Rhodiola rosea L. (Sedum roseum Scop; roseroot, golden root) from the family Crassulaceae is the arctic-alpine plant species wild-grown especially in Russia, China, Norway, Sweden, Finland, Island, Switzerland, the North America and also cultivated. The characteristic of the plant and the history of the antitumor studies on Rhodiola rosea extracts/constituents were described by Skopinska-Rozewska et al. [1] and most of them are registered in Pubmed.
It is important to note, that the first antitumor and anti-metastatic effects of an official extract of Rhodiola rosea rhizomes were established by Dement´eva and Iaremenko in 80s years in experiments on inbred and non-inbred mice and rats with transplantable NK/Ly tumor, Ehrlich's adenocarcinoma, melanoma B16 and Lewis lung carcinoma. Application of the said preparation to sarcolysin-treated animals was followed by an increase in survival [2].
The first immunological studies on Rhodiola rosea showing its antioxidative, immunomodulatory and angiogenic (using the wound-induced-angiogenesis model) activities were done by the polish research group of Prof. Ewa Skopinska-Rozewska and Prof. Miroslawa Furmanowa and documented by Furmanowa et al. [3-5] and Hartwich [6].
The influence of the plant preparation AdMax (Nulab Inc., Clearwater, FL, USA) on immunity in ovarian cancer patients was studied by Kormosh et al. [7]. The preparation was a combination of dried ethanol/water extracts from roots of Leuzea carthamoides, Rhodiola rosea, Eleutherococcus senticosus and fruits of Schizandra chinensis. Twenty eight patients with stage III-IV epithelial ovarian cancer were treated once with cisplatin and cyclophosphamide. Peripheral blood was collected 4 weeks after the chemotherapy. Subclasses of T, B and NK lymphocytes were tested for in the blood samples: CD3, CD4, CD5, CD7, CD8, CD11B, CD16, CD20, CD25, CD38, CD45RA, CD50, CD71 and CD95. Immunoglobulin G, A and M concentrations were also determined. Changes were observed in the following T cell subclasses: CD3, CD4, CD5 and CD8. In patients who took AdMax (270 mg a day) for 4 weeks following the chemotherapy, the mean numbers of the four T cell subclasses were increased in comparison with the mean numbers of the T cell subclasses in patients who did not take AdMax. In patients who took AdMax, the mean amounts of IgG and IgM were also increased. It was suggested that the combination of extracts from adaptogenic plants may boost the suppressed immunity in ovarian cancer patients who are subjected to chemotherapy.
In vitro and in vivo effects of aqueous and 50% hydroalcoholic extracts of Rhodiola rosea on non-specific and specific cellular immunity in pigs, rats and mice were shown by Siwicki et al. [8]. Mice were fed 50, 100, 200, or 400 µg of Rhodiola extracts daily, for 7 days before cellular immunity study (local GVH reaction) Blood leukocytes collected from pigs and rats were cultivated in vitro with PHA or LPS in the presence of 1-50 µg/ml of Rhodiola rosea extracts for 72 hours The metabolic activity of blood phagocytes (mostly granulocytes) was determined based on the measurement of intracellular respiratory burst after stimulation by PMA (phorbol myristate acetate), and potential bactericidal activity was determined in isolated blood leukocytes stimulated with microorganisms. Additionally, some in vitro toxicological studies were performed. For these experiments GMK (monkey’s kidney), EPC (fish epithelial cells), and KFC (Koy fins cells) cell lines, as well as lymphocytes and monocytes isolated from the blood of pigs and rats were used. Both extracts enhanced non-specific and specific cellular immunity to the various degrees; however, in higher doses or concentrations they presented inhibitory effects. In in vitro studies all extracts were non-toxic at concentrations 50, 100, 200, 400, 800, and 1000 µg/ml after 24, 48, and 72 hours of cells cultures.
Skopińska-Różewska et al. [1] have continued the studies. The aim of this next work was to study the effect of rosavin and aqueous and 50% hydroalcoholic extracts of R. rosea roots and rhizomes on neovascular reaction induced in the skin of Balb/c mice after grafting of L-1 sarcoma cells. Mice were treated per os with 50, 100, 200 and 400 µg of extracts, or were fed rosavin in daily doses 2, 4 and 8 µg. After 72 hours mice were sacrificed with lethal dose of Morbital. All newly formed blood vessels were identified and counted in dissection microscope. Both extracts in 100-400 µg daily doses and rosavin in the highest dose highly significantly decreased neovascular reaction.
In the further work [9] the effect of aqueous and 50% hydroalcoholic extracts of Rhodiola rosea, Rhodiola kirilowii and Rhodiola quadrifida roots and rhizomes on neovascular reaction induced in the skin of Balb/c mice after grafting of human kidney cancer tissue homogenate or, for comparison, L-1 sarcoma syngeneic cells was presented. Mice were fed 0.4 mg of extracts daily, for 3 days. After 72 hours mice were sacrificed with lethal dose of Morbital. All newly formed blood vessels were identified and counted in dissection microscope. Extracts of underground parts of Rhodiola rosea and Rhodiola kirilowii significantly decreased cutaneous neovascular reaction induced by human cancer homogenate, extracts prepared from Rhodiola quadrifida were ineffective in this model of angiogenesis. In syngeneic tumor cells model all extracts were effective, except aqueous extract of R. kirilowii.
The effect of feeding mice R. rosea extracts on Pseudomonas aeruginosa infection was studied by Bany et al. [10]. It was found that the infection intensity was highly significantly lower after treatment of mice for 7 days with daily dose 0.4 mg of aqueous extract than in the control group. The weaker effect of hydro-alcoholic extract was also statistically significant.
The last up to date polish immunological studies on Rhodiola rosea were documented by Skopińska-Różewska et al. [11]. The in vivo effects of 50% hydro-alcoholic extracts of R. rosea and R. quadrifida roots and rhizomes on the ex vivo chemokinetic activity of splenic lymphocytes in mice have been shown. Mice were fed for 7 days Rhodiola extracts in daily doses 40 or 200 µg. The chemokinetic activity of splenocytes was determined in 24-hour cell cultures in capillary tubes. Both extracts stimulated splenocytes mobility in lower dose, in higher dose only R. quadrifida extract was effective.
The studies have resulted in significant differences in immunological activities between aqueous and alcoholic extracts of Rhodiola rosea and in the comparison between Rhodiola rosea and other Rhodiola sp., also dose-dependent.
Blomkvist et al. discussed in the “Planta Medica” the perspectives on Roseroot (Rhodiola rosea) studies. The Rhodiola rosea (roseroot) extract was up to date a commercially successful product, primarily used to reduce the effect of fatigue on physical and mental performance. In this perspective the Authors presented own investigations of the most recent studies performed on human subjects. With a focus on the statistical methods they found considerable shortcomings in all but one of the studies that claim significant improvement from roseroot extract. Overall, the study designs have not been well explained. Experimental results have been confused and appear to be in some cases incorrect. Some of the conclusions are based on selected results and contradicting data have not been adequately taken into account. They point to other studies of higher quality performed on roseroot, several that found no significant effect and one that did. Blomkvist et al. conclude that the currently available evidence for the claimed effects is insufficient and that the effect of Rhodiola rosea is in need of further investigation before therapeutic claims can be made [12].
The presence in the extract of Rhodiola rosea rhizomes and roots, approximately 140 compounds - monoterpene alcohols and their glycosides, cyanogenic glycosides, aryl glycosides, phenylethanoids, phenylpropanoids and their glycosides, flavonoids, flavonlignans, proanthocyanidins and gallic acid derivatives was reported [13].
The rhizomes of 95 roseroot clones in the Norwegian germplasm collection were analysed and quantified by Elameen et al. for their content of the bioactive compounds rosavin, salidroside, rosin, cinnamyl alcohol and tyrosol using HPLC analysis. All five bioactive compounds were detected in all 95 roseroot clones but in highly variable quantities. The ranges observed for the different compounds were for rosavin 2.90-85.95 mg/g, salidroside 0.03-12.85 mg/g, rosin 0.08-4.75 mg/g, tyrosol 0.04-2.15 mg/g and cinnamyl alcohol 0.02-1.18 mg/g. The frequency distribution of the chemical content of each clone did not reflect a certain geographic region of origin or the gender of the plant. Significant correlations were found for the contents of several of these bioactive compounds in individual roseroot clones. A low, but not significant correlation was found between AFLP markers previously used to study the genetic diversity of the roseroot clones and their production of the chemical compounds. The maximum level of rosavin, rosin and salidroside observed were higher than for any roseroot plant previously reported in literature, and the roseroot clones characterized in this study might therefore prove to be of high pharmacological value [14]. Or can the “special great content” of the biologically active compounds in the extract initiate any health´s problems, when the dose will be too high!?
The immunological experiments of the Skopińska-Różewska´ s research group [8] showed immunomodulatory effects exerted by Rhodiola rosea extracts (obtained from rhizomes grown in the Garden of the Medicinal Plants at the Research Institute of Medicinal Plants, Poznan, Poland) in vitro and in vivo. Both types of extracts stimulated non-specific and specific cellular immunity in lower doses, and were inhibitory in the highest dose applied. However, cytotoxic effects of this highest dose was not observed, what may suggest stimulation of non-specific suppressor cells in cultures containing 50 µg/ml of the extract. In experiments in mice, feeding cell donors 400 µg daily doses of extracts resulted in suppression of splenic lymphocytes proliferative and angiogenic activity, what may suggest the presence of non-specific suppressor cells in cultured or grafted cell suspension. This dose corresponds to 200 mg human dose, unfortunately being recommended by producers of such dietary supplements as FORMA-REGENERIX-ANTYSTRES (Biofarm, Poznan) and LENTAYA (Hermes Arzneimittel GmbH). So, in the opinion of the polish immunologists, use of these dietary supplements in recommended doses may be dangerous for human immune system, leading to the suppression of some specific and, possibly, some non-specific cellular immune responses. However, in daily doses of 25 and 50 mg R. rosea extracts may mildly stimulate cellular immunity. Since 1975, the R. rosea extract (40% EtOH) was produced in a large-scale and was registered in the Pharmacopoeia of Soviet Union (1989) with the name “Rhodiola Extract liquid” as a medicine and a tonic. The Extract is standardized up-to-date on salidroside and rosavin. In Sweden, R. rosea was recognized as an Herbal Medicinal Product “Arctic Root” in 1985 and has been described as an antifatigue agent and saled by Swedish Herbal Institute. In Germany, a dietary supplement of R. rosea “Lentaya” (Hermes) was earlier (but now no more) in the sale in drugstories and/or via Internet (among many other international R. rosea products) and in Poland – a product Antistress-Forma. Many, if not most, cancer patients will try such remedies in the course of their disease, often without the knowledge of their surgeon or oncologist.
Rhodiola rosea rhizomes have a low level of toxicity. However, should be taken early in the day because it can interfere with sleep or cause vivid dreams. Rhodiola rosea rhizomes/extracts have an antidepressant effect, it should not be used in individuals with bipolar disorder who are vulnerable to becoming manic when given antidepressants or stimulants.
The risks of the complementary use of Rhodiola rosea preparations with antiestrogens tamoxifen and faslodex in breast cancer in vitro studies were also noted.
Rhodiola rosea may be effective and potent growth stimulator of the estrogen receptor-positive cell lines. Consumption of Rhodiola could, therefore, pose a significant hazard to the patients with breast cancer who have ER-positive tumors and who are being treated with antiestrogens [15]. This problem should be further, as soon as possible explained.
Conclusion
The immunological [1, 3-11] and/or phytochemical [13, 14] studies on Rhodiola rosea shown that the new e.g. anticancer/antidepressive/others supplements/potential traditional medicinal drugs in the future based on the native extract of Rhodiola rosea rhizomes/or combination of many herbal extracts, can be not enough effective! Additionally, it exists too great risk and danger for the human/animals health and life during the complementary use of the product/products.
Warning: Rhodiola rosea plants/extracts/products can contain also too high residues of pesticides/other chemicals/microorganisms/aflatoxins/. Side-effects after the use of the R. rosea products, dependent on daily nutrition/drinks and/or other used drugs, can be observed.
What do You think about this directive now?
“…the European Commission is prepared to consider extending the simplified registration procedure to products other than herbal substances with a long tradition of safe use. … The proposed extension would enable certain medicinal products from specific European or non-European medicine systems (such as – in alphabetical order – anthroposophic, Ayurvedic, Chinese, Kampo Korean, Mongolian, Thai, Tibetan Unani, or Vietnamese medicine) as well as traditional products with a longstanding tradition in the European Union (such as honey, royal jelly, propolis, fish oils, minerals, microorganisms and other substances) to be eligible for the simplified registration procedure with a view to placing them on the market as traditional medicinal products” [16].
The sale of Rhodiola rosea herbal products used often up to date in Traditional Chinese [17], Tibet o Russian Medicine should be prohibited in the EU-Drugstories and in Internet.
How might be treated responsibly i.e. effectively and safely so complicated illnesses as many cancer forms; viral diseases e.g. AIDS, Hepatitis C, flu; Alzheimer´s disease, depression and others?
My suggestion is to elaborate standardized mono-drugs of the herbal origin e.g. of the Rhodiola rosea registered as the EMA-Monograph, and often controlled during the sale-license-time! References
1. Skopińska-Różewska E, Hartwich M, Siwicki A, et al. (2008): The influence of Rhodiola rosea extracts and rosavin on cutaneous angiogenesis induced in mice after grafting of syngeneic tumor cells. Centr Eur J Immunol 33 (3): 102-7.
2. Dement'eva LA, Iaremenko KV (1987): Effect of a Rhodiola extract on the tumor process in an experiment. Vopr Onkol 33 (7): 57-60.
3. Furmanowa M, Oledzka H, Michalska* M, et al. (1995): Rhodiola rosea L. (Roseroot): In Vitro Regeneration and the Biological Activity of Roots. In Bajaj YPS (ed.) Biotechnology in Agriculture and Forestry 33; Medicianl and Aromatic Plants VIII. Springer-Verlag Berlin Heidelberg 412-26. (* now Hartwich).
4. Furmanowa M, Skopińska-Różewska E, Rogala E, Hartwich M (1998): Rhodiola rosea in vitro culture-phytochemical analysis and antioxidant action. Acta Soc Botan Pol 67: 69-73.
5. Furmanowa M, Kedzia B, Hartwich M, et al. (1999): Phytochemical and pharmacological properties of Rhodiola rosea L. Herba Polonica XLV: 108-113.
6. Hartwich M (1999): Ph.D. Thesis: Production of selected phenolic glycosides of Rhodiola rosea L. using biotechnological methods. Warsaw Medical Academy (now Medical University of Warsaw), Faculty of Pharmacy; Dept. of Biology and Pharmaceutical Botany; Warsaw, Poland (Pl; abstract Eng.): 1-177.
7. Kormosh N, Laktionov K, Antoshechkina M (2006): Effect of a combination of extract from several plants on cell-mediated and humoral immunity of patients with advanced ovarian cancer. Phytother Res 20: 424-425.
8. Siwicki AK, Skopińska-Różewska E, Hartwich M, et al. (2007): The influence of Rhodiola rosea extracts on non-specific and specific cellular immunity in pigs, rats and mice. Centr Eur J Immunol 32: 84-91.
9. Skopińska-Różewska E, Wasiutynski A, Sommer E, et al. (2008): The influence of Rhodiola rosea, Rhodiola kirilowii and Rhodiola quadrifida extracts on cutaneous angiogenesis induced in mice after grafting of human kidney cancer tissue. Centr Eur J Immunol 33 (4): 185-189.
10. Bany J, Zdanowska D, Skopińska-Różewska E, et al. (2009): The effect of Rhodiola rosea extracts on the bacterial infection in mice. Centr Eur J Immunol 34: 35-37.
11. Skopińska-Różewska E, Bychawska M, Białas-Chromiec B, Sommer E (2009): The in vivo effect of Rhodiola rosea and Rhodiola quadrifida hydro-alcoholic extracts on chemokinetic activity of spleen lymphocytes in mice. Centr Eur J Immunol 34 (1): 42-45.
12. Blomkvist J, Taube A, Larhammar D (2009): Perspective on Roseroot (Rhodiola rosea) studies. Planta Med 75 (11): 1187-1190.
13. Panossian A, Wikman G, Sarris J (2010): Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine 17: 481-493.
14. Elameen A, Dragland S, Klemsdal SS (2010): Bioactive compounds produced by clones of Rhodiola rosea maintained in the Norwegian germplasm collection. Pharmazie 65: 618-623.
15. Kim JB, Price RK, Stein RC, O’Hara MJ (2005): Risks of the complementary medicine Rhodiola rosea in breast cancer. J Nutrition (Suppl) 135: 3048-3049.
16. Action Plan for Herbal Medicines 2010-2011; EMA/831327/2009: 1-4.
17. Zhang ZH, Liu JS, Chu JN, et al. (2005): The effect of Hongjingtian (Gadol) injection on cardiac hemodynamics and myocardial oxygen consumption of dogs. Zhongguo Zhong Yao Za Zhi 30: 1001-1005.
