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Rosenroot (Rhodiola rosea): Traditional use, chemical composition, pharmacology and clinical efficacy

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The aim of this review article was to summarize accumulated information related to chemical composition, pharmacological activity, traditional and official use of Rhodiola rosea L. in medicine. In total approximately 140 compounds were isolated from roots and rhizome - monoterpene alcohols and their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives. Studies on isolated organs, tissues, cells and enzymes have revealed that Rhodiola preparations exhibit adaptogenic effect including, neuroprotective, cardioprotectiv e, anti-fatigue, antidepressive, anxiolytic, nootropic, life-span increasing effects and CNS stimulating activity. A number of clinical trials demonstrate that repeated administration of R. rosea extract SHR-5 exerts an anti-fatigue effect that increases mental performance (particularly the ability to concentrate in healthy subjects), and reduces burnout in patients with fatigue syndrome. Encouraging results exist for the use of Rhodiola in mild to moderate depression, and generalized anxiety. Several mechanisms of action possibly contributing to the clinical effect have been identified for Rhodiola extracts. They include interactions with HPA-system (cortisol-reducing), protein kinases p-JNK, nitric oxide, and defense mechanism proteins (e.g. heat shock proteins Hsp 70 and FoxO/DAF-16). Lack of interaction with other drugs and adverse effects in the course of clinical trials make it potentially attractive for use as a safe medication. In conclusion, Rhodiola rosea has robust traditional and pharmacological evidence of use in fatigue, and emerging evidence supporting cognition and mood.
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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.
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... Rhodiola rosea is a perennial flowering plant belonging to the Crassulaceae family. It grows naturally in the wild at high altitude and can be found in the Arctic and in mountainous areas of Central Asia and Europe [1]. Extracts from Rhodiola are considered as adaptogens (EMEA/HMPC/102655/2007). Adaptogens are nontoxic agents that increase resistance against physical, chemical, biological, and psychological stressors by normalizing the harmful effect of these stressors independently of the nature of the pathologic state. ...
... On the contrary, some cinnamic alcohol glycosides such as rosavin, rosarin, and rosin have been solely found in Rhodiola rosea. These compounds are referred to as "rosavins" and are represented by the phenylpropanoid rosavin [1]. Both salidroside and rosavin represent the lead marker compounds of the RRE. ...
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Background: Sustained stress with the overproduction of corticosteroids has been shown to increase reactive oxygen species (ROS) leading to an oxidative stress state. Mitochondria are the main generators of ROS and are directly and detrimentally affected by their overproduction. Neurons depend almost solely on ATP produced by mitochondria in order to satisfy their energy needs and to form synapses, while stress has been proven to alter synaptic plasticity. Emerging evidence underpins that Rhodiola rosea, an adaptogenic plant rich in polyphenols, exerts antioxidant, antistress, and neuroprotective effects. Methods: In this study, the effect of Rhodiola rosea extract (RRE) WS®1375 on neuronal ROS regulation, bioenergetics, and neurite outgrowth, as well as its potential modulatory effect on the brain derived neurotrophic factor (BDNF) pathway, was evaluated in the human neuroblastoma SH-SY5Y and the murine hippocampal HT22 cell lines. Stress was induced using the corticosteroid dexamethasone. Results: RRE increased bioenergetics as well as cell viability and scavenged ROS with a similar efficacy in both cells lines and counteracted the respective corticosteroid-induced dysregulation. The effect of RRE, both under dexamethasone-stress and under normal conditions, resulted in biphasic U-shape and inverted U-shape dose response curves, a characteristic feature of adaptogenic plant extracts. Additionally, RRE treatment promoted neurite outgrowth and induced an increase in BDNF levels. Conclusion: These findings indicate that RRE may constitute a candidate for the prevention of stress-induced pathophysiological processes as well as oxidative stress. Therefore, it could be employed against stress-associated mental disorders potentially leading to the development of a condition-specific supplementation.
... Rhodiola rosea is a perennial herb in the Rhodiola family that grows at altitudes from 1600 to 4000 m. It is vigorous and highly adaptable to its environment, growing normally even in cold, dry places and at high altitudes where there is lack of oxygen, a large temperature difference between day and night, and strong ultraviolet lights [1,2]. Due to the remarkable medicinal value of its characteristic component, Salidroside (p-hydroxyphenethyl-β-d-glucoside, SAL), Rhodiola rosea enjoys the reputation of being the "highland ginseng" and "snowy mountain herb [3]. ...
... Natural products are a rich source of chemical substances for human beings, especially plants with good medicinal value that have been utilized since ancient times. Rhodiola rosea is a high altitude plant with a wide range of antioxidant, anti-fatigue, and anti-aging activities [2,21]. SAL is a unique chemical constituent of Rhodiola rosea that exerts a plethora of pharmacological effects, particularly on neurological disorders including depression, Parkinson's disease, and Alzheimer's disease [1,3,22,23]. ...
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Objective Salidroside (SAL) is a marker glycoside of Rhodiola rosea with significant antioxidant, anti-inflammatory, and other health benefits. In this study, we determined its neuroprotective effects against Cd-induced toxicity in cultured cells and mice. Materials and methods GL261 cell and Cd-intoxicated mouse model were used. ICP-MS and MWM were performed to measure Cd content and Cd-induced cognitive impairment in mice, respectively. Results SAL attenuated Cd toxicity in GL261 cells as well as protected mice from substantial organic damage and cognitive deficits. SAL treatment alleviated Cd-induced oxidative stress, glial cell activation, and elevation of pro-inflammatory factors including TNF-α, IL-1β, and IL-6. Cd-induced cognitive deficits observed in the Morris water maze in mice were rescued by SAL. At the mechanistic level, SAL maintained the activity of antioxidant enzymes such as SOD and GSH-Px in the serum and brain, and scavenged the peroxidation product MDA, thereby restoring redox homeostasis in vivo, attenuating neuronal damage, and ultimately antagonized Cd-induced toxicity. Furthermore, Cd activated the RIP1-driven inflammatory signaling pathway and Notch/HES-1 signaling axis in the brain, leading to inflammation and neuronal loss, which could be attenuated by SAL. Conclusion SAL is a natural product with good anti-Cd effects, indicating that Rhodiola rosea is promising plant that is worthy of cultivation for health and economic benefits.
... Currently, there is not an effective pharmacological agent to treat testicular ischemia-reperfusion injury in clinical practice. Rhodiola rosea, also called Arctic root or golden root, is a medicinal plant that grows in the Arctic and mountainous regions at high altitude in Asia, Europe, and America [16]. In China, Rhodiola rosea has been widely used as a traditional Tibetan medicine for thousands of years to promote blood circulation and treat angina, apoplexy, and asthma [17]. ...
... Rhodiola rosea contains approximately 140 constituents, including salidroside, tyrosol, rosavin, gallic acid, and rosaline [16,78]. Uyeturk et al. have reported that Rhodiola rosea extract has preventive effects on testicular ischemiareperfusion injury [79]. ...
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Testicular torsion-detorsion results in testicular ischemia-reperfusion injury, which is associated with overgeneration of reactive oxygen species. Salidroside, a major bioactive ingredient extracted from Rhodiola rosea, has strong antioxidant activity. The purpose of this study was to examine the effect of salidroside on testicular ischemia-reperfusion injury. Sixty rats were randomly separated into 3 experimental groups: group A = sham-operated control; group B = testicular ischemia-reperfusion; and group C = testicular ischemia-reperfusion treated with salidroside. The rats in the sham-operated control group received all surgical procedures except testicular torsion-detorsion. The testicular ischemia-reperfusion group underwent 2 hours of left testicular torsion followed by detorsion. The rats in the salidroside-treated group received the same surgical procedure as in testicular ischemia-reperfusion group, but salidroside was injected intraperitoneally at reperfusion. Testicular malondialdehyde content (a reliable index of reactive oxygen species) and protein expression of superoxide dismutase and catalase which are primary antioxidant enzymes in testes were measured at 4 hours after reperfusion. Testicular spermatogenesis was evaluated at 3 months after reperfusion. The malondialdehyde content increased significantly, while superoxide dismutase and catalase protein expression and testicular spermatogenesis reduced significantly in ipsilateral testes of testicular ischemia-reperfusion group, as compared with sham-operated control group. Therapy with salidroside significantly reduced malondialdehyde content and significantly enhanced superoxide dismutase and catalase protein expression and spermatogenesis in ipsilateral testes, as compared with testicular ischemia-reperfusion group. The present findings indicate that treatment with salidroside ameliorates testicular ischemia-reperfusion injury by reducing reactive oxygen species level by upregulating superoxide dismutase and catalase protein expression.
... Besides the rhizomes and roots show anti-stress, cardioprotective, hepatoprotective, antioxidative, immunomodulatory, anticancer properties, stimulation of the central nervous system as well as increasing cognitive functions such as attention, memory, and learning [5][6][7][8]. The main locations of commercial roots and rhizomes of R. rosea are Mountain Altai and in south region of foothill Altai, mainly in the Ust-Kanski, Ust-Koksinski, and assays. ...
... There have been only a few reports available on cholinesterase inhibitory effect of R. rosea. Considering our present study, our findings on cholinesterase inhibitory activity of R. rosae extracts also contribute to the relevant data on this plant, which has been reported to possess a positive effect on nervous and mental diseases, neuroses, and other neurotic disorders [7]. Among plant phenolic acids, ferulic acid has been shown to display cholinesterase inhibitory activity, which could be suggested as scaffold for novel drug candidates [38]. ...
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The aim of the study was to compare the chemical composition of the water and hydromethanolic extracts of R. rosea commercial samples in relation to their biological activity. For this purpose, the HPLC method was used for the determination of eleven phenolic compounds and AAS/AES was used for determination of five essential elements. Moreover, the contents of total phenolic, total flavonoid, total phenolic acids, and L(+)-ascorbic acid were determined. The antioxidant activity was assessed by DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS radical scavenging activity, ferric-reducing/antioxidant power (FRAP), and cupric-reducing antioxidant capacity (CUPRAC) assays, while the inhibitory activity against AChE and BChE enzymes was determined using Ellman’s method. The results showed that the hydromethanolic extracts of R. rosea were richer in phenolic compounds and showed higher antioxidant and neurobiological activity than the water extracts. However, the water extracts gave higher contents of determined elements. Among the individual phenolic compounds gallic acid (2.33 mg/g DW) and sinapic acid (386.44 µg/g DW) had the highest concentrations in the hydromethanolic and water extracts, respectively. Moreover, the most extracts were observed to be more efficient on BChE. Moreover, the correlation analysis indicated a high positive relationship between chemical composition and biological activity in both extracts of R. rosea.
... Rhodiola Rosea L. has been used as an adaptogen in northern Europe and Russia and as a traditional herb in China. Research indicated that it can improve attention in cognitive function in fatigue [17]. Antioxidation, cholinergic regulation, anti-apoptosis, anti-inflammation, and improving brain metabolism are involved in Rhodiola Rosea L. improving learning and memory function [18]. ...
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Background Alzheimer’s disease (AD) is a neurodegenerative disease. Ferroptosis plays a critical role in neurodegenerative diseases. Nuclear factor E2-related factor 2 (Nrf2) is considered an important factor in ferroptosis. Studies have demonstrated that salidroside has a potential therapeutic effect on AD. The intrinsic effect of salidroside on ferroptosis is unclear. The purpose of this study was to investigate the protective effects and pharmacological mechanisms of salidroside on alleviating neuronal ferroptosis in Aβ 1−42 -induced AD mice and glutamate-injured HT22 cells. Methods HT22 cells were injured by glutamate (Glu), HT22 cells transfected with siRNA Nrf2, and Aβ 1−42 -induced WT and Nrf2 −/− AD mice were treated with salidroside. The mitochondria ultrastructure, intracellular Fe ²⁺ , reactive oxygen species, mitochondrial membrane potential, and lipid peroxidation of HT22 cells were detected. Malondialdehyde, reduced glutathione, oxidized glutathione disulfide, and superoxide dismutase were measured. The novel object recognition test, Y-maze, and open field test were used to investigate the protective effects of salidroside on Aβ 1−42 -induced WT and Nrf2 −/− AD mice. The protein expressions of PTGS2, GPX4, Nrf2, and HO1 in the hippocampus were investigated by Western blot. Results Salidroside increased the cell viability and the level of MMP of Glu-injured HT22 cells, reduced the level of lipid peroxidation and ROS, and increased GPX4 and SLC7A11 protein expressions. These changes were not observed in siRNA Nrf2 transfected HT22 cells. Salidroside improved the ultrastructural changes in mitochondria of HT22 cells and Aβ 1−42 -induced AD mice, but not in Aβ 1−42 -induced Nrf2 −/− AD mice. Salidroside increased protein expression levels of GPX4, HO1, and NQO1 and decreased protein expression of PTGS2 in Aβ 1−42 -induced AD mice but not in Aβ 1−42 -induced Nrf2 −/− AD mice. Conclusions Salidroside plays a neuroprotective role by inhibiting neuronal ferroptosis in Aβ 1−42 -induced AD mice and Glu-injured HT22 cells, and its mechanism is related to activation of the Nrf2/HO1 signaling pathway. Graphical Abstract
... This plant is also called golden root or arctic root [30], is mainstream among herbal medicines, and is commonly seen at higher altitudes in the arctic and in mountain ranges throughout Europe and Asia [31]. The medicinal application of R.rosea includes its ability to control psychological stress and mental strength, change the neurotransmitter levels and Central Nervous System (CNS) activity, resistance to high altitude sickness, treat fatigue [32][33][34][35][36], and also act as an anti-depressant and anti-inflammatory drug [37]. Phytochemical analysis on R.rosea showed that the plant is well-equipped with bioactive components like organic acids, flavonoids, monoterpenes, triterpene, and tannins, large amounts of phenolic compounds, and some specific phenylpropane derivatives like rosavins [38]. ...
Article
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The COVID-19 pandemic outbreak demands the designing of potential drugs as there is no specific treatment available. Thanks to their safety and effectiveness, phytochemicals have been used to treat various diseases, including antiviral therapeutics. Molecular docking is a simple, quick, and effective way to screen a variety of molecules for structure-based drug design. Here, we investigate molecular docking experiments on compounds present in plant species, Cocculus hirsutus and Rhodiola rosea and show their potential for the treatment of COVID-19. Almost all the components showed higher binding affinity than the built-in ligand, and those with significantly higher binding affinity were explored further. Molecular mechanics-based generalized born surface area calculations were used to re-rank the top candidates, rhodionidin and cocsoline, and their stability in association with viral protease was confirmed. Density functional theory was used for detailed investigations of the geometries, and electrical properties of rhodionidin and cocsoline. Using the frontier molecular orbitals method, the charge transfer within the molecule was calculated. Chemical reactivity and intermolecular interactions were studied using molecular electrostatic potential maps. These in silico discoveries will simulate the identification of powerful COVID-19 inhibitors, and similar research is likely to make a significant contribution to antiviral drug discovery. Supplementary information: The online version contains supplementary material available at 10.1007/s11224-022-01982-4.
... The ingredients of Rh were derived from a review, and 52 compounds were selected (28) as detailed in the supplementary material (see Figure S1). The target information about the 52 constituents of Rh and AZ was obtained by data mining and reverse docking. ...
Article
Background: Altitude sickness (AS), which is caused by rapid exposure to low amounts of oxygen at high elevations, poses a great threat to humans working and traveling in these conditions. Acute mountain sickness includes high-altitude pulmonary edema and high-altitude cerebral edema. Acetazolamide (AZ) is often used to treat pulmonary edema caused by hypoxia. Additionally, the medicinal plant Rhodiola rosea L. (Rh) is often used to prevent AS in the Qinghai-Tibet plateau. However, the mechanisms of action of Rh and AZ in the treatment of AS remain unclear. To date, no research has been conducted to determine whether their combined use has better efficacy in the treatment and prevention of AS than their separate use. Methods: We used the method of network pharmacology to analyze the mechanisms of Rh and AZ in combination in the prevention and treatment of AS, and also verified our results. Results: The hypoxia-inducible factor (HIF)-1 signaling pathway, which is related to hypoxia, and other pathways related to pulmonary hypertension, became more enriched after the combined use of the 2 drugs. Additionally, Rh and AZ regulated most nodes in the AS network. Further, compared to their separate use, the combined use of Rh and AZ further downregulated the gene expression of HIF-1α and improved hemodynamics in rats, and thus helped the body to reduce its sensitivity to hypoxic environments and pulmonary artery pressure. Conclusions: This study provides evidence supporting the combined use of AZ and Rh in the treatment of AS.
... Both green tea (L-theanine) and rhodiola offer acute functional benefits under stress conditions [39,40], and they might have contributed to the study findings. A previous study by Boyle et al. [12] highlighted the important and synergistic role of rhodiola and green tea extracts in the products' beneficial effects on acute stress. ...
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The effect of a combination of magnesium, vitamins B6, B9, B12, rhodiola and green tea/L-theanine (Mg-Teadiola) on stress was evaluated in chronically stressed, otherwise healthy individuals. Effects on stress-related quality-of-life parameters (sleep and perception of pain) were also explored. Adults with stress for ≥1 month, scoring ≥14 points on the Depression Anxiety Stress Scale (DASS)-42 questionnaire, were randomized (1:1) to receive oral Mg-Teadiola (n = 49) or a placebo (n = 51), for 28 days, with a follow-up assessment on Day 56 (NCT04391452). The primary endpoint was the change in the DASS-42 stress score from baseline to Day 28 with Mg-Teadiola versus placebo. The DASS-42 stress scores significantly decreased from baseline to Day 28 with Mg-Teadiola versus placebo (effect size, 0.29; 95% CI [0.01, 0.57]; p = 0.04). Similar reductions were observed on Day 14 (p = 0.006) and Day 56 (p = 0.02). A significant reduction in sensitivity to cold pain (p = 0.01) and a trend for lower sensitivity to warm pain was observed (p = 0.06) on Day 28. Improvements in daytime dysfunction due to sleepiness (Pittsburgh Sleep Quality Index-7 component score) were reported on Day 28, and were significant on Day 56 (p < 0.001). Mg-Teadiola is effective in managing stress in otherwise healthy individuals. Its beneficial effects on sleep and pain perception need further investigation.
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Rhodiola rosea is a widespread species in Norway. It is well known in Norwegian folk tradition, with a variety of vernacular names, of which many reflect its traditional uses. Past use as a cure for scurvy in cattle may explain names with the prefix kalv- ("calf"). Its widespread use as a hair wash is also reflected in vernacular names. In the past, Rhodiola was planted on turf roofs to protect them from fire, i.e. as an apotropaic (supposedly averting evil forces); this tradition is documented as early as the 13th century.
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The effect of feeding mice R. rosea extracts on Pseudomonas aeruginosa infection was studied. It was found that the infection intensity was highly significantly lower after treatment of mice for 7 days with daily dose 0.4 mg of aqueous extract than in the control group. The weaker effect of hydro-alcoholic extract was statistically significant.