Description of included studies
Two hundred and six unique articles were identified from the search and 11 met final inclusion criteria. Of those, 10 were described as randomized controlled trials (RCT)[17–26] and one was a controlled clinical trial (CCT)[24]. Six studies examined the effect of R. rosea on physical performance and five assessed mental fatigue. None of the studies examining R. rosea examining physical or mental fatigue measured outcomes consistently - no two studies reported the same outcomes. As such, meta-analysis could not be performed. Included studies are described in text below and Table1.
Table 1
Rhodiola rosea summary of clinical evidence
Risk of bias in trials of rhodiola rosea
As can be seen from Figure1, the majority of studies in each domain have an ‘unclear’ risk of bias in almost every domain due to how they were reported. None of the included studies are free of plausible bias (Figure1), which raises potential concern about the validity of their results. In the domain of “other risk of bias”, six studies reporting non-significant results have a low risk of bias due to lack of sample size calculation[18, 19, 21, 25, 26], one calculated a sample size but did not specify a primary outcome[24] and three reported the use of outcome measurement tools that are not validated[19, 24].
Physical fatigue
Five RCTs and one CCT of R. rosea for enhancing physical performance were identified. Two trials examine a R. rosea-only supplement, two examined R. rosea-strach combined, and another two evaluate R. rosea combined with cordyceps.
R. Rosea as single ingredient versus placebo
A three arm double blind RCT compared the effect of R. rosea (as a single ingredient) to placebo, or nothing[17]. The study examined muscle recovery in 30 adults by measuring C-reactive protein (CRP) and creatinine kinase (CK) levels in blood. Subjects underwent an exhausting physical exercise test on day 30 which consisted of cycling at 20 W on a bicycle ergometer with power increased by 10 W/min until volitional exhaustion (i.e. subject could no longer pedal at 60 rpm). Findings indicate that R. rosea significantly lowered CRP levels at 5 hours and 5 days after the test (p < 0.05) but that CK levels were not significantly different between groups. Adverse events were not reported.
A double-blind cross-over RCT examined the effect of R. rosea on exercise performance in twelve male subjects[25]. Subjects received R. rosea or identical placebo for 3 days before outcomes were measured by an exercise test and another dose on the day of the test. A wash-out period of 7 to 14 days separated cross-over to the opposite treatment. The primary outcome was muscle recovery measured by ATP levels and secondary outcomes were time to exhaustion and perceived exertion; all outcomes were measured at baseline, during the exercise test and during recovery. There was no significant difference between groups in Pi, phosphocreatine and ATP levels, time to exhaustion and perceived exhaustion. Adverse events and drop-outs were not mentioned.
R. Rosea plus starch versus starch alone
One cross-over RCT and one CCT described in a single report examined the acute and long-term effects, respectively, of R. rosea on exercise performance[20]. In both studies, endurance capacity was the primary outcome and muscle strength, speed of limb movement, reaction time and sustained attention were secondary outcomes.
In the first study on acute effects, R. rosea combined with starch or placebo was taken on each of 2 days[20]. One hour after ingestion on each day, outcomes were measured while subjects underwent a physical functioning test. After a five day washout period, subjects switched to the alternate treatment and performed the same tests. Baseline measurements were not taken. Three out of six parameters of endurance capacity (time to exhaustion, O2 uptake and CO2 output) significantly improved (p < 0.05) in the R. rosea group. There was no difference between groups in any secondary outcomes. After five days, authors stated that 12 subjects were reassigned to intervention and control groups for the long-term evaluation study. The long term study evaluated subjects receiving same intervention and control as in the acute study twice per day over a four week period[20]. The same outcomes as in the acute study were measured. Long term supplementation produced no significant difference in any outcomes between treatment groups; one participant on R. rosea dropped out during long term supplementation for medical reasons unrelated to the study protocol (reason not stated). One subject with strong headaches during acute supplementation and one with minor headaches during long term supplementation were both on placebo. One subject experienced a minor headache and another had insomnia during long term supplementation of R. rosea. It is unclear why the long-term study was not randomized.
R. Rosea plus cordyceps versus placebo
Two double blind RCTs conducted evaluate the effect of R. rosea combined with other herbs on exercise performance[18, 21]. Both studies were conducted by the same group of authors using slightly different protocols and populations. In both studies, intervention capsules were described as every 3 capsules containing 300 mg of R. rosea (s tandardized to 3.0% rosavins and 2.5% salidrosidesminimum), 1000 mg of Cordyceps sinensis, a Chinese herb reported to improve circulation[27], and 800 mg of the manufacturers ‘proprietary blend’ of substances (undisclosed).
In one of the RCTs, 17 male were randomly assigned to either the R. rosea-containing formulation or placebo for 15 days[21]. Subjects took six capsules per day for 4 days (loading dose) then three capsules per day 11 days (maintenance dose). Endurance capacity was measured by multiple parameters including peak CO2 output, power output, time to exhaustion and peak heart rate, which were measured at the beginning and end of the study period. The authors found that the herbal formulation did not have any significant effect on exercise endurance or capacity. Adverse events were not reported.
The second study involving eight male cyclists randomized to either R. rosea-containing formulation (33.0 ± 12.6) years) or placebo (23.8 ± 2.9 years), followed the same protocol as above, however the study period was only 13 days – 6 days of the loading dose and 7 days of the maintenance dose[18]. Respiratory parameters were measured in the participants. This study also found no significant difference in outcomes between groups. There were no drop outs; adverse events were not mentioned.
Mental fatigue
A double blinded RCT assessed the efficacy of a R. rosea extract, SHR-5, for stress related fatigue[22]. Sixty subjects were randomized to receive 576 mg of R. rosea preparation or placebo per day for 28 days. Mental fatigue, measured by the Pines burnout scale, was the primary outcome. Other outcomes evaluated were depression (Montgomery-Asberg Depression Rating Scale, MADRS), quality of life (Medical Outcomes Study Short form 36-item questionnaire, SF-36), attention (Conners’ Computerized Continuous Performance Test II, CCCPT II) and “anti-fatigue” effect (saliva cortisol response after awakening). All outcomes were measured before and after the treatment period. The Pines burnout scale scores ( p = 0.047) and two out of five indices of CCCPT II (p = 0.02, p = 0.001) improved in favour or R. rosea. While investigators conclude that the treatment appears to have beneficial effect, they report excluding follow-up data for at least 5 participants due to physical loss of data and protocol deviations. Per-protocol analyses (i.e. analysis of only participants who followed the protocol for the entirety of the study) may overestimate treatment effect if the reasons for incomplete data are related to the treatment effect[28, 29] – in this case, it is not explicitly stated what “protocol deviations” occurred. No adverse effects occurred during the study period.
R. rosea for non-specific fatigue was evaluated in a double-blind crossover RCT in 56 Armenian physicians[19]. Participants were randomized to either 170 mg R. rosea (standardized to 2.6% salidroside) or placebo. The study period lasted for two weeks followed by a two-week wash-out period, after which participants were crossed over for two weeks. The primary outcome was fatigue, measured using a fatigue index developed for use in this study; the tool does not appear to be validated. Measurements were carried out before and after the treatment period. Authors state that they found a significant improvement in the fatigue index after two weeks of R. rosea supplementation, but only present data for the 5 individual test scores. Since we are unable to replicate and confirm their analysis, findings of this study must be interpreted as inconclusive. Authors indicate that no adverse events occurred; whether or not anyone dropped out of the study was not reported.
A double-blinded RCT conducted in Russia evaluated the effect of two different single doses of R. rosea on mental fatigue[23]. Subjects were randomized to take R. rosea or placebo. A non-treatment group was also included, however subjects were not randomized into this group and comparisons against this group will not be considered in this review. The intervention was taken at 4:00 am while participants were on an overnight shift. Capacity for mental work, measured using a fatigue index of unknown origins and pulse pressure and rate were evaluated before night duty and one hour after taking the study medication. A self-report questionnaire evaluating general well-being was completed after taking the study medication. The fatigue index was comprised of three parameters: visual perception, short-term memory and perception of order. Improvements in favour of both doses of R. rosea were apparent in the fatigue index (p < 0.001); no significant differences between groups occurred for other outcomes. The method of randomization was unclear. One subject in the placebo group experienced hypersalivation; whether or drop-outs occurred was not reported.
A double-blinded RCT pilot study examined the effect of a repeated low dose of R. rosea on foreign students’ mental and physical well-being during their examination period[24]. Subjects were randomized into 2 groups to receive either 100 mg R. rosea once per day or identical placebo for 20 days. Hand-eye coordination (maze test), motoric speed (tapping test), mental work capacity (correction of text test), fatigue and well-being (self-evaluation questionnaire), heart rate and physical work capacity (bicycle ergometer test) were assessed. Significant improvements were observed in hand-eye coordination (p < 0.01), mental fatigue and general-well being (p < 0.01) in favour of R. rosea. Students on placebo had a significantly higher heart rate (p < 0.05). Drop-outs and adverse events were not reported by authors.
Another RCT conducted by the same group examined 60 male students in their first year of study at a Russian high school[26]. Students were randomized into 3 groups to receive either of Rhodaxon (R. rosea extract with no ethyl alcohol per day; proportions of active constituents not given), placebo or nothing for 20 days. Participants underwent the same tests for mental and physical capacity as above as well as a psychophysiological test [Lusher test[30]] to determine level of anxiety, psychological fatigue and need to rest. A comparative analysis between groups was not conducted leaving the effect of R. rosea indeterminable. Adverse events and drop-outs were not reported.
Adverse effects
Out of 446 subjects examined in the 11 included clinical studies, five adverse events were mentioned in three studies. Two subjects on 200 mg of R. rosea over a 4-week period each experienced a minor and serious headache[24]; one subject on placebo over a 2-day treatment period experienced a minor headache and another had insomnia[20]. Another subject on placebo experienced hypersalivation[23]. There appear to be few side effects associated with R. rosea supplementation; those identified are of a mild nature.