A Review of
By Alexander Panossian, PhD
and Hildebert Wagner, PhD
Schisandra Schisandra chinensis. Photo ©2011 Steven Foster
52 | HerbalGram 90 2011 www.herbalgram.org
Eleuthero Eleutherococcus senticosus.
Photo ©2011 Steven Foster
www.herbalgram.org 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-
• 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*
Silene italica & S. spp.
*This table includes plants which do and do not meet the formal
denition 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 www.herbalgram.org
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.
www.herbalgram.org 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-
Apparently, stimulating (acute/
single dose effect) and tonic (effect
of repeated/multiple administra-
tion) effects of adaptogens are
actually consequences of their
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
+ + + + +
Neuroprotective + + +
Hepatoprotective + +
Cardioprotective + + +
Gastroprotective + +
+ + + + +
Anti-atherosclerosis + + +
Wound healing + +
Antihyperglycemic + +
+ + + + +
Immunotropic + + + +
Antiviral + +
Antibacterial + +
Anti-tumor + + + +
Life-span increasing + + + +
Endocrine normalizing + + +
Anxiolytic + +
Schisandra Schisandra chinensis. Photo ©2011 Steven Foster
56 | HerbalGram 90 2011 www.herbalgram.org
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 + +
Neurosis + + + +
Visual function/vision in
Cognitive functions in
Anti-inflammatory effect + +
Common cold, influenza + + +
Pneumonia + +
Gastric dysfunctions, gastritis,
stomach and duodenal ulcers
Radiation induced disorders +
Hypertension and heart
Hypotension + +
Reduction of toxicity of
Total sickness rate in severe
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
www.herbalgram.org 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 www.herbalgram.org
Table 5. Selected Clinical Trials of Adaptogens Related to Their Effects on CNS. (Adapted from Panossian & Wikman,
20105, Panossian & Wikman, 200910).
Pharmacological activity or
Adaptogen Reference*** Study designaQuality in
Physical fatigue: Rhodiola
Adults physical and cognitive
Rhodiola Fintelman, 2007 OL 0 III
Stimulating effect: Rhodiola can
improve mental performance
after single dose administration
Rhodiola can improve attention
in cognitive function in fatigue
after single and repeated
Rhodiola has anti-fatigue effect
in physical, emotional, and
Chronic fatigue syndrome
Mild depression: Rhodiola has
an anti-depressive effect
and neurosis (stress-induced
Anxiety: improvement anxiety
Rhodiola Bystritsky, 2008 OL 0
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-
www.herbalgram.org 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
Cucurbitacin R diglucoside
60 | HerbalGram 90 2011 www.herbalgram.org
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
• The biosynthesis of
ATP, thus induc-
ing an alteration in
A hypothetical molecu-
lar mechanism of action of
adaptogens is outlined in
Typically, a cell is in one
of the following states:
• balance (dynamic
• functioning under
stasis – imbalance);
• the state of adapta-
tion (tolerance) to
stress (i.e., state of
to stress; heterosta-
with a higher level of
• the state of apop-
The Upper Panel in
Figure 5 shows that mito-
chondria generate aggressive
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
• 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.
www.herbalgram.org 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
• 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
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 www.herbalgram.org
In summary, adaptogens may be regarded as a novel pharma-
cological category of anti-fatigue agents that perform the follow-
• induce increased attention and endurance in situations of
decreased performance caused by fatigue and/or sensation
• 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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Wikman G. The Adaptogens rhodiola and schizandra modify the
response to immobilization stress in rabbits by suppressing the
increase of phosphorylated stress-activated protein kinase, nitric
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31. Panossian A, Gabrielian E, Wagner H. On the mechanism of action
of plant adaptogens with particular references on cucuirbitacin R
diglucoside. Phytomedicine. 1999;6:147-155.
32. Davydov M., Krikorian AD. Eleutherococcus senticosus (Rupr. &
Maxim.) Maxim. (Araliaceae) as an adaptogen: a closer look. J
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33. Darbinyan V, Kteyan A, Panossian A, Gabrielian E, Wikman G,
Wagner H. Rhodiola rosea in stress induced fatigue – a double blind
cross-over study of a standardized extract SHR-5 with a repeated
low-dose regimen on the mental performance of healthy physicians
during night duty. Phytomedicine. 2000;7:365-371.
34. Spasov AA, Wikman GK, Mandrikov VB, Mironova IA, Neumoin
VV. A double-blind, placebo-controlled pilot study of the stimulat-
ing and adaptogenic effect of Rhodiola rosea SHR-5 extract on the
fatigue of students caused by stress during an examination period
with a repeated low-dose regimen. Phytomedicine. 2000;7:85-89.
35. Shevtsov VA, Zholus BI, Shervarly VI, Vol’skij VB, Korovin YP,
Khristich MP, Roslyakova NA, Wikman G. A randomized trial of
two different doses of a SHR-5 Rhodiola rosea extract versus placebo
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36. Aslanyan G, Amroyan E, Gabrielyan E, Panossian A, Wikman G.
Double-blind, placebo-controlled, randomised study of the single
dose effects of ADAPT-232 on cognitive functions. Phytomedicine.
37. Narimanian M, Badalyan M, Panosyan V, Gabrielyan E, Panossian
A, Wikman G, and Wagner H. Impact of Chisan® (ADAPT-232) on
the quality-of-life and its efficacy as an adjuvant in the treatment of
acute non-specific pneumonia. Phytomedicine. 2005;12:723-772.
38. Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström
C, Panossian A. Clinical trial of Rhodiola rosea L. extract SHR-5 in
the treatment of mild to moderate depression. Nordic Journal Psych-
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blind placebo controlled parallell group study of SHR-5 extract
of Rhodiola rosea roots as treatment for patients with stress related
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Double-blind, placebo-controlled, randomised study of the single
dose effects of ADAPT-232 on cognitive functions. Phytomedi-
41. Boon-Niermeijer EK, van den Berg A, Wikman G, Wiegant FAC.
Phytoadaptogens protect against environmental stress-induced
death of embryos from the freshwater snail Lymnea stragnalis.
42. Wiegant FA, Surinova S, Ytsma E, Langelaar-Makkinje M, Wikman
G, Post JA. Plant adaptogens increase lifespan and stress resistance in
C. elegans. Biogerontology. 2009;10:27-42.
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ON, Zenina TA, Langelaar Makkinje M, Post JA, Wikman G. Plant
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