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The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials.

ARTICLE INFO

Keywords:

Rhodiola rosea

Physical and mental performance

Randomized clinical trials

Jadad score

ABSTRACT

Objective: To critically assess the current evidence from randomized clinical trials (RCTs) for or against the effectiveness or efficacy of Rhodiola rosea.

Data sources: Systematic literature searches were performed in six electronic databases: AMED (1985-July 2009), CINAHL (1982-July 2009), The Cochrane Library (search in July 2009), EMBASE (1974-July 2009), MEDLINE (1950-July 2009) and Web of Science (searched in July 2009). No language restrictions were imposed. Reference lists of all retrieved articles were searched, and experts and manufacturers were contacted for unpublished RCT.

Review methods: RCTs testing the efficacy or effectiveness of mono-preparations of R, rosea as sole treatment administered orally against a control intervention in any human individual suffering from any condition or healthy human volunteers were included. Studies were selected, data extracted, and quality assessed by two independent reviewers.

Results: Eleven RCTs met the inclusion criteria; all were placebo-controlled. Six trials investigated the effects of R. rosea on physical performance, four on mental performance, and two in patients diagnosed with mental health condition. The methodological quality of most trials was moderate or good. Only few mild adverse events were reported.

[FIGURE 1 OMITTED]

Conclusion: R. rosea may have beneficial effects on physical performance, mental performance, and certain mental health conditions. There is, however, a lack of independent replications of the single different studies. Five of the 10 RCTs reached more than three points on the Jadad score (i.e., good quality). More research seems warranted.

[C] 2010 Elsevier GmbH. All rights reserved.

Introduction

Rhodiola rosea (also known as golden root, rose root, Arctic root) belongs to the plant family Crassulaceae and genus Rhodiola (Khanum et al. 2005). It is found at high altitudes in the Arctic and mountainous regions throughout Europe and Asia, and has been used medically in Russia, Scandinavia, and many other countries for a range of conditions such as stress-induced depression and anxiety, fatigue, anaemia, impotence, infections (including colds and influenza), cancer, nervous system disorders and headache (Morgan and Bone 2005; Tuttle 2006). It is also regarded as a tonic and stimulant and used to increase physical endurance, stress resistance, attention span, memory and work productivity and resistance to high altitude sickness (Saratikov and Krasnov, 1974).

Small doses of R. rosea increase the bio-electrical activity of the brain (Khanum et al. 2005). It prolongs the actions of neurotransmitters such as adrenaline, dopamine, serotonin, and acetylcholine in the central nervous system and brain by inhibiting the activity of enzymes responsible for their degradation (Stancheva and Mosharrof 1987; cited in Kelly 2001). Consequently, the cognitive functions of the cerebral cortex, and the attention, memory and learning functions of the prefrontal and frontal cortex are enhanced (Walker and Robergs 2006). R. rosea prevents the rise in mediators of the stress response--phosphorylated stress-activated protein kinase, nitric oxide and cortisol--following immobilisation stress (Panossian et al. 2007). R. rosea prevents exercise-induced ATP decrease in mitochondria after exhaustive swimming (Abidov et al. 2003).

The Soviet Ministry of Health, in 1969, approved and registered R. rosea as a medicine and stimulant; and in 1975, it approved a rhodiola extract preparation and allowed its large-scale production (Brown et al. 2002). In Sweden, R. rosea was recognized as an Herbal Medicinal Product in 1985 and has been described as an antifatigue agent in the Textbook of Phytomedicine for Pharmacists. In the textbook of pharmacology for dispenser training in Sweden, R. rosea is mentioned as the most commonly used psychostimulant in the group of officially registered herbal medicinal products. Registered preparations Rosenrot and Arctic Root (based on proprietary extracts SHR-5) are extensively used in Sweden and other Scandinavian countries to either increase mental capacity during stress, as a psychostimulant, and or as a general tonic (Olsson et al. 2009).

Before 2004, most herbal medicines in the UK, including R. rosea, were categorised as unlicensed herbal remedies. They were exempt from the normal requirements for a medicine to hold a product license or marketing authorisation through an exemption set out in Section 12(2) of the Medicines Act 1968. However, since 30 April 2004 unlicensed manufactured herbal medicines can no longer be placed on the UK market under Section 12(2) of the Medicines Act. They now need to demonstrate the required levels of safety and quality, in order to comply with the requirements of the Traditional Herbal Registration Scheme required by the European Directive on Traditional Herbal Medicinal Products (THMP) (2004/24/EC). Currently any unlicensed manufactured herbal medicines placed on the market under Section 12(2) of the Medicines Act before 30 April 2004 can apply for transitional protection and comply with the requirements of this scheme by April 2011. In April 2009 the first R. rosea product registered as a traditional herbal medicinal product, Vitano (based on the R. rosea extracts WS 1375) was introduced in the UK (Medicines and Healthcare products Regulatory Agency 2008).

Panossian and Wikman (2010) conducted a non-systematic review that summarised the effects of adaptogen, including R. rosea, on the central nervous system and the molecular mechanisms from clinical studies. However, no systematic review is currently available of the effectiveness or efficacy of R. rosea. The aim of this systematic review was to summarise and critically evaluate the evidence from randomised clinical trials (RCTs) of R. rosea.

Search strategy

The following electronic databases were searched: AMED (1985-July 2009), CINAHL (1982-July 2009), The Cochrane Library (search in July 2009), EMBASE (1974-July 1009), MEDLINE (1950-July 2009) (via the EBSCO interface for the first two databases, and the OVID interface for the last three databases) and Web of Science (searched in July 1009). They are searched for title and abstract using the following search terms: R. rosea, SHR-5, golden radix, golden root arctic root, Aaron rod, roseroot, rosavin, rosin, rosarin, rhodaz, Vitano, and Hong Jian Tian.

A manual search was carried out using the bibliographies of the articles thus found and articles located through a scoping search in major electronic databases and through scanning our own files. References lists of all retrieved articles were hand-searched for relevant studies. Manufacturers of commercial R. rosea products were approached for any further information. In addition, clinical and herbal medicine experts were contacted to identify published and unpublished material. No language restrictions were imposed.

Inclusion and exclusion criteria

Only RCTs were included testing the efficacy or effectiveness of mono-preparations of R. rosea L. as sole treatment administered orally against a control intervention (placebo treatment, no treatment or active controls), in human individuals suffering from any condition or in healthy human volunteers were included. Trials of R. rosea in combination with other substances were excluded. Titles and abstracts of all articles thus found were screened. Those studies which, based on their abstract, appeared to meet the criteria were independently considered for inclusion by two reviewers (SKH and RP). Disagreements between reviewers were resolved through discussion. A study was included if both reviewers agree that it met all the inclusion criteria.

Data extraction

Data, including the details of study design, quality of the study, participants, intervention, outcomes and adverse events were independently extracted by two reviewers (SKH and RP) using predefined criteria. Disagreements were resolved by discussion between the two reviewers and by seeking the opinion of the third author (EE) when necessary.

Quality assessment

The methodological quality of all studies included in the review were independently evaluated by two reviewers using the Jadad score (Jadad et al. 1996). In addition, a series of other quality assessment criteria were assessed, based on recommendations from the Cochrane Handbook of Systematic Reviews of Interventions (Cochrane Collaboration 2008) and the CONSORT statement for herbal medicine (Gagnier et al. 2006). These are (1) type and appropriateness of sequence generation, (2) whether allocation was adequately concealed, (3) whether an intention to treat analysis was conducted and described, (4) similarly of groups at baseline, and (5) a total of 15 items that describe the herbal medicinal intervention (Appendix A).

Analysis

Key data of each included study were summarised in a table (Table 1). Between-group analyses of main outcome measures are presented. Secondary analyses were carried out if sufficient data was provided to perform a between-group analysis where the authors had not presented it.
Table 1
Randomised controlled trials of Rhodiola rosea extract.

First      Design                  Condition       Participants
author                                             randomised and
(year)                                             sample size (R.
                                                  rosea/control)
                                                  (age in yrs)

Shevtsov   DB;                     Work-related    121 healthy
(2003)     placebo-controlled; 4   fatigue and     volunteers
          parallel groups         stress          41/20/40/20
                                                  (range 19-21)

De Bock    DB:                     Improvement in  24 healthy
(2004)     placebo-controlled;     endurance       volunteers 12/12
          cross-over (a)          exercise        (mean age: male-
                                  performance     21.8 [+ or -]
                                                  0.3; female-
                                                  20.2 [+ or -]
                                                  0.3)

Abidov     DB; placebo             Effect of R.    36 healthy
(2004)     controlled; 3 parallel  rosea after     volunteers
          groups                  exhausting      12/12/12 (range
                                  exercise        21-24)

Olsson     DB; placebo             Fatigue         60 patients
(2009)     controlled; 2 parallel  syndrome (with  diagnosed
           groups                  identified      diagnosed with
                                   stressor)       fatigue syndrome
                                                  30/30 (mean age:
                                                  Rhodiola- 41;
                                                  Placebo-42.1)

Spasov     DB; placebo             Fatigue and     40 healthy
(2000a)    controlled; 2 parallel  stress during   volunteers 20/20
          groups                  exam period     (b)

Darbinyan  DB; placebo             Depression      60 patients
(2007)     controlled; 3 parallel                  diagnosed with
          groups                                  mild to moderate
                                                  depression 31/29
                                                  (mean age: (1)
                                                  44.9 [+ or -]
                                                  11-5, (2) 44.60
                                                  [+ or -] 25.49,
                                                  (3) 42.80 [+ or
                                                  -] 12.87)

Walker     DB;                     Volitional      12 healthy
(2007)     placebo-controlled;     fatigue         volunteers (mean
          cross-over                              age: 29.92 [+ or
                                                  -] 4.51)

Darbinyan  DB;                     Work-related    56 healthy
(2000)     placebo-controlled;     fatigue after   volunteers 26/30
          cross-over              night-duty      (mean age:
                                                  A-25.5 [+ or -]
                                                  3.8, B-27.3 [+
                                                  or -] 2.9)

Schutgens  DB;                     Experienced     30 healthy
(2009)     placebo-controlled; 3   levels of       volunteer
          parallel groups         stress and      10/10/10(mean
                                  fatigue         age: Rhodiola:
                                                  23.30 [+ or -]
                                                  10. 11; ADAPT:
                                                  20 [+ or -]
                                                  0.47; Placebo:
                                                  19.9 [+ or -]
                                                  1.2)

Spasov     Placebo-controlled:3    Study-related   60 healthy
(2000b)    parallel groups         fatigue         volunteers
                                                  20/20/20 (age
                                                  ranged from 17
                                                  to 18)

Wing       DB;                     Hypoxia and     15 healthy
(2003)     placebo-controlled;     oxidative       volunteers (e)
          cross-over              stress          (mean 25.1 [+ or
                                                  -] 3.7)

First      Intervention
author     and daily
(year)     dose

          Treatment       Control      Treatment
          group           group        duration
                                       (days)

Shevtsov   (1) 370.0 mg    Placebo      One dose
(2003)     Rhodiola dry                 only
          extract SHR-5,
          (2) dry
          extract SHR-5,
          (2) 555.0 mg
          Rhodioia dry
          extract SHR-5

De Bock    100 mg of R.    Placebo      4 (2 days of
(2004)     rosea extract                Rhodiols + 2
                                       days of
                                       placebo)

Abidov     60 mg active    (1)          36 (30 days
(2004)     substances of   Placebo,     before and 6
          R. rosea        (2) no       after
                          treatment    exercise)

Olsson     576 mg          Placebo      28
(2009)     Rhodiola
          extract

Spasov     100 mg of R.    Placebo      20
(2000a)    rosea radix
          SHR-5

Darbinyan  (1) 340 mg of   Placebo      42
(2007)     Rhodiola
          extract SHR-5.
          (2) 680 mg of
          R. extract
          SHR-5

Walker     250 mg R.       Placebo      15-22 (two
(2007)     rosea 1000 mg                4-day
          on the day of                treatment
          the test                     session with
                                       a washout
                                       period of
                                       7-14 days)

Darbinyan  170 mg R.       Placebo      42
(2000)     rosea SHR-5

Schutgens  288 mg of the   Placebo      7
(2009)     SHR-5 extract
          of R. rosea
          l., roots

Spasov     660 mg of       Placebo and  20
(2000b)    Rhodaxon        control
                          (d)

Wing       447 mg R.       Placebo      1 (hypoxic
(2003)     rosea                        exposure) + 7
                                       (no
                                       supplement) +
                                       7 (take
                                       supplement) +
                                       2 weeks
                                       interval
                                       between
                                       treatment.
                                       ~75

First
author
(year)

          Main outcome           Other outcome      Main results
          measures/assessment    measures           (between-group
          schedule                                  analysis)

Shevtsov   TAFI/pre- and          Pulse pressure;    Both treatment
(2003)     post-treatment         pulse rate         groups showed
                                                    significant (p <
                                                    .0001) benefit
                                                    after medication
                                                    comparing to
                                                    placebo

De Bock    (1) Speed of limb      None               Camparing
(2004)     movement.(2) reaction                     treatmenti group,
          time movement. (3)                        there was
          ability to sustain                        significant (p <.
          attention, (4) muscle                     05) increase in
          strength movement.                        time to
          (5) endurance                             exhaustion. VO2,
          exercise capacity                         VCO2. peak O2
                                                    output, and peak
                                                    CO2 output.

Abidov     (1) CRP, (2) serum     VO2max, weight     (1) The mean CRP
(2004)     CK                     and fat            level of the
                                 percentage (by     treatment group
                                 Moreno's method)   was significantly
                                                    (p < .05) lower
                                                    comparing to the
                                                    placebo and
                                                    control group 5 h
                                                    and 5 days after
                                                    test. (2) The
                                                    mean CK level in
                                                    all groups
                                                    significantly (p
                                                    < .05) increased
                                                    comparing before
                                                    test to 5 h after
                                                    test. However,
                                                    only the
                                                    treatment group
                                                    maintained
                                                    similar level 5
                                                    days after test;
                                                    whereas other
                                                    groups further
                                                    significantly (p
                                                    < .05) increased
                                                    5 days after test
                                                    comparing to 5 h
                                                    after test
                                                    comparing to 5 h
                                                    after test

Olsson     (1) Pine's burnout     Cortisol response  Significant (p =
(2009)     scale, (2) QoL         to awakening       0.047)
          (SF-36), (3) MADRS,                       interaction
          (5) attention                             effect between
          (CCPTH)                                   time and group
                                                    was detected in
                                                    the treatment
                                                    group the
                                                    treatment group
                                                    had benefited
                                                    more than the
                                                    placebo group.
                                                    Significant
                                                    interaction
                                                    effects between
                                                    time and group
                                                    were detected
                                                    with respect to
                                                    omissions, Hit RT
                                                    SE, and
                                                    variability
                                                    indices derived
                                                    from the CPTII,
                                                    all of which
                                                    indicated a more
                                                    positive change
                                                    in the treatment
                                                    group than in the
                                                    placebo group

Spasov     (1)PWC-170 cycle       Mean exam marks    Improvement of
(2000a)    test. (2) increase of  in each group      the treatment in
          pulse-rate fallowing                      pulse-rate
          exercise. (3)                             PWC-exercise.
          neuro-motoric fitness                     neuro-mororic
          (maze test and                            fitness (maze
          tapping test), (4)                        test), general
          mental correction                         well-being, and
          test (speed and                           mental fatigue
          accuracy), (5)                            were significant
          general well-being,                       (p < .05)
          (6) mental fatigue                        comparing with
                                                    the placebo
                                                    group

Darbinyan  (1) Mean total BDI     HAMD subgroups:    (1) Mean total
(2007)     and (2) mean total     (a) insomnia. (b)  BDI scores of
          HAMD                   emotional          group A and B
                                 instability, (c)   were
                                 somatization. (d)  significantly (p
                                 self-esteem        <. 0001) lower
                                                    compare to group
                                                    C on day 42. And
                                                    Croup B was
                                                    significantly
                                                    lower than group
                                                    A. (2) Mean total
                                                    HAMD scores of
                                                    group A and B
                                                    were
                                                    significantly (p
                                                    < .0001) lower
                                                    compare to group
                                                    C on day 42. But
                                                    not significantly
                                                    different between
                                                    group A and B

Walker     (1) Skeletal muscle    Concentrations of  (1) NO
(2007)     ATP turnover: (PCr)    Pi and ATP. and    significant
          kinetics and (2)       muscle pH          differences
          (TTE)-exercise                            observed between
          performance. (3) RPE                      treatments at any
                                                    time treatment
                                                    order have any
                                                    significant
                                                    effect on [PCr].
                                                    (2) no
                                                    significant
                                                    differences
                                                    observed between
                                                    treatment nor did
                                                    treatment order
                                                    have any
                                                    significant
                                                    effect on TTE,
                                                    (3) no
                                                    siginificant
                                                    differences
                                                    observed between
                                                    treatments at any
                                                    time on RPE

Darbinyan  Total fatigue index    None               Secondary
(2000)                                               analysis (pair t
                                                    test):
                                                    significant
                                                    improvement in R.
                                                    rosea treatment
                                                    condition compare
                                                    to placebo
                                                    condition (p <
                                                    0.0001)

Schutgens  (1) Ultra-weak photon  None               R. rosea
(2009)     emission, (2)                             significantly (p
          self-evaluated                            = 0.049)
          stress. (3)                               decreased the
          self-evaluated                            experimented
          fatigue (tiredness)                       level of
                                                    'fatigue'
                                                    (tiredness), when
                                                    compared with the
                                                    placebo. R. rosea
                                                    significantly (p
                                                    = 0.027)decreased
                                                    in photon
                                                    emission in
                                                    comparison with
                                                    the placebo

Spasov     (1) PWC-170 cyele      (1) Volume of the  No between-group
(2000b)    test, (2) accuracy of  processed          analysis
          muscular effort. (3)   information based
          tapping test. (4)      on the proof
          self-evaluation of     table, (2) number
          health. (5)            of errors in the
          activeness level,,     processed
          (6) mood. (7)          information
          willingness to work,
          (8) mental fatigue,
          (9) level of
          situation anxiety

Wing       Arterial blood gases:  Blood pressure,    No significant
(2003)     PcO2 and PcCO2         serum lipid        difference
                                 hydroperoxides     between the
                                 (LPO) and urine    control group and
                                 malondialdehyde    either treatment
                                 (MDA)              group

First
author
(year)

          Adverse events

Shevtsov   One in the placebo
(2003)     (hypersalivation)

De Bock    One in the placebo
(2004)     group (strong
          headache)

Abidov     Not mentioned
(2004)

Olsson     None
(2009)

Spasov     None
(2000a)

Darbinyan  None
(2007)

Walker     Not mentioned
(2007)

Darbinyan  None
(2000)

Schutgens  Not mentioned
(2009)

Spasov     None
(2000b)

Wing       One illness (not
(2003)     specified)

(a) DB: double blind: BDI: Back Back Depression Inventory; HAMD:
Hamilton Rating Scale for Depression; [PC.sub.1]: Phosphocreatine:
TTE: Time to exhaustion; RPE: Perceived exertion; Pi: Phosphateion;
ATP: adenosine triphosphate; PcO2: capillary blood oxygen: PcCO2:
capillary blood carbon dioxide; LOP: lipid  hydroperoxide; MDA:
malondialdehyde.
(b) Sample sizes were not clearly stated (based on sample
size calculation).
(c) Number of participants randomised to each group (i.e.,
R-P and P-R) was not mentioned.
(d) The 'control' group was not clearly specified whether it was
an active control or no-treatment control.
(e) Treatment order not reported.


Results

The literature searches identified 693 potentially relevant titles and abstracts. Initial screening of the titles and abstracts identified 17 relevant references for which full texts were retrieved for further evaluation. Seven papers were subsequently excluded for the following reasons: three references as they were not on human subjects (Bocharova et al. 1995; Maslova et al. 1994; Provalova et al. 2002), two full-text papers were excluded because they were not RCTs (Frolova et al. 1981; Komar et al. 1981). One RCT was excluded because the R. rosea capsules used contained another active substance (i.e., 5 mg of zinc/capsule) (Skarpanska-Stejnborn et al. 2009), and one duplicate paper was also excluded (Schulz 2008). Eleven RCTs (Abidov et al. 2004; Darbinyan et al. 2000; Darbinyan et al. 2007; De Bock et al. 2004; Olsson et al. 2009; Shevtsov et al. 2003; Spasov et al. 2000a; Spasov et al. 2000b; Walker et al. 2007; Wing et al. 2003; Schutgents et al. 2009) met the inclusion criteria and were included in the review. Fig. 1 is a flow chart of the trial selection process.

A summary of the main characteristics of these RCTs is presented in Table 1. The studies were published between 2000 and 2009, originated from six countries (Russia, n=4; USA, n = 2; Armenia, n = 2; Sweden, n = 1; Belgium, n= 1; Netherlands, n = 1) and were all published in English. One trial (Spasov et al. 2000a) failed to state the number of participants. The other 10 RCTs had a total of 503 participants. Sample size ranged from 12 to 121. Eight trials were carried out on healthy individuals who were submitted to hypoxia (1) (Wing et al. 2003), exam- or work-related fatigue and stress (Darbinyan et al. 2000; Spasov et al. 2000a; Spasov et al. 2000b; Shevtsov et al. 2003), or exhausting exercises (Abidov et al. 2004; De Bock et al. 2004; Walker et al. 2007). Two trials involved participants who were diagnosed with stress-related fatigue (2) (Olsson et al. 2009) and mild or moderate depression (Darbinyan et al. 2007). One trial assessed the change of photon emission, stress and fatigue in healthy subjects (Schutgents et al. 2009). All trials were carried out in participants over 18 years except for two trials that involved first year medical students, aged between 17 and 19 (Spasov et al. 2000a; Spasov et al. 2000b). All the trials were placebo-controlled.

The 11 RCTs can be divided according to indication into three groups: (1) physical performance or physiological indicators of physical performance, (2) mental performance and (3) mental health conditions.

Physical performance or physiological indicators relating to physical capacity

Seven trials investigated the effects of R. rosea on physical or physiological performance (Abidov et al. 2004; De Bock et al. 2004; Spasov et al. 2000a; Spasov et al. 2000b; Walker et al. 2007; Wing et al. 2003; Schutgents et al. 2009). In five RCTs (Abidov et al. 2004; De Bock et al. 2004; Spasov et al. 2000a; Spasov et al. 2000b; Walker et al. 2007), healthy volunteers were instructed to carry out different types of exercise, such as cycling or forearm wrist flexion, for comparing the effects of R. rosea compared to placebo. One study assessed the level of tiredness experienced in healthy students before and after the ingestion of R. rosea or placebo (Schutgents et al. 2009). The last trial in this section (Wing et al. 2003) tested the effects of R. rosea in resistance-trained men for facilitating blood oxygenation under hypoxic conditions.

Two small RCTs (n = 15 and 12) (Wing et al. 2003; Walker et al. 2007) found R. rosea did not improve blood oxygenation after induced hypoxia and skeletal muscle phosphocreatine (PCr) recovery after exhaustive exercise respectively. Other studies found significant (p < 0.005) increases in time to exhaustion (De Bock et al. 2004), mean C-re-active protein (CRP) level (Abidov et al. 2004), and neuromotoric fitness (Spasov et al. 2000a). In addition, Schutgents et al. found R. rosea can significantly (p = 0.049) improve perceived everyday tiredness in comparison with placebo (Schutgents et al. 2009).

Mental health conditions

Olsson et al. assessed the effects of R. rosea in patients diagnosed with fatigue syndrome (Olsson et al. 2009). The results showed R. rosea caused significant (p = 0.047) improvements in patients with stress-related fatigue in Pines' burnout score, which incorporates physical, emotional, and mental exhaustion. Darbinyan et al. investigated the effects of R. rosea in patients suffering from mild to moderate depression (Darbinyan et al. 2007). Patients taking R. rosea significantly (p < 0.0001) improved in terms of Hamilton Rating Scale for Depression (HAMD) and Beck Depression inventory (BDI) compared with placebo.

Mental performance

Four trials investigated the effects of R. rosea on mental performance (Darbinyan et al. 2000; De Bock et al. 2004; Shevtsov et al. 2003; Spasov et al. 2000a; Spasov et al. 2000b), Outcome measures ranged from test of short-term memory (digital recall), testing reaction time to auditory and visual stimulus, to correcting texts for concentration ability.

Two studies reported significant improvements (p<0.05) in Total Antifatigue Index (TAFI) (Shevtsov et al. 2003) and Total Fatigue Index (TFI) (Darbinyan et al. 2000) compared with placebo. The other two studies (De Bock et al. 2004; Spasov et al. 2000a) found no effects in sustained attention, visual reaction time, and concentration ability.

Adverse events

Eight RCTs (Darbinyan et al. 2000; Darbinyan et al. 2007; De Bock et al. 2004; Olsson et al. 2009; Shevtsov et al. 2003; Spasov et al. 2000a; Spasov et al. 2000b; Wing et al. 2003) reported information on adverse events (AE). Only three cases of AEs, including headache (De Bock et al. 2004), hypersalivation (Shevtsov et al. 2003) and one unknown illness (Wing et al. 2003), were reported and none of them were described as serious. The first two AEs reported were both from the placebo groups. The unspecified AE, which caused the patient to drop out of the trial, was not specified in terms of group allocation.

Discussion

We identified 11 RCTs of R. rosea. Significant positive effects were reported in eight of them. The trials differed greatly in terms of condition tested, and independent replications of any given trial are missing (Table 1).

Five of the RCTs (Darbinyan et al. 2000; Darbinyan et al. 2007; Olsson et al. 2009; Spasov et al. 2000a; Walker et al. 2007) were of good methodological quality (more than three points on the Jadad scale) (Table 2). Four had a score of 2 points or below (Abidov et al, 2004; De Bock et al. 2004; Schutgents et al 2009; Spasov et al. 2000b). Seven studies did not clearly describe allocation concealment (Abidov et al. 2004; De Bock et al. 2004; Shevtsov et al. 2003; Walker et al. 2007; Wing et al. 2003; Schutgents et al. 2009; Spasov et al. 2000b), and seven trials did not clear state whether intention-to-treat analyses were conducted or conduct all of the assessment as intention-to-treat analyses (Abidov et al. 2004; Olsson et al. 2009; Spasov et al. 2000a; Spasov et al. 2000b; Walker et al. 2007; Wing et al. 2003; Schutgents et al. 2009).
Table 2

Methodological quality of trials.

First      Was the      Was the trial  Was the        Was the
author     similarity   described as   randomization  treatment
(year)     between the  randomised?    procedure      allocation
           groups                      described and  concealed?
           compared at                 was it
           baseline?                   appropriate?

Shevtsov   Yes          Yes            Not reported   Unclear
(2003)

De Bock    No           Yes            Not reported   Not
(2004)                                                reported

Abidov     Yes          Yes            Not reported   Not
(2004)                                                reported

Olsson     Yes          Yes            Not reported   Yes
(2009)

Spasov     No           Yes            Not reported   Yes
(2000a)

Darbinyan  Yes          Yes            Not reported   Yes
(2007)

Walker     Yes          Yes            Not reported   Not
(2007)                                                reported

Darbinyan  No           Yes            Not reported   Yes
(2000)

Schutgens  Yes          Yes            Not reported   Not
(2009)                                                reported

Spasov     Yes          Yes            Not reported   Not
(2000b)                                               reported

Wing       No           Yes            Not reported   Not
(2003)                                                reported

First      Was the    Was the method  Was the number of     Was an
author     trial      of double       withdrawals/dropouts  analysis
(year)     described  blinding        in each group         conducted
           as double  described and   mentioned?            on the
           blind?     appropriate?                          intention -
                                                            to-treat
                                                            sample?

Shevtsov   Yes        Yes             No                    Yes
(2003)

De Bock    Yes        Not reported;   Yes                   Yes
(2004)                but the
                     efficacy of
                     blinding was
                     tested Not
                     reported

Abidov     Yes        Not reported    No                    Not
(2004)                                                      reported

Olsson     Yes        Yes             Yes                   No
(2009)

Spasov     Yes        Yes             Yes                   Not
(2000a)                                                     reported

Darbinyan  Yes        Yes (a)         Yes                   N/a (b)
(2007)

Walker     Yes        Yes             Yes (all completed)   No:
(2007)                                                      phosphate
                                                            data; Yes:
                                                            TTE RPE

Darbinyan  Yes        Yes             Yes (all completed)   N/a
(2000)

Schutgens  Yes        Not reported    Not reported          Not
(2009)                                                      reported

Spasov     No         N/a             Not reported          Not
(2000b)                                                     reported

Wing       Yes        Not reported    Yes                   Not
(2003)                                                      reported

First      How many items in  Jadad
author     the Section 4 of   score
(year)     the
           herbal-specific
           CONSORT statement
           were described
           fully and partly
           respectively?
           (F/P) out of the
           total 15 items

Shevtsov   4/2                3
(2003)

De Bock    3/5                2
(2004)

Abidov     2/4                2
(2004)

Olsson     6/5                4
(2009)

Spasov     5/1                4
(2000a)

Darbinyan  3/2                4
(2007)

Walker     3/4                4
(2007)

Darbinyan  5/2                4
(2000)

Schutgens  3/3                2
(2009)

Spasov
(2000b)

Wing       0/2                3
(2003)

(a) Appearence of R. rosea and placebo tablets were identical but
number of tablets taken daily between group A and B were different.

(b) Two patients dropped out of the study for non-medical reasons
before randomisation.


Only one study (Olsson et al. 2009) described the details of the R. rosea preparation in more than 10 items (out of a total of 15) of the herbal-specific CONSORT statement. Only one study (Olsson et al. 2009) described the details about the type and concentration of extraction solvent used; and two studies (Walker et al. 2007; De Bock et al. 2004) described the details about the quantity of active/marker constituents per dosage unit form. Insufficient reporting about the details of R. rosea preparation used is a common shortfall. Future trialists should adequately collect and report such information accroding to the herbal-specific CONSORT statement, in order to allow comparison of the results between RCTs.

The current data suggest that R. rosea is safe. Of the total 503 subjects randomized, only two mild AEs and one undescribed AE were reported. Two of these came from the placebo groups. Several observational studies seem to confirm that AEs after R. rosea intake are rare and tend to be mild (Bystritsky et al. 2008; Fintelmann and Gruenwald 2007; Monograph: Rhodiolo rosea, 2002).

Our review has several limitations. Even though we went to great lengths to retrieve all relevant studies, we cannot be sure that our efforts were successful. Publication bias is a problem in all medical researches (Eastbrook et al. 1991). We have shown that it can be particularly powerful in alternative medicine (Ernst and Pittler 1997; Ernst 2007). Furthermore the paucity and often low quality of the primary studies limit the conclusiveness of our findings.

Future research should aim to independently replicate the results of the published RCTs. Studies should overcome the shortcomings of the currently available data. In particular, trials should be of sufficient sample size, describe their test medication in full detail and conform with all other requirements laid down in the CONSORT guidelines.

Conclusions

R. rosea may have beneficial effects on physical performance, mental performance, and certain metal health conditions, some of which are stress-related. There is, however, a lack of independent replications and some of the primary studies were less than rigorous. No major risks have been associated with R. rosea. More research on this promising herbal medicine seems warranted.

Acknowledgments

The authors would like to thank Barbara Wider for excluding a German article, Helen Coelho for her advices on methodological quality assessment, as well as Leala Watson and Marie-Laure Despres for their help in retrieving full-text articles. SKH's research fellowship is funded by Dr. Willmar Schwabe Pharmaceuticals, Germany, the manufacturer of the R. rosea preparation, Vitano.

Appendix A. CONSORT statement for herbal medicine
Paper Section  Item               Descriptor
and Topic
Methods

Interventions  4                  Where applicable, the
                                  description of herbal
                                  intervention should
                                  include:

               4A: Herbal         1. The Latin binomial
               Medicinal product  name together with
               name               botanical authority and
                                  family name of each
                                  herbal ingredient;
                                  common name(s) should
                                  also be included.

                                  2. The proprietary
                                  product name (i.e.,
                                  brand name) or the
                                  extract name (e.g.,
                                  EGb-761) and the name
                                  of the manufacturer of
                                  the product.

                                  3. Whether the product
                                  used is authorized
                                  (licensed, registered)
                                  in the country in which
                                  the study was
                                  conducted.

               4B:                1. The part(s) of plant
               Characteristics    used to produce the
               of the herbal      product or extract.
               product

                                  2. The type of product
                                  used (e.g., raw [fresh
                                  or dry], extract).

                                  3. The type and
                                  concentration of
                                  extraction solvent used
                                  (e.g., 80% ethanol,
                                  100% [H.sub.2]O, 90% of
                                  glycerine, etc.) and
                                  the ratio of herbal
                                  drugs to extract (e.g.,
                                  2 to 1).

                                  4. The method of
                                  authentication of raw
                                  material (i.e., how
                                  done and by whom) and
                                  the lot number of the
                                  raw material. State if
                                  a voucher specimen
                                  (i.e., retention
                                  sample) was retained
                                  and, if so, where it is
                                  kept or deposited, and
                                  the reference number.

               4C: Dosage         1. The dosage of the
               regimen and        product, the duration
               quantitative       of administration, and
               description        how these were
                                  determined.

                                  2. The content (e.g.,
                                  as weight,
                                  concentration; may be
                                  given as range where
                                  appropriate) of all
                                  qualified herbal
                                  product constituents,
                                  both native and added,
                                  per dosage unit form.
                                  Added material, such as
                                  binders, filler, and
                                  other excipients (e.g.,
                                  17% ma to dextrin, 3%
                                  silicon dioxide per
                                  capsule), should also
                                  be listed.

                                  3. For standard
                                  products, the quality
                                  of active/marker
                                  constituents per dosage
                                  unit form.

               4D: Qualitative    1. Product's chemical
               testing            fingerprint and methods
                                  used (equipment and
                                  chemical reference
                                  standards) and who
                                  performed the chemical
                                  analysis (e.g., the
                                  name of the laboratory
                                  used); whether a sample
                                  of the product (i.e.,
                                  retention sample) was
                                  retained and if so,
                                  where it is kept or
                                  deposited.

                                  2. Description of any
                                  special testing/purity
                                  testing (e.g., heavy
                                  metal or other
                                  contaminant testing)
                                  undertaken, which
                                  unwanted components
                                  were removed and how
                                  (i.e.. Methods).

                                  3. Standardization:
                                  what to standardize
                                  (e.g., which chemical
                                  components of the
                                  product) and how (e.g.,
                                  chemical processes or
                                  biological/functional
                                  measures of activity).

               4E:                The rationale for the
               Placebo/control    type of control/placebo
               group              used.

               4F: Practitioner   A description of
                                  practitioners (e.g.,
                                  training and practice
                                  experience) that are a
                                  part of the
                                  intervention.

Paper Section  Examples of good
and Topic      Reporting (1)
Methods

Interventions

               The herbal medicine
               intervention used in
               this trial was an
               extract of Ginkgo
               biloba L.
               (Ginkgoaceae; maiden
               hair tree).

               The product used
               was LI 1370, an
               extract of G. biloba
               L., manufactured by
               Lichtwer Pharma
               (Berlin, Germany)
               (18).

               This product is
               registered for use
               as a natural health
               product in Canada.

                The extract was
               obtained from leaves
               of G. biloba L.

               The herbal medicine
               intervention was an
               extract of G. biloba
               L.

               The solvent used in
               the extract was
               alcohol (80%
               ethanol) and the
               ratio of herbal drug
               to extract was 5 to
               1.

               A staff botanist
               visuallly identified
               the growing plant.
               The lot number for
               the G. biloba L
               extract used in this
               study was #5507-05.
               A voucher specimen
               was retained
               (#23-673) and is
               kept at the
               manufacturer
               headquarters in
               Toronto, Canada.

               Each capsule
               contained 60 mg of
               the extract, A total
               of three capsules
               were given each day,
               1 before each of 3
               meals, for 3 months.
               This dosage regimen
               was determined by
               referring to
               previous clinical
               trails testing the
               effect of similar G.
               biloba L. extract
               for the same
               indication.

               The percentages of
               quantified chemical
               constituents per
               capsule was as
               follows: 15mg (25%)
               flavonoids, 3mg
               (5%)ginkgo!ides,
               1.8mg (3%)
               bilobalides.

               The percentage of
               marker constituents
               per capsule were as
               follows: 25%
               flavonoids, 5%
               ginkgolides, 3%
               bilobalides.

               The high pressure
               liquid
               chromatography
               chemical fingerprint
               for the extract of
               G. biloba L. can be
               seen in the figure
               (19). The method for
               performing this
               analysis was as
               follows:
               high-pressure liquid
               chromatography was
               achieved using a
               minibore Phenomenex
               Luna-5-[micro]M
               [C.sub.18] (2)
               column with
               dimensions 250 mm x
               2.00 mm at
               45[degrees]C with a
               one-step linear
               gradient using
               acetonitrile: formic
               acid (0.3%) at a
               flow rate of 0.4
               mL/min (20). The
               analysis was done by
               an individual with
               12 years' experience
               in the methods,
               CanHerba Labs Inc.
               (Windsor, Ontario,
               Canada). The product
               sample is also kept
               at CanHerba Labs
               Inc.

               Laboratory personnel
               were blinded to the
               identity of the
               extract and control
               capsules.
               Concentrations
               ([mu]g/g) of lead,
               mercury, and arsenic
               were measured by
               X-ray florescence
               spectroscopy 23
               equipped with a
               tungsten X-ray tube,
               a SKLD-semiconductor
               detector, and
               software version
               2.2R03 1 (Spectro
               Analytical
               Instruments, Kleve,
               Germany). National
               Institutes of
               Standards and
               technology solid
               standards reference
               materials 2709,
               2710, 2711, 24, and
               liquid certified
               standards (SCP
               Science, Champion,
               New York) containing
               specified heavy
               metal concentrations
               served as positive
               and negative
               controls (21).

               The G. biloba L.
               extract used in this
               trial was
               standardized to
               contain 25%
               flavonoids, 5%
               ginkolides, and 3%
               bilobalides. Methods
               included
               high-pressure liquid
               chromatography using
               a Minibore
               Phenomenex Luna
               5[micro]M [C.sub.18];
               (2) Column with
               dimensions 250 mm x
               2.00 mm at
               45[degrees]C with a
               one-step linear
               gradient using
               acetonitrile: formic
               acid (03%) at a flow
               rate of 0.4 ml/min;
               (3) We used the
               following reference
               standards:
               bilobalide (95%),
               ginkgolides A (90%),
               B (95%), C (95%), J
               (99%), purchased
               from Herbalchems
               (San Francisco,
               California) and
               Quercetin (95%)
               purchased from Sigma
               (St. Louis,
               Missouri) and
               kaempferol (90%) and
               isorhamnetin (99%)
               purchased from
               Indofine Chemical
               Company
               (Hillsborough, New
               Jersy). The purity
               of these reference
               standards was
               assumed as provided
               by the suppliers
               (3).

               The placebo capsules
               used in this trial
               were identically
               sized capsules
               filled with lactose
               powder, and colored
               (with food coloring)
               to match the G.
               biloba L. capsules.

               Clinicians choosing
               the appropriate
               treatment and dosage
               were trained as
               primary care
               physicians; were
               licensed in Ontario,
               Canada; had been
               practicing medicine
               for an average of 12
               years; and had
               attended continuing
               medical education
               lectures on
               evidence-based
               herbal medicine
               interventions.

[dagger] Examples included are not from actual publicatoins unless
directly referenced. They were developed explicity to provide
extremely specific and concise examples of good reporting for each
item. All examples are for the same herbal medicine intervention,
which contains just 1 herbal medicinal product, Ginkgo biloba L.
Referenced sections were changed slightly from the original reports
to be consistent with respect to the particular herbal medicine
intervention used across these examples.

[double dagger] This is a fictional company that was added for
the completeness of the report.


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* Corresponding author. Tel.: +44 1392 424942.

E-mail addresses: shaohung@pms.ac.uk, shao.hung@pms.ac.uk (S.K. Hung).

0944-7113/$-see front matter [c] 2010 Elsevier GmbH. All rights reserved.

doi: l0.10l6/j.phymed.20l0.08.014

(1) The hypoxic exposure was achieved by placing a Plexiglas hood over each participant. 'The decrease in oxygen combined with an ambient barometric pressure of 633 mm Hg created an oxygen content similar to that found at an elevation of 4600 m' (Wing et al. 2003, p. 11).

(2) 'Fatigue syndrome' is different to 'chronic fatigue syndrome'. 'The former requires the identification of specific stressors whilst the latter focuses on the immune system and symptoms of pain in the lymph nodes, joints, and muscles' (Olsson et al. 2009, p. 106).

Shao Kang Hung*, Rachel Perry, Edzard Ernst

Complementary Medicine, PCMD, University of Exeter, UK
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