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The Effectiveness of Rhodiola rosea L. Preparations in Alleviating Various Aspects of Life-Stress Symptoms and Stress-Induced Conditions—Encouraging Clinical Evidence

Rhodiola rosea L. has a long history of use in traditional medicine to stimulate the nervous system, treat stress-induced fatigue and depression, enhance physical performance and work productivity and treat gastrointestinal ailments and impotence. Apart from its well-established traditional use, a significant number of publications on the clinical efficacy of various R. rosea preparations can be found in the literature. The majority of these studies are related to the efficacy of R. rosea in terms of cognitive functions and mental performance, including various symptoms of life-stress, fatigue and burnout. The beneficial effects of this medicinal plant on enhancing physical performance have also been evaluated in professional athletes and non-trained individuals. Moreover, even though most evidence originates from pre-clinical trials, several clinical studies have additionally demonstrated the remediating effects of R. rosea on cardiovascular and reproductive health by addressing non-specific stress damage and reversing or healing the disrupted physiologies and disfunctions. Overall, in accordance with its aim, the results presented in this review provide an encouraging basis for the clinical efficacy of R. rosea preparations in managing various aspects of stress-induced conditions.


Introduction
Rhodiola rosea L. (syn. Sedum rhodiola DC.; Sedum roseum (L.) Scop), also known as "roseroot", "golden root" or "arctic root", belongs to the plant family Crassulaceae. The yellow-flowered herbaceous perennial naturally grows at high altitudes in dry sandy soil, on sea cliffs and in the crevices of mountain rocks of the Arctic regions of Europe and Asia (mainly Siberia), as well as the eastern coastal regions of North America [1]. R. rosea L. has appeared as a valuable medicinal plant in the traditional and popular medicine of a number of European and Asian countries, including Sweden, Norway, France, Germany and Iceland, as well as Russia and China. Traditionally, R. rosea has been used for centuries to increase physical endurance, work productivity, longevity, resistance to high-altitude sickness, to treat fatigue, depression, anemia, impotence, for gastrointestinal ailments, infections and nervous system disorders [2][3][4][5].
The long, well-established traditional medicinal use of R. rosea has stimulated extensive modern scientific research leading to the identification of R. rosea as an "adaptogen", a substance that nonspecifically increases the resistance of an organism, does not disturb normal biological parameters and has a normalizing influence on physiology [6,7]. The term adaptogen dates to 1947 and has been credited to the Russian scientist Nikolai Lazarev, who defined it as an agent that allows for an organism to counteract adverse physical, chemical, or biological stressors by generating non-specific resistance [6]. To successfully combat stress and stressful situations, adaptation is required. Adaptation might be best thought of as an organism's ability to resist a stressor by responding with either decreased or no characteristic perturbations in homeostasis. Plant adaptogens have the capacity to guide the physiological processes to start the generalized adaptation process (non-specific resistance) and handle the stressful situation in a more resourceful manner.
Based on its long-term use in traditional medicine and numerous scientific studies, in 2011, the European Medicines Agency's (EMA) herbal monograph on Rhodiola rosea L. rhizoma et radix (EMA/HMPC/232091/2011) approved its traditional use as an adaptogen for the temporary relief of symptoms associated with stress, such as fatigue, exhaustion and a general sensation of weakness [7]. The final report of the agency concluded that the long-standing use, as well as the outcome of the clinical trials, supported the plausibility of the use of R. rosea's herbal preparation in the proposed indication. At present, scientific research and clinical studies, which are predominantly conducted in Russia, Scandinavia, Germany, UK, China, USA and other countries, have largely confirmed that R. rosea is an effective psychostimulant, general strengthener and an anti-stress agent. This was successfully referenced in studies addressing stress-related depression and anxiety, fatigue, cardiovascular disease, physical strength and endurance, impotence, high-altitude sickness and nervous system disorders. As a dietary supplement, numerous preparations of R. rosea are used worldwide. The functional claim of R. rosea dietary supplements that are currently mentioned in the consolidated list of Article 13 health claims of the European Food Safety Authority (EFSA) is formulated as follows: "contributes to optimal mental and cognitive activity" [8].

Phytochemical Composition of R. rosea L.
Investigations of the chemical composition of R. rosea rhizomes revealed at least 140 isolated compounds [2,9], including the presence of six distinct groups of phytochemicals (Table 1). Between them, salidroside (rhodioloside), the trans-cinnamyl alcohol glycoside compounds (rhodiolin, rosin, rosavin, rosarin, and rosiridin), and tyrosol are thought to be the most critical plant constituents needed for therapeutic activity [1,2]. A characteristic of R. rosea is its unique presence and the relatively high rosavins content, which have not been detected in other Rhodiola species, and are now an accepted marker for genetically pure R. rosea (and its extracts) [6]. The extracts of the rhizomes of R. rosea are generally standardized to a minimum of 3.0% rosavins and 1.0% salidroside (in their naturally occurring ratio of 3:1), which serve as analytical markers. However, R. rosea rhizome extracts include an entire spectrum of chemical constituents, and the precise identification of the phytocompounds responsible for the numerous health benefits of R. rosea remains to be confirmed.

Asthenia and Resilience
The clearest indication for R. rosea extracts' administration is the management of asthenic conditions, including: a decline in work performance due to physical or intellectual strain, mental and physical fatigue, sleep disturbances, poor appetite, irritability, hypertension, headaches, etc. [1,2,4]. The extract from the rhizomes of R. rosea acts as an adaptogen that aims to increase the body's resistance to the imposed stressors and has a normalizing effect independent of the nature, either environmental or emotional, of the stress signal [6]. The plant's dual actions of cognitive stimulation and emotional calming create benefits for both immediate cognitive and memory performance, as well as for the long-term preservation of brain functions. This is the main adaptogen given the indication 'stress' by the EMA [7]. A number of clinical trials have supported these effects.
Darbinyan et al. [10] investigated the effect of the chronic administration of 170 mg of standardized R. rosea rhizome extract on aspects of mental performance and fatigue on 56 healthy male and female physicians (age 24-35) on night duty for 14 days. In a randomized, placebo-controlled, double-blind, cross-over study with a wash-out period, total mental performance was measured by calculating a Fatigue Index that reflected on the outcomes of complex perceptive and cognitive cerebral functions, such as associative thinking, attention capacity, speed of visual and auditory perception and short-term memory. A statistically significant improvement in the Fatigue Index was observed in the R. rosea treatment group. Additionally, the improved mental performance reverted to baseline values during the washout period, supporting the beneficial effects of the extract. Among people suffering from life-stress symptoms, R. rosea treatment over four weeks resulted in an overall therapeutic effect with clinically relevant improvements in stress symptoms, stress-related disabilities in work, social and family life and functional impairment. In this single-arm, multicenter study by Edwards et al. [11], various aspects of stress symptoms and psychological well-being were evaluated in 101 adult subjects with life-stress symptoms who received R. rosea root extract (200 mg, twice-daily). All outcome measurements showed significant, consistent and steady improvements in stress symptoms, fatigue, quality of life, mood, concentration, disability, functional impairment and an overall therapeutic effect.
In two separate studies, Spasov and colleagues investigated the effects of R. rosea on students during their final exam period [12,13]. During the first study, 40 medical students were randomized to receive either 50 mg of a standardized R. rosea extract or placebo twice daily for a period of 20 days [12]. The students receiving R. rosea demonstrated significant improvements in physical fitness, neuro-motoric functions, mental performance, and general well-being. Statistically significant reductions in mental fatigue, including improved sleep patterns and a reduced need for sleep, greater mood stability and a greater motivation to study were also reported in the treatment group. In a follow-up, double-blind, placebo-controlled study by the same group, 60 students received either 660 mg/day R. rosea extract, placebo, or nothing for 20 days [13]. The administration of R. rosea resulted in an increase in the physical work capacity, coordination, kinesthetic sensitivity, and general well-being of the students, along with a decrease in fatigue and situational anxiety.
A randomized, double-blind, placebo-controlled, parallel-group clinical study by Shevtsov et al. compared the effect of a single dose of either 370 mg or 555 mg of standardized R. rosea extract to placebo on the capacity for mental work against a background of fatigue and stress in 161 cadets aged from 19 to 21 years [14]. The study showed a pronounced anti-fatigue effect in both R. rosea treatment groups, with no significant difference between the two dosages. Additionally, the levels of stress and fatigue were measured by Schutgens et al. in a double-blind, placebo-controlled clinical trial [15]. Thirty subjects were randomly assigned to three groups: a placebo group, a group that took 144 mg of R. rosea extract, and a group that took a supplement called ADAPT-232, a fixed combination of Eleutherococcus senticosus Rupr. and Maxim., R. rosea L. and Schisandra chinensis (Turcz.) Baill. After 1 week of supplementation, a significant decrease in the experienced level of fatigue was observed in the Rhodiola group compared with the placebo and the ADAPT-232 groups.
R. rosea was shown to improve all dimensions of chronic fatigue and burnout-related symptoms. Investigating these effects of R. rosea, a non-interventional study was conducted in 128 primary care practices in Germany, including 330 patients with burnout indicator symptoms (exhaustion, depression, insomnia, fatigue or drop in performance). A considerable alleviation of these complaints after the administration of R. rosea over 8 weeks was reported, along with very good tolerability [16]. Likewise, in a double-blind, placebo-controlled clinical trial, 60 participants, selected according to the diagnostic criteria for fatigue syndrome, were randomized to receive R. rosea (576 mg extract/day) or placebo for four weeks [17]. R. rosea was found to exert a notable anti-fatigue effect that increased mental performance, particularly the ability to concentrate, and decreased cortisol response to awakening stress in burnout patients. In addition, another exploratory single-arm, multi-center study investigated the clinical outcomes of R. rosea intervention (200 mg of R. rosea extract) in 118 burnout patients [18]. The fatigue symptoms experienced by the patients continuously declined during the 8 weeks of intervention, with noteworthy results after only one week of treatment, and a statistically significant improvement at week 8.
Finally, an open-label, multicenter, single-arm trial by Kasper et al. [19], explored the clinical outcomes in burnout patients treated with 400 mg of R. rosea extract over 12 weeks. A wide range of outcome measures assessed in the trial, such as alertness, calmness and good mood, clearly improved over time, with considerable changes already being detected after the first week of R. rosea administration.
The ability of R. rosea to increase the non-specific resistance and exert neuroprotective properties have been primarily attributed to its capacity to influence the levels and activity of several components of the stress-response system, including monoamine neurotransmitters such as serotonin and catecholamine, and opioid peptides such as βendorphins [1,5,[20][21][22][23][24]. In small and medium doses, R. rosea administration was found to stimulate the noradrenalin, serotonin, dopamine and acetylcholine receptors in the central nervous system (CNS) [24]. It also enhanced the effects of these neurotransmitters on the brain by increasing the permeability of the blood-brain barrier to precursors of dopamine and serotonin [25]. Additionally, the literature data indicate that R. rosea may stimulate the synthesis, transport, and receptor activity of opioid receptors and peptides such as the β-endorphins [23,26]. β-endorphins attenuate the intensity of the stress response and the sudden release of opioid peptides that occurs as part of the pituitary-adrenal axis response to stress. The excess production of endorphins at stressful situations interferes with normal brain functions and can lead to heart damage. In addition, R. rosea might protect the brain and heart by reducing the secretion of corticotrophin releasing factor (CRF) under stress, decrease corticosterone levels and increase the expression of stress-responsive genes, especially in the hippocampus and prefrontal cortex [27,28].

Anxiety and Depression
Encouraging results exist regarding the use of R. rosea herbal preparations in treating mild-to-moderate depression, and generalized anxiety. As previously mentioned, R. rosea has been used in traditional medicine to alleviate the symptoms of everyday stressors, including anxiety, stress, fatigue and depression [1,2,5]. By hindering physiological stress responsivity, R. rosea can have a moderating effect on anxiety and mood. A pilot study by Bystritsky et al. [29] evaluated whether the extract of R. rosea was effective in reducing symptoms of generalized anxiety disorder (GAD). Ten participants (age 34-55 years) diagnosed with a DSM-IV of GAD were enrolled in the study, receiving a total daily dose of 340 mg R. rosea extract for 10 weeks. The results showed that individuals treated with R. rosea had a significant improvement in GAD-related symptoms, with a similar reduction in the Hamilton Anxiety Rating Scale (HAMD) scores to those found in psychopharmacological trials. Similarly, the open-label, randomized trial of Cropley et al. [30] demonstrated that participants suffering from mild anxiety responded positively to R. rosea. Stress and anxiety significantly decreased in the R. rosea treatment group during the 14-day intervention. Measures of total negative mood, anger, confusion and depression were also significantly decreased in the R. rosea group. The results indicated that people suffering from mild anxiety significantly benefited from R. rosea, while the herb also showed a protective effect against depression.
In continuation of this, Darbinyan et al. carried out a randomized, double-blind, placebo-controlled phase III clinical trial over 6 weeks with the aim of assessing the efficacy and safety of a standardized R. rosea extract in patients suffering from a current episode of mild/moderate depression [31]. A total of 91 patients aged 18-70 years, with mild to moderate depression, were randomized into three groups. One received 2 R. rosea extract (340 mg/day) tablets each day, a second received 2 tablets twice per day, with a different dose of R. rosea extract (680 mg/day), and a third received 2 placebo tablets daily. For individuals in the R. rosea treatment groups, overall depression, together with insomnia, emotional instability and somatization, significantly improved following medication. Moreover, in both R. rosea treatment groups, the HAMD scores significantly improved, showing that the standardized extract from R. rosea possesses a clear and significant anti-depressive activity in patients suffering from mild to moderate depression. A phase II clinical trial by Mao et al. compared the efficacy of R. rosea extract versus sertraline, a conventional antidepressant, in treating mild-to-moderate major depressive disorder (MDD) [32]. The study included 57 participants, randomized to 12 weeks of standardized R. rosea extract intervention, sertraline, or placebo. Clinically meaningful odds ratios of global improvement by week 12 indicated that patients taking R. rosea had 1.4 times the odds of improvement, and patients on sertraline had 1.9 times the odds of improvement versus those taking placebo, indicating that R. rosea may possess modest antidepressant effects in patients with mild-to-moderate MDD. Although R. rosea showed a lower antidepressant effect compared to sertraline, it also produced significantly fewer adverse events and was much better tolerated, suggesting that R. rosea may possess a more favorable risk-to-benefit ratio for these individuals. Furthermore, a recent study by Gao et al. evaluated the effects of R. rosea in combination with sertraline in 100 patients with mild to moderate MDD for 12 weeks [33]. The results of the study showed that R. rosea possesses a clear and significant anti-depressive activity in patients suffering from MDD and improved their quality of life and clinical symptoms. Statistically significant reductions in the level of depression, as well as in specific symptoms of depression, such as insomnia, emotional instability and somatization, could be demonstrated. In higher doses (0.6 g/day over a 12-week period), an additional positive effect was observed.
The molecular mechanisms involved in the antidepressant effects of R. rosea extracts have been examined by numerous preclinical studies [20,24,25,34,35]. A comprehensive review by Amsterdam and Panossian [25] reported that R. rosea stimulates the expression and release of neuropeptide-Y in neuroglial cells, controls more than 50 genes involved in the regulation of behavior, mood and depressive disorders, and is associated with certain key mediators of the stress response: regulation of the homeostasis of the hypothalamicpituitary-adrenal (HPA) axis and modulation of G-protein-coupled receptor signaling pathways [32,[34][35][36]. Moreover, other research has shown that R. rosea acts as an MAO-A and MAO-B inhibitor, with supporting evidence of the herb's antidepressant and cognitiveenhancing properties [23]. In depressive rats, R. rosea extract could improve serotonin levels and induce neural stem cell proliferation in the hippocampus to return to normal levels, thereby repairing the hippocampus' injured neurons [36].

Effects on Physical Strength and Endurance
R. rosea L. has a long history of use for improving physical work capacity and physical stress endurance. Professional athletes have been effectively using R. rosea for several decades as a safe non-steroidal food supplement to enhance endurance and assist in rapid muscle recovery [37]. A number of scientific studies including non-athlete individuals exposed to maximal physical work, as well as professional athletes, have shown that R. rosea increased physical work capacity and dramatically shortened the recovery time between bouts of high-intensity exercise [38]. Animal studies suggest the mechanisms that may be involved in these effects. In mice made to swim to their limit, R. rosea activated the synthesis or resynthesis of ATP in mitochondria and stimulated reparative energy processes after intense exercise [39]. Moreover, chronic R. rosea supplementation significantly improved exhaustive swimming-induced fatigue by increasing glycogen content, the energy supply of lipogenic enzyme expressions and protective defense mechanisms [40]. In obese mice fed a high-fat diet, Rhodiola supplementation prevented muscle atrophy and dysfunction and activated the Sirtuin1 pathway, while atrogenes were suppressed and mitochondrial quality control was improved [41]. Finally, other studies have shown that R. rosea enhances cell regeneration and energy metabolism by increasing the synthesis of adenosine triphosphate, ribonucleic acid, protein, and amino acids [42].
Considering human trials, in a recent study by Williams et al., the effects of short-term golden root extract (R. rosea L.) supplementation on blood lactate, catecholamines and performance during repeated bench-press exercises were examined [43]. In a double-blinded, crossover, counterbalanced study design, 10 resistance-trained males were supplemented with either 1500 mg/day of R. rosea extract or placebo for 3 days. An additional 500 mg dose was ingested 30 min prior to testing. The findings indicated that short-term R. rosea supplementation increased the mean bench press velocity; thus, supplementation with R. rosea may enhance explosive resistance training performance. In another study examining the effects of an acute oral dose of R. rosea on endurance exercise performance, aspects of perceived exertion (RPE), mood, and cognitive function were evaluated [44]. Subjects (n = 18) ingested either R. rosea extract or a carbohydrate placebo 1 hour before testing in a double-blind, random crossover manner. Exercise testing consisted of a standardized 10-minute warm-up, followed by a 6-mile time trial on a bicycle ergometer. Perceived exertion, blood lactate concentration, salivary cortisol, and salivary α-amylase were measured, and a Profile of Mood States questionnaire and a Stroop Color Test were completed before warm-up and after the trial. The results of the study showed that acute R. rosea ingestion decreases the heart-rate response to submaximal exercise and improves endurance exercise performance by decreasing the perception of effort. The higher concentration of salivary α-amylase in the R. rosea treatment group suggests increased activation of the sympathetic nervous system's response to stress. The results indicate obvious beneficial implications for recreational athletes who may choose to compete in endurance events. The acute R. rosea ingestion on substrate utilization, mood state, RPE, and exercise affect were also examined by Duncan et al. [45]. Ten young males completed two 30-minute cycling trials following the ingestion of either 3mg·kg −1 body mass of R. rosea or placebo using a double-blind, crossover design. The results revealed that the ingestion of R. rosea favorably influenced RPE and exercise affect without changes in energy expenditure or substrate utilization during submaximal cycling performance in regularly active adults. These changes support the efficacy of acute R. rosea ingestion in positively enhancing psychophysiological responses to submaximal exercise performance.
The effects of chronic supplementation of R. rosea on mental and physical performance, as well as hormonal and oxidative stress biomarkers, were investigated by Jowko et al. [46] in a double-blind, randomized trial. A total of 26 (13/13) male, healthy, physical-education students received either 600 mg of R. rosea extract or placebo for 4 weeks, underwent psychomotor tests, and performed two incremental cycle ergometer tests of volitional fatigue. Blood samples were drawn before and after the test to measure the hormonal profile (cortisol, testosterone, and growth hormone) and biomarkers of oxidative stress (lipid hydroperoxides, total antioxidant capacity, and superoxide dismutase) and muscle damage (creatine kinase). The results indicated that chronic R. rosea ingestion improved psychomotor performance (simple and choice reaction time) in young, healthy, and physically active men, but did not enhance physical performance. No changes were observed in the hormonal profile; however, R. rosea ingestion raised the plasma's total antioxidant capacity.
Considering anaerobic exercise performance, a study by Ballmann et al. investigated the effects of short-term R. rosea extract supplementation on repeated Wingate performance [47]. Eleven physically active college-aged females were supplemented with either 1500 mg/day of R. rosea extract or placebo for 3 days, and an additional 500 mg dose 30 min prior to testing. During each exercise trial, participants completed 3 × 15-s Wingate Anaerobic Tests (WAnTs). Over the three WAnTs, the outcome parameters of mean watts, mean anaerobic capacity, mean anaerobic power, mean peak watts, and mean total work were all higher in the R. rosea treatment group versus placebo. The results indicated that R. rosea supplementation enhanced anaerobic exercise performance by improving power output and total work during repeated WAnTs, and that this plant may possess ergogenic benefits.
Finally, a clinical trial performed by De Bock and colleagues examined the acute and long-term effects, respectively, of R. rosea on exercise performance [48]. In this study, 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 or placebo were taken on each of the 2 days, while the long-term effects evaluated the same outcomes over a four-week period. The results showed that three out of the six parameters of endurance capacity (time to exhaustion, O 2 uptake and CO 2 output) significantly improved in the R. rosea group. The authors concluded that acute R. rosea intake can improve the endurance exercise capacity in young, healthy volunteers. The most important clinical trials reporting on the effectiveness of R. rosea in increasing mental and physical performance are presented in Table 2.

Cardioprotective Effects
The cardioprotective effects of R. rosea have been widely investigated in pre-clinical studies, and between others, include the following: prevention of stress-induced cardiac damage, decreased levels of myocardial catecholamines and cyclic adenosine monophosphate (cAMP), and reduced adrenal catecholamine release [1,[21][22][23]. Additionally, it has been found that R. rosea was able to activate the mu-opiate receptors in animal heart muscle preventing reperfusion arrhythmias [49]. This effect could be blocked by naloxone injection (known to inhibit mu-opiate receptors), thus suggesting that the anti-arrhythmic effect of R. rosea is associated with mu-opiate receptors in myocardial muscle. Using the same mechanism, R. rosea extract supplementation decreased the systolic blood pressure and heart-rate in a dose-dependent manner in spontaneously hypertensive mice [23]. Furthermore, the oral administration of R. rosea oligomeric proanthocyanidins in atherosclerosis rats improved the progress of atherosclerosis by regulating the lipid metabolism, restoring the antioxidant capacities, attenuating pro-inflammatory cytokines and chemocytokines release, and improving the endothelial dysfunction indicated by the nitric oxide system [50]. It has been suggested that R. rosea offers some cardioprotective benefits that are not associated with other adaptogens. Its proposed ability to moderate stress-induced damage and dysfunction in cardiovascular tissue might make R. rosea the adaptogen of choice among patients at higher risk of cardiovascular disease [6].
In a study by Parisi et al. [51], the effects of chronic R. rosea supplementation on sport performance and antioxidant capacity in male athletes were examined. Following a chronic supplementation with R. rosea for 4 weeks, 14 trained male athletes underwent a cardiopulmonary exhaustion test and blood samples were taken to evaluate their antioxidant status and several biochemical parameters. Prolonged R. rosea supplementation was able to reduce both lactate levels and parameters of skeletal muscle damage after an exhaustive exercise session in the athletes. Moreover, this intake reduced, in a statistically significative manner, plasma free fatty acids levels, indicating that R. rosea supplementation seems to ameliorate fatty acid consumption. Skarpanska-Stejnborn et al. investigated the effects of a 4-week intervention with R. rosea extract on the balance of oxidants and antioxidants in the serum and erythrocytes of competitive rowers [52]. In a double-blinded study, 22 members of the Polish Rowing Team performed a 2000-m maximum test on a rowing ergometer. Several enzymatic redox parameters were assessed in erythrocytes, creatine kinase activity and total antioxidant capacity were measured in plasma samples, lactate levels were determined in capillary blood samples, and uric acid concentrations were measured in serum. After supplementation, the total plasma antioxidant capacity was significantly higher in the supplemented group compared to the placebo group, and superoxide dismutase activity in erythrocytes directly after and 24 h after the ergometry was significantly lower in the athletes who received the R. rosea extract.  (1) Ultra-weak photon emission; (2) Self-evaluated stress; (3) Self-evaluated fatigue.
A statistically significant decrease in the experienced level of fatigue and decreased photon emission observed in the Rhodiola treatment group  Overall depression, insomnia, emotional instability and somatization significantly improved following medication. R. rosea shows anti-depressive potency.  A three-arm, double-blind clinical study by Abidov et al. compared the effects of R. rosea extract supplementation on the blood levels of inflammatory C-reactive protein (CRP) and creatinine kinase (CK) in healthy untrained volunteers before and after exhausting exercise to placebo, or nothing [37]. The study examined muscle recovery in 36 healthy untrained adults that underwent an exhausting physical exercise test on day 30, which consisted of cycling on a bicycle ergometer with gradual power increases until volitional exhaustion. The findings indicated that R. rosea significantly lowered the CRP levels at 5 h and 5 days after the test (p < 0.05), while the CK levels were much lower in the R. rosea treatment group 5 days after the test and indicated a decrease towards the initial levels. It was concluded that the use of R. rosea extract could facilitate recovery after exercise and decrease the risk of cardiological disorders, in line with the cardioprotective properties of this plant. Lastly, a systematic review and meta-analysis conducted by Yu et al., including 13 randomized controlled trials involving 1672 participants, evaluated the efficacy and safety of various Rhodiola formulations in treating ischemic heart disease [53]. Overall, the results showed that the effectiveness of Rhodiola formulations was higher compared to other medicines in the control groups, with statistically significant differences observed in both symptomatic improvement and electrocardiography improvement. The authors concluded that Rhodiola formulations may have a positive effect on treating ischemic heart disease alone and in combination with routine western medicine.

Reproductive Effects
Today, the role of stress has been acknowledged as being the underlying cause for many disease processes [35]. Stress is commonly overlooked as an obstacle to natural conception, despite the fact that stress can shut down the activity of the hypothalamicpituitary-gonadal axis, which controls the reproductive system [54]. This can disrupt the connection between the brain and the ovaries and cause delayed or absent ovulation and irregular or missed menses. Better managing stress and initiating the relaxation response can help to reverse or heal the disrupted physiology that is causing infertility [55]. Traditional medicine transcripts report that R. rosea has been given to newlyweds in Siberia to boost fertility. In some mountain villages of the Republic of Georgia, a bouquet of roots is still given to couples prior to marriage to enhance fertility and assure the birth of healthy children [1,5,25]. At present, clinical trials supporting these effects of R. rosea are still extremely scarce, but those reported have nonetheless shown that R. rosea extracts are able to restore ovulation in women with amenorrhea (loss of menstrual cycle) and physicians have reported cases of women who failed to conceive using fertility drugs becoming pregnant after taking R. rosea [1,56,57].
Several animal studies have demonstrated the effect of R. rosea in fertility and sexual function. R. rosea enhanced egg maturation in female rats and produced an anabolic effect in the males of a number of species (increased muscle-building and gonad-strengthening similar to the effects of low-dose testosterone) [1]. In the majority of R. rosea-treated animals, the number of growing follicles, the oocyte's volume, the accumulation of RNA in the oocyte's cytoplasm, the proliferation of the lining and glandular cells of the uterine horns, and the preparation of uterine mucosa for fertilization all increased. The administration of R. rosea extract to sexually mature female mice over a period of 4 weeks of prolonged menstruation from 1.3 days (control) to 2.8 days (R. rosea treated), reduced the resting period from 3.8 days (control) to 2.2 days (R. rosea-treated), and increased the relative number of estrous days from 29% to 56%. Additionally, R. rosea increased the mean weight of the uterine horns and the mean weight of the ovaries [56,57]. A recent study by Kadioglu et al. investigated the effect of R. rosea root extract on stress-induced ovarian damage, infertility and reproductive disorders in female rats [58]. It was found that taking R. rosea extract had beneficial effects on the treatment of stress-induced reproductive dysfunction and significantly prevented the increase in oxidative parameters and proinflammatory cytokine levels in ovarian tissue.
These pre-clinical investigations led to a clinical study investigating the effects of R. rosea extract in women suffering from amenorrhea [5,56,57]. Forty women with amenorrhea were given R. rosea extract (either 100 mg of dried R. rosea extract orally twice a day for 14 days, or 1 mL liquid R. rosea extract intramuscularly for 10 days). In some participants, the treatment cycle was repeated 2-4 times. Normal menses was restored in 25 women, 11 of whom became pregnant. In those with normal menses, the mean length of the uterine cavity increased from 5.5 cm to 7.0 cm (considered normal) after R. rosea treatment. In line with this study, a recent four-arm parallel group, placebo-controlled, randomized, double-blind, clinical trial assessed the efficacy and safety of an herbal preparation named Menopause relief EP ® , a hybrid combination of Actaea racemosa L. (black cohosh, BC) and R. rosea (RR) root extracts in women with menopausal complaints [59]. A total of 220 women were randomly assigned to receive either BC (6.5 mg), BC500 (500 mg), Menopause Relief EP ® , or placebo once per day for 12 weeks. The study found that the menopause-symptomrelief effects of the BC-RR combination were significantly superior in all tests to the effects of BC alone and placebo. The combination BC-RR significantly improved the menopausal quality of life, mainly due to its superior effect on emotional and physical health domains. Finally, in an open study, 35 men with erectile dysfunction and/or premature ejaculation (of 1-20 years duration) took 150-200 mg/day of R. rosea extract for 3 months [60]. A total of 26 of 35 men (74%) responded to R. rosea, with substantially improved sexual function, normalization of prostatic fluid, and an increase in 17-ketosteroids in urine.

Conclusions
Rhodiola rosea L. has a well-established use in the traditional medicinal systems of the Nordic countries, Eastern Europe and Asia, with a reputation for enhancing mental and physical performance, decreasing symptoms of fatigue and depression, increasing work productivity, and providing antioxidant and anti-inflammatory effects, among others. Current research has clearly established R. rosea as a phytomedicinal plant with adaptogenic effects, which is able to enhance the body's non-specific resilience to physical and mental stresses and normalize its functions. Stress has been associated with an increased incidence of numerous health disorders of the neuroendocrine-immune system, from milder physiological conditions such as a decrease in physical and mental capacity and a sensation of weakness, to more concerning health conditions such as anxiety, depression, fatigue and burnout, cardiovascular and reproductive disfunctions. The long history of medicinal use and the extensive pre-clinical and clinical research into its stimulant and stress-protective properties have undoubtably validated the effectivity of using R. rosea L. to address all the above-mentioned stress-induced conditions and disorders.