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Evidence based efficacy of adaptogens in fatigue

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198 Current Clinical Pharmacology, 2009, 4, 198-219

Evidence-Based Efficacy of Adaptogens in Fatigue, and Molecular

Mechanisms Related to their Stress-Protective Activity
Alexander Panossian* and Georg Wikman

Swedish Herbal Institute Research and Development, Spårvägen 2, SE-432 96 Åskloster, Sweden

Abstract: The aim of this review article is to assess the level of scientific evidence presented by clinical trials of adapto-
gens 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 pharmacotherapeutic instead of
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" pro-
tein 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.
Key Words: Adaptogens, fatigue, stress, Hsp70, evidence-based.

INTRODUCTION treatment of temporary fatigue involves rest and sleep, but

Fatigue, also known as weariness, tiredness, exhaustion
or lethargy, is a common health complaint that may be gen-
erally defined as a feeling of lack of energy. Fatigue can be
of a physical and/or mental nature. Physical fatigue is the
inability to continue functioning at a level commensurate
with normal ability, while mental fatigue may manifest in the
form of decreased attention, reduced ability to concentrate,
or somnolence. Fatigue and sleepiness can affect perform-
ance at work [1], and cause transportation and industrial ac-
cidents that result in considerable loss of property, personal
injury and even death [2, 3]. It is estimated that around 20%
of Americans suffer from a form of fatigue that is suffi-
ciently intense as to interfere with the ability to enjoy a nor-
mal life [4], with physical causes being responsible for 20-
60% of fatigue cases and emotional causes responsible for
the balance.
Temporary fatigue is a minor illness somewhat akin to
the common cold. On the other hand, chronic fatigue, with a
duration of 6 months or more, can be a symptom of a large
number of different illnesses, diseases or conditions. Medica-
tion with beta blockers may also give rise to fatigue, particu-
larly after exertion, inducing a state of exercise intolerance.
Additionally, many cancer treatments, including chemother-
apy and radiotherapy, cause fatigue. The simplest and natural
*Address correspondence to this author at the Swedish Herbal Institute, Re-
search and Development, Spårvägen 2, SE-432 96 Åskloster, Sweden; Tel:
+46 702818171; Fax: +46 43023723; E-mail: alexander.panossian@shi.se
this is not efficient in the case of chronic or cancer-related
fatigue.
Many people prefer to avoid problems related to de-
creased attention and reduced ability to concentrate during
continuous mental work and resort to the use of stimulants.
Conventional stimulants, including caffeine (1,3,7-trimethyl-
xanthine) and sympathomimetics (ephedrine, fenfluramine,
phentermine, prolintane, etc) as well as tonics such as cola,
may be efficacious in some cases [5]. It is reported that
ephedrine can enhance certain physical and mental functions
related to “energy” [6], whilst caffeine is widely regarded as
a useful psychostimulant to “relieve tiredness and help main-
tain mental alertness” when administered in moderate doses.
The stimulatory effect of caffeine is most likely associated
with its ability to bind to sites on central adenosine A1 recep-
tor subtypes [7], thus blocking the action of adenosine,
which is known to be a CNS neurotransmitter inhibitor with
sedative-like properties. Regular consumers of coffee recog-
nise, however, that caffeine can disrupt sleep and that with-
drawal of caffeine is associated with various adverse effects
including fatigue and headache. Cognitive performance has
been shown to be affected adversely by acute caffeine with-
drawal and, even in the context of alertness reduced by sleep
restriction, cognitive performance is not improved by caf-
feine in the absence of withdrawal effects. Since caffeine is
also associated with increased risk factors for various car-
diovascular diseases including high blood pressure and
plasma homocysteine [8], it has been suggested that there is

1574-8847/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd.

Adaptogens in Fatigue
little benefit to be gained from caffeine consumption [9].
Additionally, the diterpenes present in unfiltered coffee also
appear to increase the risk of coronary heart disease [10].
Many plant extracts, including those from Rhodiola rosea
[11-13], Eleutherococcus senticosus [14, 15], Schizandra
chinensis [16], Panax ginseng [14, 17], Rubus coreanus [18],
Cordyceps sinensis [19], Pseudosasa japonica [20], Chinese
bamboo [21], Anoectochilus formosanus [22, 23], Camellia
sinensis [24], Allium sativum [25, 26] and brewers yeast
[27], have exhibited good stimulating and anti-fatigue effects
in experiments conducted on experimental animals. On the
other hand, only a very limited number of herbal prepara-
tions have shown significant anti-fatigue effects with in-
creased mental performance, particularly of the cognitive
function, in placebo-controlled, double-blind studies (Tables
1 – 3). Extracts derived from plant adaptogens show promise
in enhancing resistance to stress [28-31] and increasing con-
centration, performance and endurance during fatigue [28-
32]. The present review focuses on the clinical studies of the
effects of adaptogens on mental performance and stress-
induced fatigue.
CONCEPT OF ADAPTOGENS
Adaptogens were originally defined as drugs enhancing
the “state of non-specific resistance” in stress [84, 85]. This
definition implies that an organism has different levels of
resistance to stress associated with the activities of the nerv-
ous (CNS and sympathetic) and endocrine [hypothalamus-
pituitary-adrenal (HPA) axis] systems and with innate im-
munity, i.e. the activity of the non-specific immune system
(antimicrobial enzyme system, non-specific cytokines, com-
plement system, phagocytic cells and natural killer cells).
However, this representation is related to a physiological
condition, i.e. stress, but not to a specific illness. Later on
Brekhman and Dardimov [86] postulated that:
(i) adaptogens must reduce stress-induced damage, thus pre-
senting stress-protective effects such as anti-fatigue, anti-
infectious, anti-depressant and restorative activities;
(ii) adaptogens must exhibit stimulating effects, both after
single and multiple administration, leading to increased
working capacity and mental performance against a back-
ground of fatigue and stress;
(iii) the stimulating effect of adaptogens must be different
from those of conventional CNS stimulants and anabolics
that deplete the energetic and plastic resources of the organ-
ism and give rise to negative side effects such as drug with-
drawal syndrome; and
(iv) adaptogens must be innocuous and must not perturb
body functions from their normal levels but rather exert a
normalising influence on a pathological state, independent of
the nature of that state.
This definition of adaptogens was based on empirical
knowledge concerning medicinal plants that had been used
for centuries in traditional medicinal systems, together with
the assumption that some plants might fulfil these criteria.
Further studies conducted with numerous plant preparations
have demonstrated that only a few actually comply with the
Current Clinical Pharmacology, 2009, Vol. 4, No. 3 199
requirements postulated for adaptogens. Particular contro-
versy is associated with the last point relating to safety,
which is obviously dependent on the dose employed. In a
more up-to-date definition, adaptogens have been classified
as herbal preparations that can increase resistance to stress
[28, 87].
CLINICAL EFFICACY OF ADAPTOGENS IN
FATIGUE
Several reviews are available concerning the numerous
pharmacological effects of adaptogens [29-31, 88], and their
specific effects on stress-induced symptoms in fatigue are
outlined on Fig. (1). The evidence-based effect of adapto-
gens on cognitive function is supported by numerous pre-
clinical and several clinical studies. Indeed, a growing body
of evidence (Tables 1 - 3) substantiates the clinical efficacy
of adaptogens to increase mental performance, attention and
the ability to concentrate in temporary and chronic fatigue
[32, 57, 63-65, 67, 74, 89-91].
The most recently published randomised, double-blind,
placebo-controlled clinical trials involving extract SHR-5
from Rhodiola rosea L. [32] and ADAPT-232 [a fixed com-
bination of genuine (native) root extracts of E. senticosus
(Rupr. et Maxim) Harms, S. chinensis (Turzc) Baill. and R.
rosea] [92] have confirmed results obtained in the many pre-
clinical and clinical studies of adaptogens on humans and
animals that had been carried out in the former USSR [30,
31]. Thus, administration of SHR-5 in a dose of 576 mg of
native R. rosea extract / day over a 4 week period exhibited
anti-fatigue activity (as determined by Pines’ Burnout Meas-
ure) and increased attention and the ability to concentrate
(according to Conners´ Continuous Performance Test II) in
burnout patients. Similarly, administration of ADAPT-232 in
single or repeated doses to healthy subjects over a 1 week
period led to significant increases in attention in psychomet-
ric d2 and Stroop tests [92].
It is noteworthy that the beneficial effects of a single
dose of adaptogen have been observed in many studies,
while repeated administration has often produced conflicting
results in different studies (cf. the results for Ginseng shown
in Tables 1 - 3). Additionally, protracted treatment with Gin-
seng and Eleutherococcus may give rise to no beneficial ef-
fects compared with the placebo whereas, in the same stud-
ies, shorter periods of treatment may reveal statistically sig-
nificant differences between treatment and control groups
(Table 3).
MECHANISMS OF ACTION
It may be proposed that adaptogens adapt (i.e. render less
sensitive) an organism to a stressor by acting rather like a
low molecular weight “vaccine” in inducing a mild activa-
tion of the stress system in order to cope with a more severe
stress [93]. In this sense, adaptogens act as challengers and
mild stressors (stress-mimetics), giving rise to adaptive and
stress-protective effects mainly associated with the HPA
axis, a part of the stress system that also contributes to the
nervous, cardiovascular, immune, gastrointestinal and endo-
crine systems.
200 Current Clinical Pharmacology, 2009, Vol. 4, No. 3 Panossian and Wikman

Table 1. Randomised and Non-Randomised Clinical Trials of Adaptogens in Mental Fatigue, Stress-Induced Fatigue, Fatigue
Syndrome and Asthenia

Grade of
Adaptogen Number Number of Recommendation
Indication for Use and/or Pharmacological Activity
(Active Principle) of Trials Subjects
EMEAa NSRb

Mental fatigue: Rhodiola can improve attention in cognitive

3 257 A A
function in fatigue after single and repeated administration.

Fatigue syndrome: Rhodiola has anti-fatigue effect in physi-

1 60 A B
Rhodiola rosea cal, emotional, and mental exhaustion.

Mild depression: Rhodiola has an anti-depressive effect 1 89 A B

Stimulating effect: Rhodiola can improve mental perform-

3 419 B B
ance after single dose administration

Stimulating effect: Rhodioloside can improve mental per-

(Rhodioloside) 1 46 B
formance after single dose administration

Fatigue syndrome: Eleutherococcus has-anti-fatigue effect in

1 96 A B
moderate fatigue after two months of treatment

Mental fatigue: Eleutherococcus reduces mental stress in-

1 45 A B
Eleutherococcus senticosus duced blood pressure and heart rate

Single dose effect in mental fatigue 6 2191 B B

Tonic effect: Eleutherococcus can improve concentration

3 729 B B
and memory after repeated administration

Mental fatigue: Increases endurance and mental performance

7 1712 B B
Single dose effect

Increases endurance and mental performance

Schisandra chinensis 1 665 B B
Repeated administration

Asthenia: Reduces symptoms of asthenia: fatigue and weak-

5 406 C B
ness

R. rosea – E. senticosus – S. Mental fatigue: Single dose effect. 3 125 B B

chinensis (fixed combina-
tion) Repeated administration 2 120 A B

Fatigue syndrome: Ginseng has anti-fatigue effect 1 232 A B

Alzheimer disease: Ginseng improves cognitive performance 2 158 A B

Quality of life: Ginseng can improve quality of life after

2 715 A C
repeated administration
Panax ginseng
Mental fatigue: Ginseng can improve ability to perform
3 159 A C
mental arithmetic after repeated administration

Ginseng cannot improve thinking or learning concentration

2 146 B C
after repeated administration

Ginseng can improve thinking or learning after single dose

9 138 A C
administration
a
Grade of recommendation based on the European Medicines Agency Assessment Scale [33]:
Grade A. Evidence levels quality Ia, Ib - Requires at least one randomised controlled trial as part of the body of literature of overall good consistency addressing the specific rec-
ommendation;
Grade B. Evidence levels IIa, IIb, III - Requires availability of well-conducted clinical studies but no randomised clinical trials on the topic of recommendation;
Grade C. Evidence level IV - Requires evidence from expert committee reports or opinions and/or clinical experience of respected authorities but indicates absence of directly
applicable studies of good quality.
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 201

(Table 1. Contd….)
b
Grade of recommendation according to Natural Standards Evidence-Based Validated Grading Rationale:
Grade A. Strong scientific evidence - Statistically significant evidence derived from: (i) more then two properly conducted randomised controlled trials (RCT), or (ii) one prop-
erly conducted randomised controlled trial, and one properly conducted meta-analysis, or (iii) multiple RCTs with a clear majority of the properly conducted trials and with sup-
porting evidence in basic science, animal studies or theory;
Grade B. Good scientific evidence - Statistically significant evidence derived from: (i) one or two properly conducted randomised trials, or (ii) one or more properly conducted
meta-analysis, or (iii) more than one cohort/case control/non-randomised trials and with supporting evidence in basic science, animal studies or theory;
Grade C. Unclear or conflicting scientific evidence - Evidence derived from: (i) one or more small RCT without adequate size, power, statistical significance, or quality design by
objective criteria, or (ii) conflicting evidence from multiple RCTs without a clear majority of the properly conducted trials showing evidence of benefit or ineffectiveness, or (iii) more
than one cohort/case control/non-randomised trial and without supporting evidence in basic science, animal studies or theory, or evidence of efficacy only from basic science, animal
studies or theory.

Table 2. Results of Non-Randomised Studies on Humans Involving Effects of Plant Adaptogens on Mental Performance in Fatigue

Type of Number of Age Classification

Study Duration
Preparation Subjects in Range of Daily Dose Effects Recorded of Evidence Ref.
Designa of Study
Tested the Study Subjects Levelb

Salidroside PC, SB 46 20-28 2.5 mg acute Improved mental perform- IIa [34]
ance; reduced the number of
errors in Anfimov’s correc-
tion test; stimulating effect
lasting 4 h or more.

Eleutherococcus PC, CO 357 ?c 0.25, 0.5, 1.0, 2.0, acute E. senticosus improved IIa [35]
senticosus extract sailors 4.0 and mental performance in
8.0 mL correction test; increased
activity of the adrenal
cortex, the activity of the
sympathetic adrenomedullar
system, the intensity of
metabolic processes, and the
intensity of redox processes.
In stress conditions E.
senticosus decreased adrenal
Schisandra chinensis cortex activity and sympa-
extract thetic nervous system;
increased the tonus of the
parasympathetic nervous
system; moderately intensi-
fied excitation of the CNS
and of energy metabolism;
improved endurance to
hypoxia.
S. chinensis stimulated the
activity of the CNS at night;
increased tonus of the
sympathetic part of the
autonomic nervous system
(having no effect on the
parasympathetic part) after
night duty; activated the
adrenal cortex activity;
increased the activity of the
cardiovascular and respira-
tory systems; intensified
oxidation-reduction and
metabolic processes; im-
proved working ability
parameters; reduced pa-
rameters of non-specific
resistance the organism.
202 Current Clinical Pharmacology, 2009, Vol. 4, No. 3 Panossian and Wikman

(Table 2. Contd….)

Type of Number of Age Classification

Study Duration
Preparation Subjects in Range of Daily Dose Effects Recorded of Evidence Ref.
Designa of Study
Tested the Study Subjects Levelb

ADAPT-232 PC, CO, 60 ? 3 capsules acute Compared with placebo, IIa [36]
capsules [fixed DB ADAPT-232 signifi-
combination of cantly increased short-
standardised ex- term memory, speed and
tracts of Rhodiola reliability in the under-
rosea (salidroside standing of information,
3 mg), and precision and accu-
E. senticosus racy in the ability to
(syringin 3 mg), reproduce the informa-
tion in repeated highly
S. chinensis (schi-
sophisticated com-
zandrin 4 mg)]
puter-based tests (Mono-
tonic 2). ADAPT-232
was most effective
against a background of
pronounced fatigue
induced by monotonous
night work. The effect
was most marked in
complicated tests and
under extreme condi-
tions.

PC, DB, 5 ? 3 capsules acute ADAPT-232 signifi- IIa [37]

CO cosmonauts cantly decreased the
number of mistakes (cf.
with placebo) in compli-
cated psychometric tests
4 h after administration
and increased working
capacity 1.5 and 4 h
after administration to
Russian cosmonauts
during their training in
prolonged isolation (90
days) under conditions
of long-term, monoto-
nous work. No signifi-
cant effects were ob-
served in non-
complicated tests.

S. chinensis (10% PC 95 neuras- ? 15 drops 25-28 days General weakness, poor IIb [38]
tincture) tenic patients sleep and appetite, high
Panax ginseng irritability and head-
(3% tincture) aches disappeared al-
most completely in
Pantocrin (tinc-
Schisandra group, whilst
ture)
in the control group 55%
Conventional of the patients com-
treatment not plained of these symp-
specified toms.

S .chinensis (seed prospective 36 20-64 0.25 and 10 days Beneficial effects on IIIa [39]
powder) study patients 0.5 g symptoms of astheno-
depressive syndrome.
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 203

(Table 2. Contd….)

Type of Number of Age Classification

Study Duration
Preparation Subjects in Range of Daily Dose Effects Recorded of Evidence Ref.
Designa of Study
Tested the Study Subjects Levelb

S. chinensis (tinc- C 200 ? 2 mL acute and S. chinensis showed a IIb [40]

ture) sailors 2 mL repeated tonic effect for 4 - 7 h in
E. senticosus those on night duties.
200 mL
(tincture) E. senticosus was inac-
200 mL
Coffee tive
Black tea (inactive Repeated uptake (for
control) more than 2 weeks) of
coffee and S. chinensis
produced similar nega-
tive effects (insomnia,
excitability, etc).

S. chinensis (tinc- PC, CO 1327 18-24 0.5, 1.0 and acute Eleutherococcus and IIa [41]
ture) healthy sub- 2.0 mL Rhaponticum treatment
E. senticosus jects significantly increased
(tincture) precision in tremometric
test compared with pla-
Rhaponticum
cebo. Significant differ-
cartamoides (tinc- ences compared with
ture)
placebo were observed
Oplopanax elatus with various doses of all
(tincture) tested preparations in
psychometric tests in-
cluding assessment of
attention and memory
functions.

PC, CO 665 18-24 1 mL twice a 10 days Pilots were tested before IIa [42]
pilots day a flight and again 5 - 15
min later, and finally 1
and 3 h after landing.
Significant differences
compared with placebo
were observed for all
tested preparations in
tests including assess-
ment of precision, dy-
namic tremometry, sen-
somotor response, and
attention and memory
functions.

Korean white DB, PC, 12 21-27 1200 mg 3 days Significantly improved IIa [43]
Ginseng powder CO night shift typing rate under test
workers conditions.

Rhodiola rosea PC, SB 80 healthy ? 10 drops or acute Single and repeated Iia [44]
(extract) students (con- 3 x 10 and administration of adap-
trol group) drops/day togens improved func-
10 days
and tional state of the CNS
Rhaponticum 20-50 in patients with neurosis
cartamoides (ex- 70 patients 40 drops or as characterised by nor-
tract) with neurosis
3 x 10 malisation of the speed
drops/day and power of neural
processes in Ivanov-
Smolenski’s verbal test
with speech-supported
locomotor-conditioned
reflex measurement. The
memory improved and
attention became more
stable.
204 Current Clinical Pharmacology, 2009, Vol. 4, No. 3 Panossian and Wikman

(Table 2. Contd….)

Type of Number of Age Classification

Study Duration
Preparation Subjects in Range of Daily Dose Effects Recorded of Evidence Ref.
Designa of Study
Tested the Study Subjects Levelb

S. chinensis (seed CO, PC, 122 students ? 2g acute Improved attention in IIa [45]
powder) SB 2 mL text correction 2 h after
Panax ginseng drug administration.
(tincture) Both extracts increased
quality and quantity of
mental work performed.

Rhodiola rosea PC 254 19-22 20 drops acute Improved mental per- IIa [46]
(40% ethanol formance; reduced the
tincture) number of errors in
20 drops
Anfimov’s correction
E. senticosus test; increased the accu-
(40% ethanol 0.3 g racy, working capacity
tincture) and speed of information
perception. Stimulating
effect lasted 4 h or more.
Extract of R. rosea
rhizome

S. chinensis (seed, CO 20 21 3 g, acute Improved accuracy in IIb [47,48]

extract and frac- 0.036 – 0.168 error correction test.
tions, tablets and g Most active stimulating
capsules) effect was revealed by a
crystalline substance
identified as the lignan
schizandrin.

Schizandrin PC 23 21-22 0.02 g acute Schizandrin improved IIb [48,49]

Schizandrin 0.01 g accuracy in the work of
telegraph operators at
Schizandrin 0.005 g
exhaustion compared
Phenamine 0.02 g with control group (glu-
Glucose 0.5 g cose) and those given
phenamine.

S. chinensis (seed CO, PC 20 21-24 30 mL acute P. ginseng and S. IIa [48]

tincture) 30 mL chinensis improved
P. ginseng (3% accuracy in the work of
0.02 g
tincture) telegraph operators at
0.5 g exhaustion compared
Phenamine
with control group (glu-
Glucose cose) and those given
phenamine.

S. chinensis (fruit prospective 40 15-50 1 mL 16-40 days Stimulating effect – III [50]
and seed tincture, study improve mood, increases
1:5, 90% ethanol) physical and psycho-
logical vivacity, relief of
tiredness and fatigue in
asthenia and depres-
sions.

Tyrosol ? 82 ? 1, 5, 10 and ? Improved mental per- III [51]

20 mg formance, reduced the
number of errors in
Anfimov’s correction
R. rosea extract 5 drops
test.
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 205

(Table 2. Contd….)

Type of Number of Age Classification

Study Duration
Preparation Subjects in Range of Daily Dose Effects Recorded of Evidence Ref.
Designa of Study
Tested the Study Subjects Levelb

E. senticosus PC, SB, 13 21-23 2 mL acute Decreased errors in data IIa [52]
(tincture) CO 2 mL sent by radio operators
P. ginseng tincture 1 h after drug uptake.
Stimulating effect
of E. senticosus was
stronger and more stable
than the effect of
Ginseng, which was
insignificant.

P. ginseng C open 86 35-80 5 months- Ginseng did not provide IIa [53]
Ginkgo biloba label de- 2 years any quantifiable benefi-
scriptive cial effects on memory
(nutritional sup-
study performance in the long-
plements as con-
term in healthy adult
trol)
volunteers.

Rodelim tablets PC, DB 60 ? ? acute Rodelim improved men- IIa [54]

(fixed combina- tal working capacity in
tion of standard- computer and correction
ised extracts of R. tests against a back-
rosea, ground of fatigue.
E. senticosus and
S. chinensis)

S. chinensis (tinc- descriptive 250 ? ? 2-10 Effective in the treat- III [55]
ture, decoction study weeks ment of general asthenia,
and tablets) exhaustion and reduced
physical and mental
performance in group
of patients with nervous
disorders where an
increase in general
well-being and working
capacity, as well as a
decrease in sleepiness
and flabbiness, were
observed.

E. senticosus (dry PC, DB 40 23-55 120 mg acute and Improved mental IIa [56]
extract) 3 weeks performance determined
by a letter correction test

Rhodelim (R. PC, DB 60 17-18 100 mg 20 days Significant improvement IIa [57]
rosea) in physical fitness, men-
tal fatigue and neuromo-
tor tests compared
with control (p<0.01):
general well-being
was also significantly
(p<0.05) better in
the verum group. No
significance was seen in
the correction of text
tests or a neuromuscular
tapping test.
206 Current Clinical Pharmacology, 2009, Vol. 4, No. 3 Panossian and Wikman

(Table 2. Contd….)

Type of Number of Age Classification

Study Duration
Preparation Subjects in Range of Daily Dose Effects Recorded of Evidence Ref.
Designa of Study
Tested the Study Subjects Levelb

Gericomplex PC, DB 60 65-87 2 capsules 8 weeks Length of stay in hospi- IIa [58]
(ginseng, vita- tal, and activities of
mins, minerals daily living, cognitive
and trace ele- function, object learning
ments) ability, somatic symp-
toms, symptoms of
depression and anxiety
were similar both in
placebo and treatment
groups.

Eleutherococcus PC, CO 24 36-58 E. senticosus 3 months Selective memory sig- IIa [59]
(extract) (1250 mg) / nificantly improved
Ginkgo (extract) G. biloba compared with placebo
(28.2 mg (p<0.02).
flavonoids;
7.2 mg
gingkolides)

S. chinensis (tinc- prospective 30 ? 45-120 drops 10 days Stimulating effect in III [60]
ture 95% ethanol) study astheno-depressive syn-
drome with relief of
0.25 g, 0.5 g
somnolence, limpness,
S. chinensis (tab-
tiredness, fatigue
lets)

R. rosea (tincture PC 85 20-28 5-10 drops acute Improved mental per- IIb [61]
40% ethanol) formance, reduced the
number of errors in
Anfimov’s correction
test: the stimulating
effect lasted 4 h or more
a
CO - crossover; DB - double-blind; SB - single blind, NC - not controlled; PC - placebo-controlled; C – controlled.
b
According to WHO, FDA and EMEA: Ia - meta-analyses of randomised and controlled studies; Ib - evidence from at least one randomised 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.
c
? - data not listed or unavailable.

The mechanism of the anti-fatigue activity of adaptogens
is associated with their effect on:
(i) the mediators of stress response, and especially on the
formation of cortisol, nitric oxide (NO), phosphorylated
stress-activated protein kinase (p-SAPK)/c-Jun N-terminal
protein kinase (p-JNK) [94-96] and Forkhead Box O pro-
teins, such as DAF-16 in Caenorhabditis elegans [97] (Fig.
2);
(ii) the expression of heat shock proteins Hsp70 and Hsp16,
which are molecular chaperons involved in stress-induced
cytoprotection and in adaptation to repeated exposure to an
initial stressor [98-101] (Fig. 2); and
(iii) the biosynthesis of ATP, thus inducing an alteration in
energy source [102] (Figs. 2 and 3).
It has recently been demonstrated that activation of stress
response results primarily in the increased expression of NO,
Hsp, p-SAPK/p-JNK and cortisol [94-96]. The formation of
NO can strongly inhibit the production of cellular energy
(ATP) in stress and fatigue through two mechanisms,
namely:
(i) the inhibition of mitochondrial respiration by the reversi-
ble inhibition of cytochrome P450, associated with constitu-
tive isoforms of NO synthase (NOS), or by the irreversible
inhibition of P450, associated with inducible NOS (i-NOS)
[103]; and
(ii) the inhibition of glycolysis by modification of the SH-
groups of glyceraldehyde-3-phosphate dehydrogenase
(GAPDH), a key enzyme involved in ATP production [104]
(Fig. 3).
In this context, adaptogens prevent the stress-induced
increase in NO and the associated decline in ATP produc-
tion, thus resulting in increased performance and endurance
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 207

Table 3. Results of Randomised Studies on Humans Involving Effects of Plant Adaptogens on Physical and Mental Performance
Related to Fatigue

Total subjects
Jadad
(Sample Size Frequency Quality
Study Intervention/ Primary b
Score
Plant name of Verum/ Main Results of Adverse Level of Ref.
Designa Control Dosage Endpointb [62]
Control) Effects Evidence*
(Max 5)
[Age Range]

Rhodiola rosea PC 60 volunteers Extract SHR-5 (288 Symptoms of Symptoms of fa- None Ib 5 [32]
2 parallel with stress- mg twice fatigue, tigue, attention and
groups induced fatigue daily)/placebo for 4 attention, de- salivary cortisol
(30/30) weeks pression, significantly im-
QOL, salivary proved compared
[20-55 years]
cortisol with control

PC, CO 56 healthy Extract SHR-5 (170 Mental fatigue, Statistically signifi- None Ib 4 [63]
2 parallel subjects mg once perceptive and cant improvement in
groups (?/?)c daily)/placebo for 2 cognitive func- the treatment group
weeks tions such as (SHR-5) during the
[24-35 years]
associative first 2 week period
thinking, short-
term memory,
calculation and
ability of con-
centration, and
speed of audio-
visual percep-
tion

PC 40 healthy Extract SHR-5 (50 Mental fatigue, Significant im- None Ib 3 [57,
2 parallel subjects mg twice physical per- provement in physi- 64]
groups (20/20) daily)/placebo for 20 formance, cal fitness, mental
days general well- fatigue and neuro-
[17-19 years]
being motor tests com-
pared with control
(p<0.01). General
well-being was also
significantly
(p<0.05) better in the
verum group. No
significance was
seen in the correction
of text tests or a
neuromuscular
tapping test

PC 161 healthy Extract SHR-5 Capacity for Significant difference One subject Ib 3 [65]
3 parallel subjects, (single dose of 370 mental work in anti-fatigue effects in placebo
treatment (41/20/40 mg or 555 mg) in SHR-5 groups group com-
groups treated + 20 /placebo compared with control plained of
untreated) (p<0.001), whilst no hyper-
[19-21 years] significant difference salivation
between the two lasting 40
dosage groups was min after
observed intake

PC 91 patients with Extract SHR-5 (170 Depression in Significant differ- None Ib 5 [66]
3 parallel mild and mod- mg or 340 mg twice total HAMD ences in HAMD and
treatment erate depression daily)/placebo for 6 and BDI scores BDI scores and
groups (31/30/30) weeks scores reflecting
levels of insomnia,
[18-70 years]
emotional instability,
somatisation and
self-esteem in SHR-
5 groups compared
to placebo (p<0.001)
208 Current Clinical Pharmacology, 2009, Vol. 4, No. 3 Panossian and Wikman

(Table 3. Contd….)

Total subjects
Jadad
(Sample Size Frequency Quality
Study Intervention/ Primary Score
Plant name of Verum/ Main Resultsb of Adverse Level of Ref.
Designa Control Dosage Endpointb [62]
Control) Effects Evidence*
(Max 5)
[Age Range]

Eleutherococ- PC 96 patients with Extract (2.24 mg RVI measure- Significant (p<0.05) None Ib 5 [67]
cus senticosus 2 parallel chronic fatigue eleutherosides B and ment of fatigue improvement in RVI

treatment syndrome E equivalent to 2-4 g reduced compared with

groups (49/47) of herbal substance control after 2

daily)/placebo for 2 months treatment in
[21-65 years]
months and 2 months the subgroups of
of follow-up patients with moder-
ate fatigue at base-
line (RVI value 8-
12) and a history of
fatigue <5 years.
However, no signifi-
cant difference was
observed after 4
months treatment

PC 45 healthy Extract (dose not HR and systolic Significant reduction Not reported Ib 2 [68]

2 parallel volunteers reported)/placebo for BP after sub- in cardiovascular

treatment (?/?) 1 month mission to response (increased

groups stressful cogni- HR and BP) to
[18-30 years]
tive task mental stress com-
(Stroop Colour pared with placebo
Word test)

Panax ginseng PC, CO 20 healthy Extract G115 (single CDR computer- Significant Im- Not reported Ib 4 [69]
volunteers dose of 200, 400, ised assessment provements in “sec-

(?/?) 600 mg) /placebo battery test ondary memory”

acute factor (comprised of
[18-24 years]
percentage accuracy
scores from 4 secon-
dary memory tasks)
compared with
placebo

PC, CO 20 healthy Extract G115 (single CDR computer- Significant Im- Not reported Ib 4 [70]
volunteers dose of 320, 640 and ised assessment provements in “sec-

(?/?) 960 mg)/placebo battery test ondary memory”

acute factor (comprised of
[18-24 years]
percentage accuracy
scores from 4 secon-
dary memory tasks)
compared with
placebo

PC, CO 20 healthy Extract G115 (400 CDR computer- Significant Im- Not reported Ib 4 [71]
volunteers mg)/Ginseng-gingko ised assessment provements in “sec-

(?/?) (960 mg)/gingko battery test ondary memory”

(360 mg)/placebo factor (comprised of
[18-24 years]
acute percentage accuracy
scores from 4 secon-
dary memory tasks)
compared with
placebo
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 209

(Table 3. Contd….)

Total subjects
Jadad
(Sample Size Frequency Quality
Study Intervention/ Primary Score
Plant name of Verum/ Main Resultsb of Adverse Level of Ref.
Designa Control Dosage Endpointb [62]
Control) Effects Evidence*
(Max 5)
[Age Range]

PC, CO 20 healthy Extract G115 (single Cognitive load Significant im- Not reported Ib 4 [72]
volunteers dose of 200, 400, in performance provement in accu-

(?/?) 600 mg)/placebo of Serial sub- racy in demanding

acute traction mental Serial 7s task at a
[18-24 years]
arithmetic tests dose of 400 mg
compared with
placebo

PC, CO 20 healthy Extract G115 (single Cognitive Speed of attention, Not reported Ib 4 [73]
volunteers dose of performance speed of memory

(?/?) 200)/Guarana (75 and subjective and “secondary

mg) Ginseng- mood evaluated memory”
[18-24 years]
Guarana (275 by CDR as- significantly im-
mg)/placebo acute sessment bat- proved compared
tery test, Serial with placebo 4
subtraction hours after single
tasks and Bond- dose administration
Lader mood of 200 mg of G115.
scales No effect on mood

PC, CO 30 healthy Extract G115 (single Ten min battery Ginseng (200 mg) Not reported Ib 4 [74]
volunteers dose of 200, 400 mg) test comprised a significantly

(?/?) /placebo acute Serial 3s sub- improved Serial

traction task (2 7s subtraction task
[18-24 years]
min), a Serial performance and
7s task (2 min), significantly reduced
a Rapid Visual subjective mental
Information fatigue (p<0.05).
Processing task Ginseng can improve
(5 min), then a performance and
'mental fatigue' subjective feelings of
visual analogue mental fatigue
scale during sustained
mental activity

open-label 97 patients with Powder (4.5 g daily, Cognitive After Ginseng Not reported Ib 1 [75]

2 parallel Alzheimer content of ginse- performances treatment, the

groups disease nosides of 8.19%) were monitored cognitive perform-

(58/39) for 12 weeks using MMSE ance showed

and ADAS improvements that
[47-93 years]
continued up to
12 weeks (p=0.029
and p=0.009 vs.
baseline, respec-
tively). After
discontinuing
Ginseng, the im-
proved MMSE and
ADAS and scores
declined to the levels
of the control group
210 Current Clinical Pharmacology, 2009, Vol. 4, No. 3 Panossian and Wikman

(Table 3. Contd….)

Total subjects
Jadad
(Sample Size Frequency Quality
Study Intervention/ Primary Score
Plant name of Verum/ Main Resultsb of Adverse Level of Ref.
Designa Control Dosage Endpointb [62]
Control) Effects Evidence*
(Max 5)
[Age Range]

open-label 61 patients with Korean Ginseng Cognitive Patients in the high- Not reported Ib 1 [76]

3 parallel Alzheimer (KRG) powder (4.5 performances dose KRG group

groups disease g daily, content of were monitored showed significant

(15/15/31) ginsenosides of using MMSE, improvement on

8.19%; 9.0 g CDRS and CDRS and ADAS
[50-80 years]
daily)/placebo for 12 ADAS compared with those
weeks in the control group
(p=0.032 and
p=0.006, respec-
tively). The KRG
treatment groups
showed improve-
ment from baseline
MMSE when com-
pared with the con-
trol group (1.42 vs. -
0.48), but this im-
provement was not
statistically signifi-
cant

PC 32 male volun- Extract G115 (100 Cancellation Improved mental None Ib 4 [77]

2 parallel teers mg twice test, digit sym- arithmetic calcula-

groups (16/16) daily)/placebo for 12 bol substitution tions; no significant

weeks test, mental trend for attention,
[20-24 years]
arithmetic test, choice reaction time,
choice reaction auditory reaction
time test time, typing test,
recognition or visual
reaction time

PC 112 healthy Standardised extract Psychomotor Significantly better None Ib 4 [78]

2 parallel volunteers (400 mg daily)/ tests, concentra- abstraction test in

groups (55/57) placebo for 8-9 tion, learning Ginseng group

weeks and memory, compared with
[40-70 years]
abstract think- placebo (p<0.02)
ing tests

M, PC 232 patients Pharmaton capsules Fatigue score Significant differ- Not reported Ib 3 [79]
2 parallel with functional containing extract ence in favour of the

groups fatigue G115 (40 mg twice Ginseng treatment

(117/115) daily)/ placebo for 6
weeks
[25-60 years]

PC 625 healthy Extract G115, Phar- Health-related Pharmaton capsules Not reported Ib 3 [80]
2 parallel subjects with maton capsules (200 QOL deter- were more effective
groups fatigue symp- mg daily)/ multivi- mined using a (change being 11.9
toms tamin capsules for 12 standardised points) than the
(338/163; 124 weeks 11-item ques- multivitamin cap-
were excluded) tionnaire sules alone (change
being 6.4 points) in
[18-65 years]
improving QOL in a
population subjected
to the stress of high
physical and mental
activity
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 211

(Table 3. Contd….)

Total subjects
Jadad
(Sample Size Frequency Quality
Study Intervention/ Primary Score
Plant name of Verum/ Main Resultsb of Adverse Level of Ref.
Designa Control Dosage Endpointb [62]
Control) Effects Evidence*
(Max 5)
[Age Range]

PC 30 healthy Extract (200 mg Health-related After 4 weeks of None Ib 4 [81]

2 parallel subjects daily)/ placebo for 8 QOL deter- therapy, higher

groups (15/15) weeks mined using a scores in social

Short Form-36 functioning (Ginseng
[?-? years]
Health Survey 54.9+/-4.6 vs. pla-
version 2 (SF- cebo 49.2+/-6.5;
36v2) p=0.014), mental
health (Ginseng
52.2+/-7.7 vs. pla-
cebo 47.2+/-7.3;
p=0.075), and the
mental component
summary (Ginseng
51.3+/-7.4 vs. pla-
cebo 44.3+/-8.3;
p=0.019) scales were
observed in patients
randomised to Gin-
seng; these differ-
ences did not persist
to the 8-week time
point

PC 60 age-related Standardised extract QOL, ratings of Ginseng significantly Not reported Ib 3 [82]

2 parallel memory im- (400 mg daily)/ symptoms and improved QOL, and
groups paired elderly placebo for 9 months performance on symptoms and
volunteers a memory test performance on a
(?/?) memory test com-
pared with placebo
[51-65 years]

Rhodiola- PC 60 patients Standard treatment Duration of Adjuvant therapy None ib 4 [83]

Schisandra- 2 parallel suffering from (cephazoline, brom- antibiotic with ADAPT-232
Eleutherococ- groups acute non- hexine, and theo- therapy associ- had a positive effect
cus specific pneu- phylline) plus ated with the on the recovery of
monia ADAPT-232 (a clinical mani- patients by decreas-

(30/30) standardised fixed festations of the ing the duration of

combination of acute phase of the acute phase of

[18-65 years]
extracts of Rhodiola- the disease, the illness for 2 days,

Schisandra and mental per- by increasing mental

Eleutherococcus)/ formance and performance of

standard treatment self-evaluation patients in the reha-

plus placebo for 10- by WHO-QOL bilitation period, and

15 days brief question- by improving their

naires QOL
a
CO - crossover; PC - placebo-controlled; M – multi-centred;
b
QOL – quality of life; HAMD - Hamilton Depression Rating Scale; BDI - Beck Depression Inventory; RVI – Rand Vitality Index; HR – heart rate; BP – blood pressure; CDR –
Cognitive Drug Research; MMSE – Mini-mental State Examination; ADAS – Alzheimer Disease Assessment Scale; CDRS – Clinical Dementia Rating Scale;
c
? - data not listed or unavailable.

[94, 95] (Fig. 3). Moreover, it has been demonstrated that
treatment with ADAPT-232 increased the expression of
GAPDH by 2-fold in the hippocampus of rats [105].
Attenuation of NO production can be attained by inhibi-
tion of i-NOS activity and by inhibition of the synthesis of
this enzyme at the transcriptional level via mitogen-activated
protein factor JNK, which is known to activate expression of
i-NOS [106] (Fig. 2). It has been shown that extracts of E.
senticosus inhibit lipopolysaccharide (LPS) and interferon-

induced NO production in murine macrophages both in vitro
212 Current Clinical Pharmacology, 2009, Vol. 4, No. 3
Fig. (1). Effect of adaptogens on stress-induced symptoms of fatigue.
and in vivo [107]. Moreover, E. senticosus extracts attenuate
the expression of both i-NOS and i-NOS m-RNA in LPS-
stimulated murine macrophages through the inhibition of
JNK pathways [96] (Fig. 2c).
Treatment with ADAPT-232 fortified with vitamin B5
greatly potentiates the ability of mice to overcome exhaus-
tive physical exercise (i.e. forced swimming with an addi-
tional load) by a mechanism that depends, in part, on the
significant increase in circulating serum levels of Hsp72 [99]
(Fig. 2c). In a further study, repeated administration of non-
fortified ADAPT-232 to rats at a dose of 36 mg/kg per day
for 7 consecutive days stimulated the expression of induc-
ible-Hsp72 (i-Hsp72) in a manner similar to that observed in
the hippocampus of rats during physical exercise [105]. Re-
peated treatment with ADAPT-232 also stimulated the ex-
pression of constitutive HSC-73 and resulted in a significant
protective effect on the stress-induced (forced swimming)
expression of i-Hsp72 such that treated rats swam 1.5-times
longer (p<0.05) than control animals [105].
Gabai et al. [108-110] demonstrated that elevated levels
of intracellular Hsp70 inhibit a signal transduction pathway
leading to programmed cell death by preventing the stress-
induced activation of SAPK/JNK, an early step in apoptosis
(Fig. 2b). We have recently found that adaptogens inhibit
stress-induced JNK expression in rabbits [95] (Fig. 2c), a
result that is in accordance with other reports related to the
effect of adaptogens on Hsp70 [99] and DAF-16 [97]. We
therefore hypothesise that ADAPT-232 induces the activa-
tion of cytoplasmic heat shock transcription factor 1 (HSF-
1), which trimerises and gains a nuclear translocation signal.
In the nucleus, HSF-1 transcribes the synthesis of heat shock
proteins, such as Hsp72, that are transported to the extracel-
lular milieu and exert immunostimulatory effects on the im-
mune system of the host. Inside the cell, increased expres-
sion of Hsp72 inhibits detrimental stress-activated signal
transduction cascades such as JNK-induced apoptosis acti-
vated by Jun kinase kinase (JKK). Our recent experiments
suggest that Hsp72 plays an important role of FoxO1forkhead
transcription factor signaling, since the phosphorylation of
FoxO1 is the initial step in its activation/signaling and nu-
clear translocation and synthesises additional proteins con-
ferring stress-resistance and, potentially, increased longevity
[97, 111, 112]. ADAPT strongly activates Hsp72 synthesis
and the phosphorylation of FoxO1 in isolated human mono-
cytes in a dose-dependent fashion. ADAPT activates Hsp72
Panossian and Wikman
before activating FoxO1, since silencing of Hsp72 seriously
inhibits the phosphorylation of FoxO1 (Fig. 2c).
Such studies are highly significant on account of the cur-
rent interest in the role of circulating serum Hsp72 as a dan-
ger signal, and the biological significance of the protein to
human physiology [113]. The danger theory postulates that
immune activation involves danger/non-danger molecular
recognition schemes and suggests that innate immune cells
are activated by danger signals that are derived from stressed
or damaged self-proteins [114]. It is now widely accepted
that circulating serum Hsp72 acts as a danger signal [115],
and there is now considerable interest in finding agents that
can augment the level of circulating Hsp72 for therapeutic
gain in various human diseases. Thus, Hsp72 inducers may
have therapeutic application in the treatment of neurodegen-
erative diseases in which increased chaperon expression
could reduce the levels of misfolded or aggregated proteins
that trigger the development of the pathological condition
[116]. Moreover, Hsp inhibitors may be of particular benefit
in the treatment of cancer, since tumour cells typically ex-
press higher levels of these proteins than normal cells [117].
The clinical significance of the results obtained with
ADAPT-232 can be associated with its application in the
treatment of patients during the period of convalescence
from infectious disease when the immune system has to be
supported and normal physiological functions recovered. The
beneficial effect of ADAPT-232 is probably related to the
upregulation of Hsp 72, which in turn stimulates the immune
system and reverses the process of protein denaturation that
is dramatically increased in the acute phase of inflammation.
Moreover, adjuvant therapy with ADAPT-232 has a positive
effect on the recovery of patients by decreasing the duration
of the acute phase of the illness, by increasing mental per-
formance of patients in the rehabilitation period, and by im-
proving quality-of-life [83].
Cortisol is a stress-hormone involved in the feed-back
regulation of stress responses that help to restore homeosta-
sis. Subjecting animals and humans to stress produces char-
acteristic changes in the HPA axis, including an increase in
cortisol, and reduced sensitivity of the HPA to feedback
down-regulation. Increased levels of cortisol in the serum
and saliva have been observed in association with physical
exertion and various stressors. In chronic stress, prolonged
secretion of cortisol causes muscle wastage, hyperglycemia,
and suppresses immune/inflammatory responses [118, 119].
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 213
214 Current Clinical Pharmacology, 2009, Vol. 4, No. 3 Panossian and Wikman

(Fig. 2. Contd….)

Fig. (2). Simplified hypothetical molecular mechanism by which ADAPT-232 induces stress resistance (adaptation to stress) and increases
cognitive functions and, possibly, longevity. Typically, a cell is either in balance (dynamic equilibrium - homeostasis), as depicted in (a), or
functioning under stressful conditions (threatened homeostasis – imbalance), as in (b). Two further states are possible, namely, that in which
the cell is adapted (tolerant) to stress (i.e. state of non-specific resistance to stress; heterostasis – homeostasis with higher level of equilib-
rium), as displayed in (c), or the state of apoptosis (dying).
Panel (a) shows that mitochondria generate aggressive oxygen-containing radicals that can damage native or repaired proteins by distorting
their 3-D structure so that they can no longer fulfil their functions in the cell.
There are many “players” involved in the regulation of homeostasis at both the cellular level and the whole organism level. Amongst these
are:
- the stress hormone cortisol (a molecule that is secreted from glands and regulates the functions of organs and systems of the organism);
- glucocorticoid receptors that modulate/regulate cortisol secretion (feedback regulation);
- NO, an intracellular signalling 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 longevity.
Panel (b) shows that in stress (infection, cold, heat, radiation, physical load, emotional stress, etc) an external 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 neuronal development, activation of the immune system and programmed cell death (apoptosis). In particular, JNK:
- increases the formation of aggressive radicals and nitric oxide, which in turn suppresses the generation of energy providing molecules
ATP. As a result of lack of energy, many proteins cannot work, many functions are suppressed, and the first symptoms of fatigue and ex-
haustion are observed. ATP is also required for the normal functioning of heat shock proteins such as Hsp70, which are produced as a de-
fence response to stress and assist in the repair of misfolded and damaged proteins;
- suppresses glucocorticoid receptors (GR) such that the feedback inhibition of cortisol secretion ceases to function and levels of circulatory
cortisol increase. Cortisol inhibits the immune system, has anti-inflammatory effects on the body and is required in order to protect the
organism from over-reaction/over-activation in response to stress. However, chronically high levels of cortisol are associated with depres-
sion, chronic fatigue and impaired cognitive function, including decreased attention and learning ability;
- activates translocation of FoxO to the nucleus and initiates the synthesises of proteins that confer stress-resistance and increased longev-
ity.
Adaptogens in Fatigue Current Clinical Pharmacology, 2009, Vol. 4, No. 3 215

(Fig. 2. Contd….)

Panel (c) shows that adaptogens such as ADAPT-232 decrease NO, cortisol and JNK in 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:
- enhances the repair of damaged proteins;
- inhibits the stress-induced expression of NO genes and, since the reduced levels of NO cannot suppress the formation of energy providing
molecules, ATP is increased to normal levels in the adapted cell;
- inhibits JNK and consequently apoptotic death 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 phosphorilation of FoxO and its translocation into the nucleus of isolated cells
(i.e. human monocytes) or simple organisms (i.e. DAF-16 in C.elegance) and, consequently, with increased resistance to stress and in-
creased life span.
In summary, ADAPT-232 works like a stress vaccine (stress-mimetic) by activating stress-induced self-defence mechanisms in order to adapt
the call and organism to mitigate stress-induced harmful effects.

Fig. (3). Schematic representation of the hypothetical molecular mechanism by which NO formation can strongly inhibit the production of
cellular energy through two mechanisms, namely, the inhibition of mitochondrial respiration by reversible (from constitutive isoforms of
NOS) and irreversible (from iNOS) inhibition of cytochrome P450 [103], and the inhibition of glycolysis through modification of SH-groups
of GAPDH [104]. In anaerobic glycolysis, muscle glycogen is converted via glucose-6-phosphate to lactic acid, yielding 3 ATP molecules for
each glucose residue. Aerobic oxidation of glucose is required for sustained exercise and provides, via the Krebs cycle and the respiratory
chain, 34 ATP molecules per glucose residue. This process occurs 1 min after anaerobic ATP generation: if it does not produce a sufficient
supply of ATP, anaerobic glycolysis is continued. NO increases during stress and consequently reduces performance by inhibiting ATP pro-
duction. Adaptogens prevent the stress-induced increase in NO and, consequently, ATP production remains efficient, and performance and
endurance are increased [95].
216 Current Clinical Pharmacology, 2009, Vol. 4, No. 3
The reduction or preclusion of stress-induced damage by
adaptogens is characterised by a decrease in, or total preven-
tion of, hormonal changes peculiar to stress, including in-
creased serum cortisol [28, 95, 120].
It has been shown that patients with chronic fatigue ex-
hibit a higher cortisol response to awakening stress than non-
fatigued individuals [121]. In a recent clinical trial of R. ro-
sea in chronic fatigue, cortisol response to awaking stress
was found to be significantly different in the treatment group
compared with the control group after 4 weeks of treatment
[32]. Additionally, when rabbits were treated repeatedly with
R. rosea SHR-5 extract for 7 consecutive days, stress-induced
increase of cortisol in blood of rabbits was prevented [95]. It
is suggested that the inhibitory effect of this adaptogen on
the increased basal level of cortisol results in an improve-
ment in cognitive function. Such a proposal is in accord with
other studies demonstrating that optimal corticosteroid levels
are a requirement for efficient cognitive function since sig-
nificant changes in levels of corticosteroids (either increased
or reduced) result in cognitive impairment [122].
Generally, hypersecretion of cortisol is regarded as a
marker of a state of depression that remits with clinical im-
provement [119, 123]. It can be speculated that inhibition by
Rhodiola of the cortisol response in stress (the anti-stress
effect) might be associated not only with an anti-fatigue ef-
fect and increased attention, but also with the recently dem-
onstrated anti-depressive effect of SHR-5 in patients suffer-
ing from mild to moderate depression [66].
In summary, adaptogens may be regarded as a novel
pharmacological category of anti-fatigue drugs that:
(i) induce increased pharmacotherapeutic attention and en-
durance in situations of decreased performance caused by
fatigue and/or sensation of weakness, and
(ii) reduce stress-induced impairments and disorders related
to the function of stress (neuro-endocrine and immune) sys-
tems.
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