The effectiveness and efficacy of Rhodiola rosea L.: a systematic review of randomized clinical trials.
Physical and mental performance
Randomized clinical trials
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 Reference lists of all retrieved articles were searched, and experts and manufacturers were contacted for unpublished RCT.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.
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.
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, 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.
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).
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.
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.
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.
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.
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.
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.
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.
Abidov, M., Grachev, S., Seifulla, R.D., et al., 2004. Extract of Rhodiola rosea radix reduces the level of C-reactive protein and creatinine kinase in the blood. Bulletin of Experimental Biology and Medicine 138(1), 63-64.
Abidov, M., Crendal, F., Grachev, S., et al., 2003. Effect of extracts from Rhodiola rosea and Rhodiola crenulata (Crassulaceae) roots on ATP content in mitochondria of skeletal muscles. Bulletin of Experimental Biology and Medicine 136, 585-587.
Bocharova, O.A., Matveev, B.P., Baryshnikov, A.I., et al., 1995. The effect of a Rhodiola rosea extract on the incidence of recurrences of a superficial bladder cancer (experimental clinical research) [Russian]. Urologiia i Nefrologiia (2), 46-47.
Brown, R.P., Gerbarg, P.L., Ramazanov, Z., 2002. Rhodiola rosea: a phytomedicinal overview. HerbalGram 56, 40-52.
Bystritsky, A., Kerwin, L, Feusner,J., 2008. A pilot study of Rhodiola rosea (Rhodaz [R]) for generalized anxiety disorder (GAD). The Journal of Alternative and Complementary Medicine 14 (2), 175-180.
Cochrane Collaboration, 2008. Cochrane Handbook: Assessing Risk of Bias in Included Studies (Chapter 8). Accessed online at: http://www.cochrane-handbook.org/ (on 20/05/2009).
Darbinyan, V., Kteyan, A., Panossian, A., et al., 2000. Rhodiola rosea in stress induced fatigue-a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine 7 (5), 365-371.
Darbinyan, V., Aslanyan, G., Amroyan, E., et al., 2007. Clinical trial of Rhodiola rosea L extract SHR-5 in the treatment of mild to moderate depression. Nordic Journal of Psychiatry 61 (6), 503.
De Bock, K., Eijnde, B.O., Ramaekers, M., et al., 2004. Acute Rhodiola rosea intake can improve endurance exercise performance. International Journal of Sport Nutrition & Exercise Metabolism 14 (3), 298-307.
Eastbrook, P.J., Berlin, J.A., Gopalan, R., Matthews, D.R., 1991. Publication bias in clinical research. Lancet 337, 867-872.
Ernst. E., 2007. Publication in complementary/alternative medicine. Journal of Clinical Epidemiology 60, 1093-1094.
Ernst, E., Pittler, M.H., 1997. Alternative therapy bias. Nature 385, 480.
Fintelmann, V., Gruenwald, J., 2007. Efficacy and tolerability of a Rhodiola rosea extract in adults with physical and cognitive deficiencies. Advanced in Natural Therapy 24(4), 929-939.
Frolova. G.I., Prosandeeva, G.F., Larionova, LV.,et al., 1981. Use of golden root (Rhodiola rozea) tincture in the treatment of parodontosis [Russian]. Stomatologiya 60(1), 81-82.
Gagnier, J.J., Boon, H., Rochon, P., et al., 2006. Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement. Annals of Internal Medicine 144 (5), 364-367.
Jadad, A.R., Moore. R.A., Carroll, D., et al., 1996. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Controlled Clinical Trials 17 (1) 1-12.
Kelly, G.S., 2001. Rhodiola rosea: a possible plant adaptogen. Alternative Medicine Reviews 6 (3), 293-302.
Khanum, F., Bawa, A.S., Singh, B., 2005. Rhodiola rosea: a versatile adaptogen. Comprehensive Reviews in Food .Science and Food Safety 4, 55-62.
Komar, V.V., Kit, S.M., Sishchuk. L.V., et al., 1981. Effect of Rhodiola rosea on the human mental activity [Ukrainian]. Farmatsevtichnii Zhurnal 36 (4), 62-64.
Maslova, L.V., Kondrat'ev, B.I., Maslov, L.N., et al., 1994. The cardioprotective and antiadrenergic activity of an extract of Rhodiola rosea in stress [Russian]. Eksperimentalnaia i Klinicheskaia Farmakologiia 57 (6), 61-63.
Medicines and Healthcare products Regulatory Agency, 2009. Vitano Film-coated Tablets--THR 05332/0004. http://www.mhra.gob.uk/home/groups/I-unitl/documents/websiteresources/co n025812.pdf (accessed 01/12/2009).
Morgan, M., Bone, K., 2005. Rhodiola rosea-Rhodiota 47,1-4. Copyright MediHerb Pty Ltd.
Olsson. E.M.G., von Scheele, B., Panossian, A.G., 2009. A randomized, double-blind, placebo-controlled, parallel-group study of the standardized extract SHR-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Medica 75, 105-112.
Panossian, A., Hambardzumyan, M., Hovhanissyan, A., et al., 2007. The adaptogens Rhodiola and Schizandra modify the response to immobilization stress in rabbits by suppressing the increase of phosphorylated stress-activated protein kinase, nitric oxide and Cortisol. Drug Target Insights 1, 39-54.
Panossian, A., Wikman, G., 2010. Effects of adaptogens on the central nervous system and the molecular mechanisms associated with their stress-protective activity. Pharmaceuticals 3 (l), 188-224.
Provalova, N.V., Skurikhin, E.G., Suslov, N.I., Dygai, A.M., Gold'berg, E.D., 2002. Effects of adaptogens on granulocytopoiesis during paradoxical sleep deprivation. Bulletin of Experimental Biology and Medicine 3, 261-264.
Saratikov, A.S., Krasnov, E.A., 1974. Rhodiola rosea (Golden root), forth edition, revised and enlarged. Tomsk University Publishers, Tomsk, pp. 22-41.
Schulz, V., 2008. Rhodiola rosea radix extract for the treatment of mild to moderate depression? [German]. Zeitschrift fur Phytotherapie 29 (2), 75-76.
Schutgents, F.W.G., Neogi, P., can Wijk, E.P.A., van Wijk, R., Wikman, G., Wiegant, F.A.C., 2009. The influence of adaptogens on ultraweak biophoton emission: a pilot-experiment. Phytotherapy Research 23, 1103-1108.
Shevtsov, V.A., Zholus, B.I., Shervarly, V.I., et al., 2003. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine 10 (2-3), 95-105.
Skarpanska-Stejnborn, A., Pilaczynska-Szczesniak, L., Basta, P., et al., 2009. The influence of supplementation with Rhodiola rosea L extract on Selected redox parameters in professional rowers. International journal of Sport Nutrition and Exercise Metabolism 19 (2), 186-199.
Spasov, A.A., Wikman, G.K., Mandrikov, V.B., et al., 2000a. A double-blind, placebocontrolled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen, Phytomedicine 7, 85-89.
Spasov. A.A., Mandrikov, V.B., Mitonova, I.A., 2000b. The effect of Dhodaxonon psycho-physiologic and physical adaptation of students to the academic load. Experimental and Clinical Pharmacology 63 (1), 76-78.
Stancheva, S.L., Mosharrof. A., 1987. Effect of the extract of Rhodiola rosea L. on the content of the brain biogenic monamines. Medical Physiology 40, 85-87.
Tuttle, D., 2006. Rhodiola: the cellular energy-boosting herb. LE Magazine 2006; accessed online at: http://www.lef.org/magazine/mag2006/ feb2006_report_rhodiola_01.htm (on 21/05/2009).
Walker, T.B., Altobelii, S.A., Caprihan, A., et al., 2007. Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men. Metabolism: Clinical & Experimental 56 (8), 1111-1117.
Walker, T.B., Robergs, R.A., 2006. Does Rhodiola rosea possess ergogenic properties? International journal of Sport Nutrition and Exercise Metaboiism 16, 305-315.
Wing, S.L., Askew, E.W., Luetkemeier, M.J., et al., 2003. Lack of effect of Rhodiola or oxygenated water supplementation on hypoxemia and oxidative stress. Wilderness and Environmental Medicine 14 (1), 9-16.
* Corresponding author. Tel.: +44 1392 424942.
E-mail addresses: firstname.lastname@example.org, email@example.com (S.K. Hung).
0944-7113/$-see front matter [c] 2010 Elsevier GmbH. All rights reserved.
(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
|Printer friendly Cite/link Email Feedback|
|Author:||Hung, Shao Kang; Perry, Rachel; Ernst, Edzard|
|Publication:||Phytomedicine: International Journal of Phytotherapy & Phytopharmacology|
|Date:||Feb 15, 2011|
|Previous Article:||Herbal Medicine: Trends and Traditions.|
|Next Article:||Soy isoflavones, diet and physical exercise modify serum cytokines in healthy obese postmenopausal women.|