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Review Article
Rosenroot (Rhodiola rosea): Traditional use, chemical composition,
pharmacology and clinical efficacy
A. Panossian
a,n
, G. Wikman
a,n
, J. Sarris
b,c,n
a
Swedish Herbal Institute Research and Development, ˚
Askloster, Sweden
b
The University of Melbourne, Department of Psychiatry, Melbourne, Australia
c
Swinburne University of Technology, Brain Sciences Institute, Melbourne, Australia
article info
Keywords:
Rhodiola rosea
Herbal medicine
Adaptogen
Pharmacology
Fatigue
Clinical trials
abstract
The aim of this review article was to summarize accumulated information related to chemical
composition, pharmacological activity, traditional and official use of Rhodiola rosea L. in medicine. In
total approximately 140 compounds were isolated from roots and rhizome - monoterpene alcohols and
their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their
glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives. Studies on isolated
organs, tissues, cells and enzymes have revealed that Rhodiola preparations exhibit adaptogenic effect
including, neuroprotective, cardioprotectiv e, anti-fatigue, antidepressive, anxiolytic, nootropic, life-
span increasing effects and CNS stimulating activity. A number of clinical trials demonstrate that
repeated administration of R. rosea extract SHR-5 exerts an anti-fatigue effect that increases mental
performance (particularly the ability to concentrate in healthy subjects), and reduces burnout in
patients with fatigue syndrome. Encouraging results exist for the use of Rhodiola in mild to moderate
depression, and generalized anxiety. Several mechanisms of action possibly contributing to the clinical
effect have been identified for Rhodiola extracts. They include interactions with HPA-system (cortisol-
reducing), protein kinases p-JNK, nitric oxide, and defense mechanism proteins (e.g. heat shock proteins
Hsp 70 and FoxO/DAF-16). Lack of interaction with other drugs and adverse effects in the course of
clinical trials make it potentially attractive for use as a safe medication. In conclusion, Rhodiola rosea has
robust traditional and pharmacological evidence of use in fatigue, and emerging evidence supporting
cognition and mood.
&2010 Elsevier GmbH. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Traditional and Current Medical Use of Rhodiola . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
Chemical composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 482
Pharmacological activity and mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 486
Clinical trials in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 488
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 490
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 491
Introduction
Recently, a narrative review article entitled ‘‘Perspective on
Roseroot (Rhodiola rosea) studies’’ by Blomkvist, Taube and
Larhammar, was published online 2009, May 25, Planta Medica
(Blomkvist et al., 2009), where the performance of statistical
analyses of several selected clinical trials on Rhodiola were
criticized for purported methodological weaknesses. In the
conclusion the focus on the paper was primarily on finding
failings of the studies without any systematic assessment of the
level of scientific evidences of the efficacy of Rhodiola rosea
(Rhodiola).
ARTICLE IN PRESS
Contents lists available at ScienceDirect
journal homepage: www.elsevier.de/phymed
Phytomedicine
0944-7113/$ - see front matter &2010 Elsevier GmbH. All rights reserved.
doi:10.1016/j.phymed.2010.02.002
n
Corresponding authors.
E-mail addresses: alexander.panossian@shi.se (A. Panossian), georg.wikman@
shi.se (G. Wikman), j.sarris@uq.edu.au (J. Sarris).
Phytomedicine 17 (2010) 481–493
ARTICLE IN PRESS
The aim of this review article is to systematically assess
Rhodiola clinical trials in accordance with existing standards and
guidelines of EMEA and Natural Standards. This is in order to
estimate the level of scientific evidences of efficacy and grade of
recommendations for use of the plant in the treatment of specific
conditions (e.g. fatigue, depression). In addition to a review of
clinical efficacy, an overview of the traditional use, and a
comprehensive analysis of the adaptogenic mechanisms of action
by Rhodiola’s constituents are outlined.
Traditional and Current Medical Use of Rhodiola
Rhodiola rosea L. (Crassulaceae, syn. Sedum rhodiola - DC.
Sedum rosea - (L.) Scop cop, is known by the common names
Rhodiola, Roseroot, Rosenroot, Golden Root, Arctic Root, Orpin
Rose, Rhodiole Rougeˆ
atre), and has a long history as a valuable
medicinal plant having appeared in the Materia Medica of a
number of European countries (Linne
´, 1749;Sparschuch, 1775;
Pharmacope
´eFranc-aise, 1976;Virey, 1811). The plant grows in
crevices of mountain rocks and on sea cliffs of Arctic regions of
Europe, Asia (mainly in Siberia) and N. America, including Britain,
further south on mountains. The main source of commercially
available roots and rhizome are Mountain Altai and in south
region of foothill Altai, mainly in Ust-Kanski, Ust-Koksinski,
Charishki regions (Saratikov and Krasnov, 2004). In all, there are
approximately 24 different species of genus Rhodiola including
eight species containing phenolic compounds and growing in
Altay region that can be mis-identified with Rhodiola rosea L
(Kurkin et al., 1985a, 1985b;Kurkin and Zapesochnaya, 1986a).
According to some sources, Rhodiola rosea was in use as far
back as the Vikings as a medicine and for its strengthening action
on hard work (Magnusson, 1992;Dragland and Galambosi, 1996),
but this is somewhat speculative. In Linne
´sMateria medica (Linne
´,
1749) the root of the rose is recommended in the treatment of
headaches, ‘‘hysteria’’, hernias, discharges, and as an astringent.
The use of the root is also found in the first Swedish national
pharmacopoeia (Sparschuch, 1775). In an old book of useful
plants from Iceland (Halldorsson, 1783) the following statement
about Rhodiola is written - ‘‘Infusion of stone crop taken dries and
astringes, heals pain in the mouth, heals kidneys from sand which
forms stones, stops diarrhea and cures headache and also
strengthens head and also hair growth in the head is washed
with it. The root may also be suitable for severe skin conditions.
Grinded, pressed and mixed with butter it is considered to relieve
swellings and decreases back pain and pains in joins and other
painful conditions, especially if heat is applied. The dried root has
been used to cures swellings, removes freckles and is strengthen-
ing for the head’’ (Halldorsson, 1783). It is also seen to ‘‘enhance
the intellect’’, ‘‘tonic against infirmity’’ and ‘‘restores weak
nerves’’ (Halldorsson, 1783). Alm (Alm, 2004) mentioned the
use of Rhodiola in folk medicine against scurvy, being also
medically used as a stimulant and an astrigent in France (as
described by Virey in a medicine textbook in 1811). The recent
use of the herbal medicine in traditional medicine in Sweden is
reported in northern J¨
amtland. During interviews with Lapps it
has been mentioned that they chewed on bits of roots during long
journeys (Magnusson, 1992;Dragland, 2001). It is also said to
have been used against headaches and when washing hair.
In the textbook of pharmacology for dispenser training in
Sweden, Rhodiola rosea is mentioned as a plant with a stimulant
effect. It is further ascribed the vasoconstrictive and haemostatic
effects on haemorrhoids (Sandberg and Bohlin, 1993). Also in the
Pharmaceutical Book (L¨
akemedelsboken) 97/98 Rhodiola rosea is
mentioned as one of the more common herbal medicines and its
effect is specified as a ‘‘general strengthener’’ and ‘‘psychostimu-
lantium’’ (Strandberg and Aly, 1997).
Preparations of the drug now form part of the official medicine
of some of various countries (M¨
uller-Dietz, 1969;Mashkovskij,
1977;Muravijeva, 1978;Turova and Sapozhnikova, 1984;
National Pharmacopoeia of the USSR, 1990;National Pharmaco-
poeia Committee, 1996;Estonian Ministry of Health Affairs,
1998). Rhodiola rosea is one of the most popular plant adaptogens
utilized in Russia today, and has been published on extensively
(Fig. 1). It was first recommended in 1969 by the Pharmacological
Committee of the Ministry of Health of the USSR for use as a
stimulant against fatigue by patients who suffered asthenic states
and by healthy people who showed astheny during periods of
high mental exertion or after intensive physical work. The drug
can also be applied in cases of borderline nervous-mental
diseases, neuroses, neurotic disorders and psychopathies. In
psychiatric practice, extracts of Rhodiola rosea are indicated for
the correction of neurological side-effects associated with
psychopharmacological therapy, and for the intensification and
stabilization of remissions of asthenic and apathistical-aboulic
type schizophrenia patients (Saratikov et al., 1965;Krasik et al.,
1970a, b;Saratikov, 1973;Komar et al., 1981;Mikhailova, 1983;
Brichenko et al., 1986;Saratikov and Krasnow, 1987).
As a dietary supplement, numerous preparations of
Rhodiola extracts are used world-wide (Khanum et al., 2005).
The functional claim of Rhodiola dietary supplements cur-
rently mentioned in the Consolidated list of Article 13 health
claims of the European Food Safety Authority (EFSA) is
formulated as following – ‘‘contributes to optimal mental
and cognitive activity’’ [http://www.efsa.europa.eu/EFSA/
efsa_locale-1178620753812_article13.htm]
In Sweden Rhodiola tablets containing Rhodiola rosea SHR-5
extract have been on the market since 1985 . They are currently
registered as Traditional Herbal medicinal product (THMP)
indicated as an adaptogen (Box 1) in situations of decreased
performance such as fatigue and sensation of weakness.
Chemical composition
Rhodiola rhizomes contains essential oils, fats, waxes, sterols,
glycosides, organic acids (oxalic, citric, malic, gallic, succinic),
phenolics including tannins and proteins (Zapesochnaya and
Kurkin, 1983;Zapesochnaya and Kurkin, 1982;Kurkin et al.,
1985a;Kurkin and Zapesochnaya, 1986a, b;Rohloff, 2002;
Tolonen et al., 2003;Saratikov and Krasnov, 2004;Akgul et al.,
2004;Ma et al., 2006; Yousef et al., 2006; Ali et al., 2008).
1960 1970 1980 1990 2000 2010
0
10
20
30
40
50
Russian literature, n = 357*
Cited on Medline, n = 258**
* - References from Saratikov&Krasnov, Golden Root, 2004
** - http://www.ncbi.nlm.nih.gov/sites/entrez
Year
Fig. 1. demonstrates increasing interest to this plant in scientific community. In
total about 600 scientific publication on Rhodiola rosea can be found in the
literature.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493482
ARTICLE IN PRESS
The dried rhizomes contained 0.05% essential oil with the main
chemical classes: monoterpene hydrocarbons (25.40%), mono-
terpene alcohols (23.61%) and straight chain aliphatic alcohols
(37.54%). n-Decanol (30.38%), geraniol (12.49%) and 1,4-p-
menthadien-7-ol (5.10%) were the most abundant volatiles
detected in the essential oil, and a total of 86 compounds were
identified (Rohloff, 2002). Geraniol was identified as the most
important rose-like odor compound besides geranyl formate,
geranyl acetate, benzyl alcohol and phenylethyl alcohol. Its
oxygenated metabolite Rosiridol is an aglycon of Rosiridin (Kurkin
et al., 1985a;Kurkin and Zapesochnaya, 1986b) - one of the most
active constituents of Rhodiola in bioassay guided fractionation of
Rhodiolathe extract (van Diermen et al., 2009). Rosiridin was
found to inhibit monoamine oxidases A and B in vitro implying its
potential beneficial effect in depression and senile dementia (van
Diermen, 2009).
More than 50 polar compounds were isolated from the water
alcoholic extracts, they are
monoterpene alcohols, their glycosides and cyanogenic glycosides
(Fig. 2). In Fig. 3 are listed phyhylethanoids, phenylpropanoids,
flavonoids, aryl glycosides, proanthocyanidins and other gallic acid
derivatives. (Zapesochnaya and Kurkin, 1983, 1983;Kurkin et al.,
1985a;Kurkin and Zapesochnaya, 1986a, b;Ganzera et al., 2001;
Tolonen et al., 2003;Saratikov and Krasnov, 2004;Akgul et al., 2004;
Ma et al.2006,Yousefetal.,2006,Ali et al.,2008; Avula et al., 2009).
Biologically active compounds include phenolic and/or cyanogenic
glycosides with antidepressive, anti-fatigue, cognitive-enhancing,
anti-anoxia, hepatoprotective, anti-allergy, anti-inflammatory,
Box 1–Adaptogenic definitions
Adaptogens comprise a pharmacotherapeutic group of herbal preparations used to:
increase attention and endurance in fatigue, and
prevent/mitigate/reduce stress-induced impairments and disorders related to neuro-endocrine and immune systems [Panossian
and Wikman, 2009a, b].
Other definition of adaptogens are associated with physiological conditions:
Adaptogenic substances are stated to have the capacity to normalize body functions and strengthen systems compromised by
stress. They are reported to have a protective effect on health against a wide veriety of environmental assults and emotional
conditions EMEA/HMPC/102655/2007,
Adaptogens are compounds which could increase ‘‘the state of non-specific resistance’’ in stress [Lazarev, 1958;Lazarev et al.,
1959]
Adaptogens are innocuous agents, nonspecifically increasing resistance against physically, chemically, biologically and
psychologically noxious factors (‘‘stressors’’), normalizing effect independent of the nature of pathologic state [Brekhman and
Dardymov, 1968].
Adaptogens are substances which elicit in an organism a state of non-specifically raised resistance allowing them to counteract
stressor signals and to adapt to exceptional strain [Wagner et al., 1994].
Geraniol
Cyanogenic glycosides
Rhodiocyanoside A
O
HO
HO
HO OH
OOH
HO
Rhodiolosid A
O
R1O
HO
R2OOH
O
HO
R1- H, R2 - Glu - Rhodiolosid B
R1 - Glu, R2 - H - Rhodiolosid C
R1 - H, R2 - H - Rosiridin
O
HO
HO OH
O
R1- OH, R2 - H-Rhodiolosid D
R1 - H, R2 - Ara -Rhodiolosid El
OH
R1O
R2O
HO
HO
HO
O
HO
HO
HO OH
OCN
O
HO
HO
HO OH
OCN
Lotaustralin
Rosiridol
Fig. 2. Monoterpene alcohols and their glycosides.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493 483
ARTICLE IN PRESS
properties (Kurkin, and Zapesochnaya, 1986a;Panossian et al.,
2008a;van Diermen et al., 2009;Diaz-Lanza et al., 2001). The
constituent with known therapeutic activity was found is p-
hydroxyphenylethyl-O-ß-D-glucopyranoside (Syn.salidroside,
rhodioloside, rhodosin) (Aksenova et al., 1968).
Proanthocyanidins constituting a fairly large portion of the
Rhodiola extracts (ca. 30% of the 70% acetone dry crude extract)
(Yousef et al., 2006), were also noted for significant bioactivities
including antioxidant, anti-cancer, anti-inflammatory, anti-aller-
gic, anti-mutation, anti-aging and improving liver function
(Yousef et al., 2006). The MAO-B inhibitory activity of EGCG has
been described by van Diermen et al., 2009, however this effect is
attributed rather to its denaturant effect on proteins than to a
specific mechanism of inhibition (van Diermen et al., 2009).
The phytochemical constituents in Rhodiola are species-depen-
dent (Kurkin et al., 1985a, b, 1986;Kurkin and Zapesochnaya, 1986a;
Yousef et al., 2006), although salidroside production in other species
including R. quadrifida (Pall.) Fisch and Mey, R algila(Ledeb.) Fisch R.
sachalinensis, R. kirilowii,R. crenulata R. heterodonta and R. semenovii
has also been reported (Kurkin and Zapesochnaya, 1986a, b;
Saratikov and Krasnov, 2004;Wu et al., 2003;Yousef et al., 2006;
van Diermen et al., 2009). Characteristic feature of R. rosea is
presence of cynnamic alcohol glucosides and relatively high content
of phenylpropanoids rosavin, which was not detected in other 21
Phyhylethanoids and phenylpropanoids and their glycosides
Proanthocyanidins and gallic acid derivatives
O
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
Galloyl - G
OG
OH
OH
OH
OH
(-)-Epigallocatechin-
-3-O-gallate (4 S)
EGCG
EGC
Prodelphinidin -gallate esthers
O
O
O
O
OH
HO
OH
OH
OH
HO
H
OH
O
OO
HO
OO
OH
OH
HO
HO
O
OO
HO
OH
OH
OH
HO HO
O
OO
OO
HO
OH
OH
OH
HO HO
OMe
HO
OO
OH
OH
HO
HO
OMe
HOOC
OH
OH
OO
OO
OH
OH
OH
HO HO
HO
O
OO
OH
OH
HO
OMe
O
HO
OH
OH
OOMe
HO
OH
OH
O
HO
OH
OH
OH
EGCG
EGC-EGCG
2EGCG
2EGC-EGCG
EGC-2EGCG
3EGCG
2EGC-2EGCG
EGC-3EGCG
4EGCG
2EGC-3EGCG
Tyrosol Caffeic acid Cinnamic alcohol
Triandrin Rosarin
Salidroside/Rhodioloside RosavinRosin
OO
OH
OH
OH
HO
Fig. 3. Phyhylethanoids, phenylpropanoids and their glycosides, proanthocyanidins and gallic acid derivatives, flavolignans, aryl glycosides and flavonoids.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493484
ARTICLE IN PRESS
genus Rhodiola species morphologically similar to R. rosea (Kurkin
et al., 1985a, b, 1986;Kurkin and Zapesochnaya, 1986a;Yousef et al.,
2006). Commercial preparations based on R. rosea must be free of
morphologically similar R. quadrifida (Pall.) Fisch and Mey,R
algila(Ledeb.) Fisch and Mey, and other foreign plant materials.
Typical HPLC fingerprint is shown on the Fig. 4.
Flavolignans
Rhodiolin (optically inactive mixture of two diastereoisomers)
Aryl glycosides
Flavonoids
O
OH
OMe
OMe
HO
GlcO O
O
OH
OMe
OMe
HO
HO
O
O
HO
HO
OH
OH
O
O
HO
HO
O
OH
OGlc
O
HO
OH
O
OH
RhamO
O
OH
OMe
OMe
HO O
GlcO
O
HO
HO
OH
OH
O
OAra
O
HO
HO
OH
OH
O
OCH3
O
HO
OH
OH
O
OH
Glc(1-3)Rham-O
O
HO
HO
OH
O
OXyl
OGlc
O
HO
OH
OH
O
OGlc
RhamO
O
HO
OH
OH
O
OH
RhamO
O
HO
HO
OH
OH
O
OXyl
O
HO
OH
OH
O
OH
RhamO
OGlc
O
HO
OH
OH
O
OH
OH
RhamO
O
HOCH2
HO
OH
OH
O
CHO
O
HOCH2
HO
OH
OH
O
O
OGlc
OH
HO
OCH3
O
O
O
HO
OH
OH
O
H
H
HO
OH
CH3O
O
O
O
HO
OH
OH
O
H
H
OH
HO
OCH3
OCH3
Fig. 3. (Continued)
A. Panossian et al. / Phytomedicine 17 (2010) 481–493 485
ARTICLE IN PRESS
Various new methods of analysis of active constituents in the
extracts of herbal substance, herbal preparations and biological
fluids were developed during last decade (Avula et al., 2009;
Chang et al., 2007;Ganzera et al., 2001;Mao et al., 2007a;Mao
et al., 2007b;Peng et al., 2008 ;Petsalo et al., 2006;Tolonen and
Uusitalo, 2004;Wiedenfeld et al., 2007;Wu et al., 2004).
Pharmacological activity and mechanisms of action
Results of more than few hundred pharmacological studies of
Rhodiola rosea are reviewed in several review articles and books
(Saratikov et al., 1968; Saratikov, 1976; Saratikov and Krasnov,
2004; Panossian and Wagner, 2005; Brown et al., 2002; Kelly,
2001; Panossian, 2003;Panossian and Wikman, 2005, 2009a;
Panossian and Wagner, 2005).
Pharmacological effects of Rhodiola rosea extracts described in
these studies are summarized below:
Adaptogenic and stress- protective (neuro-cardio and hepato-
protective ) effects
Cardioprotective effects
Antioxidant effect
Stimulating effect on the central nervous system including effects
on cognitive functions such as attention, memory and learning
Anti-fatigue effect
Antidepressive and anxiolytic effects
Endocrine activity normalizing
Life-span increasing effect
Stress-protective effect of Rhodiola, that increased survival of
simple organisms and isolated cells in oxidative stress is not
purely associated with its antioxidant or pro-oxidant effects
(Schriner et al., 2009;Wiegant et al., 2008, 2009), because the
ability of Rhodiola to enhance survival against oxidative stress at
dose levels that do not elevate the major antioxidant defenses,
activate the antioxidant response element or degrade H
2
O
2
(Schriner et al., 2009).
The adaptogenic effect of Rhodiola root SHR-5 extract have been
shown in several double blind, randomized controlled clinical trials,
Table 3. Orally administrated for 2-6 weeks dry SHR-5 extract
prepared with ethanol-water (ethanol 70% (V/V) in the daily doses of
288 – 680 mg (1-4 tablets), have been shown to improve mood
(Darbinyan et al., 2007), cognitive performance, attention (Olsson
et al., 2009;Darbinyan et al., 2000;Shevtsov et al., 2003;Spasov
et al., 2000) and relief fatigue (Olsson et al., 2009;Darbinyan et al.,
2000;Shevtsov et al., 2003;Spasov et al., 2000;Schutgens et al.,
2009) in stress related conditions. A single dose effect is achieved in
one-two hours after the administration of Rhodiola extracts
(Perfumi and Mattioli, 2007;Mattioli and Perfumi, 2007;Panossian
et al., 2009b;Mattioli et al., 2008;Panossian et al., 2009a).
The adaptogenic effect of Rhodiola root water-acloholic extracts
have been confirmed in many preclinical studies (Saratikov, 1976;
Saratikov et al., 1968;Aksenova et al., 1968;Panossian and
Wagner, 2005;Jafari et al., 2007;Perfumi and Mattioli, 2007;
Mattioli et al., 2008;van Diermen et al., 2009;Abidov et al., 2003;
Iaremiı
˘and Grigor’eva, 2002;Qin et al., 2008;Siwicki et al., 2007;
Wang et al., 2009;Pooja et al., 2009;Zdanowska et al., 2009)and
several controlled clinical trials (Aksenova et al., 1968a,b;
Dieamantet al., 2008;Bystritsky et al., 2008;Earnest et al., 2004;
Xu et al., 2003;Ha et al., 2002;Zhang et al., 1999;Fintelmann and
Gruenwald, 2007;Spasov et al., 2000;Bocharova et al., 1995).
In numerous in vitro and in vivo studies on animals, CNS
stimulating (Saratikov, 1976;Sokolov et al., 1985, 1990;Barnau-
lov et al., 1986;Saratikov et al., 1968; 1978a, b;Aksenova et al.,
1968a, b; Kurkin et al., 2003;Panossian and Wagner, 2005;
Perfumi and Mattioli, 2007 ;Mattioli et al., 2008;Qin et al., 2008),
neuro-,cardio- and hepato-protective effects (Wang et al., 2008;
Iaremiı
˘and Grigor’eva, 2002;Saratikov and Krasnov, 2004), life-
span increasing (Jafari et al., 2007;Wiegant et al., 2009), MOA
inhibitory (van Diermen et al., 2009), immunotropic (Siwicki
et al., 2007), antiviral (Wang et al., 2009), anti-inflammatory
(Pooja et al., 2009) and antibacterial activity (Zdanowska et al.,
2009) has been demonstrated.
Using animal models, bioassay-guided fractionation of various
extracts of plant adaptogens have shown that the active principles
are mainly phenylpropane and phenylethane derivatives includ-
ing salidroside, rosavin, syringin, triandrin, tyrosol, etc.
(Aksyonova, 1968;Kurkin and Zapesochnaya, 1986a;Zapesoch-
naya et al., 1995;Barnaulov et al., 1986;Sokolov et al., 1990;
Saratikov and Krasnov, 2004). Of these, rhodioloside/salidroside
and triandrin was reported to be the most active in a number
6.606
16.724
17.441
Rosarin - 30.020
Rosavin - 30.705
Rosin - 32.115
Sorbic acid - 33.515
35.370
Methyl 4-hyroxybensoate - 36.683
39.535
Cinnamylalcohol - 42.621
Salidrosid - 13.946
AU
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Minutes
2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00 40.00 42.00 44.00 46.00 48.00 50.00
Fig. 4. HPLC fingerprints overlay from Rhodiola rosea L. roots extract (DER
native
2,5-5.0 :1, extraction solvent 70% ethanol) containing 2.7% salidroside, 6.0% rosavin and 0.8%
tyrosol, detected at 221 nm (black line, peak of Salidroside is in red color) and 252 nm (red line) by photodiode array detector (Waters model 996). The HPLC column
packed with octadecyl silica (LiChrospher RP-18) was eluted with the solvent system containing gradually increasing concentration (from 5 to 95%) of acetonitrile in water
solution of 0.001 M ortho phosphoric acid. Broad band of background absorption with max at 270-275 nm from 28 min to 50 min is due to unresolved
epigallcatechingallate oligomers. Sorbic acid and methylboezoate – preservatives added to the extract.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493486
ARTICLE IN PRESS
of different test systems (Barnaulov et al., 1986;Sokolov et al.,
1990).
Rhodioloside and salidroside - active principles of the SHR-5
extract, were found to have neuro-cardio-and hepato- protective
activity preventing/mitigating/reducing stress-induced impair-
ments and disorders related to neuro-endocrine and immune
systems by:
Protection from oxidative damage in fatigue (Ma et al., 2009)
Protection of liver tissue from the acetaminophen -induced
oxidative damage via preventing or alleviating intracellular
GSH depletion and oxidation damage, which suggested that it
would be a potential antidote against APAP-induced hepato-
toxicity (Wu et al., 2008)
Inhibition of lipid peroxidation and oxidative stress in rat
hepatic stellate cells (Zhang and Liu, 2005)
Hepatoprotection against tacrine-induced cytotoxicity in hu-
man liver-derived Hep G2 cells (Song et al., 2003)
Promotion of the recovery of hematopoietic function of the
bone marrow depressed anemia (Zhang et al., 2005; 2006)
Stimulation of CNS system (Saratikov et al., 1968;Aksenova
et al., 1968;Panossian and Wagner, 2005;Saratikov and
Krasnov, 2004)
Reduction of the degree of cerebral edema of rats with global
cerebral ischemia-reperfusion injury, relieving the metabolism
abnormity of free radical and improving the function of
cognition (Zou et al., 2009)
Blockage of H(2)O(2)-induced apoptosis in rat neuronal PCl2
cells (Cai et al., 2008)
Attenuation of glutamate-induced apoptotic cell death in
primary cultured hippocampal neurons of rats (Chen et al.,
2008)
Protection of the cultured neuronal cell PC12 cells against
hypoglycemia and serum limitation-induced cytotoxicity
possibly by the way of the modulation of apoptosis-related
gene expression, the restoration of the mitochondrial
membrane potential, and the inhibition of the intracellular
ROS production (Yu et al., 2008)
Protection of cultured neuronal cells from sodium azide and
glutamate induced injuries (Cao et al., 2005, 2006)
The effect of anti-neuronal apoptosis relating to its function of
decreasing intracellular free calcium concentration (Zhang
et al., 2004; 2007)
Protection rat neuronal PCl2 cells against amyloid beta-
peptide (Abeta)-induced cytotoxicity reducing accumulation
of reactive oxygen species and malondialdehyde (MDA) (Jang
et al., 2003)
Protection of cultured myocardial cells from anoxia and
reoxygenation induced injuries of cell membrane, endoplasmic
reticulum, and mitochondria (Ye et al., 1993)
Protection of cardiomyocytes against hypoxia-induced necro-
sis and apoptosis (Zhang et al., 2009)
Significant inhibition of tumour – induced neovascular reac-
tions (Skopn
´ska-Ro
´zewska et al., 2008)
Normalizing effect on elevated or reduced glucose level in
blood of stressed-animals (Saratikov et al., 1968)
Promotion of the 3H-glucose uptake, suppresses the differ-
entiation and down-regulates the expression of PPAR-gamma
and C/EBP-alpha mRNA in 3T3-L1 adipocytes (Wang et al., 2004)
Stimulation of glucose uptake in skeletal muscle cells by
activating phosphorilation of AMP-activated protein kinase (Li
et al., 2008)
Antiviral effect against cultured CVB3 cells, indication on a
potential effect in viral myocarditis (Wang et al., 2008)
Some of these findings might raise a possibility of potential
therapeutic applications of salidroside for preventing and treating
cerebral ischemic and neurodegenerative diseases (Yu et al.,
2008). Salidroside can be further developed as potential com-
pound for the anti-diabetic therapy (Li et al., 2008).
Several mechanisms of action possibly contributing to the
clinical effect have been identified for whole SHR-5 extract both in
Table 1
Randomized and non-randomized clinical trials of Rhodiola in mental fatigue, stress-induced fatigue, fatigue syndrome and asthenia.
Adaptogen
(active
principle)
Indication for use and/or pharmacological activity Number of
trials
Number of
subjects
Grade of
recommendation
EMEA
a
NSR
b
Rhodiola rosea Mental fatigue: Rhodiola can improve attention in cognitive function in fatigue after single and
repeated administration.
3 257 A A
Fatigue syndrome: Rhodiola has anti-fatigue effect in physical, emotional, and mental exhaustion. 1 60 A B
Mild depression: Rhodiola has an anti-depressive effect 1 89 A B
Stimulating effect: Rhodiola can improve mental performance after single dose administration 3 419 B B
(Rhodioloside) Stimulating effect: Rhodioloside can improve mental performance after single dose administration 1 46 B
a
Grade of recommendation based on the European Medicines Agency Assessment Scale [EMEA/HMPC/104613/2005]:
Grade A.Evidence levels quality Ia, Ib - Requires at least one randomized controlled trial as part of the body of literature of overall good consistency addressing the
specific recommendation;
Grade B. Evidence levels IIa, IIb, III - Requires availability of well-conducted clinical studies but no randomized 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.
b
Grade of recommendation according to Natural Standards Evidence-Based Validated Grading Rationale (Basch and Ulblicht, 2005):
Grade A. Strong scientific evidence - Statistically significant evidence derived from: (i) more than two properly conducted randomized controlled trials (RCT), or (ii) one
properly conducted randomized controlled trial, and one properly conducted meta-analysis, or (iii) multiple RCTs with a clear majority of the properly conducted trials
and with supporting evidence in basic science, animal studies or theory;
Grade B. Good scientific evidence - Statistically significant evidence derived from: (i) one or two properly conducted randomized trials, or (ii) one or more properly
conducted meta-analysis, or (iii) more than one cohort/case control/non-randomized 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-randomized trial and without supporting evidence in basic science, animal studies or theory, or evidence
of efficacy only from basic science, animal studies or theory
A. Panossian et al. / Phytomedicine 17 (2010) 481–493 487
ARTICLE IN PRESS
human (Olsson et al., 2009) and animal studies (Panossian and
Wikman, 2009a;Panossian et al., 1999; 2007; 2008c; 2009a;
Boon-Niermeijer et al., 2000;Wiegant et al., 2008, 2009) . They
include interactions with HPA-system, particularly inhibition of
stress induced secretion of cortisol (Olsson et al., 2009;Panossian
et al., 2007; 2009a;Lishmanov et al., 1987), protein kinases p-JNK
(Panossian et al., 2007; 2009a), nitric oxide (Panossian et al.,
2007; 2009a), heat shock proteins Hsp 70 (Lishmanov et al., 1996;
Prodius et al., 1997;Panossian et al., 2008c, 2009a;Wiegant et al.,
2008) and expression of FoxO/DAF-16 proteins (Wiegant et al.,
2009) proteins involved in defense mechanisms to cope with
stress and stress-induced disorders.
It has been demonstrated that beneficial stress-protective
activity of Rhodiola is associated with the hypothalamic-pitui-
tary-adrenal axis and the regulation of key mediators of stress
response including molecular chaperons (e.g. Hsp70) (Lishmanov
et al., 1996;Prodius et al., 1997; Panossian et al., 2008c, 2009a;
Wiegant et al., 2008), stress-activated c-Jun N-terminal protein
kinase 1 (JNK1) (Panossian et al., 2007), Forkhead box O (FOXO)
transcription factor DAF-16 (Wiegant et al., 2009), cortisol (Olsson
et al., 2009;Panossian et al, 2007), nitric oxide (Panossian et al.,
2007) and betta-endorphine (Lishmanov et al., 1987;Maslov
et al., 1997;Maı
˘meskulova et al., 1997). Anti-depressive effect of
Rhodiola can be associated both by its effect on mono-amine
oxidase A (van Diermen et al., 2009), and on stress-system,
namely on secretion of cortisol (Darbinyan et al., 2007; Olsson
et al., 2009) and JNK mediated effects on glucocorticoid receptors
(Panossian et al., 2007).
Other possible mechanisms of action Rhodola extracts are not
excluded, such as a possible effect on neuropeptide Y receptors
(Larhammar and Salaneck, 2004) and expression of neuropeptide
Y which is known play important role in regulation of energy
balance, memory and learning, anxiety and depression (Heilig,
2004;Sajdyk, 2005;Tasan et al., 2009).
Concomitant treatment of rats with theophylline and SHR-5
did not give rise to significant effects on the pharmacokinetics of
theophylline. Simultaneous administration of SHR-5 and warfarin
did not alter significantly the pharmacokinetics or the anti-
coagulant activity of warfarin. It was concluded that SHR-5 might
be of value in the treatment of patients with mild or moderate
depression, and that its interaction with co-administered drugs is
likely to be negligible (Panossian et al., 2008b).
Clinical trials in humans
Post-Russian ‘Western’ research on Rhodiola has grown over
the past decade. Results of some clinical trials are discussed in
several review articles (Kelly, 2001;Brown et al., 2002;Khanum
et al., 2005;Walker and Robergs, 2006;Blomkvist et al., 2009;
Panossian and Wikman, 2009a,b). In total, more than 30
publications on clinical efficacy of various Rhodiola preparations
can be found in Pubmed database. The majority of these studies
(of varying methodological rigor) are related to efficacy of
Rhodiola on cognitive functions and mental performance in
fatigue. Results of these studies are summarized in Tables 1–3.
Table 2
Results of non-randomized studies on humans involving effects of Rhodiola on mental performance in fatigue.
Type of
preparation
tested in the
study
Study
design
a
Number of subjects
in the study
Age
range
of
subjects
Daily
dose
Duration
of study Effects recorded
Classification
of evidence
level
b
Ref.
Salidroside PC, SB 46 20-28 2.5 mg acute Improved mental performance; reduced the number
of errors in Anfimov’s correction test; stimulating
effect lasting 4 h or more.
IIa Aksenova,
1968
Rhodiola rosea
(extract)
PC, SB 80 healthy students
(control group) and
70 patients with
neurosis
? 10 drops
or 3x10
drops/
day
acute and
10 days
Single and repeated administration of adaptogens
improved functional state of the CNS in patients
with neurosis as characterized by normalization of
the speed 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.
IIa Kaliko and
Tarasova
(1966)
20-50 40 drops
or 3x10
drops/
day
Rhaponticum
cartamoides
(extract)
Rhodiola rosea
(40% ethanol
tincture)
PC 254 19-22 20 drops acute Improved mental performance; reduced the number
of errors in Anfimov’s correction test; increased the
accuracy, working capacity and speed of
information perception. Stimulating effect lasted 4 h
or more.
IIa Komar,
1981
E. senticosus (40%
ethanol
tincture)
20 drops
Extract of R.
rosea rhizome
0.3 g
Tyrosol ? 82 ? 1, 5, 10
and
20 mg
? Improved mental performance, reduced the number
of errors in Anfimov’s correction test.
III Marina et al.
(1994)
R. rosea extract 5 drops
R. rosea (tincture
40% ethanol)
PC 85 20-28 5-10
drops
acute Improved mental performance, reduced the number
of errors in Anfimov’s correction test: the
stimulating effect lasted 4 h or more
IIb Zotova,
1965
R. rosea (extract
in combination
with vitamins
and minerals)
C 120 50-89 2
capsules
12 weeks Improved in cognitive deficiencies (concentration
deficiencies, forgetfulness, decreased memory,
susceptibility to stress, irritability)
III Fintelmann,
2007
1
capsule
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 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.
c
? - data not listed or unavailable.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493488
ARTICLE IN PRESS
Table 3
Results of randomized studies on humans involving effects of Rhodiola preparations on mental performance related to fatigue
Plant
name
Study
design
a
Total subjects
(sample size of
verum/control) [age
range]
Intervention/control
dosage
Primary endpoint
b
Main results
b
Frequency of
adverse effects
Quality
level of
evidence
n
Jadad score
(max 5)
(Jadad
et al., 1996)
Ref.
Rhodiola
rosea
PC 2 parallel
groups
60 volunteers with
stress-induced fatigue
(30/30) [20-55 years]
Extract SHR-5 (288
mg twice daily)/
placebo for 4 weeks
Symptoms of fatigue, attention,
depression, QOL, salivary cortisol
Symptoms of fatigue, attention
and salivary cortisol significantly
improved compared with control
None Ib 5 Olsson
et al.,
(2009)
PC, CO 2
parallel
groups
56 healthy subjects
(?/?)
c
[24-35 years]
Extract SHR-5 (170
mg once daily)/
placebo for 2 weeks
Mental fatigue, perceptive and
cognitive functions such as
associative thinking, short-term
memory, calculation and ability
of concentration, and speed of
audio-visual perception
Statistically significant
improvement in the treatment
group (SHR-5) during the first 2
week period
None Ib 4 Darbinyan
et al.,
(2000)
PC 2 parallel
groups
40 healthy subjects
(20/20) [17-19 years]
Extract SHR-5 (50 mg
twice daily)/placebo
for 20 days
Mental fatigue, physical
performance, general well-being
Significant improvement in
physical fitness, mental fatigue
and neuromotor tests compared
with control (po0.01). General
well-being was also significantly
(po0.05) better in the verum
group. No significance was seen
in the correction of text tests or a
neuromuscular tapping test
None Ib 3 Spasov
et al. 2000
PC 3 parallel
treatment
groups
161 healthy subjects,
(41/20/40 treated +
20 untreated) [19-21
years]
Extract SHR-5 (single
dose of 370 mg or 555
mg) /placebo
Capacity for mental work Significant difference in anti-
fatigue effects in SHR-5 groups
compared with control
(po0.001), whilst no significant
difference between the two
dosage groups was observed
One subject in
placebo group
complained of
hyper-salivation
lasting 40 min
after intake
Ib 3 Shevtsov
et al.,
(2003)
PC 3 parallel
treatment
groups
91 patients with mild
and moderate
depression (31/30/30)
[18-70 years]
Extract SHR-5
(170 mg or 340 mg
twice daily)/placebo
for 6 weeks
Depression in total HAMD and
BDI scores
Significant differences in HAMD
and BDI scores and scores
reflecting levels of insomnia,
emotional instability,
somatisation and self-esteem in
SHR-5 groups compared to
placebo (po0.001)
None Ib 5 Darbinyan
et al.,
(2007)
a
CO - crossover; PC - placebo-controlled; M – multi-centre;
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;
n
According to WHO, FDA and 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.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493 489
ARTICLE IN PRESS
A systematic review of these studies shows that Rhodiola SHR-5
standardized extract demonstrate significant beneficial specific effects
on stress-induced symptoms in fatigue (Panossian and Wikman,
2009). For instance in patients with fatigue syndrome, classified as a
reaction to severe stress (subjects must exhibit daily symptoms of
fatigue, enduring for at least 2 weeks, related to a specific stressor that
has been present for at least 6 months, and their daily functioning
must be significantly negatively affected). Rhodiola significantly
reduced symptoms of fatigue and improved attention after four
weeks of repeated administration (Olsson et al., 2009). Additionally, it
was suggested that the inhibitory effect of Rhodiola on the increased
basal level of salivary cortisol results in an improvement in cognitive
function. This proposal is in line with other studies demonstrating
that optimal corticosteroid levels are a requirement for efficient
cognitive function since significant changes (up or down) in
circulating levels of corticosteroids results in cognitive impairment
(Herbertetal.,2006).Theanti-fatigueeffectofRhodiolaSHR-5
extract, together with improvement in cognitive functions in fatigue
and under stressful conditions, have been reported in healthy
volunteers who had received single and repeated doses of the
medication (Darbinyan et al., 2000;Spasov et al., 2000;Shevtsov et al.,
2003). It is concluded that repeated administration of R. rosea extract
SHR-5 exerts an anti-fatigue effect that increases mental performance,
particularly the ability to concentrate in healthy subjects and burnout
patients with fatigue syndrome.
Results of five clinical trials examining ergogenic properties of
Rhodiola rosea are conflicting. Statistically significant improvement of
physical performance measured as PWC-170 in ergometry test, and as
oxygen uptake peak in endurance exercise capacity tests (Spasov
et al., 2000;De Bock et al., 2004) was found in two studies, while for
the majority of other parameters, such as muscle strength, peak
power, ventilatory threshold, lactate threshold and oxygen uptake,
tested in tree studies, Rhodiola did not demonstrate significant
difference compared to placebo groups (De Bock et al., 2004;Earnest
et al., 2004; Colson et al., 2005).
One of the most important subjects of discussion is related to
seemingly contradictory results of different studies where some
Rhodiola preparations were effective, while some other not (De
Bock et al., 2004;Earnest et al., 2004;Colson et al., 2005). Possible
explanation of this might be found when two important
circumstances are taken into account: dose-effect dependence
pattern and variety in composition of active constituents of
different preparation. The effect of Rhodiola on CNS, and other
body systems does not depend linearly on the dose. The dose
dependent curve has a bell shape: in small doses Rhodiola is
inactive, in intermediate dose level active, and in high dosed
inactive again (Kurkin et al., 2003;Perfumi and Mattioli, 2007;
Wiegant et al. 2009 ;Schriner et al., 2009). This phenomenon is
well known in pharmacology and can have different explanations,
including feedback regulation of several signaling systems,
working in parallel in a whole body/system level. These mechan-
isms are very specific for many systems and yet not fully
scientifically investigated.
It can be suggested that in some studies where effect was not
observed the dose of Rhodiola was inappropriate, e.g. De Bock et al.,
2004; Earnest et al., 2004;Colson et al., 2005 studies, where only one
dose was used. It must be pointed out that the content of active
ingredients in herbal preparations depends on many factors, such as
in which geographic and climate zone it was grown, in which season
and whether conditions it was harvested, how it was dried, extracted
and prepared into final dosage form. For example, a high degree of
inter clone variation was found for all tested constituents (salidroside,
tyrosol, rosavin, rosarin, rosin and cinnamic alcohol) in six samples of
Rhodiola rosea roots collected in various regions of Norway. The
highest variation was found for Salidroside and tyrosol, showing an
inter clone variation of 92.8 and 87.8%, respectively (Hellum et al.,
2009). Therefore, the preparations obtained by different producers
can have quite different active dose level.
‘‘A randomized double-blind placebo controlled parallelgroup
study of SHR-5 extract of Rhodiola rosea rootsastreatmentfor
patients with stress related fatigue’’ by Olsson et al, published in
Planta medica. 2009, 75:105-112, clearly demonstrated an antifatigue
and attention improving effect of a Rhodiola rosea extract (SHR-5) in
patients with stress-induced fatigue. The authors pointed out that
these results were in line with other studies demonstrating an
antifatigue effect together with an increase of mental work capacity
(quantitatively/qualitatively) against a background of strain and
stress, which is characteristic of an adaptogen. This conclusion is
questioned in a recent review article ‘‘Perspective on Roseroot
(Rhodiola rosea)studies’’byBlomkvist et al., 2009 saying ‘‘(the
mentionedstudy)appearstobetheonlyoneamongthesewehave
investigated has used a satisfactory experimental protocol and
statistical methods’’.
Whilewerespectsomeoftheconclusionsmadebytheauthors,
and support further more robust studies of Rhodiola, our review of
theevidence(detailedinTables 1–3) provides a different perspective
to the Blomkvist et al. 2009 review. The quality assessment seems to
be according to a binary scale, 0 or 1, (the authors are not explicitly
stating this but is implied from their discussion). The attention of this
paper is ‘‘focused mainly on the statistical analysis to determine if
conclusions (of published articles) are valid’’. While they have pointed
out many pertinent minor weaknesses, it is adventurous to challenge
the efficacy of interventions primarily on findings of technical errors
in a sample of selected articles.
It might be appropriate in this context to point out some
misunderstandings due to printing errors. For instance in
Darbinyan et al. (2007) study in Tables 2 and 3 a misprint
‘‘paired’’ – instead of ‘‘unpaired’’ t-test was published. Actually,
unpaired t-test was used originally in that study and the
difference between groups is very significant. However, if this
method would have been used, a comparison in both groups
would yield even higher significance.
Conclusions
Rhodiola rosea L. is a popular plant in traditional medical
systems in the Nordic countries, Eastern Europe and Asia, with a
reputation for stimulating the nervous system, decreasing
depression, enhancing work performance, eliminating fatigue,
and preventing high altitude sickness. The traditional medicinal
use of the plant, in addition to modern clinical use as referenced
in scientific publications and official pharmacopoeias contribute
to substantiate the well-established medicinal use.
Based on the proposed mechanism of action and available
experimental data, Rhodiola appears to offer an advantage over
other adaptogens in circumstances of acute stress. A single dose of
Rhodiola rosea (SHR-5)prior to acute stress produces favorable
results and prevents stress-induced disruptions in function and
performance. Since many stressful situations are acute in nature,
and sometimes unexpected, an adaptogen that can be taken
acutely in these circumstances, rather than requiring chronic
advance supplementation, could be potentially very useful.
Rhodiola also offers some cardio-protective benefits not
associated with other adaptogens. Its proposed ability to
moderate stress-induced damage and dysfunction in cardiovas-
cular tissue might make Rhodiola the adaptogen of choice among
patients at higher risks for cardiovascular disease (Maslov et al.,
1997). However, it is important to reproduce and confirm the
non-clinical studies and plan for GCP conducted human trials.
The clearest emerging indication for Rhodiola rosea preparation
is as a drug as a tonic during convalescence to increase both
A. Panossian et al. / Phytomedicine 17 (2010) 481–493490
ARTICLE IN PRESS
mental and physical work capacity against a background of
fatigue and/or stress.
Some animal and preliminary clinical evidence suggest the
need for a well defined range of therapeutic dosage of Rhodiola.
Itmaybeconcludedfromthereviewofevidencepresentedinthis
paper that encouraging support exists for Rhodiola’s beneficial effect
on cognitive function and fatigue, as demonstrated by numerous pre-
clinical and several clinical studies. Rhodiola’s adaptogenic effect
increases attention and endurance in situations of decreased
performance caused by fatigue and sensation of weakness, and
reduces stress-induced impairments and disorders related to the
function of neuro-endocrine and immune systems.
Conflicts of interest
J.Sarris declares no conflict of interest. G.Wikman and
A.Panossian are associated with the Swedish Herbal Institute, a
company that researches and commercialises Rhodiola -derived
functional products.
References
Abidov, M., Crendal, F., Grachev, S., Seifulla, R., Ziegenfuss, T., 2003. Effect of
extracts from Rhodiola rosea and Rhodiola crenulata (Crassulaceae) roots on
ATP content in mitochondria of skeletal muscles. Bull. Exp. Biol. Med. 136,
585–587.
Akgul, Y., Ferreira, D., Abourashed, E.A., Khan, I.A., 2004. Lotaustralin from Rhodiola
rosea roots. Fitoterapia 75, 612–614.
Aksenova, R.A., Zotova, M.I., Nekhoda, M.F., Cherdintsev, S.G., 1968. Comparative
characteristics of the stimulating and adaptogenic effects of Rhodiola rosea
preparations. In: Saratikov, A.S. (Ed.), Stimulants of the Central Nervous
System, vol. 2. Tomsk University Press, Tomsk, pp. 3–12.
Aksyonova, R.A., 1968. Pharmacology of Rhodioloside. Ph.D. Thesis in Pharmacol-
ogy, Tomsk State University, Tomsk, USSR. pp. 1–14.
Ali, Z., Fronczek, F.R., Khan, I.A., 2008. Phenylalkanoids and monoterpene
analogues from the roots of Rhodiola rosea. Planta Med. 74, 178–181.
Alm, T., 2004. Ethnobotany of Rhodiola rosea (Crassulaceae) in Norway. SIDA
Contrib. Bot. 21, 321–344.
Avula, B., Wang, Y.H., Ali, Z., Smillie, T.J., Filion, V., Cuerrier, A., Arnason, J.T., Khan,
I.A., 2009. RP-HPLC determination of phenylalkanoids and monoterpenoids in
Rhodiola rosea and identification by LC-ESI-TOF. Biomed. Chromatogr. 23,
865–872.
Barnaulov, O.D., Limarenko, A.Y., Kurkin, V.A., Zapesochnaya, G.G., Shchavlinskij,
A.N., 1986. A comparative evaluation of the biological activity of compounds
isolated from species of Rhodiola. Khim. Pharm. Z. 23, 1107–1112.
Basch, E.M., Ulbricht, C.E., 2005. Natural Standards. Herb & Supplement Handbook.
The Clinical Bottom line. Elsevier Mosby Inc., St. Luis 963pp.
Blomkvist, J., Taube, A., Larhammar, D., 2009. Perspective on Roseroot (Rhodiola
rosea) studies. Planta Med. 75, 1187–1190.
Bocharova, O.A., Matveev, B.P., Baryshnikov, Alu., Figurin, K.M., Serebriakova, R.V.,
Bodrova, N.B., 1995. The effect of a Rhodiola rosea extract on the incidence of
recurrences of a superficial bladder cancer (experimental clinical research).
Urol. Nefrol. (Mosk.) 2, 46–47.
Boon-Niermeijer, E.K., van den Berg, A., Wikman, G., Wiegant, F.A., 2000. Phyto-
adaptogens protect against environmental stress-induced death of embryos
from the freshwater snail Lymnaea stagnalis. Phytomedicine 7, 389–399.
Brekhman, I.I., Dardymov, I.V., 1968. New substances of plant origin which
increase non-specific resistance. Ann. Rev. Pharmacol. 8, 419–430.
Brichenko, V.S., Kupriyanova, I.E., Skorokhodova, T.F., 1986. The use of herbal
adaptogens together with tricyclic antidepressants in patients with psycho-
genic depressions. In: Goldberg, E.D. (Ed.), Modern Problems of Pharmacology
and Search for New Medicines, vol. 2. Tomsk University Press, Tomsk, pp.
58–60.
Brown, R.P., Gerbarg, P.L., Ramazanov, Z., 2002. Rhodiola rosea: a phyto medicinal
overview. Herbal. Gram 56, 40–52.
Bystritsky, A., Kerwin, L., Feusner, J.D., 2008. A pilot study of Rhodiola rosea
(Rhodax) for generalized anxiety disorder (GAD). J. Altern. Complement. Med.
14, 175–180.
Cai, L., Wang., H., Li, Q., Qian, Y., Yao, W., 2008. Salidroside inhibits H
2
O
2
-induced
apoptosis in PC12 cells by preventing cytochrome c release and inactivating of
caspase cascade. Acta Biochim. Biophys. Sin. (Shanghai) 40, 796–802.
Cao, L.L., Du, G.H., Wang, M.W., 2005. Effect of salidroside on mitochondria injury
induced by sodium azide. Yao Xue Xue Bao. 40, 700–704.
Cao, L.L., Du, G.H., Wang, M.W., 2006. Effect of salidroside on cell damage induced
by glutamate and intracellular free calcium in PC12 cells. J. Asia. Nat. Prod. Res.
8, 159–165.
Chang, Y.W., Yao, H.T., Hsieh, S.H., Lu, T.J., Yeh, T.K., 2007. Quantitative
determination of salidroside in rat plasma by on-line solid-phase extraction
integrated with high-performance liquid chromatography/electrospray ioni-
zation tandem mass spectrometry. J. Chromatogr. B Anal. Technol. Biomed. Life
Sci. 857, 164–169.
Chen, X., Liu, J., Gu, X., Ding, F., 2008. Salidroside attenuates glutamate-induced
apoptotic cell death in primary cultured hippocampal neurons of rats. Brain
Res. 1238, 189–198.
Colson, S.N., Wyatt, F.B., Johnston, D.L., Autrey, L.D., Fitz Gerald, Y.L., Earnest, C.P.,
2005. Cordyceps sinensis- and Rhodiola rosea-based supplementation in male
cyclists and its effect on muscle tissue oxygen saturation. J. Strength Cond. Res.
19, 358–363.
Darbinyan, V., Aslanyan, G., Amroyan, E., Gabrielyan, E., Malmstr ¨
om, C., Panossian,
A., 2007. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of
mild to moderate depression. Nordic J. Psychiatry 61, 2343–2348.
Darbinyan, V., Kteyan, A., Panossian, A., Gabrielian, E., Wikman, G., Wagner, H.,
2000. 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 7,
365–371.
De Bock, K., Eijnde, B.O., Ramaekers, M., Hespel, P., 2004. Acute Rhodiola rosea
intake can improve endurance exercise performance. Int. J. Sport Nutr. Exerc.
Metab. 14, 298–307.
Diaz-Lanza, A.M., Abad-Martinez, M.J., Fernandez-Matellano, L., Recuero Carretero,
C., Villaescusa-Castillo, L., Silvan-Sen, A.M., Bermejo-Benito, P., 2001. Lignan
and phenyl propanoid glycosides from Phillyrea latifolia and their in vitro anti-
inflammatory activity. Planta Med. 67, 219–223.
Dieamant Gde, C., Velazquez Pereda Mdel, C., Eberlin, S., Nogueira, C., Werka, R.M.,
Queiroz, M.L., 2008. Neuroimmunomodulatory compound for sensitive skin
care: in vitro and clinical assessment. J. Cosmet. Dermatol. 7, 112–119.
Dragland, S., 2001. Rosenrot botanikk, innholdsstoff, dyrkning og bruk. Grøn
Forskning, Planteforsk p. 9.
Dragland, S., Galambosi, B., 1996. Medisinplanter, Rosenrot, Forskningsparken i
˚
As., pp. 143–145.
Earnest, C.P., Morss, G.M., Wyatt, F., Jordan, A.N., Colson, S., Church, T.S., Fitzgerald,
Y., Autrey, L., Jurca, R., Lucia, A., 2004. Effects of a commercial herbal-based
formula on exercise performance in cyclists. Med. Sci. Sports Exerc. 36, 504–509.
EMEA/HMPC/102655/2007. Reflection Paper on the Adaptogenic Concept. Eur-
opean Medicines Agency, London, 8 May 2008.
EMEA/HMPC/104613/2005. European Medicines Agency. Committee on Medi-
cinal Products. Available at /http://www.emea.europa.eu/pdfs/human/hmpc/
10461305en.pdfS(Accessed 01/03/2009).
Estonian Ministry of Health Affairs, 1998. Regulation no. 7, Annex 1, 21 January,
Government of Estonia, Tallin.
Fintelmann, V., Gruenwald, J., 2007. Efficacy and tolerability of a Rhodiola rosea
extract in adults with physical and cognitive deficiencies. Adv. Ther. 24,
929–939.
Ganzera, M., Yayla, Y., Khan, I.A., 2001. Analysis of the marker compounds of
Rhodiola rosea L. (golden root) by reversed phase high performance liquid
chromatography. Chem. Pharm. Bull. (Tokyo) 49, 465–467.
Ha, Z., Zhu, Y., Zhang, X., Cui, J., Zhang, S., Ma, Y., Wang, W., Jian, X., 2002. The effect
of rhodiola and acetazolamide on the sleep architecture and blood oxygen
saturation in men living at high altitude. Zhonghua Jie He He Hu Xi Za Zhi. 25,
527–530.
Halldorsson, B., 1783. Grasnytjar. Stein A.F., Copenhagen, (reprinted In Akureyri
1983, pp. 241–242).
Heilig, M., 2004. The NPY system in stress, anxiety and depression. Neuropeptides
38, 213–224.
Hellum B.H., Tosse A., Hoybakk K., Thomsen M., Rohloff J., Georg Nilsen O., 2009.
Potent in vitro inhibition of CYP3A4 and P-glycoprotein by Rhodiola rosea.
Planta Med. 29 September 2009 [Epub ahead of print].
Herbert, J., Goodyer, I.M., Grossman, A.B., Hastings, M.H., de Kloet, E.R., Lightman,
S.L., Lupien, S.J., Roozendaal, B., Seckl, J.R., 2006. Do corticosteroids damage the
brain? J Neuroendocrinol. 18, 393–411.
Iaremiı
˘, I.N., Grigor’eva, N.F., 2002. Hepatoprotective properties of liquid extract of
Rhodiola rosea. Eksp. Klin. Farmakol. 65, 57–59.
Jadad, A.R., Moore, R.A., Carroll, D., Jenkinson, C., Reynolds, D.J., Gavaghan, D.J.,
McQuay, H.J., 1996. Assessing the quality of reports of randomized clinical
trials: is blinding necessary? Control Clin Trials 17, 1–12.
Jafari, M., Felgner, J.S., Bussel, I.I., Hutchili, T., Khodayari, B., Rose, M.R., Vince-Cruz,
C., Mueller, L.D., 2007. Rhodiola: a promising anti-aging Chinese herb.
Rejuvenat. Res. 10, 587–602.
Jang, S.I., Pae, H.O., Choi, B.M., Oh, G.S., Jeong, S., Lee, H.J., Kim, H.Y., Kang, K.J., Yun,
Y.G., Kim, Y.C., Chung, H.T., 2003. Salidroside from Rhodiola sachalinensis
protects neuronal PC12 cells against cytotoxicity induced by amyloid-beta.
Immunopharmacol. Immunotoxicol. 25, 295–304.
Kaliko, I.M., Tarasova, A.A., 1966. Effect of Leuzea and Golden Root extracts on
dynamic peculiarities of the highest neural performance. In: Saratikov, A.S.
(Ed.), Stimulants of the Central Nervous System. University Publishing Press,
Tomsk, pp. 115–120.
Kelly, G.S., 2001. Rhodiola rosea: a possible plant adaptogen. Altern. Med. Rev. 6,
293–302.
Khanum, F., Bawa, A.S., Singh, B., 2005. Rhodiola rosea: a versatile adaptogen.
Comp. Rev. Food Sci. Food Saf. 4, 55–62.
Komar, V.V., Kit, S.M., Sitschuk, L.V., Sitschuk, V.M., 1981. The effect of carpatian
Rhodiola rosea on human mental activity. Farmatsevtich. Zhurnal. 4, 62–64.
Krasik, E.D., Morozova, E.S., Petrova, K.P., Ragulina, G.A., Shemetova, L.A., Shuvaev,
V.P., 1970a. Therapy of asthenic conditions: clinical perspectives of application
A. Panossian et al. / Phytomedicine 17 (2010) 481–493 491
ARTICLE IN PRESS
of Rhodiola rosea extract (golden root). In: Avrutskiy, G.Y. (Ed.), Proceedings
Modern Problems in Psycho-pharmacology. Siberian Branch of Russian
Academy of Sciences, Kemerovo City, pp. 298–330.
Krasik, E.D., Petrova, K.P., Rogulina, G.A., 1970b. About the adaptogenic and
stimulating effect of Rhodiola rosea extract. In: Avrutskiy, G.Y. (Ed.), Proceed-
ings of All-Union and 5th Sverdlovsk Area Conference of Neurobiologists,
Psychiatrists and Neurosurgeons—26–29 May 1970. Sverdlovsk Press,
Sverdlovsk, pp. 215–217.
Kurkin, V.A., Zapesochnaya, G.G., 1986a. Chemical composition and pharmacolo-
gical properties of Rhodiola rosea L. Khim. Pharm. Z. 20, 1231–1244.
Kurkin, V.A., Zapesochnaya, G.G., Shchavlinskii, A.N., Nukhimovsky, B.L., Van-
dishev, V.V., 1985b. Methods of analysis of identity and quality of Rhodiola
rosea roots. Khim. Prir. Soedin. 19, 185–190.
Kurkin, V.A., Dubishchev, A.V., Titova, I.N., Volotsueva, A.V., Petrova, E.S.,
Zhestkova, N.V., Klimova, I.Yu, 2003. Neurotropic properties of some
phytopreparations containing phenylpropanoids. Rastit. Resursi. 3, 115–122.
Kurkin, V.A., Zapesochnaya, G.G., Shchavlinskii, A.N., 1985a. Terpenoids of Rhodiola
rosea roots and rhizoama. Khim. Prir. Soedin. 5, 632–636.
Kurkin, V.A., Zapesochnaya, G.G., 1986b. Terpenoids of Rhodiola rosea roots and
rhizoama. Khim. Prir. Soedin. 5, 643–644.
Kurkin, V.A., Zapesochnaya, G.G., Borunov, Y., Nukhimovskii, E., Shreter, A.,
Shchavlinskii, A., 1986. Chemical investigation of some species of the genera
Rhodiola L. and Sedum L. and problems of their chemotaxonomy. Rastitel’nye
Resursy 22, 310–319.
Larhammar, D., Salaneck, E., 2004. Molecular evolution of NPY receptor subtypes.
Neuropeptides 38, 141–151.
Lazarev, N.V., 1958. General and specific in action of pharmacological agents.
Farmacol. Toxicol. 21, 81–86.
Lazarev, N.V., Ljublina, E.I., Rozin, M.A., 1959. State of nonspecific resistance. Patol.
Fiziol. Experim. Terapia 3, 16–21.
Li, H.B., Ge, Y.K., Zheng, X.X., Zhang, L., 2008. Salidroside stimulated glucose uptake
in skeletal muscle cells by activating AMP-activated protein kinase. Eur.J.
Pharmacol. 588, 165–169.
Linne
´, C., 1749. Materia Medica. Liber I. de Plantis, Stockholm, p. 168.
Lishmanov, Iu.B., Trifonova, Zh.V., Tsibin, A.N., Maslova, L.V., Dement’eva, L.A.,
1987. Plasma beta-endorphin and stress hormones in stress and adaptation.
Biull. Eksp. Biol. Med. 103, 422–424.
Lishmanov, Yu.B., Krylatov, A.V., Maslov, L.N., Nariznaya, N.V., Zamotinkii, 1996.
Effect of Rhodiola rosea on the level of inducible Hsp-70 in miocard in stress.
Bull. Exp. Biol. Med. 121, 256–258.
Ma, G., Li, W., Dou, D., Chang, X., Bai, H., Satou, T., Li, J., Sun, D., Kang, T., Nikaido, T.,
Koike, K., 2006. Rhodiolosides A-E, monoterpene glycosides from Rhodiola
rosea. Chem. Pharm. Bull. (Tokyo) 54, 1229–1233.
Ma, L., Cai, D.L., Li, H.X., Tong, B.D., Wang, Y., Pei, S.P., 2009. Protective effects of
salidroside on oxidative damage in fatigue mice. Zhong Xi Yi Jie He Xue Bao 7,
237–241.
Magnusson, B., 1992. F¨
agningar. v¨
axter som ber ¨
or os, O
¨stersund.
Maı
˘meskulova, L.A., Maslov, L.N., Lishmanov, Iu.B., Krasnov, E.A., 1997. The
participation of the mu-, delta- and kappa-opioid receptors in the realization
of the anti-arrhythmia effect of Rhodiola rosea. Eksp. Klin. Farmakol. 60,
38–39.
Mao, Y., Li, Y., Yao, N., 2007a. Simultaneous determination of salidroside and
tyrosol in extracts of Rhodiola L. by microwave assisted extraction and high-
performance liquid chromatography. J. Pharm. Biomed. Anal. 45, 510–515.
Mao, Y., Zhang, X., Zhang, X., Lu, G., 2007b. Development of an HPLC method for
the determination of salidroside in beagle dog plasma after administration of
salidroside injection: application to a pharmacokinetics study. J. Sep. Sci. 30,
3218–3222.
Marina, T.F., Mikhaleva, L.K., Suslov, N.I., 1994. Comparative effects of para-tyrosol
and Rhodiola extract on the central nervous system. In: Proceedings of a joint
plenary session of pathophysiologists and pharmacologists of Siberia and the
Far East on mechanisms of the development of pathological processes.
Kemerovo State University Press, Kemerovo, pp. 66-68.
Mashkovskij, M.D., 1977. Medicines (Manual of Pharmacotherapy for Doctors),
Part I, 8th ed. Meditsina, Moscow, p. 133.
Maslov, L.N., Lishmanov, Iu.B., Naumova, A.V., Lasukova, T.V., 1997. Do endogenous
ligands of peripheral mu- and delta-opiate receptors mediate anti-arrhythmic
and cardioprotective effects of Rhodiola rosea extract? Biull Eksp. Biol. Med.
124, 151–153.
Mattioli, L., Funari, C., Perfumi, M., 2008. Effects of Rhodiola rosea L. extract on
behavioural and physiological alterations induced by chronic mild stress in
female rats. J. Psychopharmacol. 23, 130–142.
Mattioli, L., Perfumi, M., 2007. Rhodiola rosea L. extract reduces stress- and CRF-
induced anorexia in rats. J. Psychopharmacol. 21, 742–750.
Mikhailova, M.N., 1983. Clinical and experimental substantiation of asthenic
conditions therapy using Rhodiola rosea extract. In: Goldsberg, E.D. (Ed.),
Current problems of Psychiatry. Tomsk State University Press, Tomsk, pp.
126–127.
Muravijeva, D.A., 1978. Pharmacognosy (with Fundamentals of Biochemistry of
Medicinal Herbs). Meditsina, Moscow pp. 541–546.
M¨
uller-Dietz, H., 1969. Arzneipflanzen in der Sowietunion. Berichte Osteuropa
Inst. Freien Univ. Berlin 44, 91–93.
National Pharmacopoeia Committee, 1996. Pharmacopoeia article PA 42-2163-96,
Extractum Rhodiolae fluidum. The Russian Federation Ministry of Health and
Medical Industry, Moscow.
National Pharmacopoeia of the USSR, 1990. 11th Ed.—Pharmacopoeia paper 75,
Rhizome and roots of Rhodiola rosea. The USSR Ministry of Health, Moscow,
Meditsina 2(1), 317–319; update no. 2 dated 19 May 1999.
Olsson, E.M.G., von Sche
´ele, B., Panossian, A.G., 2009. A randomized double-blind
placebo controlled parallell group study of SHR-5 extract of Rhodiola rosea
roots as treatment for patients with stress related fatigue. Planta Med. 75,
105–112.
Panossian, A., Wikman, G., Andreeva, L., Boykova, A., Nikiforova, D., Timonina, N.,
2008c. Adaptogens exert a stress protective effect by modulation of expression
of molecular chaperons. Planta Med. 74, 1018.
Panossian, A., 2003. Adaptogens: tonic herbs for fatigue and stress. Alt. Comp.
Therap. 9, 327–332.
Panossian, A., Hambartsumyan, M., Hovanissian, A., Gabrielyan, E., Wikman, G.,
2007. The adaptogens rhodiola and schizandra modify the response to
immobilization stress in rabbits by suppressing the increase of phosphorylated
stress-activated protein kinase, nitric oxide and cortisol. Drug Targets Insights
1, 39–54 /http://www.la-press.com/the-adaptogens-rhodiola-and-schizan-
dra-modify-the-response-to-immobili-a260S.
Panossian, A., Hovhannisyan, A., Abrahamyan, H., Gabrielyan, E., Wikman, G.,
2008b. Pharmacokinetic and pharmacodynamic study of interaction of
Rhodiola rosea SHR-5 extract with warfarin and theophylline in rats.
Phytotherapy Res. 23, 351–357.
Panossian, A., Hovhannisyan, A., Abrahamyan, H., Wikman, G., 2009b. Pharmaco-
kinetics of active constituents of Rhodiola rosea L. special extract SHR-5. In:
Compendium of Bioactive Natural Products Vol. 2: Efficacy, Safety & Clinical
Evaluation (Part-1) Stadium Press LLC, USA, pp. 1–23.
Panossian, A., Nikoyan, N., Ohanyan, N., Hovhannisyan, A., Abrahamyan, H.,
Gabrielyan, E., Wikman, G., 2008a. Comparative study of Rhodiola preparations
on behavioral despair of rats. Phytomedicine 15, 84–91.
Panossian, A., Wagner, H., 2005. Stimulating effect of adaptogens: an overview
with particular reference to their efficacy following single dose administration.
Phytother. Res. 19, 819–838.
Panossian, A., Wikman, G., 2005. Effect of adaptogens on the central nervous
system. Arq. Bras. Fitomed. Cient. 2, 108–130.
Panossian, A., Wikman, G., 2009a. Evidence-based efficacy of adaptogens in
fatigue, and molecular mechanisms related to their stress-protective activity.
Curr. Clin. Pharmacol. 4, 198–219.
Panossian, A., Wikman, G., 2009b. Evidence-based efficacy of adaptogens in fatigue
and molecular mechanisms relared to their stress-protective activity. In: Bonn,
K. (Ed.), International Evidence-Based Complementary Medicine Conference,
13–15 Macrh, University of New England, Armidale. p. 10.
Panossian, A., Wikman, G., Kaur, P., Asea, A., 2009a. Adaptogens exert a stress
protective effect by modulation of expression of molecular chaperons.
Phytomedicine 16, 617–622.
Panossian, A., Wikman, G., Wagner, H., 1999. Plant adaptogens: new concepts on
their mode of action. Phytomedicine 6, 1–14.
Peng, Y., Luo, J., Lu, Q., Chen, X., Xie, Y., Chen, L., Yang, W., Du, S., 2008. HPLC
analysis, semi-preparative HPLC preparation and identification of three
impurities in salidroside bulk drug. J. Pharm. Biomed. Anal. 49, 828–832.
Perfumi, M., Mattioli, L., 2007. Adaptogenic and central nervous system effects of
single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice.
Phytother. Res. 21, 37–43.
Petsalo, A., Jalonen, J., Tolonen, A., 2006. Identification of flavonoids of Rhodiola
rosea by liquid chromatography–tandem mass spectrometry. J. Chromatogr. A
1112, 224–231.
Pharmacope
´e Franc-aise, 1976. 9th Ed.—Premiere Partie Monographs, vol. II-214,
La Commission Nationale de Pharmacopee, Paris, pp. 100–101.
Pooja, Bawa, A.S., Khanum, F., 2009. Anti-inflammatory activity of Rhodiola
rosea—‘‘a second-generation adaptogen’’. Phytother. Res. 23, 1099–1102.
Prodius, P.A., Manukhina, E.B., Bulanov, A.E., Wikman, G., Malyshev, I.I., 1997.
Adaptogen ADAPT modulates synthesis of inducible stress protein HSP 70 and
increases organism resistance to heat shock. Biull. Eksp. Biol. Med. 123,
629–633.
Qin, Y.J., Zeng, Y.S., Zhou, C.C., Li, Y., Zhong, Z.Q., 2008. Effects of Rhodiola rosea on
level of 5-hydroxytryptamine, cell proliferation and differentiation, and
number of neuron in cerebral hippocampus of rats with depression induced
by chronic mild stress. Zhongguo Zhong Yao Za Zhi. 33, 2842–8246.
Rohloff, J., 2002. Volatiles from rhizomes of Rhodiola rosea L. Phytochemistry 59,
655–661.
Sajdyk, T.J., 2005. Neuropeptide Y receptors as therapeutic targets in anxiety and
depression. Drug Dev. Res. 65, 301–308.
Sandberg, F., Bohlin, L., 1993. Fytoterapi, V¨
axtbaserade l¨
akemedel. H¨
alsokostr ˚
adets
F¨
orlag AB, Sweden p. 131.
Saratikov, A.S., Krasnow, E.A., 1987. Rhodiola rosea is a Valuable Medicinal Plant.
Medical Institute Tomsk, Tomsk p. 252.
Saratikov, A., Marina, T.F., Fisanova, L.L., 1978a. Effect of golden root extract on
processes of serotonin synthesis in CNS. J. Biol. Sci. 6, 142.
Saratikov, A.S., Krasnov, E.A., 2004. Rhodiola rosea (Golden root) Fourth edition,
Revised and Enlarged. Tomsk State University Publishing House, pp. 22–41.
Saratikov, A.S., 1973. The Golden Root (Rhodiola rosea). Tomsk University
Publishing, Tomsk, p. 126.
Saratikov, A.S., 1976. Adaptogenic action of Eleutherococcus and Golden Root
preparations. In: Brekhman, I.I. (Ed.), Adaptation Processes and Biologically
Active Compounds pp. 54–62.
Saratikov, A.S., Krasnov, E.A., Chnikina, L.A., Duvidson, L.M., Sotova, M.I., Marina,
T.F., Nechoda, M.F., Axenova, R.A., Tscherdinzeff, S.G., 1968. Rhodiolosid, a new
A. Panossian et al. / Phytomedicine 17 (2010) 481–493492
ARTICLE IN PRESS
glycoside from Rhodiola rosea and its pharmacological properties. Pharmazie
23, 392–395.
Saratikov, A.S., Marina, T.F., Fisanova, L.L., 1978b. Mechanism of action of
salidrozide on the metabolism of cerebral catecholamines. Vopr. Med. Khim.
24 (5), 624–628.
Saratikov, A.S., Marina, T.F., Kaliko, I.M., 1965. The stimulating effect of Rhodiola
rosea on the higher brain structures. Vestnik. Sibirskog Otdeleniya, USSR Acad.
Sci. 8, 120–125.
Schriner, S.E., Avanesian, A., Liu, Y., Luesch, H., Jafari, M., 2009. Protection of human
cultured cells against oxidative stress by Rhodiola rosea without activation of
antioxidant defenses. Free Radic. Biol. Med. 47, 577–584.
Schutgens, F.W., Neogi, P., van Wijk, E.P., van Wijk, R., Wikman, G., Wiegant, F.A.,
2009. The influence of adaptogens on ultraweak biophoton emission: a pilot-
experiment. Phytother. Res. 23, 1103–1108.
Shevtsov, V.A., Zholus, B.I., Shervarly, V.I., Vol’skij, V.B., Korovin, Y.P., Khristich,
M.P., Roslyakova, N.A., Wikman, G., 2003. A randomized trial of two different
doses of a SHR-5 Rhodiola roseaextract versus placebo and control of capacity
for mental work. Phytomedicine 10, 95–105.
Siwicki, A.K., Skopin
˜ska-Ro
´¿ewska, E., Hartwich, M., 2007. The influence of
Rhodiola rosea extracts on non-specific and specific cellular immunity in pigs,
rats and mice. Centr. Eur. J. Immunol. 32, 84–91.
Skopn
´ska-Ro
´zewska, E., Wo
´jcik, R., Siwicki, A.K., Sommer, E., Wasiutyn
´ski, A.,
Furmanowa, M., Malinowski, M., Mazurkiewicz, M., 2008. The effect of
Rhodiola quadrifida extracts oncellular immunity in mice and rats. Pol. J. Vet.
Sci. 11, 105–111.
Sokolov, S.Y., Boyko, V.P., Kurkin, V.A., Zapesochnaya, G.G., Rvantsova, N.V.,
Grinenko, H.A., 1990. A comparative study of the stimulant property of certain
phenylpropanoids. Khim. Pharm. Z. 24, 66–68.
Sokolov, S.Y., Ivashin, V.M., Zapesochnaya, G.G., Kurkin, V.A., Shavlinskiy, A.N.,
1985. Study of neurotropic activity of new substances isolated from Rhodiola
rosea. Khim. Pharm. Z. 19, 1367–1371.
Song, E.K., Kim, J.H., Kim, J.S., Cho, H., Nan, J.X., Sohn, D.H., Ko, G.I., Oh, H., Kim, Y.C.,
2003. Hepatoprotective phenolic constituents of Rhodiola sachalinensis on
tacrine-induced cytotoxicity in Hep G2 cells. Phytother. Res. 17, 563–565.
Sparschuch, H., 1775. Pharmacopoae Svecia, Holmia, p. 39.
Spasov, A.A., Wikman, G.K., Mandrikov, V.B., Mironova, I.A., Neumoin, V.V., 2000. A
double-blind, placebo-controlled pilot study of the stimulating and adapto-
genic 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 7, 85–89.
Strandberg, K., Aly, K.-O., 1997.L¨
akemedelsboken 97/98, Naturl¨
akemedel, Apo-
teksbolaget AB, pp. 870–879.
Tasan, R.O., Lin, S., Hetzenauer, A., Singewald, N., Herzogm, H., Sperkm, G., 2009.
Increased novelty-induced motor activity and reduced depression-like
behavior in neuropeptide Y (NPY)-Y4 receptor knockout mice. Neuroscience
158, 1717–1730.
Tolonen, A., Pakonen, M., Hohtola, A., Jalonen, J., 2003. Phenylpropanoid glycosides
from Rhodiola rosea. Chem. Pharm. Bull. (Tokyo) 51, 467–470.
Tolonen, A., Uusitalo, J., 2004. Fast screening method for the analysis of total
flavonoid content in plants and foodstuffs by high-performance liquid
chromatography/electrospray ionization time-of-flight mass spectrometry
with polarity switching. Rapid Commun. Mass Spectrom. 18, 3113–3322.
Turova, A.D., Sapozhnikova, E.N., 1984. Medicinal Plants of the USSR and their Use
4th edn Meditsina, Moscow pp. 35–37.
Wagner, H., Norr, H., Winterhoff, H., 1994. Plant adaptogens. Phytomedicine 1,
63–76.
Walker, T.B., Robergs, R.A., 2006. Does Rhodiola rosea possess ergogenic properties?
Int J. Sport Nutr. Exerc. Metab. 16, 305–315.
van Diermen, D., Marston, A., Bravo, J., Reist, M., Carrupt, P.A., Hostettmann., K.,
2009. Monoamine oxidase inhibition by Rhodiola rosea L. roots. J. Ethnophar-
macol. 122, 397–401.
Wang, H., Ding, Y., Zhou, J., Sun, X., Wang, S., 2009. The in vitro and in vivo antiviral
effects of salidroside from Rhodiola rosea L. against coxsackievirus B3.
Phytomedicine 16, 146–155.
Wang, S.H., Wang, W.J., Wang, X.F., Chen, W.H., 2008. Effects of salidroside on
carbohydrate metabolism and differentiation of 3T3-L1 adipocytes. Zhong Xi
Yi Jie He Xue Bao. 2, 193–195.
Wiedenfeld, H., Dumaa, M., Malinowski, M., Furmanowa, M., Narantuya, S., 2007.
Phytochemical and analytical studies of extracts from Rhodiola rosea and Rhodiola
quadrifida. Pharmazie 62, 308–311 Erratum in: Pharmazie. 2007 62, 400.
Wiegant, F.A., Surinova, S., Ytsma, E., Langelaar-Makkinje, M., Wikman, G., Post,
J.A., 2009. Plant adaptogens increase lifespan and stress resistance in C. elegans.
Biogerontology. 10, 27–42.
Wiegant, F.A.C., Limandjaja, G., de Poot, S.A.H., Bayda, L.A., Vorontsova, O.N.,
Zenina, T.A., Langelaar Makkinje, M., Post, J.A., Wikman, G., 2008. Plant
adaptogens activate cellular adaptive mechanisms by causing mild damage.
In: Lukyanova, L., Takeda, N., Singal, P.K. (Eds.), Adaptation Biology and
Medicine: Health Potentials, vol. 5. Narosa Publishers, NewDelhi, pp. 319–332.
Virey, J.-J., 1811. Traite de pharmacie the
´orique et pratique, p. 92.
Wu, S., Zu, Y., Wu, M., 2003. High yield production of salidroside in the suspension
culture of Rhodiola sachalinensis. J Biotechnol. 106, 33–43.
Wu, Y.L., Piao, D.M., Han, X.H., Nan, J.X., 2008. Protective effects of salidroside against
acetaminophen-induced toxicity in mice. Biol. Pharm. Bull. 31, 1523–1529.
Wu, Z., Su, W.W., Wang, Y.G., 2004. GC–MS analysis of supercritical carbon dioxide
extraction products from Rhodiola tibetica. Zhongguo Zhong Yao Za Zhi. 29,
239–241.
Xu, K.J., Zhang, S.F., Li, Q.X., 2003. Preventive and treatment effect of composite
Rhodiolae on acute lung injury in patients with severe pulmonary hyperten-
sion during extracorporeal circulation. Zhongguo Zhong Xi Yi Jie He Za Zhi. 23,
648–650.
Ye, Y.C., Chen, Q.M., Jin, K.P., Zhou, S.X., Chai, F.L., Hai, P., 1993. Effect of salidroside
on cultured myocardial cells anoxia/reoxygenation injuries. Zhongguo Yao Li
Xue Bao. 14, 424–426.
Yousef, G.G., Grace, M.H., Cheng, D.M., Belolipov, I.V., Raskin, I., Lila, M.A., 2006.
Comparative phytochemical characterization of three Rhodiola species.
Phytochemistry 67, 2380–2391.
Yu, S., Liu, M., Gu, X., Ding, F., 2008. Neuroprotective effects of salidroside in the
PC12 cell model exposed to hypoglycemia and serum limitation. Cell. Mol.
Neurobiol. 28, 1067–1078.
Zapesochnaya, G.G., Kurkin, V.A., 1983. Flavonoids of Rhodiola rosea roots II. Khim.
Prir. Soedin. 1983 (19), 23–32.
Zapesochnaya, G.G., Kurkin, V.A., 1982. Glycosides of cinnamic alcohol from
Rhodiola rosea roots and rhizoma. Khim. Prir. Soedin. 18, 723–727.
Zapesochnaya, G.G., Kurkin, V.A., Boyko, V.P., Kolkhir, V.K., 1995. Phenylpropa-
noids—promising biologically active compounds of medicinal plants. Khim.
Pharm. Z. 29, 47–50.
Zdanowska, D., Skopinska-Roewska, E., Sommer, E., Siwiski, A.K., Wasiutynski, A.,
Bany, J., 2009. The effect of Rhodiola rosea extracts on the bacterial infection in
mice. Centr. Eur. J. Immunol. 34, 35–37.
Zhang, J., Liu, A., Hou, R., Zhang, J., Jia, X., Jiang, W., Chen, J., 2009. Salidroside
protects cardiomyocyte against hypoxia-induced death: a HIF-1alpha-acti-
vated and VEGF-mediated pathway. Eur. J. Pharmacol. 607, 6–14.
Zhang, L., Yu, H., Sun, Y., Lin, X., Chen, B., Tan, C., Cao, G., Wang, Z., 2007. Protective
effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y
human neuroblastoma cells. Eur. J. Pharmacol. 564, 18–25.
Zhang, S., Gao, W., Xu, K., Guo, Y., Lin, S., Xue, X., Lu, G., Li, N., Liu, H., Liu, W., 1999.
Early use of Chinese drug rhodiola compound for patients with post-trauma
and inflammation in prevention of ALI/ARDS. Zhonghua Wai Ke Za Zhi. 37,
238–240.
Zhang, W.S., Zhu, L.Q., Niu, F.L., Deng, R.C., Ma, C.X., 2004. Protective effects of
salidroside on injury induced by hypoxia/hypoglycemia in cultured neurons.
Zhongguo Zhong Yao Za Zhi. 29, 459–462.
Zhang, X., Zhu, B., Jin, S., Yan, S., Chen, Z., 2006. Effects of salidroside on bone
marrow matrix metalloproteinases of bone marrow depressed anemic mice.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi. 23, 1314–1319.
Zhang, X.S., Zhu, B.D., Hung, X.Q., Chen, Y.F., 2005. Effect of salidroside on bone
marrow cell cycle and expression of apoptosis-related proteins in bone
marrow cells of bone marrow depressed anemia mice. Sichuan Da Xue Xue Bao
Yi Xue Ban. 36, 820–823.
Zhang, Y., Liu, Y., 2005. Study on effects of salidroside on lipid peroxidation on
oxidative stress in rat hepatic stellate cells. Zhong Yao Cai. 28, 794–796.
Zotova, M.I., 1965. The effect of Rhodiola rosea extract on mental working activity
in man. In: Collection of Reports at Third Scientific Conference Of Physiolo-
gists. Tomsk, Biochemists and Pharmacologists of Western Siberia., pp.
298–299.
Zou, Y.Q., Cai, Z.Y., Mao, Y.F., Li, J.B., Deng, X.M., 2009. Effects of salidroside-
pretreatment on neuroethology of rats after global cerebral ischemia-
reperfusion. Zhong Xi Yi Jie He Xue Bao. 7, 130–134.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493 493
