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Adaptogens. A Review of their History, Biological Activity, and Clinical Benefits.

A Review of
their History,
Activity, and
Clinical Benefits
By Alexander Panossian, PhD
and Hildebert Wagner, PhD
Schisandra Schisandra chinensis. Photo ©2011 Steven Foster
52 | HerbalGram 90 2011
Eleuthero Eleutherococcus senticosus.
Photo ©2011 Steven Foster 2011 HerbalGram 90 | 53
The term adaptogen was introduced into scientific literature
by Russian toxicologist Nikolay Lazarev in 1957 to refer to
substances that increase the “state of non-specific resistance” in
stress.1,2 His concept was based on Hans Selye’s theory of stress
and general adaptation syndrome,3 which has 3 phases: alarm
phase, phase of resistance, and phase of exhaustion (Figure 1).*
Later, another Soviet scientist, pharmacologist Israel Brekhman,
postulated that adaptogens must be safe and normalize body
functions irrespective of the nature of stressors.6,7
Other definitions of adaptogens are also associated with physi-
ological conditions:
• Adaptogenic substances are stated to have the capacity to
normalize body functions and strengthen systems compro-
mised by stress. They are reported to have a protective
effect on health against a wide variety of environmental
assaults and emotional conditions.8
• Adaptogens are innocuous agents, nonspecifically increas-
ing resistance against physically, chemically, biologically,
and psychologically noxious factors (“stressors”), normaliz-
ing effect independent of the nature of pathologic state.6,7
• Adaptogens are substances that elicit in an organism a
state of nonspecifically raised resistance, allowing them
to counteract stressor signals and to adapt to exceptional
As a pharmacotherapeutic group, adaptogens were recently
defined as herbal preparations that increased attention and endur-
ance in fatigue, and reduced stress-induced impairments and disor-
ders related to the neuro-endocrine and immune systems.5,10 This
definition was based on evidence obtained from clinical trials,
which authors evaluated in accordance with the European Medi-
cines Agency Assessment Scale and the Jadad scale—a recognized,
evidence-based, validated grading rationale for clinical trials. Today,
the term adaptogen is widely used by many herbalists although it
has yet to gain prominence in mainstream pharmacology.
In this context, the pharmacological profile of various adapto-
genic plants might be different from plant to plant, but what is
common for true adaptogens is their ability to increase the state
of non-specific resistance and to be safe in long-term use in the
appropriate dose level.4,5 ,9 -16 The term adaptogen is often applied
to plants (Table 1) even when the criteria of an adaptogen have
not been met, such as the important and significant general adap-
tive effect on stress involving the whole organism and its main
functions.16 Indeed, systematic pharmacological assessment of
traditionally used tonics (possible adaptogens) show that some
of them do not meet criteria common for adaptogens by defini-
Table 1. Plants Mentioned in Literature as Adaptogens*
Alstonia scholaris
Emblica ocinalis
Piper longum
Anacyclus pyrethrum
Eucommia ulmoides
olacoides, Olacaceae
Aralia mandshurica
Evolvulus alsinoides
Argyreia nervosa
Gentiana pedicellata
Rhodiola heterodonta
Asparagus racemosus
Glycyrrhiza glabra
Rhodiola rosea
Bacopa monnieri
Schisandra chinensis
Bryonia alba
Scutellaria baicalensis
Caesalpinia bonduc
Hoppea dichoroma
Serratula inermis
Centella asiatica
Hypericum perforatum
Sida cordifolia
borivilianum, Liliaceae
Lepidium peruvianum
Silene italica & S. spp.
Cicer arietinum
Melilotus ocinalis
Codonopsis pilosula
Morus alba
Convolvulus pluricaulis
Nelumbo nucifera
Terminalia chebula
Curculigo orchioides
Ocimum sanctum
Tinospora cordifolia
Dioscorea deltoide
Panax ginseng
Trichilia catigua
Drypetes roxburghii
Panax pseudoginseng
Trichopus zeylanicus
Echinopanax elatumi
Paullinia cupana
Turnera diusa
senticosus, Araliaceae
Pfaa paniculata
Withania somnifera
*This table includes plants which do and do not meet the formal
denition of adaptogen.
*For this review, the authors used original full-text Russian articles published from 1943. The word adaptogen is not found in any publication before 1958, even in
N.V. Lazarev’s comprehensive book Evolution of Pharmacology (1947) or any of his or I.I. Brekhman’s publications (or conference abstrac ts) pre-1958. The first study
on nonspecif ic resistance (adaptogenic) activity of a synthetic drug Dibazol was published in 1956 (and a conference abstract in 1947), but with no mention of
“adaptogen” or “adaptogenic activity.” Earlier studies on schisandra were initiated and published in 1943-47; they discussed its stimulating activity.
Figure 1. Adaptogens increase the state of nonspecific
resistance in stress and decrease sensitivity to stressors—which
results in stress protection—and prolong the phase of resistance
(stimulatory effect). Instead of exhaustion, a higher level of
equilibrium (the homeostasis) is attained—the heterostasis. The
higher the equilibrium is, the better the adaptation to stress.
Thus, the stimulating and anti-fatigue effect of adaptogens has
been documented in both animals and humans.4,5
54 | HerbalGram 90 2011
It is not easy to find true scientific information about adapto-
gens on the Internet, since original scientific data and articles are
significantly diluted by the plethora of pseudo-scientific compila-
tions,18 -28 deliberately used by opponents of adaptogens in order to
criticize and discredit the entire adaptogenic concept and the large
body of research that has been conducted during last the 50 years.
In this review, the authors have attempted to summarize the
research on adaptogens from the very beginning to the present
time, with particular concentration on their evidence-based phar-
macological and clinical effects and the molecular mechanisms of
History of Research on Adaptogens
The history of modern scientific research on adaptogens begins
with World War II, with the enhanced need to increase stamina,
endurance, and performance of soldiers, pilots, sailors, and civil-
ians engaged in production of weapons and war material.
For example, the first scientific studies on
the stimulating and tonic effects of schisan-
dra (Schisandra chinensis, Schisandraceae) were
published in Soviet World War II-era military
journals (Figure 2).13
Apparently, the Russian interest in S. chinensis
(known as limonnik in Russian) arises from ethno-
pharmacological investigations by V.L. Komarov
(1895) and V. Arsenyev (1903-1907) in far-eastern
Siberia and northern Manchuria. The berries and
seeds were determined to have been used by Nanai
hunters (a native people of far-eastern Siberia and
Chinese Manchuria, who are also known as Goldis
or Samagir) as a tonic; to reduce thirst, hunger and
exhaustion; and to improve night-time vision.13
In the early 1960s, the study of adaptogens devel-
oped into a field of biomedicinal research in its own
right in the former USSR. The extent of the research
carried out was enormous, with over 1,000 studies
published in the USSR until 1982. Most of these
studies concerned extracts or isolates prepared from
eleuthero (Eleutherococcus senticosus, Araliaceae;
formerly referred to as “Siberian ginseng” in the
United States) root, schisandra berry, Asian ginseng
(Panax ginseng, Araliaceae) root, and golden root
(Rhodiola rosea, Crassulaceae) root.6, 7, 12-14, 29, 30
Extensive research revealed that adaptogens possessed stimula-
tory effects, and on this basis, adaptogens achieved recognition in
the official medicine of Russia in the early 1960s. Adaptogens were
determined to be useful in the Soviet space exploration program
as well as Arctic and Antarctic expeditions, Olympic games, chess
competitions, in the nuclear energy industry, and many other stress-
ful situations and conditions in the former USSR.
However, all these studies were published in Russian-language
journals; thus, they are relatively difficult to access. Several review
articles on adaptogens published in English in the 1980s and
1990s by Brekhman and Dardimov (19686); Farnsworth et al.
(198529); Wagner et al. (19949, 19 9511); Panossian et al. (19994,31);
and Davydov and Krikorian (200032) increased to some extent
professional attention to adaptogens. This professional interest
particularly occurred in Indian and Chinese scientists who were
researching medicinal plants such as the traditional Ayurvedic
tonic ashwagandha (Withania somnifera, Solanaceae) and the
Figure 2. Title pages of scientific journals where the first articles on S. chinensis
were published. The main goal of these studies was formulated in the resolution
No. 4654-p of the People’s Commissars Council of the USSR.
Figure 3. The number of publications on rhodiola and schisandra in USSR/Russia and worldwide since 1940. 2011 HerbalGram 90 | 55
revered Asian (also known as Chinese) ginseng (P. ginseng). Each
plant is used in its respective traditional medicinal system as a tonic
and nourishing agent for fatigue and deficiency of prana (the life
vital energy, activating body and mind in Ayurveda) and qi (v ital
energy in Traditional Chinese Medicine [TCM]) and jing (essence
or the state of health and lifespan in TCM), respectively. Figure 3
reflects the significant growth and interest in adaptogen research
since 1940, the growth in the past few decades—due in part to
the impact of the Swedish Herbal Institute and its contribution of
controlled clinical trials of adaptogens33- 40 —and studies on eluci-
dation of molecular mechanisms of their action.15,41- 4 6 .
Some of the most interesting developments are pharmacological
studies which clearly indicate that certain adaptogenic substances
can activate the protective mechanisms of cells, which is linked to
an increase in survival rate both in vitro and in vivo.41- 47 These
studies have so far been directed at the regulation of molecular
chaperones (Heat Shock Proteins), such as Hsp7045,46 and other
key stress mediators.15
Possible Indications for Use
for Adaptogens and the Level
of Scientific Evidence
The normal therapeutic medi-
cal paradigm—one drug for
one disease—is not appropri-
ate for adaptogens as they can
have numerous pharmacological
effects and indications. Tables 2
and 3 show their pharmacologi-
cal profiles, which are different,
but similar in terms of their stress-
protective action. Therefore, all of
these pharmacological effects can
be combined into the groups asso-
ciated with stimulating and stress-
protective effects in the central
nervous system (CNS) and vegeta-
tive nervous systems, the endo-
crine system, and the immune
system, comprising by definition
the parts of a neuroendocrine-
immune complex-stress-system.
Apparently, stimulating (acute/
single dose effect) and tonic (effect
of repeated/multiple administra-
tion) effects of adaptogens are
actually consequences of their
stress-protective activity.
The CNS-stimulating and tonic
effects of adaptogens are well
documented in numerous publi-
cations and reviews.14 In contrast
to conventional stimulants, such
as sympathomimetics (e.g., ephed-
rine, fenfluramine, phentermine,
prolintane) and general tonics, the
adaptogens do not possess addic-
tion, tolerance, and abuse poten-
tials; they do not impair mental
function; and they do not lead to
psychotic symptoms in long-term
use (see Table 4). Their clinical and
pharmacological effects are due
Table 2. Pharmacological Profile of Adaptogens: Summary of In Vitro and In Vivo Studies
(Adapted from Panossian & Wikman, 20105)
System Effect Rhodiola Eleuthero Schisandra Ginseng Withania
enhancing of physical
cognitive performance
and memory)
+ + + + +
Neuroprotective + + +
Hepatoprotective + +
Cardioprotective + + +
Gastroprotective + +
Oxidative stress/
+ + + + +
Anti-atherosclerosis + + +
+ +
Wound healing + +
Antihyperglycemic + +
+ + + + +
Immunotropic + + + +
Antiviral + +
Antibacterial + +
Anti-tumor + + + +
Antimetastatic +
Life-span increasing + + + +
Endocrine normalizing + + +
Antidepressive +
Anxiolytic + +
Antitoxic +
Schisandra Schisandra chinensis. Photo ©2011 Steven Foster
56 | HerbalGram 90 2011
to a different mode of action.
Their stimulating effect is more
pronounced against a back-
ground of fatigue and stress.
The most important charac-
teristics of adaptogens, such as
stress-protection and a stimu-
latory effect, are common to
all adaptogens. However, the
effects may differ under vari-
ous circumstances (Tables 2
and 3) as has been documented
in a number of clinical stud-
ies (Table 5) and reviews. One
such review29 focused on over
35 clinical trials on E. senticosus
in healthy human subjects
(ca. 6,000 subjects, ages 19 to
72), which were performed in
normal and stressful conditions
(e.g., high-temperature environ-
ment, forced work periods, loud
noise conditions, motion sick-
ness, varying degrees of deaf-
ness, heavy physical burden,
hypertension, mountain rescu-
ers under forced conditions,
athletes, deep-sea divers,
intense mental work and physi-
cal work, and factory workers
under extreme working condi-
tions). There was an improve-
ment of the physical and mental
work capacities in all cases. In
addition, over 35 studies have
focused on the effect of E.
senticosus on more than 2,200
patients with a pathology. The
studies included patients with
atherosclerosis, acute pyelone-
phritis, diabetes, hypertension,
trauma, neuroses, rheumatic
heart disease, chronic bron-
chitis, insomnia, cancer, and
several other ailments. In most
cases, a moderate improvement
relative to the initial conditions
was observed.7 The extracts
were well-tolerated and no adverse effects were
However, the most convincing evidence of the
efficacy of adaptogens were found in studies related
to their neuro-protective effects, effects on cogni-
tive functions and mental performance in fatigue,10
and on their efficacy in asthenia and depression.5,10,
33-40 The evidence suggests that adaptogens may be
beneficial on neurodegenerative disorders.
Adaptogens in Fatigue, Effect on Cognitive Functions
In total, more than 30 publications on the clini-
cal efficacy of various R. rosea preparations can be
found in the US National Library of Medicine’s
PubMed database. The majority of these studies are
Table 3. Pharmacological Profile of Adaptogens: Clinical Efficacy in Humans
Pathophysiological condition Rhodiola Eleuthero Schisandra Ginseng Withania
Physical fatigue + + + + +
Mental fatigue (declining
+ + + + +
Stress-induced chronic fatigue + + +
Astheno-depressive syndrome + +
Depression +
Anxiety +
Neurosis + + + +
Schizophrenia +
Visual function/vision in
+ +
Cognitive functions in
Alzheimer’s disease
Anti-inflammatory effect + +
Common cold, influenza + + +
Pneumonia + +
Gastric dysfunctions, gastritis,
stomach and duodenal ulcers
immuno -suppression
Radiation induced disorders +
Wounds +
Hypertension and heart
+ +
Hypotension + +
Cardiotonia +
Atherosclerosis +
Diabetes +
Reduction of toxicity of
Total sickness rate in severe
climatic conditions
Quality of life + + +
Table 4. The Differences in Properties Between Adaptogens and Other
Stimulants (Adapted from Panossian & Wikman, 20105).
Characteristic Stimulants Adaptogens
1. Recovery process after exhaustive physical load Low High
2. Energy depletion Yes No
3. Performance in stress - Increased
4. Survival in stress - Increased
5. Quality of arousal Poor Good
6. Addiction potential Yes No
7. Adverse effects Yes Rare
8. DNA/RNA and protein synthesis Decreased Increased
Ashwagandha Withania somnifera. Photo ©2011 Steven Foster 2011 HerbalGram 90 | 57
of varying methodological rigor and concern cognitive functions
and mental performance under fatigue (Table 5).
The clinical trials using S. chinensis (13 studies) and E. senti-
cosus (11 studies) on mental performance in humans have been
the subject of a recent review.10 A systematic review showed that
adaptogens have a significant, beneficial, and specific effect on
stress-induced symptoms under fatigue.10 It was observed that R.
rosea, in particular, significantly reduced symptoms of fatigue and
improved attention after 4 weeks of repeated administration.39
Moreover, studies on healthy volunteers receiving single and repea-
ted doses of the proprietary SHR-5® extract (R. rosea root; Swedish
Herbal Institute; Gothenberg, Sweden) have demonstrated an
anti-fatigue effect and improvement in cognitive functions during
fatigue and in stressful conditions.33,34 Thus, one may conclude
that repeated administration of R. rosea extract (SHR-5) exerts an
anti-fatigue effect on healthy subjects and burnout patients expres-
sing fatigue syndrome. This in turn increases the patient’s mental
performance and ability to concentrate.
Adaptogens in Asthenia and Psychiatric Disorders5
In general, the clinical studies carried out in the USSR are
the most questionable and poorly documented, as standardi-
58 | HerbalGram 90 2011
Table 5. Selected Clinical Trials of Adaptogens Related to Their Effects on CNS. (Adapted from Panossian & Wikman,
20105, Panossian & Wikman, 200910).
Pathophysiological condition:
Pharmacological activity or
effect recorded
Adaptogen Reference*** Study designaQuality in
Classification of
evidence levelb
Physical fatigue: Rhodiola
DeBock, 2004
Earnst, 2004
Tuzov, 1968
Lapaev, 1982
Adults physical and cognitive
Rhodiola Fintelman, 2007 OL 0 III
Stimulating effect: Rhodiola can
improve mental performance
after single dose administration
Zotova, 1965
Marina, 1994
Komar, 1981
Mental fatigue:
Rhodiola can improve attention
in cognitive function in fatigue
after single and repeated
Olsson, 2009
Darbinyan, 2000
Spasov, 2000
Shevtsov, 2003
Fatigue syndrome:
Rhodiola has anti-fatigue effect
in physical, emotional, and
mental exhaustion
Chronic fatigue syndrome
Olsson, 2009
Berdishev, 1995
Hertz, 2004
Mild depression: Rhodiola has
an anti-depressive effect
Darbinyan, 2007
Brychenko, 1987**
Staritsina, 1946
Astheno-depressive syndrome
and neurosis (stress-induced
mild depression)
Krasik, 1970
Mikhailova, 1983
Mesheryakova, 1975
Saratikov, 1965*
Kaliko, 1966
Zakharov, 1956
Leman, 1952
Rossijskij, 1952
Anxiety: improvement anxiety
Rhodiola Bystritsky, 2008 OL 0
Schizophrenia Schisandra
Zakharova, 1948
Lastovetskiy, 1963
a R - randomized; OL- open label; PC - placebo-controlled; UC - uncontrolled; CO - crossover; DB - double blind; SB - single blind.
b According to the World Health Organization (WHO), US Food and Drug Administration (FDA), and European Medicines Agency (EMEA): Ia
- meta-analyses of randomized and controlled studies; Ib - evidence from at least one randomized study with control ; IIa - evidence from at
least one well-performed study with control group; IIb - evidence from at least one well-performed quasi-experimental study; III - evidence
from well-performed non-experimental descriptive studies as well as comparative studies, correlation studies, and case-studies; and IV -
evidence from expert committee reports or appraisals and/or clinical experiences by prominent authorities.38
* - mixed patient population, sick/healthy subjects.
** - adjuvant therapy with antidepressants, control group – tricyclic antidepressants.
*** - Reference on the first author of publication mentioned in reviews5,10
zed psychological measures were not used in the earlier studies.
Indeed, some of them did not use randomization or blinding
of subjects. However, the main problem in assessment of these
studies is that the Soviet diagnostic criteria were different from
commonly used criteria in the rest of the world. The diagnostic
criteria used in the USSR prior to 1990 for schizophrenia was
particularly idiosyncratic, overused, and misapplied to other
conditions. The diagnoses of asthenia and neuroasthenia include
a very heterogeneous group of patients with mixed psychological
and physical disorders, making the studies more difficult to inter-
pret. Nevertheless, despite numerous shortcomings that reduced
the quality of evidence obtained in the early clinical studies in the
USSR, this scientific evidence provides important information
about the efficacy and safety of adaptogens in the treatment of
psychiatric disorders (Table 5). For example, encouraging results
from a randomized, double-blind, placebo-controlled study exist
for use of SHR-5 rhodiola extract in mild-to-moderate depres-
sion.38 2011 HerbalGram 90 | 59
Active Principles and Molecular Mechanisms of Action of Selected
The phenolic compounds include phenylpropanoids and phenylethane
derivatives such as salidroside (rhodioloside), rosavin, syringin, triandrin,
tyrosol, and lignans such as eleutheroside E and schisandrin B. They
are structurally similar to the catecholamines—the mediators of the
sympathoadrenal system (SAS) involved in activation of the stress system
in the early stages of stress response. The tetracyclic triterpenoids, such
as cucurbitacin R diglucoside, ginsenosides, and phytosterol-glycosides
(e.g., eleutheroside A, sitoindosides, daucosterol) structurally resemble
the corticosteroids that act as stress hormones involved in protective
inactivation of the stress system. Salidroside—the primary active principle
of rhodiola extracts—was found to have neuroprotective activity, which
reduced stress-induced impairments and disorders related to the neuro-
endocrine and immune systems. A number of these findings might
raise the possibility of potential therapeutic applications of salidroside
in preventing and treating cerebral ischemic and neurodegenerative
diseases. Tyrosol—another active principle of rhodiola extract—increases
phosphorylation of nitric oxide synthase eNOS and Forkhead box O
(FOXO) transcription factor FOXO3a, which are key molecular targets
involved in this mechanism. Furthermore, tyrosol has recently been shown
to induce the expression of the longevity protein SIRT1.49
Administration of the amino acid tyrosine, which is a common precursor
of biosynthesis of tyrosol, salidroside, and catecholamines (Fig: 4), alleviates
both stress-induced depletion of brain catecholamines (norepynephrine and
dopamine in the alarm phase of stress syndrome) and reduces fatigue, as
noted in animal task performances.50 A number of clinical studies suggest
sthat supplementation of tyrosine might improve stress-induced (e.g., cold,
noise, anxiety, and fatigue) accuracy of mental performance.51
Indeed, schisandrin B has a similar pharmacological profile associated
with stress-protective activity. Apparently, the neuroprotective effect of
schisandrin B52,53 is associated with the expression of heat shock proteins
Hsp70.54-58 Schisandrin B stimulates the expression of Hsp70 in normal
cells, which is associated with the enhancement of mitochondrial gluta-
thione status, antioxidant activity, adenosine triphosphate (ATP) genera-
tion, mitigation of age-related impair-
ments in mitochondrial antioxidant
status and functional ability in various
tissues, enhancement in cognitive func-
tions, and an increase in the survival of
aging in rodents.58,59
The stress-protective effect of adapto-
gens has been demonstrated on simple
organisms and on isolated cells.41,43,47
Thus, there may be an association
with regulation and homeostasis of the
neuro-endocrine-immune complex. In
addition, there may also be a connec-
tion with more evolutionary, conser-
vative mechanisms of regulation in
cellular homeostasis and the adaptive/
defense response to external stressors.
Such a defense system is apparently
common for all cells and living organ-
isms and probably includes heat shock
proteins among the number of key
mediators of innate nonspecific resis-
tance to stressors.
The same mechanism can be found in
stress tolerance and lifespan extension,
which makes them parallel phenom-
ena. Therefore, it is not surprising that
adaptogens prolong the lifespan of the Figure 4. Adaptogenic chemical compounds
Eleuthero Eleutherococcus senticosus.
Photo ©2011 Steven Foster
Eleutheroside E
Cucurbitacin R diglucoside
Sitoindosides IX,X
60 | HerbalGram 90 2011
nematode Caenorhabditis elegans42 and Drosophila melanogaster59
in a dose-dependent manner.
The beneficial stress-protective activity of adaptogens was asso-
ciated with the hypothalamic-pituitary-adrenal axis and the regu-
lation of key mediators of the stress response common to all cells,
such as the following:
• Heat shock proteins Hsp70 and Hsp16, which are molecular
chaperones involved in stress-induced cytoprotection and in
adaptation of repeated exposure to an initial stressor;43, 45,46
• Stress-activated c-Jun N-termina l protein kinase 1 ( JNK1);15
• FOXO transcription factor DAF-16;42
• HPA-axis, including cortisol and glucocorticoid receptors
• Beta-endorphine;5
• NO15
• The biosynthesis of
ATP, thus induc-
ing an alteration in
energy source.5
A hypothetical molecu-
lar mechanism of action of
adaptogens is outlined in
Figure 5.5,10
Typically, a cell is in one
of the following states:
• balance (dynamic
• functioning under
stressful conditions
(threatened homeo-
stasis – imbalance);
• the state of adapta-
tion (tolerance) to
stress (i.e., state of
nonspecific resistance
to stress; heterosta-
sis—or homeostasis
with a higher level of
equilibrium); or
• the state of apop-
tosis (normally
programmed cell
The Upper Panel in
Figure 5 shows that mito-
chondria generate aggressive
oxygen-containing radicals
that can damage native or
repair proteins by distorting
their 3-D structure, so that
they can no longer fulfill
their functions in the cell.
There are many “players”
involved in the regulation
of homeostasis at both the
cellular level and the organ-
ism level, such as:
• the stress hormone
cortisol (a molecule
that is secreted from
glands and regulates the functions of organs and systems of
the organism);
• GRs that modulate/regulate cortisol secretion (feedback regu-
• NO, an intracellular signaling molecule that mediates stress
response and modulates stress-induced activation of hormonal,
nervous, and immune systems;
• FoxO, a Forkhead protein that controls the synthesis of
proteins involved in stress resistance, cell survival, and longev-
ity. When it is in the cytoplasm of the cell, DNA produces
proteins involved in growth and development of cells, when
FoxO is translocated into the nucleus and binds to DNA. The
cell starts to produce other proteins that are involved in resis-
tance to stress and increases survival and longevity.
Figure 5. A simplified schematic showing the hypothetical molecular mechanism of the proprietary
phytomedicinal combination ADAPT-232® (containing extracts of R. rosea, S. chinensis, and E. senticosus;
Swedish Herbal Institute) as it induces stress resistance (adaptation to stress) and enhances cognitive
functions and, possibly, longevity. 2011 HerbalGram 90 | 61
Under stress (e.g., infection,
cold, heat, radiation, physical
load, emotional stress), an exter-
nal stress signal activates a cascade
of “signalling” proteins/enzymes
including JNK, a stress-activated
enzyme that plays important roles
in the regulation of a diverse array
of cellular functions such as neuro-
nal development, activation of the
immune system, and programmed
cell death (apoptosis). The func-
tions of JNK are as follows:
• To increase the forma-
tion of aggressive radicals
and NO, which in turn
suppresses the generation
of energy-providing mole-
cules, e.g., ATP. As a result
of lack of energy, many
proteins cannot function
properly, several factions
are suppressed, and the first
symptoms of fatigue and exhaustion are observed. ATP
is also required for the normal functioning of heat shock
proteins (e.g., Hsp70), which are produced as a defense
response to stress and assist in the repair of misfolded and
damaged proteins;
• To regulate a diverse array of cellular functions, including
neuronal development, activation of immune system, and
programmed cell death (apoptosis).
• To suppress GRs such that the feedback inhibition of
cortisol secretion ceases to function and levels of circula-
tory cortisol increase. The cortisol inhibits the immune
system, and has anti-inf lammatory effects on the body.
It is also required to protect the organism from over-
reaction/over-activation in response to stress. However,
chronically high levels of cortisol are associated with
depression, chronic fatigue, and impaired cognitive func-
tion, such as decreased attention and learning ability.
• To activate translocation of FOXO to the nucleus and
initiates the synthesis of proteins that confer stress-resis-
tance and increased longevity.
The lower panel in Figure 5 shows that adaptogen prepara-
tions, such as ADAPT-232, decrease inducible NO, cortisol, and
JNK under stress and stimulate/activate the expression of Hsp70
and p-FOXO1.
The stimulation of Hsp70 biosynthesis is a key point in the
mechanism of action of adaptogens since the heat shock protein
is responsible for the following actions:
• enhances the repair of damaged proteins;
• inhibits the stress-induced expression of NO genes and,
since the reduced levels of inducible NO cannot suppress
the formation of energy providing molecules, ATP is
increased to normal levels in the adapted cell;
• inhibits JNK and consequently apoptotic deaths and
suppression of immune system via activation of GR and
other mechanisms. Normal GR function and normal
ATP levels are associated with the anti-fatigue and anti-
depressive effects of adaptogens and with normal cogni-
tive function (good attention, memory, and learning);
• is probably associated with the effect of adaptogens on
the phosphorylation of FOXO and its translocation into
the nucleus of isolated cells (i.e., human monocytes) or
simple organisms (i.e., DAF-16 in C. elegans and, conse-
quently, with increased resistance to stress and increased
In summary, ADAPT-232 works like a stress vaccine (stress-
mimetic) by activating stress-induced self-defense mechanisms
in order to adapt the cell and organism to mitigate stress-
induced harmful effects.
It seems that activation of Hsp70 expression is a key point
in the mode of action of adaptogens. Studies demonstrate that
adaptogens induce an increase of serum Hsp72 in animals.
This induction is considered a defense response to stress, which
increases tolerance to stress in a combination of physical and
emotional stresses. This data suggest that increased tolerance
to adaptogen-induced stress is associated with its stimulation
of expression of circulating serum Hsp72.45,46 In fact, Hsp72
expression and release is a known mediator of the stress response
involved in repairing proteins during physical load. The work-
ing hypothesis of this research is that adaptogens adapt (or
make less sensitive) the organism to stress. Thus, adaptogens act
like low molecular weight “vaccines” or stress-mimetics, which
induce mild activation of the stress system in order to cope with
more severe stress. The adaptogens act as challengers and mild
stressors (stress-mimetics). This gives rise to adaptive and stress-
protective effects, which are mainly associated with the hypotha-
lamic-pituitary-adrenal (HPA) axis, a part of the stress system
that also contributes to the nervous, cardiovascular, immune,
gastrointestinal, and endocrine systems.
The antidepressive effect of R. rosea38,4 4 may be associated
with parts of the stress system (e.g., secretion of cortisol and the
JNK-mediated effects on the glucocorticoid receptors).15
Conclusions and Perspectives
Recent pharmacological studies of some adaptogens give a
rationale to their effects at the molecular level. Research demon-
strates that the beneficial stress-protective effect of adaptogens is
related to the regulation of homeostasis via several mechanisms
of action, which are associated with the HPA axis and the regu-
lation of key mediators of the stress response, such as molecular
chaperones (e.g., Hsp70), stress-activated JNK1, FOXO tran-
scription factor, cortisol, and NO.5,10
Asian Ginseng Panax ginseng.
Photo ©2011 Steven Foster
62 | HerbalGram 90 2011
In summary, adaptogens may be regarded as a novel pharma-
cological category of anti-fatigue agents that perform the follow-
ing functions:
• induce increased attention and endurance in situations of
decreased performance caused by fatigue and/or sensation
of weakness;
• reduce stress-induced impairments and disorders related
to the function of stress (neuro-endocrine and immune)
Adaptogens have not only specific therapeutic effects in some
stress-induced and stress-related disorders, but may also have an
impact on the quality of life of patients when implemented as
adjuvants in the standard therapy of many chronic diseases and
pathological conditions (e.g., post-surgery recovery, asthenia,
congestive heart failure, chronic obstructive pulmonary disease).
Adaptogens may also have potential use in age-related disorders,
such as neurodegenerative diseases and cardiovascular diseases.
Thus, elderly people may be able to maintain their health status
on a normal level, improve their quality of life, and may increase
longevity. However, further research is needed to evaluate the
efficacy of adaptogens as geriatric agents and to elucidate molec-
ular mechanisms of action of these complex herbal extracts and
their active principles.
Alexander Panossian, PhD, Dr.Sci., is Research Projects Director
at the Swedish Herbal Institute, a forprofit company which produces
proprietary phytomedicines, most of which are adaptogenic. He
obtained his scientific degrees in Moscow Institute of Bioorganic
chemistry in 1975, and in Moscow Institute of Fine Chemical Tech-
nology in 1986. After the collapse of USSR in 1991, Dr. Panossian
was made a Full Professor of Chemistry of Natural and Physiologi-
cally Active Compound in the Russian Federation and later served
as Director of Laboratory of Quality Control of Drugs of the Medi-
cal Drug Agency of the Republic of Armenia. In 2003, he moved
to Sweden where he is currently working at Swedish Herbal Insti-
tute. During his scientific career he was temporarily working as a
guest scientist in the laboratory of Nobel Laureate B. Samuels-
son at the Karolinska Institute (1982-83), at Munich University
(1993-5) and at King’s College in London, 1996. He has written
or co-authored more than 170 articles in peer-reviewed journals.
Hildebert Wagner, PhD, is Professor Emeritus at the Institute for
Pharmaceutical Biology at the University of Munich in German. He
is the author of 7 books including: Plant Drug Analysis (Springer
Verlag Heidelberg, 1996), and Drugs and Drug Constituents
(Wissenschaftliche Verlagsgesellschaft Stuttgart, 1998), as well as
authoring over 900 scientific publications. Dr. Wagner was made a
full professor of pharmacognosy in 1965, and later served as director
of the Institute of Pharmaceutical Biology in Munich until 1999.
He has been distinguished by many international scientific institu-
tions including the Universities of Ohio, Budapest and Debrecen,
Dijon, and Helsinki for his work in pharmacognosy. Dr. Wagner
sits on advisory/editorial boards for Phytochemistry, the Jour-
nal of Ethnopharmacology, the Journal of Natural Products,
as well as serving as Founding Editor for the international jour-
nal Phytomedicine. He is the recipient of the American Botanical
Council’s Norman R. Farnsworth Excellence in Botanical Research
Award in 2008.
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... Seminal works and various nutritional and/or managerial strategies were applied to mitigate heat stress, yet the poultry productivity losses are still high during hot seasons. Although they are known for more than 60 years in traditional medicine (for review see Panossian and Wikman, 2011), the use of in feedadaptogens in livestock just begins to gain popularity (Selvam et al., 2018). Adaptogens, plant extracts, also known as stress response modifiers, are defined as metabolic regulators, which increase the ability of an organism to adapt to environmental stressors and to avoid damage from such stressors (Wagner et al., 1994;Wikman, 2009, 2010). ...
... Fueled by consumer preferences for natural products, there is growing interest in using phytobiotic feed additives in the animal food system (American Meat Science Association [AMSA], 2012). Although they are known for more than 60 years in medicine and pharmacosanation (Wagner et al., 1994), and their original plant sources have been used for centuries in traditional medicine (Wagner et al., 1994;Panossian and Wikman, 2011), adaptogens are just recently begin to be used as feed additive in poultry (Selvam et al., 2018;Marimuthu et al., 2020). Herbal adaptogens are plant-derived biologically active substances originally defined as stress-response modifiers and metabolic regulators that increase the ability of an organism to adapt to environmental stressors and, thereby, protect against cellular damage from such stressors (Duraisami et al., 2010;Giri et al., 2011Giri et al., , 2013Singh et al., 2017). ...
... NR-PHY-30 contains Indian gooseberry (Emblica officinalis), holy basil (Ocimum sanctum), and winter cherry (Withania somnifera) (Natural Remedies, personal communication), and the adaptogenic properties of these plants have been already reported (Wagner et al., 1994;Panossian and Wikman, 2011) as well as their beneficial therapeutic effects (Pattanayak et al., 2010;Malik et al., 2016;Dutta et al., 2019). As expected and in agreement with previous studies, including our own (Flees et al., 2017;Rajaei-Sharifabadi et al., 2017;Liu et al., 2020;Tabler et al., 2020;Wasti et al., 2020), heat stress increased both surface and body core temperatures and reduced feed intake and body weight in modern broilers. ...
Full-text available
Heat stress has strong adverse effects on poultry production and, thereby, threats its sustainability, which energized scientists to search for innovative and effective solutions. Here, we undertook this study to evaluate the effects of in-feed herbal adaptogen (stress response modifier) supplementation on growth performances, meat quality, and breast amino acid profile in chronic cyclic heat-stressed broilers. Day-old male Cobb 500 chicks ( n = 720) were randomly assigned, in environmental chambers ( n = 12, 24 pens), to three diet-treatments: a three-phase corn-soybean based diet fed as such (Control, C), or supplemented with the herbal adaptogen at 500 g/1000 kg control diet (NR-PHY-500) or at 1 kg/1000 kg control diet (NR-PHY-1000). From d29 to d42, birds from 9 chambers were exposed to cyclic heat stress (HS, 35°C from 9:30 am-5:30 pm), however, the rest of the chamber were maintained at thermoneutral conditions (24°C, TN), which creates 4 experimental groups: C-TN, C-HS, NR-PHY-500HS, and NR-PHY-1000HS (6 pens/group, 168 birds/group). HS altered growth performance via depression of feed intake and body weight. Adaptogen supplementation stimulated feed intake and averaged 65.95 and 83.25 g better body weight and 5 and 10 points better FCR at low and high dose, respectively, compared to heat-stressed birds. This increase in body weight was mirrored in enhanced weights of body parts (breast, tender, wings, and legs). Adaptogen supplementation modulated also breast amino acid profile, pH, color, and quality. Together, these data suggested that adaptogen supplementation could be a promising solution to alleviate heat stress, however further in-depth investigation for its mode of action and its underlying mechanisms are warranted.
... Adaptogens are defined as herbal extracts or preparations that increase tolerance to stressors, enhance attention and mental endurance, increase tolerance to mental fatigue and physical exhaustion, and reduce stress-induced disorders related to the immune and neuro-endocrine systems [7][8][9]. Examples of plants that have been studied for their anti-stress activities include Rhodiola, Schizandra, Eleutherococcus, Withania, Emblica and Glycyrrhiza [7,[9][10][11][12][13]. ...
... Adaptogens are defined as herbal extracts or preparations that increase tolerance to stressors, enhance attention and mental endurance, increase tolerance to mental fatigue and physical exhaustion, and reduce stress-induced disorders related to the immune and neuro-endocrine systems [7][8][9]. Examples of plants that have been studied for their anti-stress activities include Rhodiola, Schizandra, Eleutherococcus, Withania, Emblica and Glycyrrhiza [7,[9][10][11][12][13]. ...
... Historically, the term "adaptogen" was introduced into the scientific literature by N. Lazarev in 1957 who referred to plantderived substances that increased "the state of non-specific resistance". For detailed historical reviews see Panossian and Wagner [8,9]. Because the pharmacological profiles of plants used for their adaptogenic properties vary widely, combinations of plant extracts are commonly used in the preparation of adaptogenic products [9,14,15]. ...
... Antidepresivo (Deyama et al. 2001). Adaptógeno (Panossian 2003;Panossian & Wagner 2011). ...
... Potenciador del aprendizaje y de la memoria (Pachauri et al. 2013 Adaptógeno (Ma et al. 2007;Arenas et al. 2011;Jiménez Martínez et al. 2013 Potenciador del aprendizaje, la atención y la memoria (Petkov et al. 1994;Kennedy et al. 2004;Panossian & Wagner 2011;Dwivedi et al. 2012). Neuroprotector: desórdenes neurodegenerativos, Alzheimer, Parkinson, Huntington, esclerosis múltiple (Werneke et al. 2006;Cho 2012;Mahomoodally et al. 2013), deterioro cognitivo, demencia (Geng et al. 2010Hügel et al. 2012), accidente cerebrovascular (Rastogi et al. 2014). ...
... Neuroprotector: desórdenes neurodegenerativos, Alzheimer, Parkinson, Huntington, esclerosis múltiple (Werneke et al. 2006;Cho 2012;Mahomoodally et al. 2013), deterioro cognitivo, demencia (Geng et al. 2010Hügel et al. 2012), accidente cerebrovascular (Rastogi et al. 2014). Ansiolítico: trastornos de ansiedad, "neurosis" (Panossian & Wagner 2011;Sharma et al. 2012). Anticonvulsivo: epilepsia (Nsour et al. 2000;Quintans et al. 2011). ...
Full-text available
Recebido em agosto de 2015. Aceito em dezembro de 2015. Publicado em dezembro de 2015. ___________________________________________________________________________________________________________ RESUMEN – Este trabajo presenta resultados parciales de una línea de investigación en Etnobotánica urbana, desarrollada por el Laboratorio de Etnobotánica y Botánica Aplicada (LEBA) en el Área Metropolitana de Buenos Aires, Argentina. Se incluyen datos sobre 30 especies de plantas medicinales cuyos productos se comercializan como potenciadores cognitivos, vinculados con distintas condiciones neurológicas y psicológicas. Muchas de estas especies se emplean asimismo como adaptógenos. Se relevaron 145 sitios de expendio pertenecientes al circuito comercial general y al circuito restringido de dos segmentos de inmigrantes: boliviano y chino. Para cada especie se indican productos, muestras y usos asignados, con sus estudios de validación. La discusión contribuye a la comprensión de la complejidad del conocimiento botánico en los contextos pluriculturales urbanos, y a la dinámica de su transmisión sobre la base de la difusión de los productos relevados. PALABRAS CLAVE: Etnobotánica urbana, potenciadores cognitivos, adaptógenos, conocimiento botánico, Buenos Aires. ___________________________________________________________________________________________________________ THE BOTANICAL KNOWLEDGE IN URBAN AREAS: COGNITIVE ENHANCERS MARKETED IN THE METROPOLITAN AREA OF BUENOS AIRES, ARGENTINA ABSTRACT – This paper presents partial results of a research line on urban Ethnobotany, developed by the Laboratorio de Etnobotánica y Botánica Aplicada (LEBA) in the Metropolitan Area of Buenos Aires, Argentina. Data on 30 species of medicinal plants whose products are marketed as cognitive enhancers, linked to various neurological and psychological conditions are included. Many of these species are also used as adaptogens. 145 outlets belonging to general commercial circuit and the limited scope of two segments of immigrants (Bolivian and Chinese) were surveyed. Products, samples and assigned uses (with studies that validate them), are indicated for each species. The discussion contributes to the understanding of the botanical knowledge complexity in multicultural urban contexts and the dynamics of its transmission based on the diffusion of the products surveyed. KEY WORDS: Urban ethnobotany, cognitive enhancers, adaptogens, botanical knowledge, Buenos Aires. ___________________________________________________________________________________________________________ O CONHECIMENTO BOTÂNICO EM ÁREAS URBANAS: ESTIMULADORES COGNITIVOS COMERCIALIZADOS NA ÁREA METROPOLITANA DE BUENOS AIRES, ARGENTINA RESUMO-Este artigo apresenta resultados parciais de uma pesquisa em Etnobotânica urbana, desenvolvida pelo Laboratorio de Etnobotánica y Botánica Aplicada (LEBA) na Área Metropolitana de Buenos Aires, Argentina. São apresentados dados sobre 30 espécies de plantas medicinais, cujos produtos são comercializados como estimuladores cognitivos, ligados a várias condições neurológicas e psicológicas. Muitas destas espécies também são consumidas como adaptógenos. Cento e quarenta e cinco pontos de venda foram pesquisados, pertencentes ao circuito comercial geral e ao circuito restrito de dois grupos de imigrantes: bolivianos e chineses. Para cada espécie são indicados: produtos, amostras, e usos atribuídos com seus estudos de validação. A discussão ajuda a compreender a complexidade do conhecimento botânico em contextos multiculturais urbanos, e sua dinâmica de transmissão com base na difusão dos produtos pesquisados.
... Ketika sirkulasi darah dalam tubuh lancar, maka tingkat kebugaran seseorang juga akan bertambah. Dalam penelitian yang dilakukan oleh Prastiwi (2015) membuktikan, tanaman pegagan memberi efek positif terhadap daya rangsang saraf otak dan memperlancar transportasi darah pada pembuluh-pembuluh otak. ...
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Background: Fitness is the state of the body does not experience significant fatigue after doing routine activities. While in Traditional Chinese Medicine (TCM), fitness is defined as the good circulation of Qi-energy and Xue-blood that can cause the function of the organs of Zhang Fu to run well. Physical predisposition is influenced by various factors and assessed in various ways, one of which is by measuring VO2 max calculated by doing cooper test that is running for 12 minutes on the track 400 meters. A person’s VO2 max level indicates the level of physical fitness. Based on the examination that has been done, the patient is exposed to excessive heat pathogens in the Stomach, there are humid pathogens in the body, and Qi and Xue are not sufficient. Purpose: To find out the effect of acupuncture therapy and herbal administration in complementary traditional medicine on improving fitness. Methods: To improve fitness is done acupuncture therapy and herbal therapy. Acupuncture therapy is performed at the Zusanli point (ST 36) and Sanyinjiao point (SP 6). Herbal therapy given during treatment is infusion of leaves Gotu Kola (Centella asiatica (L). Urb) and Liquorice (Glycyrrhiza glabra L.). To improve fitness, acupuncture therapy was performed 12 times in 4 stages of therapy. For herbal therapy infusa leaves Gotu Kola fresh as much as 2.5 grams and 2 grams of Liquorice, taken daily 3 times a day. Results: Acupuncture and herbal therapy that has been done for 26 days showed good results. This is evidenced by the results of copper test VO2 max increased 44.3% and no more complaints felt by patient. Conclution: Acupuncture therapy at the point of Zusanli (ST36), Sanyinjiao (SP6) accompanied by gotu kola herbs (Centella asiatica (L.) Urb) and liquorice (Glycyrrhiza glabra L.) can improve fitness.
... The use of natural health products to enhance recovery and reduce fatigue in athletes has become a topic of discussion and importance in sport medicine. In this context, adaptogens are considered to be the most suitable supplements, which are safe by definition and enhance " nonspecific resistance to stress "[4][5][6][7][8][9]. At the cellular and molecular levels, adaptogens initiate the activation of adaptive stress response pathways, resulting in increased expression of heat-shock proteins, neuropeptide Y, antioxidant enzymes and anti-apoptotic proteins[10,11]. ...
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Abstract Objective: The aim of this randomized, double-blinded, placebocontrolled trial was to assess the efficacy of adaptogens on the physical and emotional stress-induced loss of concentration, coordination, fatigue and hormonal changes in 215 elite athletes. This study explores two formulations, ADAPT-232S and ADAPT-S, that had standardized contents of salidroside, schisandrin, eleutherosides B and E, ecdisterone and pantothenic acid. Methods: Standard psychological scales and computerized neurophysiological and blood tests were used to assess the efficacy of the treatments at the baseline and then after 7, 8, 28 and 29 days of daily oral administration. Fatigue was chosen as one of the primary outcomes and was measured as selective inattention and impulsivity in the Conners’ computerized continuous performance test (CCPT) and three standard psychological rating scales, the fatigue severity score (FSS), the perceived stress score (PSS) and the Shirom-Melamed burnout score (SMBS). The anabolic index (blood testosterone/cortisol ratio) and blood lactate were selected as primary outcomes in the phase of recovery of athletes on the second day after heavy physical exercise or competitions. Results: Significant differences (p<0.01) between the placebo and verum groups in favor of ADAPT-232S and ADAPT-S were found in the primary and some secondary outcomes: Conners’ computerized continuous performance test parameters of selective attention and impulsivity, anabolic index, cortisol and lactate levels in blood, fatigue severity score, perceived stress score, and physical performance tests. The sport achievements of athletes were in favor of the ADAPT groups. All of the treatments were well tolerated. The total numbers of adverse events did not differ among the three groups. Conclusions: The adaptogenic preparations, ADAPT-232S or ADAPT-S, are safe and effective supplements for enhancing tolerance to physical and emotional stress as well as for the recovery of athletes during and after high–intensity exercise and competitions. Keywords Sport medicine; ADAPT; Fatigue; Randomized controlled trial
... The use of natural health products to enhance recovery and reduce fatigue in athletes has become a topic of discussion and importance in sport medicine. In this context, adaptogens are considered to be the most suitable supplements, which are safe by definition and enhance " nonspecific resistance to stress " [4][5][6][7][8][9]. At the cellular and molecular levels, adaptogens initiate the activation of adaptive stress response pathways, resulting in increased expression of heat-shock proteins, neuropeptide Y, antioxidant enzymes and anti-apoptotic proteins [10,11]. ...
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Efficacy of Adaptogenic Supplements on Adapting to Stress: A Randomized, Controlled Trial Objective: The aim of this randomized, double-blinded, placebocontrolled trial was to assess the efficacy of adaptogens on the physical and emotional stress-induced loss of concentration, coordination, fatigue and hormonal changes in 215 elite athletes. This study explores two formulations, ADAPT-232S and ADAPT-S, that had standardized contents of salidroside, schisandrin, eleutherosides B and E, ecdisterone and pantothenic acid. Methods: Standard psychological scales and computerized neurophysiological and blood tests were used to assess the efficacy of the treatments at the baseline and then after 7, 8, 28 and 29 days of daily oral administration. Fatigue was chosen as one of the primary outcomes and was measured as selective inattention and impulsivity in the Conners’ computerized continuous performance test (CCPT) and three standard psychological rating scales, the fatigue severity score (FSS), the perceived stress score (PSS) and the Shirom-Melamed burnout score (SMBS). The anabolic index (blood testosterone/cortisol ratio) and blood lactate were selected as primary outcomes in the phase of recovery of athletes on the second day after heavy physical exercise or competitions. Results: Significant differences (p<0.01) between the placebo and verum groups in favor of ADAPT-232S and ADAPT-S were found in the primary and some secondary outcomes: Conners’ computerized continuous performance test parameters of selective attention and impulsivity, anabolic index, cortisol and lactate levels in blood, fatigue severity score, perceived stress score, and physical performance tests. The sport achievements of athletes were in favor of the ADAPT groups. All of the treatments were well tolerated. The total numbers of adverse events did not differ among the three groups. Conclusions: The adaptogenic preparations, ADAPT-232S or ADAPT-S, are safe and effective supplements for enhancing tolerance to physical and emotional stress as well as for the recovery of athletes during and after high–intensity exercise and competitions.
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Adaptogens comprise a category of herbal medicinal and nutritional products promoting adaptability, resilience, and survival of living organisms in stress. The aim of this review was to summarize the growing knowledge about common adaptogenic plants used in various traditional medical systems (TMS) and conventional medicine and to provide a modern rationale for their use in the treatment of stress-induced and aging-related disorders. Adapto-gens have pharmacologically pleiotropic effects on the neuroendocrine-immune system, which explain their traditional use for the treatment of a wide range of conditions. They exhibit a biphasic dose-effect response: at low doses they function as mild stress-mimetics, which activate the adaptive stress-response signaling pathways to cope with severe stress. That is in line with their traditional use for preventing premature aging and to maintain good health and vitality. However, the potential Med Res Rev. 2020;1-74. | 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Adaptogens are stress-response modifiers that increase an organism's nonspecific resistance to stress by increasing its ability to adapt and survive. The classical reductionist model is insufficiently complex to explain the mechanistic aspects of the physiological notion of "adaptability" and the adaptogenic activity of adaptogens. Here, I demonstrate that (1) the mechanisms of action of adaptogens are impossible to rationally describe using the reductionist concept of pharmacology, whereas the network pharmacology approach is the most suitable method; and (2) the principles of systems biology and pharmacological networks appear to be more suitable for conceptualizing adaptogen function and are applicable to any phytochemical. Molecular targets, signaling pathways, and networks common to adaptogens have been identified. They are associated with stress hormones and key mediators of the regulation of homeostasis. In this context, the mechanisms of action of adaptogens are specifically related to stress-protective activity and increased adaptability of the organism. Consequently, adaptogens exhibit polyvalent beneficial effects against chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, cancer, and other aging-related diseases. Current and potential uses of adaptogens are mainly related to stress-induced fatigue and cognitive function, mental illness, and behavioral disorders. Their prophylactic use by healthy subjects to ameliorate stress and prevent age-related diseases appears to be justified. It is very unlikely that the pharmacological activity of any phytochemical is specific and associated only with one type of receptor, particularly adaptogenic compounds, which affect key mediators of the adaptive stress response at intracellular and extracellular levels of communication.
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Background: Menopausal women are challenged by the adverse effects of estrogen loss on energy, mood, cognitive function, and memory. These stresses are compounded by increased risks for cardiovascular disease, osteoporosis, and cancer. Known to have neuroprotective, cardio-protective, anti-oxidative and anti-carcinogenic effects, Rhodiola rosea extracts have also been shown to improve energy, mood, cognitive function and memory. Purpose: We propose that R. rosea be investigated for use as a potential selective estrogen receptor modulator (SERM) in the prevention and treatment of menopause-related fatigue, stress, depression, cognitive decline, memory impairment, cardiovascular disease, osteoporosis and cancer. Method: This paper briefly reviews the relationship between estrogen decline and menopause-related health risks, the molecular mechanisms underlying estrogenic effects on health, and the evidence indicating beneficial effects of R. rosea extracts on these mechanisms and health risks. Mechanisms include non-genomic and genomic effects, for example: activation of intra-cellular signal transduction pathways by binding to estrogen receptors, ERα-mediated activation of endothelial nitric oxide synthase with increased nitric oxide release; and anti-inflammatory effects, counteracting TNFα by inhibiting nuclear factor-Kappa-B (NF-KB) and protection of osteoblasts from hydrogen peroxide. A clinical case illustrating treatment of a menopausal woman with R. rosea is presented. Risks, benefits, gaps in knowledge, and future directions are discussed. Conclusion: Numerous lines of evidence indicate that R. rosea should be investigated as a potential selective estrogen receptor modulator (SERM) to prevent, delay or mitigate menopause-related cognitive, psychological, cardiovascular and osteoporotic conditions.
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The ability of plant adaptogens to enhance the “state of non-specific resistance” of an organism to stress by augmenting resistance to physical, biological, chemical and psychological stresses, and increasing concentration, performance and endurance during fatigue have placed it in a unique position among medicinal plants. However, the molecular mechanism by which plant adaptogens exerts its beneficial effects is thus far incompletely understood. This chapter focuses on recent advances in the understanding the molecular mechanism exerted by ADAPT-232 forte, a plant adaptogens consisting of a fixed combination of three extracts of Eleutherococcus senticocus, Schisandra chinensis and Rhodiola rosea. Our studies suggest that ADAPT-232 exerts its beneficial effect, in part, by a mechanism dependent on the upregulation of Hsp70 expression. A concise discussion of the effect of adaptogens on endurance and a comparison of hormetins and adaptogens will also be discussed Keywords:Adaptogens- Eleutherococcus senticocus -heat shock proteins-hormesis-longevity- Rhodiola rosea - Schisnadra chinesis
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The aim of this review article was to summarize accumulated information related to chemical composition, pharmacological activity, traditional and official use of Rhodiola rosea L. in medicine. In total approximately 140 compounds were isolated from roots and rhizome - monoterpene alcohols and their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives. Studies on isolated organs, tissues, cells and enzymes have revealed that Rhodiola preparations exhibit adaptogenic effect including, neuroprotective, cardioprotectiv e, anti-fatigue, antidepressive, anxiolytic, nootropic, life-span increasing effects and CNS stimulating activity. A number of clinical trials demonstrate that repeated administration of R. rosea extract SHR-5 exerts an anti-fatigue effect that increases mental performance (particularly the ability to concentrate in healthy subjects), and reduces burnout in patients with fatigue syndrome. Encouraging results exist for the use of Rhodiola in mild to moderate depression, and generalized anxiety. Several mechanisms of action possibly contributing to the clinical effect have been identified for Rhodiola extracts. They include interactions with HPA-system (cortisol-reducing), protein kinases p-JNK, nitric oxide, and defense mechanism proteins (e.g. heat shock proteins Hsp 70 and FoxO/DAF-16). Lack of interaction with other drugs and adverse effects in the course of clinical trials make it potentially attractive for use as a safe medication. In conclusion, Rhodiola rosea has robust traditional and pharmacological evidence of use in fatigue, and emerging evidence supporting cognition and mood.
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Adaptogens were initially defined as substances that enhance the “state of nonspecific resistance” in stress, a physiological condition that is linked with various disorders of the neuroendocrine-immune system. Studies on animals and isolated neuronal cells have revealed that adaptogens exhibit neuroprotective, anti-fatigue, antidepressive, anxiolytic, nootropic and CNS stimulating activity. In addition, a number of clinical trials demonstrate that adaptogens exert an anti-fatigue effect that increases mental work capacity against a background of stress and fatigue, particularly in tolerance to mental exhaustion and enhanced attention. Indeed, recent pharmacological studies of a number of adaptogens have provided a rationale for these effects also at the molecular level. It was discovered that the stress—protective activity of adaptogens was associated with regulation of homeostasis via several mechanisms of action, which was linked with the hypothalamic-pituitary-adrenal axis and the regulation of key mediators of stress response, such as molecular chaperons (e.g., HSP70), stress-activated c-Jun N-terminal protein kinase 1 (JNK1), Forkhead box O (FOXO) transcription factor DAF-16, cortisol and nitric oxide.
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The aim of this review article is to assess the level of scientific evidence presented by clinical trials of adaptogens in fatigue, and to provide a rationale at the molecular level for verified effects. Strong scientific evidence is available for Rhodiola rosea SHR-5 extract, which improved attention, cognitive function and mental performance in fatigue and in chronic fatigue syndrome. Good scientific evidence has been documented in trails in which Schisandra chinensis and Eleutherococcus senticosus increased endurance and mental performance in patients with mild fatigue and weakness. Based on their efficacy in clinical studies, adaptogens can be defined as a pharmacological group of herbal preparations that increase tolerance to mental exhaustion and enhance attention and mental endurance in situations of decreased performance. The beneficial stress-protective effect of adaptogens is related to regulation of homeostasis via several mechanisms of action associated with the hypothalamic-pituitary-adrenal axis and the control of key mediators of stress response such as molecular chaperons (e.g. Hsp70), stress-activated c-Jun N-terminal protein kinase (JNK1), Forkhead Box O transcription factor DAF-16, cortisol and nitric oxide (NO). The key point of action of phytoadaptogens appears to be their up-regulating and stress-mimetic effects on the "stress-sensor" protein Hsp70, which plays an important role in cell survival and apoptosis. Hsp70 inhibits the expression of NO synthase II gene and interacts with glucocorticoid receptors directly and via the JNK pathway, thus affecting the levels of circulating cortisol and NO. Prevention of stress-induced increase in NO, and the associated decrease in ATP production, results in increased performance and endurance. Adaptogen-induced up-regulation of Hsp70 triggers stress-induced JNK-1 and DAF-16-mediated pathways regulating the resistance to stress and resulting in enhanced mental and physical performance and, possibly, increased longevity.
The molecular mechanism in which plant adaptogens induce a state of adaptive resistance in cells is unclear. In this paper we used different mammalian cell lines to study the effect of Eleutherococcus senticosus and of Rhodiola rosea on the expression of seven different heat shock proteins (hsp27, hsp32, hsp47, hsp60, hsp70i, hsc70 and hsp90). We could demonstrate that plant adaptogens only induce hsp32 (also know as heme oxygenase or HO-1), which performs a crucial function in cellular antioxidative defense. Moreover, it is demonstrated that the enhanced synthesis of heme oxygenase is induced by a pro-oxidant action of the plant adaptogens in cells. Plant adaptogens are shown to initially consume glutathione (GSH) and to cause oxidation of lipids as well as of cytoplasmic components. As a result of this damage endogenous cellular defense and repair mechanisms are activated leading to an enhanced synthesis of heme oxygenase and to an increased synthesis of GSH. As a consequence of these induced protective mechanisms an enhanced cellular (oxidative) stress resistance is observed in different mammalian cell cultures 24 hours after exposure to plant adaptogens. It is proposed that part of the action of plant adaptogens can be explained by an hormetic induction of defense mechanisms. In summary, we have demonstrated that plant adaptogens enhance cellular resistance by causing mild damage first. The detection of damage leads to an activation of endogenous cellular repair-and resistance programs, such as an enhanced presence of heme oxygenase and increased levels of GSH, which explains the enhanced adaptive state induced by plant adaptogens.
Mitochondrial decay is a major cause of aging, leading to the subsequent death of aerobic organisms including humans. In the present study, we examined the effects of supplementation with schisandrin B (Sch B, a dibenzocyclooctadiene derivative isolated from the fruit of Schisandra chinensis), administered at 0.012% (w/w) of diet, starting from the age of 36 weeks, on age-dependent changes in mouse mitochondrial antioxidant status and functional ability in various tissues (brain, heart, liver, and kidney) up to the age of 120 weeks. We also monitored survival of male and female C57BL/6J mice. Aging caused progressive impairment in mitochondrial antioxidant status in various tissues, as evidenced by decreases in reduced glutathione and alpha-tocopherol levels, and Mn-superoxide dismutase activity. Impairments in mitochondrial antioxidant status were invariably associated with increases in mitochondria-driven reactive oxygen species (ROS) production in tissue homogenates, as well as decreased mitochondrial ATP-generation capacities (ATP-GCs), in all tested tissues. Diet supplementation with Sch B ameliorated impairment in mitochondrial antioxidant status during aging. The effects were more pronounced in younger than in older mice, when compared to age-matched non-supplemented controls. Sch B supplementation also suppressed mitochondria-driven ROS production and enhanced mitochondrial ATP-GC in various tissues during aging. The beneficial effects of Sch B supplementation on mitochondrial antioxidant status and functional ability were paralleled by survival improvement in aging male mice, when compared with controls. Sch B supplementation also improved the survival in female mice. In conclusion, long-term Sch B supplementation mitigated age-dependent impairments in mitochondrial antioxidant capacity and functional ability, thereby retarding the aging process in mice, particularly during early aging.