Ali Ibn Sina (Avicenna), Amirdovlat, and other medieval physicians and philosophers.110
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.111,112
In pre‐Christian 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.113,114 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.114,115 The Bryonia root has been used to treat a wide range of conditions and
PANOSSIAN ET AL. | 641
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.110,111,114
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.114 Preparations from
Bryonia alba L. root extract (“Loshtak” tablets) 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, radiation‐ and chemotherapy‐induced 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
vitality.
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 high‐potency 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.
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.
642 | PANOSSIAN ET AL.
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.114–118 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.116,119
In addition to homeopathy, other traditions also pay close attention to self‐healing and coping with adverse
situations. Anthroposophical medicine is a complementary medical tradition founded in the 1920s by Rudolf
Steiner,120 who advocated for the use of Viscum album L. (the European white‐berry mistletoe) in cancer.121 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.122 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.123 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.123
In homeostatic doses, the mistletoe preparations Iscador, Eurixor, Helixor, Abnoba‐viscum, 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.124 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 well‐being.125–128 Mistletoe treatment also alleviates the adverse effects from
chemotherapies.129
In conclusion, the same substance can have dose‐dependent reversal effects.130 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 shape” dose‐effect 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.
The concept of adaptogens is based on Hans Selye's theory of stress and homeostasis. The word “stress” is
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 homeostasis131
PANOSSIAN ET AL. | 643
• Stress is a state of threatened homeostasis,132 depending on severity and duration, stress can have quite a different
impact on the organism—from 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 neuroendocrine–immune complex, Adaptive stress system includes all physiological systems
involved in the process of adaptation to stress.133
• 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.135
• 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.136
• 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.137
• Resilience is the ability to maintain or quickly return to a stable physical and psychological equilibrium despite
experiencing stressful events.138
• Adaptive homeostasis is defined as the transient reversible adjustments of the homeostatic range in response to
exposure to signaling molecules or events.131 Adaptive homeostasis is the cellular or organismal capability to adjust
the homeostatic range in response to herbal adaptogens.17 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 syndrome–three 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.139,140
• 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.
(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 low‐level 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 self‐protection against microorganisms, insects, and other
pests, as well as to mitigate harmful environmental conditions.142–144 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-
sponses.145 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.142,144
644 | PANOSSIAN ET AL.
F I G U R E 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 “normal” or 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 years141 [Color figure can be viewed at wileyonlinelibrary.com]
This phenomenon has been categorized as hormesis or as adaptive stress response, pre‐conditioning.146,147
The multiple mediators of the stress signaling system (the neuroendocrine–immune complex) including different
growth factors, antioxidants, and stress‐resistant proteins such as heat shock proteins (Hsps) are involved in
stress‐induced responses of the innate and adaptive defence systems.17,148,149 We suggest that adaptogens are the
first line of plant secondary metabolites activating adaptive stress response pathways17 (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.150 With cellular maintenance on overdrive, the
organism can continue to protect himself from chronic inflammation, which causes a range of serious illnesses,
particularly aging‐related 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
PANOSSIAN ET AL. | 645
F I G U R E 2 Adaptive stress response factors, mediators, and effectors (updated and adapted from
Reference [143] and authors’ drawings.17 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 humans’ brain cells [Color
figure can be viewed at wileyonlinelibrary.com]
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 molecules—stressors (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 stimulus‐response system is known as the adaptive stress
response system of the body responding to environmental stress.16,58,143,148,149,151
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.
3 | A D A P T O G E N I C P LA N T S A N D TH E I R A C T I V E C O M P O U N D S
The principal active constituents of adaptogenic plants (as investigated to date, Table 7) can be divided into three
main chemical groups16:
o compounds with a tetracyclic skeleton like cortisol and testosterone—terpenoids ginsenosides, sitoindosides,
cucurbitacines, and withanolides,
o structural analogues of catecholamines or tyrosine—lignans (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 resolvins152—oxylipins (polyhydroxylated polyunsaturated fatty acids16).
646 | PANOSSIAN ET AL.
F I G U R E 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, brain‐mitochondrial 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
element‐binding 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; NF‐B,
nuclear factor B; NRF2, nuclear regulatory factor 2 NQO1, NAD(P)H‐quinone oxidoreductase 1 (updated and
adapted from Reference [59] and from authors’ drawings16 [Color figure can be viewed at wileyonlinelibrary.com]
The number of plants reported as being adaptogenic has increased exponentially during the past dec-
ades. However, it should be emphasized that only a few comply with the most important criterium—
exhibiting multitarget effects on the neuroendocrine‐immune 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
(corticotropin‐ and gonadotropin‐releasing hormones, urocortin, cortisol, melatonin, Hsp70, and neuro-
peptide Y) and their receptors.16–20,28
Various adaptogens and their active principles—for example, salidroside,320–326 schisandrin A,327 schisandrin
B,328 withaferin A,329–334 Ginsenoside 20(S)‑Rg3,335 Ginsenoside 20(S)‐Rh2,336 compound K,337,338 and 20(S)‐25‐
methoxy‐protopanaxatriol339,340—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/MAPK341 and STAT3 signaling
pathways.320–340
It was found that compound K, an intestinal microbiome metabolite of ginsenoside Rb1,342 one of the major
ginsenosides of Panax ginseng, has much stronger cancer chemopreventive activity than its precursor (Rb1 in HCT‐
PANOSSIAN ET AL. | 647
F I G U R E 4 Effects of adaptogens on adaptive stress response intracellular signaling pathways (updated from
authors’ drawings17). Activation of the PI3K/AKT/mTOR signaling pathway positively regulates cell cycle,
proliferation, neural long‐term potentiation (memory cognitive functions and longevity. AC, adenylate cyclase;
AMPK, 5' AMP‐activated protein kinase; AP‐1, activator protein 1 transcription factor; CREB, cyclic AMP response
element‐binding protein; DAG, diacylglycerol; Fos, Fos proto‐oncogene, AP‐1 transcription factor subunit; FOXOs,
forkhead box proteins; IP3, inositol 1,4,5‐trisphosphate; JNK, c‐Jun N‐terminal kinases; MaM‐kinase, Ca2+/
calmodulin‐dependent protein kinase II; MAPK–MEK (MAPK/ERK), mitogen‐activated protein kinases; NF‐κB,
nuclear factor kappa‐light‐chain‐enhancer of activated B cells; NRF2, nuclear regulatory factor 2; PDE, 3',5'‐cyclic‐
AMP phosphodiesterase; PI3K, phosphoinositide 3‐kinase; PIP3, phosphatidylinositol (3,4,5)‐trisphosphate; PIP2,
phosphatidylinositol (4,5)‐bisphosphate; PKA, cAMP‐dependent protein kinase; PKB‐Akt, serine/threonine‐specific
protein kinase; PKC, protein kinase C; PLC, phospholipase C
116 and HT‐19 human colorectal cancer cell lines), suggesting that Rb1 may have potential clinical significance in
the prevention of inflammatory‐associated colorectal cancer343 because of the regulation of the microbiome
balance and compound K.343,344
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.345 Salidroside was shown to exhibit antioxidant, anti‐
inflammatory, and anticancer effects in human breast cancer in vitro and in vivo experimental models.346 Sali-
droside treatment significantly inhibits MCF‐7 breast cancer cell proliferation, colony formation, migration, inva-
sion, apoptosis, and cell‐cycle arrest at the G0/G1 phase in vitro and significantly suppressed tumor growth in
vivo.346
In vitro and in vivo experiments demonstrated that salidroside enhances the chemotherapeutic effect of
apatinib in gastric cancer. 347 Ginseng potentiates the effects of chemotherapeutic agents via synergistic
activities, supported by cell‐cycle evaluations, apoptotic observations, and computer‐based docking
analysis. 348
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).349
648 | PANOSSIAN ET AL.
T A B L E 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
antistressa specific medical systems
Referenceb TCM—qi tonifying Ayurveda
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for References supporting such use in
antistressa specific medical systems
Referenceb TCM—qi tonifying Ayurveda
(Continues)
650 | PANOSSIAN ET AL.
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for References supporting such use in
antistressa specific medical systems
Referenceb TCM—qi tonifying Ayurveda
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for References supporting such use in
antistressa specific medical systems
Referenceb TCM—qi tonifying Ayurveda
(Continues)
652 | PANOSSIAN ET AL.
TABLE 7 (Continued)
Plants reported in Literature as adaptogens (1)* and for References supporting such use in
antistressa specific medical systems
Referenceb TCM—qi tonifying Ayurveda
Stress‐protective and stimulating effects are characteristic and common pharmacological effects of adapto-
gens,73,350,351 which have been observed in many animals and humans’ studies. The effects of adaptogens on
cognitive functions and physical endurance in stress are summarized in several reviews.10,22,26,27,350,352
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).27,352
Primarily, adaptogens have potential benefits in cases of behavior‐related disorders, mental illness, stress‐
induced fatigue (Figure 5), and cognitive function.11,14,15,26,27,48,74,75,216,275,350,353–367 In a number of clinical stu-
dies, the beneficial effects of adaptogens have been demonstrated on healthy subjects in stress condi-
tions.26,27,48,74,75,324,353,356,357,359,362 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
demonstrated.275,355,358,360,363,366
The prophylactic use of adaptogens seems to be justified in healthy subjects for preventing aging‐related
diseases, and to attenuate stress‐induced harmful effects.26,27,95,317,368–371
Several systematic reviews and assessment reports have been conducted on the clinical efficacy and safety of
ginseng,2,372–374 Eleutherococcus,375 Rhodiola,376–382 Withania,383–388 and other adaptogens on several indications
Stimulants Adaptogens
F I G U R E 5 Chronic stress‐induced symptoms and effect of adaptogens, updated from authors’ drawings14
[Color figure can be viewed at wileyonlinelibrary.com]
such as cognitive function,33,72 cardiovascular diseases,389 chronic pulmonary disease,390 prevention of common
cold,391 and erectile dysfunction.392 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.393 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, well‐designed 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.386 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.383 There is some evidence from randomized, placebo‐controlled, double‐blind trials
regarding the benefits of W. somnifera on cognitive function, such as improved performance on cognitive tasks,
attention, and reaction time.385 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.394 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.375 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 “well‐established use” scientific evidence
sufficient to grant a marketing authorization, although in total, the data available are sufficient to justify further
research on the concept of adaptogens.3
654 | PANOSSIAN ET AL.
Similar decisions were made in 2011 and 2012 regarding Rhodiola1 and ginseng.2 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 well‐established use in 2012 because of the heterogeneity of the investigated pre-
parations, limited numbers of participants, differences in study design, and methodological quality.2 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 well‐established 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.1
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 meta‐analysis of 11 RCTs of R. rosea, Hung et al.381 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.395,396 The use of various ginseng extracts to treat mice infected with influenza
virus decreased the interleukin (IL)‐6 and IL‐8 cytokines and increased antiviral cytokine interferon (IFN) upon
influenza virus infection.397–400 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.401
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 (TNF‐α)/inducible nitric oxide synthase
(iNOS)‐producing dendritic cells (tipDCs) in mouse lungs.402 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.403–405
The efficacy and safety of Andrographis‐containing preparations were studied in patients with common cold in
Scandinavia, South America, and India.406–411 Evidence from a meta‐analysis 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.411
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.3 Eleutherococcus is an
effective antiviral agent that induces IFN‐γ production412–416 and increases leukocyte, cytotoxic T‐cell, T‐helper,
and B‐ and T‐lymphocyte counts in peripheral blood.412,417–420 The efficacy of adaptogens in the treatment of
acute respiratory tract diseases is possibly also partially associated with the downregulation of proinflammatory
NF‐kB 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 well‐established use (“naturläkemedel”) in Denmark since 1997 for re-
ducing the severity and duration of symptoms of common cold.3 This combination was tested in controlled clinical
trials for the treatment of common cold and influenza‐associated uncomplicated upper respiratory infections as
well as for the prevention of common colds.421–424 The studies confirmed the safety and superior efficacy of this
combination regimen as compared with monodrug therapy,425 presumably because of its antiviral effects,426–432
effects on innate and adaptive immunity,433–437 and anti‐inflammatory, antioxidant, and detoxifying effects438–441
of both adaptogenic plants as well as due to their synery.25 It should be noted that the postmarketing pharma-
covigilance assessment of Kan Jang showed a high benefit–risk ratio: one adverse event in about 100,000 patients
PANOSSIAN ET AL. | 655
was recorded for the 23‐year 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 COVID‐19 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/ADAPT‐232, 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).354 Both the clinical and laboratory results of the present study suggest that
Chisan (ADAPT‐232) 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,21,69,87,160,161,261,318,442–446 while in China, Korea, Japan, Russia,
and some neighbor countries various pharmaceutical forms of adaptogenic plants form a part of official medi-
cine.447–449 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.1–4,10,13,15,17,21,44,57,69,278,444 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.57 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 radiotherapy‐ or chemotherapy‐induced toxicity,348 for example, nausea and vomiting.114,450
Supplementation with adaptogens is also considered a promising therapy for cancer‐related fatigue, a debilitating
syndrome that persists for years in many cancer survivors.88
More evidence from controlled clinical studies supporting health claims and indications for use in diseases are
required.
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
drug—single receptor interaction is insufficient and not valid. Adaptogens have many molecular targets16,17 in-
volved in the metabolic regulation of homeostasis at both the cellular and systemic levels and play a role of stress
response modifiers.11,16,17,19–28,49,56,60
Network pharmacology with the use of the systems biology offers exciting new opportunities for under-
standing such complex systems.16 During the past several decades, many molecules, signaling pathways, and
networks targeted by adaptogens have been identified.11,16,18–28,49,56,60 They include stress hormones and some
other important mediators of homeostasis regulation such as the molecular chaperons Hsp70, neuropeptide Y, G
protein‐coupled receptors (GPCRs), dopamine‐cAMP‐PKA‐CERT, IP3, PLC, DAG, phosphoinositide 3‐kinase (PI3K),
nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB)‐mediated signaling pathways,
656 | PANOSSIAN ET AL.
stress‐activated kinase c‐Jun N‐terminal kinase (JNK), forkhead box protein O3 (FOXO3), cortisol, estrogens, and
nitric oxide (NO).11,16,18–28,49,56,60 The mechanisms of action of adaptogens are mainly associated with metabolic
regulation via extracellular communication of hypothalamic–pituitary–adrenal (HPA)‐axis hormones and activation
of intracellular adaptive stress response signaling pathways.16
The hypothetical mechanism of adaptogens’ action on HPA‐axis 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
F I G U R E 6 Hypothetical mechanism of action underlying the effects of adaptogens on the adaptive stress
response in the hypothalamic–pituitary–adrenal axis: forkhead box O, neuropeptide‐Y (NPY), and Hsp70 signaling.
Persistent chronic stress induces and blockage of negative feedback regulation of cortisol and disruption of ATP
synthesis. During stress, corticotropin‐releasing 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 oxygen‐containing
molecules including nitric oxide, which inhibits ATP formation. The stress‐induced signaling protein c‐Jun
N‐terminal 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 animals12,357 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’
drawings26) [Color figure can be viewed at wileyonlinelibrary.com]
PANOSSIAN ET AL. | 657
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) ligand‐binding 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 neuropeptide‐Y (NPY).23,28 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 stress‐protective 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 aging‐related diseases. The antinarcotic effects of adaptogens are mediated by NPY, which is an
important intermediate involved in morphine tolerance and opioid dependence.
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.17,23–25,451,452 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-
sponse.17 Genes encoding neurohormones, transmembrane channels, and receptors, transcription regulators and
ligand‐dependent nuclear receptors, protein kinases phosphatases, peptidases, metabolic enzymes, chaperones and
other intermediates of intra‐ and extracellular communications (Table 9) are key elements in several canonical
pathways involved in defence response, survival, longevity, and in maintaining of cellular and organismal
homeostasis.
Some of these proteins play key roles in regulating numerous processes. As an example, all adaptogens
upregulate TLR9, a member of the PI3K (complex) gene‐encoding transmembrane receptor that plays key roles in
regulating 152 signaling pathways including glucocorticoid receptor signaling, interleukins IL‐2, IL‐3, IL‐4, IL‐6, IL‐7,
IL‐8, IL‐9, ILK, IL‐12, IL‐15, IL‐17A, IL‐17 signaling, B‐ and T‐cell receptor signaling, leukocyte extravasation,
extracellular signal‐regulated protein kinase (ERK)/MAPK, PI3K/AKT signaling in the pathogenesis of influenza,
lipopolysaccharide‐stimulated 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, IGF‐1 and insulin receptor signaling, prolactin signaling, AMPK
17
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, Nrf2‐mediated oxida-
tive stress response, production of NO and ROS in macrophages, mTOR signaling, NF‐κB activation by viruses,
calcium‐induced 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, dopamine‐DARPP32 endothelin‐1 signaling, α‐adrenergic signaling, nNOS signaling in neu-
rons, synaptic long‐term potentiation and synaptic long‐term depression signaling pathways.17
All adaptogens upregulate mitogen‐activated 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 ligand‐specific nuclear
658 | PANOSSIAN ET AL.
Number of
signaling
pathways
Type(s) Symbol Entrez gene name regulated
Note: Upregulated genes are in red color while downregulated genes are in blue color text.
PANOSSIAN ET AL. | 659
F I G U R E 7 Effect of Rhodiola extract on the eicosanoids signaling pathway. Upregulated genes are shown in red
color, while downregulated genes—in green color452
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.17
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.452
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).452
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.11,16,18–28,44,49,56,60,453–473 Numerous molecular network interactions (including feedback reg-
ulation of the neuroendocrine and immune systems) resulting in agonist‐dependent antagonism are presumably the
most suitable model for understanding the mechanism of action of adaptogens.16
Interactive pathway analysis has demonstrated that adaptogens targets mediators of extracellular commu-
nications, intracellular networks, and signaling pathways, which are involved in stress‐induced and aging‐related
disorders such as chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic dis-
orders, and cancer.17,23–25,368 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-
pression: ADRA2B, AQP4, CACNB2, CCKBR, CHRNA1, CHRNB4, CHRNG, ESR1, GRIA3, GRIN1, KCNK2, MYOM1,
NCAM1, and PDE11A.24,275
660 | PANOSSIAN ET AL.
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.1–4,9,26,27,69,71,474 Extensive research on E.
senticosus reveals its antitoxic, neuroprotective, hepatoprotective, cardioprotective, antioxidant, im-
munomodulating, and antiviral activities along with stress‐protective, antifatigue, hypoglycaemic, antidepressant
and antiproliferative effects.3,8,46,474–481 As an example, E. senticosus inhibits the cadmium‐induced apoptosis and
mitosis of hepatocytes in mice, and significantly decreased cadmium concentration in their liver and blood.478 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.226 Repeated administration of E. senticosus preparation decreased isoproterenol induced
cardiotoxicity and increased ventricular fibrillation threshold in rats with post‐infarction cardio-
sclerosis.480,481 Eleutherococcus reduces the toxic effects of cytostatic drugs (cyclophosphane, etimidine, benzotef,
sarcolisyne, ribomicine, 6‐mercaptopurine, 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]).482–485
The antioxidant and hepatoprotective activity of Eleutherococcus and Andrographis paniculate preparations have
been reviewed in EMA assessment report.3,4 The chemopreventive effects of A. paniculata and Andrographolide
against cyclophosphamide (CTX)‐induced urothelial toxicity were previously demonstrated.486 Both substantially
lowered the elevated levels of IL‐2 and IFN‐γ and reduce CTX‐induced toxicity during CTX treatment.486 In
another study, the aqueous extract of A. paniculata was shown to attenuate gentamicin‐induced nephrotoxicity
decreasing blood levels of urea, creatinine, and urea nitrogen levels in rats.487
A. paniculata and andrographolide exhibit an extremely wide array of pharmacological activities4,425,488–492
including adaptogenic,160 antioxidant, chemopreventive,4 and neuroprotective activities.361,493–496
The cytoprotective effect of several adaptogenic plant extracts on chemotherapeutics‐induced dramatic im-
pact on transcriptome‐wide RNA microarray profiles of neuroglia cells culture have been recently studied.497–499
The fixed combination 5‐fluorouracil, 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 FEC‐induced 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 FEC‐induced 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 FEC‐induced deregulation of genes involved in the
regulation of cell morphology, synaptic, mitochondrial function, and protein‐related functions suggesting their
potential neuroprotective and hepatoprotective effects, which are associated with FEC‐induced adverse events in
cancer chemotherapy. The authors concluded that adjuvant treatment with adaptogens can prevent mild cognitive
impairments and “chemobrain” effect associated with cancer chemotherapy.497 It is noteworthy that adaptogens
potentiate the cytotoxic effects of chemotherapeutics in human T98G glioblastoma cells.498
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).
PANOSSIAN ET AL. | 661
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 aging‐related
disorders including atherosclerosis, angiogenesis, and neurodegeneration.502 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 NF‐κB and FOXO
transcription factors are important in neuronal stress adaptation.503–506
F I G U R E 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
Kelch‐like ECH‐associated protein‐1 (Keap1). Upon exposure of cells to oxidative stress, Nrf2 is phosphorylated in
response to PKC, phosphatidylinositol 3‐kinase (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 S‐transferase, 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 response500,501
associated with the antioxidant effects of medicinal plants, and particularly of adaptogenic plants, which are useful
in stress‐ and aging‐related diseases
662 | PANOSSIAN ET AL.
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 Nrf2.151
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 aging‐related disorders include their effects on Hsp70 and FOXO expression (Figure 10).
Aging‐associated 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 stress‐induced 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 aging‐related 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.507,508 When cells are
exposed to stress resulting in protein damage, HSF1 initiates the production of molecular chaperone Hsp70,508
which repairs proteins by folding denatured parts of proteins and promotes the degradation of irreversibly
PANOSSIAN ET AL. | 663
F I G U R E 10 Hypothetical mechanism of action of adaptogens in the regulation of the innate antioxidant system
and oxidative stress‐induced 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
by‐products 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 aging‐associated 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/DAF‐16 to nucleus triggering
activation antioxidant systems and antiaging programs. Updated from authors’ drawings16 [Color figure can be
viewed at wileyonlinelibrary.com]
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.509,510 It is associated
with the accumulation of protein aggregates of β‐amyloid peptide and cytoskeletal protein.511 Aging‐related de-
cline of hepatic Hsp70 expression results in decreased liver detoxification512 and protection from toxic sub-
stances.513 Decrease of Hsp70 is coupled with upregulation of stress‐activated protein kinase (JNK) dependent
apoptosis and progression of cancer Stress‐induced decline in induction of Hsp70 observed in humans, is asso-
ciated with aging and aging‐related disease.514 Amazingly, in some individuals which are more than 100 years old,
Hsp70 does not decrease with age.515
In young age, the balance between pro‐ and antiaging JNK‐mediated 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 JNK‐stimulated 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 aging‐related diseases. The ability to respond effectively to stress by generating increased Hsp70
correlates with high adaptability and increased life span.516 Thus, the onset of neurodegenerative diseases and
other aging‐related illnesses may be delayed by modulating these two pathways.517
The adaptogens R. rosea, S. chinensis, and E. senticossus, alone and in combination, up‐regulate transcription
factor HSF1, and increase generation of molecular chaperon Hsp70 in vitro and in vivo.19–21,28,42,518–521 Adap-
togens also inhibit stress‐activated protein kinase JNK,18 a key mediator of apoptosis and aging (Figure 11).
Furthermore, adaptogens trigger translocation of transcription factor DAF‐16 (FOXO) from the cytoplasm into the
nucleus.95 The protective effect against myocardial ischemia‐reperfusion injury via increase of Hsp25 and Hsp70
expression in rat hearts was described for schizandrin B, an active constituent of S. chinensis.518 Induction of Hsp27
664 | PANOSSIAN ET AL.
F I G U R E 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; P‐53, p‐53 transcription factor;↓ or ←, for activation;
x, for blocking; |, for inhibition; bold text for the prevailing process [Color figure can be viewed at
wileyonlinelibrary.com]
and Hsp70 genes and protein expression were observed in a dose‐dependent manner after oral administration of
schizandrin B to rats.520
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-
gaster,370,371,522,523 the nematode Caenorhabditis elegans,95,317,524 and yeast Saccharomyces cerevisiae.525 Oral
supplementation with salidroside or extracts of E. senticosus, S. chinensis, and R. rosea significantly decreased stress‐
induced elevation of p‐SAPK/p‐JNK in rabbits subjected to restraint stress.18 Based on these observations, it was
suggested that adaptogens acts as mild stressors inducing enhanced stress resistance and an extended life span.368
Adaptogens regulate G‐protein signaling phosphatidylinositol and phospholipase C pathways (Figure 4). R.
rosea, S. chinensis, and E. senticossus up‐regulate the expression of PLCB1 gene, which encodes phosphoinositide‐
specific phospholipase C (PLC), and the PI3KC2G gene, which encodes PI3Ks.23 G‐protein activated, phospholipase
C (PLC) catalyzes the hydrolysis of phosphatidylinositol 4,5‐bisphosphate (PIP2) into diacylglycerol (DAG) and
inositol‐1,4,5‐triphosphate (IP3) 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 NF‐kB‐mediated defence responses and apoptosis as well as to long‐
term potentiation of neurotransmission, which improves memory and learning.526,527
23
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 low‐density lipoproteins (LDL) and high‐density lipoproteins (HDL).528 Inhibiting of expression of CETP
may be helpful in the treatment of atherosclerosis, cardiovascular and metabolic diseases.529
Adaptogens downregulate the ESR1 gene.23 ESR1 encodes estrogen receptor α (ERα), which is overexpressed
in some cancers.530–532 Downregulation of expression of ESR1 by Rhodiola and other adaptogens may be effective
for preventing and treating some aging‐related cancers such as breast cancer, ovarian, colon, prostate, and en-
dometrial cancers.23,24 The neuroprotective effects of adaptogens533–542 may be also partially associated with the
upregulation of ESR1 in glia cells, as estrogen signaling through ERα decreases the inflammatory neurodegen-
eration via its effect on astrocytes. Since pretreatment with adaptogens is known to adapt the cell to stress12,95,351
PANOSSIAN ET AL. | 665
it is possible that the adaptogens‐mediated downregulation of ERα gene expression signals the glia cells to initiate
feedback regulation of ERα. This concept is usually associated with inflammation, a protective reaction to infection
(‘turn on’ defense system). A feedback mechanism that downregulates pathogen‐induced inflammatory response is
triggered (e.g., increased secretion of cortisol and release of anti‐inflammatory cytokines) to prevent an over-
reaction (“turn off” defence system). Because mild stress is generally a protective reaction to activate innate
immunity, in this context, adaptogens initiate stimulation of the innate defence system, including ERα, as one
element of the stress system.
Along with canonical mode of steroid receptor action related to regulation of transcription of target genes in
the nucleus, estrogen activated membrane bound CRα triggers PI3K/PLC signaling pathways in brain cells to
modulate neuronal function and apoptosis.434,444 Estrogen treatment attenuates transcription at estrogen re-
sponse elements sites in glioma cells.444 Since Rhodiola upregulates PLCB1, PI3KC2G, and c‐AMP related genes,
and modulates NO and JNK it was suggested that Rhodiola and estrogens interfere with each other in some
way.340 While both are neuroprotective, it is remaining unclear whether they are mimetic and in competition or are
naturally antagonistic.
Since adaptogens downregulate adenylate cyclase (AC) and upregulate phosphodiesterase (PDE) genes’ ex-
pression Panossian et al. 2013, concluded that adaptogens decrease the level of the cyclic adenosine monopho-
sphate (cAMP) in brain cells.23 The authors suggested that cAMP‐mediated prefrontal cortex signaling
model542–544 provides one possible explanation of CNS stimulating activity of adaptogens.23 Working memory is
preserved by recurrent excitation as well as by functional interaction of G‐proteins coupled α2‐adrenoreceptors
with colocalized in dendritic spines hyperpolarization‐activated channels (HCN) of prefrontal cortical neurons,
Figure 12. This interaction is mediated via endogenous cAMP, which at high level promotes opening, while at low
level, induces blockage of HCN channels. HCN channels opening shunts synaptic transmission onto dendritic
spines, decreases cognitive performance in animals performing working memory tasks and thus improving quality
of arousal and working memory, which is essential for abstract thinking, planning, and executive functions.542–544
Stimulation of α 2A‐adrenoreceptor decreases cAMP level and blockade of HCN channels that enhances the
working memory in behavioral studies. Overall, cAMP inhibition strengthens connectivity of prefrontal cortex
neuronal networks, while excessive cAMP has negative effect on the network strength.542–544 Since adaptogens
downregulate AC and upregulate PDE that decreases cAMP level in brain cells (Figure 3), it was hypothesized that
beneficial effects of adaptogens on stress‐induced and aging‐related weakening of cognitive functions in some
extend is associated with their effect on cAMP–HCN mediated signaling pathway,23 which is increasing in
F I G U R E 12 Effect on cAMP‐mediated signaling in prefrontal cortex neurons. HCN channel opening shunts
synaptic inputs onto dendritic spines and reduces strength of prefrontal cortex network activity. cAMP opens HCN
channel that decreases the efficacy of cortical inputs. Adaptogens downregulate AC and upregulate PDE that
decreases cAMP level in brain cells followed by closing of HCN channel. That increases efficacy of synaptic
imputes, neuronal activity and working memory.23 cAMP, cyclic adenosine monophosphate;
HCN, hyperpolarization‐activated channels [Color figure can be viewed at wileyonlinelibrary.com]
666 | PANOSSIAN ET AL.
stress.542–544 This hypothesis is consistent with studies in which adaptogens improved cognitive function in
humans.27
Overproduction of ROS and their inadequate elimination by the innate antioxidant system in aging relate
directly to transcription factors that control the expression of genes associated with cell proliferation, in-
flammation, and ROS production. As an example, age‐related changes in the expression of AP‐1, NF‐kB, FoxO, and
Nrf2 transcription factor‐mediated signaling pathways in vascular smooth muscle cells lead to the progression of
inflammaging (i.e., aging‐related low‐grade chronic inflammation) and atherosclerosis.502
Aging is associated with the activation of AP‐1, NF‐kB, and Nrf2 and inhibition of FoxO transcription factor‐
mediated intracellular signaling pathways.502 Translocation of NF‐kB into the nucleus triggers the expression of
multiple genes involved in inflammation.502
• Adaptogens downregulate NF‐kB translocation and expression, NF‐kB signaling, and NF‐kB mediated
inflammation326,336,434,436,437,441,545–560;
• adaptogens downregulate Fos and Jnk, the components of AP‐1 transcription factor (Table 9), which regulates
many genes involved in cell proliferation, migration, ROS production, and extracellular matrix
degradation17,502,561;
• adaptogens switch FoxO‐dependent responses from apoptosis promotion to stress‐resistance in response to
oxidative stress95; and
• adaptogens activate Nrf2 signaling. Normally, Nrf2 is located in bound form in the cytosol with reduced kelch‐
like ECH‐associated protein 1 (Keap1). Dissociated Nrf2 translocates to the nucleus, where it triggers the
transcription of phase II or other adaptive response genes, including enzymes involved in GSH metabolism,
NQO1,2, and HO‐1.226,550,553,554,558,561–577
The efficacy of adaptogens in the treatment of acute respiratory tract diseases is possibly also partially
associated with the downregulation of proinflammatory NF‐kB signaling in various cells and tissues involved in the
acute inflammatory response.
In conclusion, the observed beneficial effects of adaptogens in aging‐related disorders (Table 10) include
neurodegeneration, atherosclerosis, and impaired apoptosis.23,368,369
Adaptogens prevent stress‐induced increases in NO, and as such, ATP production remains efficient and perfor-
mance and endurance are increased.18 Putative mechanisms of ATP generation are shown in Figure 13.
In addition to this possible source of ATP generation stimulated by adaptogens, apparently there are some
other mechanisms of regulation of energy homeostasis by adaptogens. Thus, adaptogens presumably decrease
c‐AMP level in brain cells by deregulation the expression of genes involved in regulation of cAMP.23 Consequently,
low levels of c‐AMP decreases protein kinase A (PKA) overall activity. PKA activation effects vary with the cell
type; for example, PKA stimulates lipases in adipocytes, while in myocytes and hepatocytes PKA increases glucose
formation and its catabolic transformation to pyruvate (glycolysis). This provides free energy in the form of
adenosyl triphosphate (ATP) and nicotine adenine dinucleotide, reduced (NADH), which are important in stress
response. The regulation of cAMP levels and PKA activity is one of mechanisms of regulation of energy home-
ostasis, somewhat a metabolic switch between catabolism and anabolism. Stress‐induced catabolic transformations
are induced by downregulation of cAMP and PKA by adaptogens. Apparently, PKA is involved in “energy‐saving”
effect of adaptogens that favors ATP‐consuming anabolic pathways. Increased intracellular ATP levels and pre-
vention of ATP‐conversion (to cAMP) is due to an inhibition of adenylate cyclase by adaptogens. An increased
storage of ATP seems to represent an energy source for other ATP‐dependent metabolic conversions. This is
PANOSSIAN ET AL. | 667
Hypoestrogenism ESR1downregulated
consistent with the concept of ATP generation induced by adaptogens and their potential benefits in aging‐related
diseases and fatigue.23
5.2 | Synergy and antagonism of several plants as background for the discovery of new
drugs with better efficacy and safety
Kampo tradition uses fixed combinations of medicinal plants in standardized proportions. The idea to combine two
or more plants or substances, which will be stronger than any ingredient alone, is very attractive for several
668 | PANOSSIAN ET AL.
F I G U R E 13 Schematic representation of the potential molecular mechanism by which generation of nitric oxide
(NO) strongly inhibits the production of cellular energy through two mechanisms: inhibition of mitochondrial
respiration by reversible (from constitutive isoforms of nitric oxide synthase [NOS]) and irreversible (from
inducible NOS [iNOS]) inhibition of cytochrome P450578; and glycolysis inhibition through modification of the
SH‐groups of glyceraldehyde 3‐phosphate dehydrogenase.579 In anaerobic glycolysis, muscle glycogen is converted
to lactic acid via glucose‐6‐phosphate, yielding three ATP molecules for each glucose residue. Aerobic oxidation of
glucose is required for the sustained exercise and provides 34 ATP molecules per glucose residue via the Krebs
cycle and the respiratory chain, a process that occurs 1 min after anaerobic ATP generation. If a sufficient supply of
ATP is not generated, anaerobic glycolysis is continued. NO levels increase during stress, consequently decreasing
performance by inhibiting ATP production. Adaptogens prevent stress‐induced increases in NO,18 and as such, ATP
production remains efficient and performance and endurance are increased.26 Updated from authors’ drawings26
[Color figure can be viewed at wileyonlinelibrary.com]
reasons: the ingredients may have different targets and mechanisms of action in human organisms, and therefore
better effect as a combination; and the combination can be used at lower doses and may be less toxic if any
ingredient contains a toxic impurity. The ingredients can also act synergistically, thereby providing new unique
effects that are not possible to obtain by any ingredient independently. Synergistically means that the combination
is active, while the ingredients separately are inactive.17,23,25,451 Synergy can be also interpreted as the generation
of new pharmacological activity, which is only specific for the combination of two or more ingredients.17,23,451,580
This is a fantastic phenomenon that has yet to be fully understood; however, it is has been observed in various
interactions at different intracellular, extracellular, organism, social, and other levels of communications.
This comparison is in line with our observations made during our analysis of the gene expression
transcriptome‐wide microarray profiles of isolated neuroglia cells after incubation with several adaptogenic plant
extracts, their combinations, and purified compounds.17,23,25,451 It was concluded this experimental model is very
useful for assessing synergistic and antagonistic interactions of various plant extracts, with the aim to discover an
unexpected pharmacological activity of new combinations or to rid of adverse effects of ingredients due to their
PANOSSIAN ET AL. | 669
interactions within intracellular molecular networks.17,25 Further downstream effect analysis of mRNA microarray
data enables prediction of pharmacological effects of fixed combinations.17,25,451
For example, it was found that the fixed combination of Eleutherococcus and Andrographis might be useful for
the treatment of encephalitis because of the synergistic inhibition of the expression of a number of genes of the
molecular network involved in the development of encephalitis, whereas neither Eleutherococcus nor Andrographis
individually has an effect on these genes.25 Although microarray analysis did not provide the final proof of the
efficacy of this fixed combination in humans with encephalitis after its oral administration, it provided information
regarding its predictable (z‐score > 2) effects on diseases and biological functions as well as insights into putative
genes and directions for future research and possible implementation into practice.
This approach was implemented for the assessment of the synergistic and antagonistic interactions of R. rosea
(RR), W. somnifera (WS), E. senticosus (ES), Rhaponticum carthamoides (RC), Bryonia alba (BA), and melatonin (M), with
the purpose of predicting the potential pharmacological and toxicological profiles of their combinations (RR–BA,
RR–WS, WS–M, RC–ES–WS).17,25,451
It was found that WS in combination with melatonin synergistically deregulates several genes involved in the
regulation of glucagon, the main catabolic hormone that increases the concentration of glucose and fat in the
bloodstream, suggesting that WS–M might be useful for the prevention of type 2 diabetes.17 Another synergistic
interaction of WS with RR induced the deregulation of 20 genes, 10 of which contribute to the predicted activation
of neuronal development, suggesting a beneficial effect of this combination on age‐related decline in memory and
cognitive functions.17
These models take into account interactions within the biological network, which are important if medications
act at various targets in the network or if homeostatic feedback mechanisms are effective. System pharmacology
models are useful to describe synergistic mechanisms of action of complex combinations of medicinal plants. The
term synergy is appropriate for interactions of two or more ingredients leading to qualitatively new pharmaco-
logical effects, e.g., to the expression of genes that cannot be obtained by any single ingredient independently. On
the contrary, antagonism occurs as a result of the interaction of several ingredients in a combination, which leads
to the absence, reduction or prevention of the effects of any individual ingredient in this combination.17,23,25,452
6 | C H A L LE N G E S A N D RE G U L AT O R Y IS S U E S
6.1 | Terminology
The term adaptogens, like the terms antioxidants and vitamins, is not yet commonly used to refer to a distinct
pharmacological group despite the fact that the terms adaptogenic activity and adaptogen have been adopted by
drug regulatory authorities and general practitioners in Europe, the United States, and Asia.
In 2008, the European Medicines Agency published “Reflection Paper on the Adaptogenic Concept,” which was
based on and which refers to the 18 review articles published in 1947–2005 mainly including studies on Eleu-
therococcus and a few other adaptogens.581 It this review, HMPC (anonymous authors) concluded:
• The principle of an adaptogenic action needs further clarification and studies in the preclinical and clinical area. As such,
the term is not accepted in pharmacological and clinical terminology that is commonly used in the EU.
• The HMPC is aware of the fact that numerous preclinical and clinical studies have been performed with the view to
proving the concept of an adaptogen. However, the clinical data have a number of shortcomings such as deficiencies in
the description of inclusion and exclusion criteria, description of the medication, diagnosis, study design, analysis, etc.
There is a wide range of clinical conditions that have been investigated and in some studies the number of patients was
very small. None of the studies would be sufficient to substantiate efficacy of Eleutherococcus preparations in a clearly
670 | PANOSSIAN ET AL.
defined clinical condition, although, in total, the data available are sufficient to justify further research into the concept
of adaptogens.
• As the term “adaptogen” is considered not appropriate for a marketing authorization, more clinical studies and data on
the efficacy in a well‐defined clinical condition would be necessary.
• The concept of adaptogens is sufficient to be considered in the assessment of traditional herbal medicinal products
(e.g., monograph on Eleutherococcus root).3
Since the publication of “Reflection Paper on the Adaptogenic Concept,” an enormous number of studies that
significantly enrich the current knowledge of the pharmacology, clinical efficacy, and mechanisms of action of
adaptogens have been published. The term adaptogens has been used in numerous publications indexed in PubMed
that clearly show that the statement “as such, the term is not accepted in pharmacological and clinical terminology
that is commonly used in the EU” is now far from reality.
Various adaptogenic herbal medicinal products, which are formally divided into two categories (EC–traditional,
used for at least 30 years, including at least 15 years within the EU; and well‐established use, used within the EU
for at least 10 years, with recognized efficacy and an acceptable level of safety), have a commonly acceptable level
of safety and efficacy in various diseases. Nevertheless, more evidence from large‐scale, well‐controlled clinical
trials of high‐quality uniform botanicals and their phase III pharmacovigilance data are essential for further im-
plementation in common practice, at least for decreasing the risk of disease progression and as adjuvant therapy in
infections and chronic diseases.
In other assessment reports,1,2 the HMPC concluded that the preparations of three adaptogenic plants can be
officially used as traditional herbal medicinal products.
• Rhodiola: for temporary relief of symptoms of stress, such as fatigue and sensation of weakness, in Austria, Italy,
the Netherlands, Spain, Sweden, and the United Kingdom.1
• Ginseng2 and Eleutherococcus3: for the relief of symptoms of asthenia (abnormal loss of strength and energy)
such as tiredness and weakness in France, Germany, Lithuania, Poland, Spain, and Sweden.2,3
Furthermore, several Eleutherococcus products have marketing authorization in Germany and Denmark as
herbal medicinal products with well‐established use as tonics for invigoration in individuals with fatigue and
impairment, in decreasing capability and power of concentration as well as against tiredness, and in periods of
convalescence.3
Similarly, a large number of ginseng products have marketing authorization in Austria, Belgium, Denmark,
France, Germany, Ireland, Latvia, Poland, Portugal, and Spain as herbal medicinal products indicated for use “as a
tonic in case of tiredness and weakness and decreased mental and physical capacity as well as in concentration,” in
“asthenia, such as lack of concentration, fatigue, weakness, tiredness, lack of vitality or in convalescence,” and in
“exhaustion fatigue and at convalescence; can be tried in lack of concentration in middle‐aged and elderly when
other causes to the condition have been excluded.”2
The most important challenge is related to the evidence of the clinical efficacy of adaptogens for the treatment of
many stress‐induced and aging‐related diseases, which should be demonstrated in large‐scale randomized, double‐
blind, comparator‐controlled unbiased clinical studies.
Studies on well‐defined preparations often show contradictory results, which is a common trait of herbal
preparations per se. Although numerous studies of adaptogens have suggested an advantageous safety and tol-
erability profile as compared with conventional drugs, we also acknowledge several disadvantages of herbal
PANOSSIAN ET AL. | 671
preparations per se. Herbal preparations, although standardized to active constituents, are still very complex
mixtures of many compounds and may have variable positive and negative effects depending on factors that have a
crucial impact on the reproducibility of pharmacological activity (e.g., growing conditions, regional territory, and
genus differences). Difficulties in manufacturing place herbal preparations at a disadvantage against conventional
drugs, which are single compounds that remain identical and reproducible from batch to batch during production.
In addition, various differently standardized herbal preparations of the same medicinal plant may have different
pharmacokinetic and pharmacodynamic dose–effect responses. For example, the maximal active antifatigue, an-
tidepressant, and antistressor dose of the SHR‐5 brand of R. rosea extract355–357,360 might be inactive for a
different extract of R. rosea despite the fact that both products are extracted from Rhodiola roots that have
different chemical compositions.350,582 Finally, we acknowledge the difficulties in producing herbal medicinal
products that provide reproducible effectiveness over time, and this represents a serious challenge and limitation
of herbal medicinal products and dietary supplements in general. However, despite these limitations, the devel-
opment of herbal preparation for the prevention and treatment of many diseases is of great interest and has
promising potential for safe, effective, and affordable therapies with superior tolerability and a low incidence of
adverse events. More evidence from properly controlled clinical studies is required to support health claims and
indications of pharmaceutical‐grade herbal preparations for use in disease treatment.
6.3 | Network pharmacology and systems biology models for assessment of pleotropic
activity of adaptogens
doses, but proapoptotic genes at high doses beyond a certain threshold. Possibly, adaptogens regulate different
genes in different cell types, causing apoptosis in some cells (e.g., cancer cells) while promoting survival in others
(e.g., in neurons and glia cells). Importantly, the induction of apoptosis by adaptogens may cause the death of
damaged or abnormal cells, which may extend the lifespan of the entire organism.
The adaptogenic process is can be studied very well using “systems biology” and “network pharmacology”
approaches, which has the potential to provide plant‐based treatments for complex diseases, chronic conditions,
and syndromes. This is a remarkably complex system of synergistic interactions of molecular networks and cellular
communication systems that quite literally add up to more than the sum of the parts. It also requires a detailed
understanding of disease concepts, as we have outlined in this MS and second, the use of suitable pharmacological
models to understand such effects. There can be no one to one correlation between use as an adaptogens and a
specific model, and the suitability of a model needs to be assessed carefully before starting experimental ap-
proaches. Such approaches can help understanding these complex systems better and this is a key challenge in the
future.
The published literature on Rhodiola, Eleutherococcus, Withania, ginseng, and Schisandra does not provide reasons
for safety concerns, and herbal preparations containing adaptogens are not harmful when prepared and used in
specified conditions. No serious adverse events have been reported from clinical trials, epidemiological studies, or
pharmacovigilance reporting that can be clearly correlated with the ingestion of adaptogens (EMA assessment
reports 2012–2014).1–4 It might be suggested that such a high tolerance in humans and a low rate of adverse
events might be due to their poor absorption and low bioavailability. However, the data available on absorption,
distribution, metabolism, and excretion of the active constituents of adaptogenic plants show that some of these
have high bioavailability and are quickly absorbed and widely distributed in all organs and tissues involved in the
regulation of the neuroendocrine–immune system. Others are metabolized into more active metabolites or sig-
nificantly affect gut microbiota, which plays an important role in the maintenance of homeostasis and the de-
velopment of several chronic diseases, including colitis‐associated colorectal cancer, among others.
Thus, the earliest pharmacokinetic studies of adaptogens584–586 that intraperitoneally administered 3H‐
labeled eleutheroside B (with radioactivity localized in the aglycone, 52 µCi/mmol) in rats demonstrated that
eleutheroside B is quickly absorbed into the blood and distributed in the liver, kidneys, adrenals, pancreas, thymus,
spleen, heart, testes, brain, and hypophysis. The extent to which a compound is distributed throughout the body
has a large impact on its therapeutic utility.
The highest concentration of the label in the blood was observed 15 min after administration of the 3H‐labeled
eleutheroside B, and this concentration dropped sharply within 4 h and was eliminated mainly through the renal
system with urine. Approximately 35% of the labeled drug was eliminated via the urine 2 h after administration,
55% after 4 h, and 90% after 48 h. A small amount of radioactivity (2.5%–3%) was eliminated with the feces. Most
of the labeled drug accumulated rapidly in the organs and tissues. In fact, after only 15 min, 88% was absorbed and
retained at a high level for a rather long duration. After 8 h, up to 30% of the administered drug was still retained in
the organs and tissues. This represents an exceptionally high level of incorporation of labeled eleutheroside B into
the liver and kidneys with subsequent rapid removal from these organs. The high levels of labeled eleutheroside B
in the pancreas can probably be attributed to its active participation in the digestion process and to its synthesis of
two important hormones: insulin and glucagon. The accumulation of eleutheroside B in the adrenals for up to 4 h
suggests its influence on the hypophysis–adrenal cortical system. In the brain, a minimal level of incorporation of
the radioactive label with an insignificant reduction over time was observed. Eleutheroside B does not pass the
blood–brain barrier.584–586 Interestingly, the bioavailability of individual eleutherosides B and E after oral ad-
ministration of an aqueous extract of E. senticosus was significantly increased as compared with the oral
PANOSSIAN ET AL. | 673
administration of single compounds. Both eleutherosides are metabolized and excreted primarily from the liver and
kidney.587 The absorption of orally administered eleutherosides588 and isofraxidin589 was also rapid, with the
maximum concentration noted at 0.4 and 0.2 h, respectively.
Lipophilic compounds such as lignans are well distributed in the tissues and organs, where their content is
higher than that in blood plasma.590
The absorption of any potential therapeutic is a critical consideration, especially for oral dosing. Many phar-
macokinetic studies of other adaptogens, including clinical trials, have been performed.339,584–611 Some of these
studies provided evidence of the level and steady‐state concentration of active compounds in the blood of human
subjects who received oral administration of the herbal drugs in therapeutic doses. These concentrations were in
line with those used in in vitro studies.591,598 As an example, the concentration of andrographolide (the active
compound of Andrographis and its combination with Eleutherococcus) in blood plasma of human subjects was
approximately 3.5 µM at 2 h after drug uptake,591 which is adequate for exhibiting an anti‐PAF effect in vitro
(EC50, 5 µM).440 A comparison of the results obtained in humans and rats showed that the pharmacokinetics of
andrographolide are similar in both species. It was found that andrographolide is rapidly and almost totally
absorbed (T1/2abs of about 25 min) into the blood (bioavailability = 91%, F = 0.91) after oral administration of
Andrographis extract at a therapeutic dose (20 mg/kg). Thus, in the absorption phase, the concentration of an-
drographolide in the blood is not significantly changed during the first 1.5 h and increases to a maximal level 2 h
after oral administration. It binds intensively with blood proteins and is redistributed between blood and tissues
within 1 to 2 h. The elimination half‐time is in the range of 2–7 h.591 The tissue distribution study of andro-
grapholide revealed the highest tissue concentration in kidney, followed by the liver, spleen, and brain, whereas an
almost identical concentration was observed in the heart and lungs.592
The pharmacokinetics of three active compounds (tyrosol, rhodioloside, and rosavin) of R. rosea extracts were
studied in rodents597–603 and healthy volunteers.597 Salidroside was quickly absorbed into the blood of rats
(tmax = 1 h; bioavailability: 75%–90%) and metabolized to tyrosol within 2 h after oral administration of the R. rosea
extract. The concentration of tyrosol attained its maximum value within 1.5–2.0 h and then decreased ex-
ponentially to basal level within 3 h after oral administration of the extract. Many of the measured pharmacoki-
netic parameters of purified salidroside were significantly different when the pure compound was administered
(Cmax, Vdis, AUC, t‐1/2, and higher tmax and CI) rather than the plant extract. Rosavin had a lower bioavailability
(20%–26%) and was eliminated from the blood within 2 h. The pharmacokinetics of rosavin in humans are different
from that in rats. For example, both tmax (2 h) and elimination rate were longer in humans after oral administration
of Rhodiola tablets in a therapeutic daily dose. The maximal concentration and elimination half‐life of salidroside
were two‐ to threefold higher than those of rosavin. The elimination of salidroside from the blood was 1.8‐fold
longer than the elimination time of rosavin. The beneficial effect of R. rosea on mental performance in humans,
which was observed 1 h after oral administration and lasted for more than 3 h, is worth noting. During this time
period, the concentration of salidroside in human blood was about 587 ng/ml after 1 h and 483 ng/ml after 4 h.597
It was found that after intravenous administration, salidroside was extensively metabolized to tyrosol and then
distributed to various organs and cleared rapidly. The highest levels of p‐tyrosol were detected in the heart,
followed by the spleen, kidney, liver, and lungs.603
It should be noted that many of the measured pharmacokinetic parameters of purified salidroside were
significantly different when the pure compound was administered (Cmax, Vdis, AUC, t‐1/2, and higher tmax and CI)
rather than the total plant extract,597 indicating an interaction with the other constituents of the plant extract.
It should also be emphasized that the biological activity of the preparations of R. rosea is not entirely due to
salidroside and tyrosol but rather to the entire complex of substances that are extracted from R. rosea. That is also
true for ginseng, Schisandra, and presumably for all other adaptogens.
The pharmacokinetics of different active ginseng compounds have been studied in both animals and humans.2
The bioavailability of ginsenosides is low after oral administration, but the pharmacokinetic behavior differs among
various ginsenosides.35,611 The highly glycosylated ginsenosides Rb1, Rb2, Rc, Rd., Re, Rg1, and Rg2 have poor
674 | PANOSSIAN ET AL.
stability in the gastrointestinal tract, and they are easily converted into monoglycosides and aglycone ginsenosides
(e.g., CK, Rh2, Rh1, and F1) by gastric acid and/or the intestinal flora.35,611–616
After oral administration, blood concentrations of ginsenosides are high, but their absorption rate is low. Both
the absorption profile of ginsenosides in the intestinal mucosa and the availability of intact ginsenosides and their
metabolites from the intestines are exceptionally low.35,611 The maximal concentration of ginsenosides in plasma is
reached within 2 h, suggesting that they are rapidly absorbed and distributed in tissues. Rg1, Re, Rb1, and Rc reach
the brain, but their concentrations decline rapidly over time.35,617 Rg1 and Re are more readily distributed in the
brain, and they are considered the main components directly affecting the neurons of the CNS.617 The plasma level
of ginsenosides indicates that protopanaxadiol ginsenosides have higher concentrations and longer half‐lives than
protopanaxatriol ginsenosides.35,617 After the biotransformation of ginsenosides, the microbiota in the gut pro-
duces deglycosylated products.358,618–620 The intestinal bacteria isolated from human feces and some food‐derived
microorganisms as well as fungi from soil around ginseng roots convert glycosylated ginsenosides to compound
K,612,620,621 which has great potential for cancer chemoprevention.342 Compound K was the only ginsenoside
detected in plasma and urine after the oral administration of Rb1.622 Deglycosylated products are better absorbed
than ginsenosides based on their greater ability to permeate biological membranes.623
EMA assessment of the available literature suggests that ginsenoside metabolites contribute substantially to
the pharmacological effects of ginseng.2 The metabolites are well distributed to most of the tissues.593 It was
concluded that metabolites of ginsenosides produced by gut microbiota might be more biologically active than
their precursors.2 The results of recent studies624,625 are in line with this conclusion: the ginseng preparation with
a higher content of rare ginsenosides was more active in its ability to prevent symptoms of stress such as fatigue,
impaired memory, reduced concentration, and attention deficit related to daily work in healthy subjects624 as well
as enhanced long‐term potentiation in rat hippocampal slices.625 An active ginseng metabolite may differ in
distribution and clearance from its parent compound, and the parent compound and its metabolite may be
bioactive by similar or different mechanisms.342
The results of herb–drug interaction studies of various adaptogens are contradictory.1–4,598,626–628 Interac-
tions with some CYP isoenzymes have been observed in vitro studies only in high concentrations of herbal extracts
that are far beyond their blood levels when taken in the standard therapeutic doses and not associated with active
markers.1,598,626–628 Few poorly conducted clinical studies in limited number of healthy subjects (lack of placebo,
proper randomization, procedure for treatment compliance, pharmacokinetic data, sufficiently controlled con-
sumption of CYP‐active food ingredients, etc.) do not provide strong, evidence supporting the clinical relevance of
the interaction effects observed in vitro.
Overall, the pharmacokinetics of various compounds from adaptogenic plant extracts is different depending on
their chemical structure, lipophilicity, water solubility, metabolic activity, concentration as well as the presence of
other bioactive compounds in test samples. Adaptogens are distributed in all organs and tissues involved in the
regulation neuroendocrine‐immune
system where they trigger the expression of hormones and key metabolic regulators of defense responses and
cellular homeostasis. That is one of the likely explanations of the pleotropic effects of adaptogens. Finally, some
adaptogens actively interact with gut microbiota that results in prevention of progression of chronic inflammatory
diseases.
7 | O V ERA L L CO N C L U S I O N S
The adaptogenic concept does not have a long history as analogues of TMS, even though adaptogenic plants have
been used in TMS as rejuvenating herbs, qi tonics, rasayanas, and restoratives for centuries and are formally
considered to be “traditional” by drug regulatory authorities in Europe and the United States. It is supported by an
evidence‐based approach and statistical assessments of pharmacological and clinical studies of efficacy and safety
PANOSSIAN ET AL. | 675
of standardized herbal medicinal products as well as their mechanisms of action. The efficacy of plants used in TMS
has been investigated using modern theories and methods of system biology and network pharmacology. In this
review, we summarized our knowledge about common adaptogenic plants used as officinal medical preparations in
USSR/Russia and in traditional Chinese medicine, Ayurveda medicine, and other TMS and alternative medical
systems, and to provide a modern rationale for their use in the treatment of stress‐induced and aging‐related
disorders. Overall, the basic principles of TMS are in line with those of the adaptogenic concept, which uses
systems biology and network pharmacology models to understand the fundamentals of TMS such as “life vital
energy”/qi (Chinese)/prana (Indian)/pneuma (Greece)/zorutyun (Armenian)/od (German)/ruah (Hebrew), and mana
(Polynesian), which are related to adaptability. Yin‐yang balance can be interpreted as “homeostasis”, whereas
“shanghuo”—as a state of threatened homeostasis and decreased resistance to stress, which is increased by
adaptogens.
Adaptogens play key roles in defending organisms against environmental challenges including harmful bac-
teria, diseases carried by insects, excessive ultraviolet rays from the sun, and challenges from pollution, excess heat
and cold, and hypoxia.
The key to understanding adaptogens is their role in establishing and maintaining adaptive homeostasis by
building the body's natural resistance to stressors, which may be physical, chemical, biological, and psychological in
nature. Adaptogens function like stress vaccines to activate the body's defence system and metabolic rate, re-
versing the negative physical effects of stress and restoring the body's balance and health.
• If the immune system is not functioning properly by overreacting or underreacting to challenges, adaptogens
help restore the proper immune response.
• If the immune system is overly active, triggering allergies and asthma, rheumatoid arthritis or lupus, adaptogens
lower the immune system's response and returns it to a normal level.
• If the immune system is underactive, leading to frequent colds, bronchitis, sinus or ear infections, and even
pneumonia or causing anemia or digestive problems such as ulcers or chronic diarrhea, adaptogens can help
strengthen the immune response, thereby ending the cycle of illness.
• If the brain chemistry is unbalanced, adaptogens can restore the balance, having profound effects on cognitive
function, memory, and mood.
• Adaptogens can correct imbalances in cellular division cycles that cause cells to divide in an uncontrolled
manner, eventually causing cancer.
• Adaptogens have a potential to prevent or postpone chronic diseases associated with aging, recognizing their
uncanny ability to fix what's wrong, boost what's right, keep the body in balance, and prevent the body's
functions from deteriorating.
• Adaptogenic effects like those seen in Ginseng, Rhodiola, Eleutherpcoccus, Withania, and Schisandra have been
scientifically validated as being effective against chronic inflammation, atherosclerosis, neurodegenerative
cognitive impairment (e.g., Alzheimer's disease and other forms of dementia), metabolic disorders, diabetes,
cancer and a host of other aging‐related diseases.
Overall, in this review for the first time we compare and analyze common basic principles, concepts, and uses
of adaptogenic plants using a cross‐cultural, comparative approach. We demonstrate that the concept of adap-
togens provides a scientific rationale for adaptogenic plants traditionally used in stress‐induced and aging‐related
diseases. In conclusion, the basic principles of TMS are in line with those of the adaptogenic concept, which uses
systems biology and network pharmacology models to understand the fundamentals of TMS.
676 | PANOSSIAN ET AL.
C O NF L IC T O F IN T E R ES T S
Alexander G. Panossian is self‐employed by the research and development company, Phytomed AB. He has an
Independent Contractor Agreement with Europharma USA Inc. He has no shares or financial interest in any
pharmaceutical company. All other authors declare no conflict of interests.
AUTHOR CONTRIBUTIONS
Alexander G. Panossian initiated this project, planned and wrote the first and final draft of the manuscript. All
other authors added specific parts, critically reviewed and edited the drafts, and approved the final version of the
manuscript.
ORCID
Alexander G. Panossian https://orcid.org/0000-0002-8467-4525
Thomas Efferth http://orcid.org/0000-0002-2637-1681
R EF E RE N C E S
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A U T H O R B IO G R A P H I E S
Alexander Panossian, Ph.D., Dr.Sc, is the Founder of Phytomed AB in Sweden and Head of Research &
Development of Europharma USA Inc. since 2016. He has multiple advanced degrees in bioorganic chemistry
and chemistry of natural and physiologically active compounds. He completed his doctorate in organic
chemistry at the Yerevan State University in Armenia in 1971 and obtained his scientific degrees from Moscow
Institute of Bioorganic Chemistry in 1975 and Moscow Institute of Fine Chemical Technology in 1986. Dr.
Panossian was made a full professor of bioorganic chemistry and chemistry of natural and physiologically
active compounds in the Russian Federation, and later served as Director of the Laboratory of Quality Control
of Drugs of Medical Drug Agency of the Republic of Armenia (1993–2003). In 2003, he moved to Sweden to
act as head of research and development at the Swedish Herbal Institute. He has the honor of participating as a
guest scientist in the Laboratory of Nobel Laureate Bengt Samuelsson at the Karolinska Institute in Stockholm
(1982–1983), at Munich University (1993–1995), and at King College in London, 1996. He was the editor‐in‐
chief of Phytomedicine, International Journal of Phytopharmacology and Phytotherapy (Elsevier, Germany) from
2014 to 2017. He has authored or co‐authored about 200 articles in peer‐reviewed journals. His main research
interest is focused on plant adaptogens, anti‐stress compounds that are involved in the regulation of
neuroendocrine and immune system.
Professor Dr. Prof. h. c. mult. Thomas Efferth is chair of the Department of Pharmaceutical Biology, Institute of
Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. He is a biologist by training
(Technical University of Darmstadt, Germany). His doctoral thesis was completed at the German Cancer
Research Center (DKFZ), Heidelberg, Germany (1990). Dr. Efferth was awarded the Ludolf‐Krehl‐Prize of the
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Southwest German Association for Medicine (1991), the Willmar‐Schwabe‐Award of the German Society for
Medicinal Plant Research (2006), the citizen medal of the City of Heidelberg, Germany (2008), the CESAR
Award for Translational Oncology (2011), the SCENTEDdrop Award on medicinal and flagrant herbs (2015),
and the Qihuang International Award of the Chinese Association of Chinese Medicine (2017). Since 2018, he is
a full member of the World Academy of Sciences. He headed a research group for Pharmaceutical Biology at
DKFZ (2005–2009) and was an adjunct professor (apl.) at the University of Heidelberg (2007–2009). In 2009,
he took over the Chair of Pharmaceutical Biology (full professorship) at the Johannes Gutenberg University,
Mainz. Furthermore, he is an honorary professor at the Northeast Forestry University, Harbin, and at the
Zhejiang Chinese Medical University, Hangzhou, China. He is a visiting professor at the Zhejiang University of
Science and Technology, Hangzhou, China and an honorary adjunct professor at the Chinese University
Hong Kong.
Alexander Shikov, Ph.D., Dr. pharm.Sci., is the Professor at the Department of Pharmaceutical Formulations at
the St. Petersburg State Chemical Pharmaceutical University since 2016. He completed his Ph.D. at the Saint‐
Petersburg State Chemical Pharmaceutical Academy in 1995 and obtained his Dr. Pharm.sci. degree from
Saint‐Petersburg State Chemical Pharmaceutical Academy in 2006. Dr. Shikov began his career with the St‐
Petersburg State Chemical Pharmaceutical Academy in 1992 as a professor assistant at the department of
drugs technology and phytopreparations. He became a Deputy of the general director in science at the
Interregional Center “Adaptogen,” St‐Petersburg, Russia in 1998, deputy of the general director at the St‐
Petersburg institute of Pharmacy in 2008, and was promoted to Professor at the Department of Pharmacology
of the North West State Medical University named after I.I. Mechnikov, St‐Petersburg, Russia in Sept. 2009. He
served as associate editor of Journal of Ethnopharmacology (Elsevier BV, The Netherlands) from 2015, associate
editor of Frontiers in Pharmacology Ethnopharmacology (Frintiers Media S.A.) from 2018, and as member of
editorial board Phytomedicine, International Journal of Phytopharmacology and Phytotherapy (from 2009), Chinese
Herbal Medicine (from 2013), Chinese Journal of Natural Medicine (from 2013), Synergy (from 2013), and World
Journal of Traditional Chinese Medicine (from 2014). He has authored and co‐authored about 200 articles in
Russian and international peer‐reviewed journals. His main research interest is focused on plant adaptogens,
standardization of natural products (herbal and marine), pharmacokinetic of natural compounds, and
approaches to improvement of bioavailability of natural molecules.
Olga Pozharitskaya, Ph.D.(pharm)., is the senior scientist at the Murmansk Marine Biological Institute, Kola
Scientific Center of the Russian Academy of Sciences since 2020. She completed her Ph.D. at the Saint‐
Petersburg State Chemical Pharmaceutical Academy in 1998. Dr. Pozharitskaya began her career with the St‐
Petersburg State Chemical Pharmaceutical Academy in 1989 as a scientist at the department of drugs
technology and phytopreparations. She became a head of the department of new technologies at the
Interregional Center “Adaptogen”, St‐Petersburg, Russia in 2002, deputy of the general director in
standardization and new technologies at the St‐Petersburg institute of Pharmacy in 2008. She has authored
or co‐authored about 180 articles in Russian and international peer‐reviewed journals. Her main research
interest is focused on natural product research, plant adaptogens, chemistry and pharmacology of marine
organisms and seaweeds, pharmacokinetic of natural compounds and improvement of bioavailability of natural
molecules.
Dr. rer.nat. Kenny Kuchta, FLS, is an honorary Professor at the Zhejiang Institute of TCM and Natural
Medicine, Hangzhou, China. He is currently establishing Special Research on Far Eastern Medicine at
Göttingen University, Germany. He obtained his doctorate in 2012 at the Chair of Pharmaceutical Biology at
the University of Leipzig with a focus on pharmacognosy. He became University lecturer (Koushi) and faculty
member at Sanyo Gakuen University, Okayama, Japan in 2012, with a research focus on East Asian Drugs of
PANOSSIAN ET AL. | 701
Kampo Medicine as chair of the Teaching and Research Center for Complementary and Alternative Medicine,
which was subsequently restructured to the chair of Natural Products Chemistry Research in 2014. For his
research on this field, he was awarded the Egon Stahl Award 2014 of the Society for Medicinal Plant and
Natural Product Research (GA). From 2015 to 2017, he served as a visiting Professor at the National Institute
of Health Science (NIHS), Division of Pharmacognosy, Phytochemistry, and Narcotics, funded by the Japan
Society for the Promotion of Science (JSPS) of the Japanese Ministry of Education, Science and Technology as
Research fellow with a focus on phytochemistry, regulatory implications for the internationalization of Kampo
medicine and the implementation of Western phytotherapy in Japan. Furthermore, he serves as an advisor of
the “Kampo Industralization Consortium”—founded amongst others by the Japanese prefectures Kanagawa,
Toyama, and Nara as well as Mitsubishi Research Institute. He has co‐authored about 40 articles in peer‐
reviewed journals and several book contributions, for example, the 13th edition of the “Lehrbuch
Phytotherapie.”
Professor Pulok K. Mukherjee is working as the Director, Institute of Bioresources and Sustainable
Development Department of Biotechnology (IBSD‐DBT), Ministry of Science and Technology, Govt of India
Imphal, Manipur, India. He was formerly the Director, School of Natural Product Studies, Jadavpur University,
Kolkata, India. His research/academic works highlights on traditional medicine inspired drug discovery from
Indian medicinal plants to make them available from “Farm to Pharma.” He has to his credit more than 200
publications in peer reviewed impact journals, several patents. Prof. Mukherjee has authored/edited 5 books
and 18 book chapters. His research publications have a cumulative Impact Factor of 241; h‐Index‐ 60, i10‐
index—252; which has been cited for over >18,755 times. Dr. Mukherjee is a Fellow of the Royal Society of
Chemistry (FRSC), Fellow of National Academy of Sciences, India (FNASc) and has been awarded with so many
laurels from Govt. of India and abroad; to name a few: awarded with the prestigious Commonwealth Academic
Staff Fellowship from Association of Commonwealth Universities [ACU], UK; TATA innovation fellowship, by
Department of Biotechnology, Govt. of India; Outstanding Service Award from Drug Information association
[DIA], USA; Career Award for Young Teacher from All India Council for Technical Education (AICTE), Govt. of
India; Best Pharmaceutical Scientist of the Year, from the Association of Pharmaceutical Teachers’ of India
(APTI); IASTAM Award for Contributions to Development of Ayurvedic and Herbal Pharmaceutics by Indian
Association for the Study of Traditional Asian Medicine (IASTAM) and many others.
Subhadip Banerjee is a senior research scholar at the School of Natural Product Studies, Jadavpur University
where he is pursuing his doctoral research under Prof. Pulok K. Mukherjee Director, IBSD‐DBT since 2016
after graduating from the same university with a major in Ayurveda Pharmacy. He obtained his M.Pharm.
(Ayurveda) in pharmacology in the year 2015. His work focuses on establishing integrated approaches for drug
development from Indian traditional medicine to understand the synergy based on network pharmacology and
metabolomics. His work on traditional medicine inspired drug discovery based on systems biology approaches
focus on development of leads from natural resources as adaptogens, hypolipidemic and immunomodulatory
agents for safe health care.
Michael Heinrich is a Professor of Ethnopharmacology and Medicinal Plant Research (Pharmacognosy) and
was until recently the head of the research cluster “Biodiversity and Medicines” at the UCL School of
Pharmacy. He currently serves as the joint chair of UCL's Research Ethics Committee (with Dr. L. Ang, Institute
of Education). The group's research is based on a transdisciplinary perspective integrating approaches from the
biomedical and social sciences with an overall aim of tackling the fast changing global health needs. Key areas
of interest include the prevention and early stage management of diabetes/metabolic syndrome and cancer
chemoprevention based on the use of traditional medicines as well as value chains of (herbal) medicinal
products. The research integrates methodological approaches from ethnopharmacology, natural product
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research, public health research, and anthropology. He is Specialty Editor in Chief of Frontiers in Pharmacology
(Ethnopharmacology) and Reviews Editor of the Journal of Ethnopharmacology as well as an associate editor of
the Journal of Pharmacy and Pharmacology, among other roles.
Wanying Wu is a professor and doctoral supervisor at the Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, China. She received her Ph.D. degree from Beijing University of Chinese Medicine and
finished her postdoctoral fellowship at the School of Pharmaceutical Sciences, Peking University. After that, Dr.
Wu joined the Shanghai Institute of Materia Medica and was later promoted to associate professor and
professor. She is now the committee of the 11th Chinese Pharmacopoeia Commission, a member of the United
States Pharmacopeia (USP) Herbal Medicines Compendium—East Asia Expert Panel, director and Secretary
General of the Specialty Committee of traditional Chinese Medicine (TCM) Pharmaceutical Analysis of World
Federation of Chinese Medicine Societies, the editor of the SCI journal Phytomedicine and the English edition of
Chinese herbal medicine. As the major performer, she established 32 TCM standards that were accepted by
USP or European Pharmacopoeia. Another major accomplishment is that she developed an innovative TCM
prescription named “Dan Qi Tong Mai Tablet” that had been approved by CFDA for a clinical trial in 2009 in
China. Her research interests are mainly in the systematic analysis of complex TCM systems by exploring the
mechanisms of TCM pharmacology and its bioactive ingredients, establishing modern standards of TCM quality
control, and promoting the drug discovery from TCM.
Dr. De‐an Guo serves as director of the Shanghai TCM Research Center as well as The National Engineering
Laboratory for TCM Standardization Technologies which focused on the new technology development for
TCM chemical analysis and international standard elaboration of TCM quality at Shanghai Institute of Materia
Medica, Chinese Academy of Sciences. He received his Ph.D. Degree of Pharmacognosy at Beijing Medical
University in 1990 and engaged in his postdoctoral research at Texas Tech University (1993–1996). He has
been serving as the chair of Natural Medicine Expert Committee of Chinese Pharmacopoeia Commission since
2000, expert member of Botanical and Herbal Medicine Expert Committee United States Pharmacopoeia
(2008‐present) and TCM Working Party Expert Member of European Pharmacopoeia, EDQM (2014‐present).
He is also the editor in chief, associate editors or editorial board members of 18 international journals. To date,
he has published 470 papers cited in SCI journals with 10,000 plus citations. He received a number of
renowned national and international awards including National Natural Science Award and Science and
Technology Progress Award, American Botanical Council Norman Farnsworth Award, American Society of
Pharmacognosy Varo Tyler Prize, Cheung An Tak International Award for Outstanding Contribution to
Chinese Medicine, National Innovation & Contending Prize, Ho Leung Ho Lee Foundation Prize, China
Standard Innovation Award, and so forth. His main research focus is on the comprehensive phytochemical
analysis and quality standard elaboration of herbal medicines, mainly traditional Chinese medicines.
Professor em. Dr. Dr. h.c.mult. Hildebert Wagner is one of the most outstanding scientists in the field of
phytopharmacology. He headed the Institute of Pharmaceutical Biology, Ludwig‐Maximilian University, Munich
Germany since 1965 for more than 25 years. His extraordinary scholarly activity and research have garnered
him worldwide recognition. Multiple awards and prizes, including the Egon Stahl Gold Medal and, honorary
doctorates, have been given to Prof. Wagner over the course of his long research and scholarly career. He has
also been Distinguished Visiting Professor (Columbus, OH, USA), Dean of the Faculty of Chemistry/Pharmacy
(Munich), Member of the Hungarian Academy of Science, Ph.D. honoris causae of the Universities of Budapest
and Debrecen (Hungary), Dijon (France), Helsinki and Iaci. He is a Member of the Editorial/Advisory Boards of
several journals in the field of natural products research, including Phytochemistry, Journal of Ethnopharma-
cology, and Journal of Natural Products. In June 1994 Professor Wagner and Professor Norman Farnsworth,
became editors of the newly established journal Phytomedicine, International Journal of Phytotherapy and
PANOSSIAN ET AL. | 703
Phytopharmacognosy. He was Editor in Chief of the journal for 18 years. He has published more than 950 (!)
original papers, 40 review articles, and several handbooks. Coveringa very wide range of research areas in
pharmacognosy, from the phytochemical analysis of numerous plants and their secondary metabolites (e.g.,
alkaloids, cardiac glycosides, flavonoids, and lignans) to pharmacological studies of various natural compounds
in bioassays, animals and human clinical studies, mainly associated with defense responses, immune systems,
and adaptation to stress. His TLC and HPLC atlases are unique encyclopedias of plant analysis used in the
industry for quality control of herbal substances and herbal preparations. His research interests are mainly
related to chemistry, quality proof, and pharmacology of medicinal plants of Traditional Chinese Medicine,
Synergy effects of herbal drug combinations for multitarget therapy, Genomic and Proteonomic biotechnology
for evaluation of synergy effects of drug combinations and adaptogens.
How to cite this article: Panossian AG, Efferth T, Shikov AN, et al. Evolution of the adaptogenic concept
from traditional use to medical systems: Pharmacology of stress‐ and aging‐related diseases. Med Res Rev.
2021;41:630–703. https://doi.org/10.1002/med.21743