Rosenroot (Rhodiola rosea): Traditional use, chemical composition,
pharmacology and clinical efﬁcacy
, G. Wikman
, J. Sarris
Swedish Herbal Institute Research and Development, ˚
The University of Melbourne, Department of Psychiatry, Melbourne, Australia
Swinburne University of Technology, Brain Sciences Institute, Melbourne, Australia
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.
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
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
ARTICLE IN PRESS
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journal homepage: www.elsevier.de/phymed
0944-7113/$ - see front matter &2010 Elsevier GmbH. All rights reserved.
E-mail addresses: firstname.lastname@example.org (A. Panossian), georg.wikman@
shi.se (G. Wikman), email@example.com (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;
´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¨
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/
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.
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
Russian literature, n = 357*
Cited on Medline, n = 258**
* - References from Saratikov&Krasnov, Golden Root, 2004
** - http://www.ncbi.nlm.nih.gov/sites/entrez
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
A. Panossian et al. / Phytomedicine 17 (2010) 481–493482
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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
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
Adaptogens are compounds which could increase ‘‘the state of non-speciﬁc resistance’’ in stress [Lazarev, 1958;Lazarev et al.,
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
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].
R1- H, R2 - Glu - Rhodiolosid B
R1 - Glu, R2 - H - Rhodiolosid C
R1 - H, R2 - H - Rosiridin
R1- OH, R2 - H-Rhodiolosid D
R1 - H, R2 - Ara -Rhodiolosid El
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-
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
Galloyl - G
-3-O-gallate (4 S)
Prodelphinidin -gallate esthers
Tyrosol Caffeic acid Cinnamic alcohol
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
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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.
Rhodiolin (optically inactive mixture of two diastereoisomers)
Fig. 3. (Continued)
A. Panossian et al. / Phytomedicine 17 (2010) 481–493 485
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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
Stimulating effect on the central nervous system including effects
on cognitive functions such as attention, memory and learning
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
(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;
˘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;
˘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
Rosarin - 30.020
Rosavin - 30.705
Rosin - 32.115
Sorbic acid - 33.515
Methyl 4-hyroxybensoate - 36.683
Cinnamylalcohol - 42.621
Salidrosid - 13.946
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
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.,
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
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
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.,
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-
´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
Randomized and non-randomized clinical trials of Rhodiola in mental fatigue, stress-induced fatigue, fatigue syndrome and asthenia.
Indication for use and/or pharmacological activity Number of
Rhodiola rosea Mental fatigue: Rhodiola can improve attention in cognitive function in fatigue after single and
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
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
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.
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.
Results of non-randomized studies on humans involving effects of Rhodiola on mental performance in fatigue.
tested in the
Number of subjects
in the study
of study Effects recorded
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.
PC, SB 80 healthy students
(control group) and
70 patients with
? 10 drops
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
IIa Kaliko and
20-50 40 drops
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
E. senticosus (40%
Extract of R.
Tyrosol ? 82 ? 1, 5, 10
? Improved mental performance, reduced the number
of errors in Anﬁmov’s correction test.
III Marina et al.
R. rosea extract 5 drops
R. rosea (tincture
PC 85 20-28 5-10
acute Improved mental performance, reduced the number
of errors in Anﬁmov’s correction test: the
stimulating effect lasted 4 h or more
R. rosea (extract
C 120 50-89 2
12 weeks Improved in cognitive deﬁciencies (concentration
deﬁciencies, forgetfulness, decreased memory,
susceptibility to stress, irritability)
CO - crossover; DB - double-blind; SB - single blind, NC - not controlled; PC - placebo-controlled; C – controlled.
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.
? - data not listed or unavailable.
A. Panossian et al. / Phytomedicine 17 (2010) 481–493488
ARTICLE IN PRESS
Results of randomized studies on humans involving effects of Rhodiola preparations on mental performance related to fatigue
(sample size of
et al., 1996)
PC 2 parallel
60 volunteers with
(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
PC, CO 2
56 healthy subjects
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
improvement in the treatment
group (SHR-5) during the ﬁrst 2
None Ib 4 Darbinyan
PC 2 parallel
40 healthy subjects
(20/20) [17-19 years]
Extract SHR-5 (50 mg
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
161 healthy subjects,
(41/20/40 treated +
20 untreated) [19-21
Extract SHR-5 (single
dose of 370 mg or 555
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
lasting 40 min
Ib 3 Shevtsov
PC 3 parallel
91 patients with mild
(170 mg or 340 mg
for 6 weeks
Depression in total HAMD and
Signiﬁcant differences in HAMD
and BDI scores and scores
reﬂecting levels of insomnia,
somatisation and self-esteem in
SHR-5 groups compared to
None Ib 5 Darbinyan
CO - crossover; PC - placebo-controlled; M – multi-centre;
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;
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
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
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
investigated has used a satisfactory experimental protocol and
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.
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.
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
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