Rhodiola Rosea

Rhodiola

The genus Rhodiola (Crassulacea) consists of nearly 200 species 1), in which at least 20 species are used in the traditional medicine of Russia, Scandinavia and Asia countries (e.g. China and India) for various health-promoting effects 2). The best known is Rhodiola Rosea also known as Arctic root, Golden root, Rose root or King’s crown, which is now cultivated also in Europe and North America, and present on the market as dietary supplement 3). Other Rhodiola species, including Rhodiola heterodonta, Rhodiola quadrifida, Rhodiola kirilowii, Rhodiola imbricata, Rhodiola algida, and Rhodiola crenulata also have been used in traditional herbal medicines in different regions of the world, such as the mountainous regions of Southwest China and the Himalayas, the alpine regions of Asia and Europe and Arctic regions of North America, but less studied 4).

Rhodiola Rosea is a perennial plant found in colder regions such as Scandinavia, the mountains of Central Asia, and the Arctic 5). Rhodiola is the common name for the underground stem (or rhizome) and root of the plant Rhodiola rosea L. The plant is cultivated or gathered to obtain the underground organs (root and rhizome) for medicinal use. In traditional herbal medicine, Rhodiola rosea is used as an “adaptogen” to enhance physical and mental performance and reduce fatigue and fighting stress in healthy population 6). Currently, Rhodiola Rosea extracts are used as a dietary supplement throughout Europe, Asia, and the United States for similar indications 7). Rhodiola rosea preparations are obtained from the dried extracts prepared by ethanol extraction (a technique used to extract compounds from plant material by dissolving them in ethanol). Extracts of Rhodiola roots and rhizome comprise about 140 distinct compounds, including monoterpene alcohols and their glycosides, polyphenols salidroside (rhodioloside), cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives, rosin, and rosavin. The major compounds with important pharmacological values are salidroside, tyrosol, rosavin, rosin, and cinnamyl alcohol, which belong to phenyletanes and phenylpropanoids, but it remains unclear which—if any—confers Rhodiola’s purported benefits 8). Due to their bioactivity effects, salidroside and rosavin have been recommended to be used as markers for quality evaluation of Rhodiola rosea 9), 10), 11). Thus, Rhodiola rosea extracts used in most clinical studies have been standardized to contain 0.8–1% salidroside and a minimum of 3% rosavin 12). Herbal supplements containing Rhodiola rosea are usually available in solid forms to be taken by mouth. Rhodiola rosea can also be found in combination with other herbal substances in some herbal medicines. While Rhodiola supplements are generally safe for healthy people, there is very little evidence that they have cognitive benefits.

Historically, people in northern regions have used Rhodiola rosea for anxiety, fatigue, anemia, impotence, infections, headache, and depression related to stress. Traditional folk medicine used Rhodiola rosea to promote work endurance, increase longevity, and to promote resistance to high altitude sickness, fatigue, depression and other health conditions 13). Rhodiola rosea may enhance mood and affect via its complex effect on central biogenic amines and β-endorphins. For example, Rhodiola rosea appears to stimulate noradrenalin, serotonin, dopamine, and acetylcholine receptors in brain regions involved in mood and affect 14). In in-vitro bioassay studies, Rhodiola rosea has also been shown to inhibit monoamine oxidase A and B enzymes 15). Further, studies suggest that Rhodiola rosea may have antidepressant activity via its ability to increase endogenous β-endorphin levels while preventing stress-induced elevation of β-endorphin 16) and via its action in prolonging the ‘forced swim test’ in rats 17). Today, people use Rhodiola rosea as a dietary supplement to increase energy, stamina, and strength, to improve attention and memory, and to enhance the ability to cope with stress. Rhodiola rosea root extracts are also available in capsule or tablet form.

The chemical composition of the extracts from the Rhodiola rosea root and rhizomes was studied by East-European research groups mainly 18). A decade of investigation 19) revealed evidences about the presence of different biological active substances in the rhizome of golden root unlike some other Rhodiola species.

Six different groups of chemical components with pharmaceutical interest could be found in the Rhodiola rosea roots and rhizomes: (1) phenylpropanoids—alcohol derivatives of the cinnamon acid and glycosides like rosavin (2.1%) 20), rosin and rosarin (which are classified under the general name of “rosavins”) 21); (2) phenylethanoids—salidroside (rhodioloside) (0.8%), p-tyrosol22); (3) flavonoids—including rodiolin, rodionin, rodiosin, acetylrodalgin, tricin 23), and tannins 16–18% 24); (4) monoterpenes, including rosiridol and rosidarin; (5) triterpenes, such as daucosterol and betasitosterol; (6) phenolic acids such as chlorogenic, hydroxycinnamic, gallic acids 25) and essential oils 26). All these substances determine the specificity of the Rhodiola extracts. However, the roots have many other substances like phenolic antioxidant, including proanthocyanidins, quercetin, gallic acid, and chlorogenic acid 27).

Rosavins (rosavin, rosarin, and rosin) and the salidroside or rhodioloside, as well as rodiolin, rodonizid, and roziridine are the most important, and are mainly used as active substances for production of medical preparations. Tyrosol is also a crucial active ingredient; though to a less extent than the other two standards. The rosavins complex is specific for Rhodiola rosea unlike salidroside which presents in other Rhodiola species and in some plants from other genera 28).

One of the major results of the research is the detection of differences in the content of biologically active substances in the roots of Rhodiola rosea depending on their habitats 29). Investigation of Rhodiola rosea root from different Bulgarian mountains areas indicated the highest amount of salidroside of 1.55% in Rila mountain sites, and, respectively, the lowest of 0.72% in Pirin Mountain sites 30). The stem and the leaves contain less salidroside, while there is no substantial difference in the levels of polyphenols accumulation in the epigeous parts of the plant.

Rhodiola species contain a range of antioxidant compounds, including p-tyrosol, organic acids (gallic acid, caffeic acid, and chlorogenic acid), and flavonoids (catechins and proanthocyanidins) 31). The stimulating and adaptogenic properties of Rhodiola rosea are attributed to p-tyrosol, salidroside (synonym: rhodioloside and rhodosin), rhodioniside, rhodiolin, rosin, rosavin, rosarin, and rosiridin 32). Rosavin is the constituent currently selected for standardization of extracts 33). p-Tyrosol has been shown to be readily and dose-dependently absorbed after an oral dose 34); however, pharmacokinetic data on the other adaptogenic compounds found in Rhodiola rosea is unavailable.

Figure 1. Rhodiola rosea extracts bioactive compounds

Rhodiola rosea extracts bioactive compounds
[Source 35) ]

Rhodiola benefits

Currently, many studies have claimed that Rhodiola rosea extracts and its bioactive compounds wide variety of other medicinal properties and/or biological activities, which include anti-aging, anti-inflammation, anti-stresses, antioxidant, antibacterial , anti-viral and anti-cancer effects, as well as increasing immunity, enhancing DNA repair and modulating adaptation to hypoxia and angiogenesis 36). While some clinical trials have examined the effects of Rhodiola rosea on cognitive function, the quality of many were suboptimal and none have directly tested whether it can prevent age-related cognitive decline or dementia.

Rhodiola is reported to enhance energy levels and control how the body responds to stress, both of which can affect brain health, but the clinical evidence to support these assertions is lacking due to the low quality of many trials. No clinical studies have tested whether Rhodiola can prevent age-related cognitive decline or dementia. In one well-conducted randomized, controlled clinical trial in male students (17–19 years old), researchers found no improvement in cognitive scores after 20 days of supplementation 37). And a double-blind cross-over study with 18 healthy adults prescribed 3 mg/kg of Rhodiola found no effects on mood or cognitive function 38). A systematic review examining the role of Rhodiola Rosea on mental fatigue reported that it was effective in some studies while not in others, but methodological flaws in the studies precluded accurate assessment of its efficacy 39). More rigorous randomized controlled trials are needed to determine the effect of Rhodiola Rosea on mental fatigue.

While preclinical test tube studies have suggested potential benefits, the research is inconclusive. One study, for example, showed that Rhodiola can act as a powerful antioxidant, but was toxic to isolated neurons 40).

Rhodiola rosea anti-stress effects

Rhodiola rosea extracts act as an adaptogen to provide nonspecific resistance to physical, chemical and biological stresses 41). The stress-protective effects of Rhodiola rosea extracts have been shown to be engaged with the hypothalamic-pituitary-adrenal (HPA) axis 42) and several key mediators of stress responses, such as heat shock proteins 43), stress-activated c-JUN N-terminal protein kinase 1(JNK1) 44), Forkhead box O (FOXO) transcription factor DAF-1 45), cortisol 46), nitric oxide 47) and beta-endorphine 48). Xia et al 49) reported that Rhodiola rosea extracts reduced the serum levels of corticotropin-releasing hormone and corticosterone via down-regulating the expression of c-FOS in the hypothalamus of rats subjected to stress. It was also showed that Rhodiola rosea extract treatment of pond snail Limnaea stagnalis larvae resulted in the resistance to both 600 μM menadione and heat shock under 43°C 50). Rhodiola rosea extract also enhanced the stress resistance in the silkworm, against heat stress (37 °C) and starvation 51). In Caenorhabditis elegans (roundworm), 10–25 microg/ml Rhodiola rosea extracts increased stress resistance against a relatively short period of time of heat shock (35 °C for 3 hours) as well as chronic heat treatment at 26 °C by activating DAF-16/FOXO via promoting its nuclear translocation 52). Rhodiola rosea extract also protected C2C12 myotubes from oxidative stress by increasing the expression of HSP70 and HSP72 and the release of neuropeptide Y (NPY) 53). Salidroside as a predominant compound in Rhodiola rosea extracts protected against beta-amyloid peptide induced oxidative stress by inhibiting its mediated phosphorylation of JNK and p38 MAP kinase, but not ERK1/2, which suggested the usefulness of salidroside for treating or preventing neurodegenerative diseases.

The chemical structures of the main bioactive compounds in Rhodiola rosea extracts, rosin and its derivatives and salidroside, contain phenolic hydroxyl groups and unsaturated bonds. These compounds were shown to be effective at scavenging reactive oxygen species (ROS). In addition, Rhodiola rosea extracts and salidroside was able to increase the expression of antioxidant enzymes (e.g. GPx) and activate the nuclear erythroid 2-related factor 2 (Nrf2) pathways in rats to protect against bleomycin-induced pulmonary fibrosis in rats 54) and to reverse ultraviolet B (UVB) induced DNA damages in HaCaT cells 55), respectively.

Chronic or long-term stress can lead to symptoms like anxiety, depression, sleep problems and weak immune system, as well as disease status such as cardiovascular and metabolic diseases 56). There is increasing data that indicate an intriguing relationship between stress resistance and slowed-aging although the causal effects between two remain unclear 57). Stress resistance is believed to be related to hallmarks of aging, including altered intra- and intercellular communication, dysregulated nutrient sensing, mitochondrial health, cell senescence, stem cell exhaustion, genomic instability (DNA damage), telomere attrition, and certain patterns of gene expression 58). Moreover, accumulating evidences have supported that chronic stress promote cancer progression in many experimental models 59). Based on these results, the unique property of Rhodiola rosea extracts for enhancing resistance to general stresses deserves its further investigation in both anti-aging and cancer prevention.

Rhodiola rosea anti-hypoxic and angiogenesis effects

Rhodiola is well known for its functions in enhancing adaptation to high-altitude and hypoxic conditions. The master regulators of the adaptive response to hypoxia are believed to be heterodimeric transcription factors consisting of O2-regulated α subunits (HIF1A/HIF-1α or EPAS1/HIF-2α), and a constitutively expressed ARNT/HIF-1β subunit 60). Qi et al 61) reported that an aqueous extract of a Tibetan herb, Rhodiola algida var. tangutica down-regulated the expression of HIF-1α and -2α under hypoxic conditions in breast cancer MCF7 cells. In an in vitro studies using co-culturing of mouse endothelial and L-1 sarcoma cells, Rhodiola extracts inhibited proliferation and migration of endothelial cells 62). Rhodiola extracts and salidroside and rosavin were also shown to inhibit in vivo neovascularization that was induced by the implantation of syngeneic tumor cells 63) or human kidney cancer homogenate 64).

In contrast to the limited studies of Rhodiola on hypoxia and cancer, there are more studies focused on Rhodiola extracts and its active compounds (mainly salidroside) for protecting against hypoxia-induced damage of normal functions and on the underlying mechanisms of actions 65). Salidroside was shown to increase the expression of erythropoietin (EPO) mRNA by inducing the accumulation of HIF-1α protein, but not HIF-2α in human embryonic kidney fibroblast (HEK293T) and human hepatocellular carcinoma (HepG2) cells 66). HIF-1α/HIF-2α) are tightly regulated by the HIF-prolyl hydroxylases 67). Zhang et al 68) have demonstrated that salidroside specifically reduced the mRNA and protein expression PHD3, but not PHD1 and PHD2 through its binding to estrogen receptor alpha (ERα) and inhibition of ERα mediated PHD3 transcription. In addition, intramuscular administration of salidroside resulted in a robust increase in neovascularization and blood perfusion recovery in a mouse model of hind-limb ischemia through promoting skeletal muscle cell migration and FGF2/FGF2R and PDGF-BB/PDGFR-β pathways mediated paracrine function 69).

Rhodiola rosea anti-aging effects

Rhodiola rosea extracts can extend lifespan in a range of model organisms, such as fruit flies, worms, and yeast 70), without affecting its daily food intake, body weight, or fecundity. Rhodiola rosea extract also delayed the age-related decline of physical activity and immune functions, and increased stress resistance 71). Rhodiola rosea extract SHR-5 was shown to increase the mean and maximum life-span of the fruit fly up to 24% and 31%, respectively 72). Rhodiola rosea extracts can extend lifespan at different caloric levels. The effect of Rhodiola rosea extracts on lifespan was independent of caloric restriction-related signaling pathways, including SIR2 proteins, insulin and insulin-like growth factor signaling, and the TOR in fruit flies 73), but dependent on diet composition (in particular protein-to-carbohydrate ratios or sucrose contents) and expression of Msn2/Msn4 and Yap1 regulatory proteins 74). The lifespan extension of Rhodiola rosea extracts was not seen in diets with high protein-to-carbohydrate ratios 75). In addition, the physiological state of an organism affected the beneficial effect of Rhodiola rosea extracts on longevity 76). Individuals with moderate robustness appears to benefit most from the intake of Rhodiola rosea extracts 77). Aqueous Rhodiola rosea extracts also exhibited a concentration-dependent effect on long-term survival and stress resistance of budding yeast Saccharomyces cerevisiae: Low concentrations increased yeast lifespan, whereas high concentrations shortened yeast lifespan 78). Nevertheless, mechanisms for the anti-aging effects of Rhodiola rosea extracts are still largely unknown. In addition, the anti-aging properties of Rhodiola rosea extracts are necessary to be tested in animals before its translation into human studies.

Rhodiola rosea anti-cancer effects

There are several studies demonstrating the anticancer activities of Rhodiola rosea extracts. Udintsev SN et al 79) showed that Rhodiola rosea extracts inhibited the growth of transplanted solid Ehrlich adenocarcinoma and Pliss lymphosarcoma, decreased their metastases to the liver, and extended survival time of rats bearing the tumors. In a model which angiogenesis was induced in the skin of Balb/c mice by grafting of syngeneic L-1 sarcoma cells 80), Rhodiola quadrifida extract and salidroside highly significantly reduced tumor-induced angiogenesis. In addition, Rhodiola rosea extracts in combination with the anti-tumor agent cyclophosphamide resulted in enhanced anti-tumor and anti-metastatic efficacy of drug treatment, as well as reduced drug-induced toxicity 81). In cell culture studies, Rhodiola rosea inhibits cell proliferation and induces cell apoptosis in various cells and cell lines, including human urinary bladder cancer cell lines 82), breast cancer cell lines 83), colorectal cancer cells 84), gastric cancer cells 85), glioma cells 86), lung cancer cells 87) and sarcoma 88). Among them, estrogen receptor negative breast cancer cell line MDA-MB-231 and lung cancer cell line A549 appeared to be more sensitive to the cytotoxic effect of salidroside with IC50 of 10.7 and 14.3 μM, respectively 89). However, given data on the in vivo anti-tumor activity of Rhodiola rosea extracts and salidroside against different cancers are currently very limited, it is still unclear whether specific types of cancer may be particularly responsive to the anti-cancer effect of Rhodiola rosea extracts and salidroside. We and others also showed that Rhodiola rosea extracts and salidroside induced autophagy in bladder, gastric and colorectal cancer cell lines 90). Tu et al 91) showed that Rhodiola crenulata extracts inhibited the proliferation, motility, and invasion of breast cancer cell lines with minimal effect on normal human mammary epithelial cells. Mishra KP et al 92) reported that aqueous Rhodiola crenulata extract inhibited growth of an erythro leukemic cell line K-562 by inducing apoptosis and cell cycle arrest at G2/M phase. Anecdotal evidence from a clinical study 93) showed that oral administration of Rhodiola rosea extracts to patients with superficial bladder carcinoma (T1, G1–2) reduced the average frequency of relapses by half. Nevertheless, none of these above studies have linked the anticancer effects of Rhodiola to its antiaging effect. It is also unknown whether active compounds (Salidroside or Rosavin) or the ratio of active compounds in Rhodiola rosea extracts will be determining factors for its anti-cancer activities.

Rhodiola rosea anti-inflammation activity

Rhodiola rosea extracts first demonstrated its anti-inflammation activity in formaldehyde-induced arthritis, carrageenan- and nystatin-induced paw edema at a concentration of 250 mg/kg body weight in rat model 94). Rhodiola rosea extracts more effectively inhibited cyclooxygenase-2 (COX-2) and Phospholipase A2 activity than COX1 activity 95). Salidroside also exerted its anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) through the blocking of the NF-κB and MAPK signaling pathways both in vitro in RAW 264.7 macrophages and in vivo in mice challenged with lipopolysaccharide 96). Further studies revealed that salidroside inhibited the activation of NLRP3 inflammasome and subsequent caspase-1 cleavage as well as IL-1β secretion both in vivo and in vitro through up-regulation of SIRT1 expression 97). In addition, salidroside can inhibit the JAK2-STAT3 pathway by suppressing nuclear localization of STAT3 98).

Rhodiola rosea immunostimulating activity

Rhodiola rosea extracts have been documented with immunostimulating activity both in vitro in human peripheral blood mononuclear cells and in vivo in animals 99). Rhodiola rosea extracts increased total CD3+ and memory CD4+ T cell pools, but decreased the number and function of cytotoxic CD8+ T cells in a mouse model of caecal ligation and puncture-induced sepsis 100). Rhodiola rosea extracts increased production of Th1 cytokines (i.e. IFN-γ, IL-2 and IL-12), reduced spleen and thymus lymphocyte apoptosis and enhanced their survival through downregulation of tumor necrosis factor-α-induced protein 8-like-2 expression in septic rats 101). Salidroside not only improved total T cell (CD3+) and Th1 cells (CD4+), but also promoted the production of immunoglobulins (total IgG, IgG1 and IgG2α) for the delayed-type hypersensitivity response to vaccine in aged, 21 months old rats 102). In addition, Rhodiola rosea extracts and salidroside exerted vaccine adjuvant effect by stimulating the proliferation of concavalin A treated T cells in ovalbumin-immunized mice 103). Furthermore, salidroside and the antigen ovalbumin have been encapsulated into liposome for investigating its usefulness as an effective sustained-release vaccine delivery system 104). The salidroside liposome adjuvant was shown to stimulate dendritic cells on mixed leukocyte reaction and improve the antigen presenting ability and maturation of dendritic cells in vitro 105). This adjuvant also led to a marked Th1 immunostimulant activity in mice by increasing lymphocyte proliferation and serum concentrations of IgG, IL-2, and IFN-γ 106).

Rhodiola uses

Traditionally, Rhodiola was used as a herbal medicine for a treatment for headaches, hysteria, “hernias”, and discharges, as well as for improving high-altitude sickness and as an astringent 107). Recently, numerous Rhodiola extracts have been sold as a dietary supplement or as an adaptogen to increase attention and endurance in fatigue and to prevent/reduce stress induced impairments and disorders related to neuro-endocrine and immune system 108). Athletes and Russian astronauts have used it to prevent fatigue and improve performance as Rhodiola is allowed by sports regulators 109). In addition, Rhodiola rosea extracts were also indicated for age related conditions 110) and depression 111). There is no evidence that Rhodiola rosea supplements can treat dementia. While there is some evidence that Rhodiola may help combat symptoms experienced by dementia patients, such as insomnia, fatigue, and anxiety 112), 113), none of these trials included patients with dementia.

On the basis of its long-standing use, Rhodiola rosea can be used for the temporary relief of symptoms of stress, such as fatigue and sensation of weakness. Furthermore, Rhodiola rosea supplements should only be used in adults over the age of 18 years and should not be taken for longer than two weeks without seeking medical advice. The use in children and adolescents under 18 years of age has not been established due to lack of adequate data.

Rhodiola dosage

Rhodiola rosea supplements are commercially available in both capsule and liquid forms. However, quality and composition of Rhodiola rosea supplements can vary widely by manufacturer. Although there is no official recommended Rhodiola rosea dose, clinical studies have used doses from 50 to 1500 mg/day with no reports of major adverse effects. Most commonly used Rhodiola rosea extract doses that are proposed to be safe range from 200 to 600 mg/day in capsules or tablets 114).

Rhodiola side effects

Rhodiola rosea medicines are considered generally safe for healthy adults 115). Although rare, reported side effects include headache, mild dizziness, dry mouth, sleepiness, insomnia, hyperactivity, jitteriness, agitation, and diarrhea 116), 117). Rhodiola rosea safety has not been assessed extensively for treatment exceeding three months. At the present time, no interactions have been reported with Rhodiola rosea supplements 118), 119). Evidence on the safety and appropriateness of Rhodiola rosea supplementation during pregnancy and lactation is currently unavailable.

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