Rhodiola rosea: A Possible Plant Adaptogen
Gregory S. Kelly, ND

Abstract

Rhodiola rosea is a popular plant in traditional medical systems in Eastern Europe and Asia with a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, eliminating fatigue, and preventing high altitude sickness. Rhodiola rosea has been categorized as an adaptogen by Russian researchers due to its observed ability to increase resistance to a variety of chemical, biological, and physical stressors. Its claimed benefits include antidepressant, anticancer, cardioprotective, and central nervous system enhancement. Research also indicates great utility in asthenic conditions (decline in work performance, sleep difficulties, poor appetite, irritability, hypertension, headaches, and fatigue) developing subsequent to intense physical or intellectual strain. The adaptogenic, cardiopulmonary protective, and central nervous system activities of Rhodiola rosea have been attributed primarily to its ability to influence levels and activity of monoamines and opioid peptides such as beta-endorphins.
(Altern Med Rev 2001;6(3):293-302)

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Introduction

Rhodiola rosea ("golden root" or "rose root") is widely distributed at high altitudes in Arctic and mountainous regions throughout Europe and Asia. It is a popular plant in traditional medical systems in Eastern Europe and Asia, with a reputation for stimulating the nervous system, decreasing depression, enhancing work performance, eliminating fatigue, and preventing high altitude sickness.1 In addition to Rhodiola rosea, over 200 different species of Rhodiola have been identified and at least 20 are used in traditional medical systems in Asia, including R. alterna, R. brevipetiolata, R. crenulata, R. kirilowii, R. quadrifida, R. sachalinensis, and R. sacra.

Rhodiola rosea has been intensively studied in Russia and Scandinavia for more than 35 years. Although the majority of this research on Rhodiola rosea is unavailable for review, available literature is supportive of its adaptogenic properties. Similar to other plant adaptogens investigated by Russian researchers, such as Eleutherococcus senticosus (Siberian ginseng) and Panax ginseng (Korean ginseng), extracts of this plant produce favorable changes in a variety of diverse areas of physiological function, including neurotransmitter levels, central nervous system activity, and cardiovascular function.

Rhodiola rosea has been categorized as an adaptogen by Russian researchers due to its observed ability to increase resistance to a variety of chemical, biological, and physical stressors. Origination of the term adaptogen has been dated to 1947 and credited to a Russian scientist, Lazarev. He defined an "adaptogen" as an agent that allows an organism to counteract adverse physical, chemical, or biological stressors by generating non-specific resistance. Inherent in his definition is the concept that administration of the adaptogenic agent allows an organism to pre-adapt itself in a manner that allows it to be more capable of responding appropriately when diverse demands are eventually placed on it. In 1969, Brekhman and Dardymov proposed specific criteria that need to be fulfilled in order for a substance to qualify as an adaptogen.

Subjecting animals and humans to a period of stress produces characteristic changes in several hormones and parameters associated with the central nervous system and the hypothalamic-pituitary-adrenal axis (HPA). HPA changes include an increase in cortisol, a reduced sensitivity of the HPA to feedback down-regulation, and a disruption in the circadian rhythm of cortisol secretion. Central nervous system changes include the stress-induced depletion of catecholamine neurotransmitters such as norepinephrine and dopamine. An acute increase in beta-endorphin levels is also observed under stressful conditions.

To successfully combat stress and stressful situations, adaptation is required. Adaptation might be best thought of as the ability to be exposed to a stressor, while responding with either decreased or no characteristic hormonal perturbations. Adaptation also implies being prepared to and capable of rapidly reassuming homeostasis after the stressor is withdrawn. As an example, a well-trained athlete can participate in an event that would induce a large HPA perturbation (stress response) in a sedentary person, and yet the athlete will be relatively unaffected. This is a result of adaptation that has occurred during the athlete's training process. Additionally, if athletes are exposed to stressors they were not trained for, hormonal perturbations characteristic of a stress response would be expected; however, this response might not be as great as that found in less fit individuals. Furthermore, after the stress ended, their physiology would be expected to re-establish homeostasis rapidly. This is a result of non-specific resistance to stress gained by virtue of a training-induced higher level of fitness.

The utility of plant adaptogens is analogous to the training an athlete undergoes in order to prepare for competition. Plant adaptogens cause our physiology to begin the adaptation process to stress. When a stressful situation occurs, consuming adaptogens generates a degree of generalized adaptation (or non-specific resistance) that allows our physiology to handle the stressful situation in a more resourceful manner.

As an example of this process, Rhodiola rosea administration promotes a moderate increase in the amount of serum immunoreactive beta-endorphin in rats under basal conditions. This moderate increase is similar to that found when rats are adapted to exercise. When Rhodiola rosea-treated rats were subjected to a 4-hour period of non-specific stress, the expected elevation in beta-endorphin was either not observed or substantially decreased. Consequently, the characteristic perturbations of the HPA were decreased or totally prevented.3 In these rats administration of Rhodiola rosea appears to have generated non-specific resistance and prepared the rats to respond more appropriately to the eventual stressful situation.

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Chemical Composition

The chemical composition and physiological properties of Rhodiola species are to a degree species-dependent, although some overlap in constituents and physiological properties does exist in many Rhodiola species.

Twenty-eight compounds have been isolated from the roots and above-ground parts of Rhodiola rosea, including 12 novel compounds. The roots contain a range of biologically active substances including organic acids, flavonoids, tannins, and phenolic glycosides. The stimulating and adaptogenic properties of Rhodiola rosea were originally attributed to two compounds isolated from its roots, identified as p-tyrosol and the phenolic glycoside rhodioloside. Rhodioloside was later determined to be structurally similar to the known glycoside salidroside found in several other plant species. Salidroside, rhodioloside, and occasionally rhodosin are used to describe this compound and are considered to be synonyms. Additional glycoside compounds isolated from the root include rhodioniside, rhodiolin, rosin, rosavin, rosarin, and rosiridin. These glycoside compounds are also thought to be critical for the plant's observed adaptogenic properties.1,4

A range of antioxidant compounds have been identified in Rhodiola rosea and related species, including p-tyrosol, organic acids (gallic acid, caffeic acid, and chlorogenic acid), and flavonoids (catechins and proanthocyanidins).5,6 Significant free-radical scavenging activity has been demonstrated for alcohol and water extracts of Rhodiola sp. and is attributed to the variety of antioxidant compounds.5,6 p-Tyrosol has been shown to be readily and dose-dependently absorbed after an oral dose,7,8 and appears to produce a significant antioxidant8 and modest 5-lipoxygenase inhibitory activity9 in vivo.

Salidroside (rhodioloside), the additional salidroside-like glycoside compounds (rhodiolin, rosin, rosavin, rosarin, and rosiridin), and p-tyrosol are thought to be the most critical plant constituents needed for therapeutic activity.1,2 The contents of salidroside and p-tyrosol in root samples gathered from various areas in China have been shown to range from 1.3-11.1 mg/g and 0.3-2.2 mg/g, respectively.4 These two compounds have been found in all studied species of Rhodiola; however, the other active glycosides, including rosavin, rosin, and rosarin, have not been found in all examined Rhodiola species.5,6 Because of this variation within the Rhodiola genus, verification of Rhodiola rosea by high performance liquid chromatography (HPLC) is dependent on the content of the additional glycosides (rather than salidroside and p-tyrosol); rosavin is the constituent currently selected for standardization of extracts.10

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Proposed Mechanisms of Action

The adaptogenic properties, cardio-pulmonary protective effects, and central nervous system activities of Rhodiola rosea have been attributed primarily to its ability to influence levels and activity of monoamines and opioid peptides such as beta-endorphins.

Oral administration of a water extract of Rhodiola rosea to rats for 10 days modulated biogenic monoamines in the cerebral cortex, brain stem, and hypothalamus. In the cerebral cortex and brain stem, levels of nor-epinephrine and dopamine decreased, while the amount of serotonin increased substantially. In the hypothalamus, the results were reversed with a 3-fold increase in the amount of norepinephrine and dopamine, and a trend toward reduced serotonin levels. It is believed these changes in monoamine levels are a result of Rhodiola rosea inhibiting the activity of the enzymes responsible for monoamine degradation, monoamine oxidase and catechol-O-methyltransferase. It is also believed Rhodiola rosea facilitates the transport of neurotransmitters within the brain.11 In addition to these central effects on monoamines, Rhodiola rosea has been reported to prevent both catecholamine release and subsequent cAMP elevation in the myocardium, and the depletion of adrenal catecholamines induced by acute stress.12

Abstracts of untranslated Russian research indicate that a great deal of the activity of Rhodiola rosea might be secondary to an ability to induce opioid peptide biosynthesis and through the activation of both central and peripheral opioid receptors.3,13-15 Lack of current availability of the complete text of these articles make verification of these effects impossible.

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Experimental Studies

Adaptogenic Activity

Rhodiola rosea appears to offer generalized resistance against physical, chemical, and biological stressors in rats and other animals studied. Evidence also suggests cardioprotective and anticancer benefits in animals.

In the test of swimming "to the limit," Rhodiola rosea administration increased the swimming time of rats 135-159 percent. Working capacity of the rats consistently improved throughout the supplementation period.16

Eggs from the freshwater snail Lymnaea stagnalis were incubated in water extracts of Rhodiola rosea and subsequently exposed to a variety of environmental stressors, including heat shock (43°C for four minutes), oxidative stress (600 µM menadione for two hours), and heavy metal-induced stress (one-hour exposure to 150 µM copper sulphate or 20 µM cadmium chloride). Exposure to these environmental stressors kills 80-90 percent of larvae within four days post-exposure. Pre-incubation with Rhodiola rosea extract afforded a significant degree of non-specific resistance against each of these environmental stressors as measured by rate of survival. While only nine percent of the control population survived exposure to heat shock, approximately 90 percent of snail larvae pre-incubated with Rhodiola rosea (40.5 µg/ml) survived. Pre-incubation with Rhodiola resulted in non-specific resistance to oxidative stress (survival of approximately 68 percent) and heavy metal stress (approximately 28-35 percent of larvae survived depending on the metal exposure).10

Two experiments have suggested possible benefit on various aspects of learning and memory in rats under certain experimental conditions. Rhodiola rosea extract administered orally at a dose of 0.1 mL/day for 10 days resulted in a non-significant trend toward protection against impairments in memory, as assessed by step-down passive avoidance, induced by electroshock in rats.17 Rhodiola rosea extract was administered in a single dose of 0.10 mL. Improvements in both learning and memory retention, as determined by using a maze test with negative reinforcement, were observed. Repeated dosing with the same quantity of the extract over a 10-day period generated significant improvement in long-term memory as assessed by the maze test with negative enforcement and the "staircase" method with positive enforcement. However, in this experiment two other doses were tested (0.02 and 1.0 mL) and were found to have no substantial effect on learning and memory.1

This suggests the possibility of an efficacious dose of Rhodiola rosea administration, above and below which beneficial physiological effects might be less likely. In the other experimental conditions investigated (active avoidance with negative reinforcement using a "shuttle box" and passive avoidance using "step down" and "step through") no beneficial effects on either learning or memory were observed with any of the administered doses of Rhodiola rosea.1

Cardioprotective Activity

Rhodiola rosea has been shown to moderate against stress-induced damage and dysfunction in cardiovascular tissue. Treatment with Rhodiola rosea extract prevents the decrease in cardiac contractile force secondary to environmental stress in the form of acute cooling and contributes to stable contractility. In animals, acute cooling leads to a decrease in myocardial contractile activity that partially recovers during the first 18 hours after the cold-stress is removed. This recovery is viewed as only partial, since the heart tissue is incapable of stable contractility during perfusion. Pretreatment with Rhodiola rosea extracts appears to create a beneficial adaptive response in this type of stress. When Rhodiola pretreated rats were exposed to acute cooling, the decrease in contractility was prevented and stable contractility of heart tissue occurred during perfusion.18

Other reports suggest administration of Rhodiola rosea protects cardiovascular tissue from stress-induced catecholamine release12 and mitigates against adrenaline-induced arrhythmias in rats.13,14,19 The antiarrhythmic effect of Rhodiola rosea is suggested to be secondary to an ability to induce opioid peptide biosynthesis13 and related to the stimulation of peripheral kappa-opioid receptors.14

Anticancer Activity

Administration of Rhodiola rosea appears to have potential as an anticancer agent, and might be useful in conjunction with some pharmaceutical antitumor agents. In rats with transplanted solid Ehrlich adenocarcinoma and metastasizing rat Pliss lymphosarcoma, supplementation with Rhodiola rosea extract inhibited the growth of both tumor types, decreased metastasis to the liver, and extended survival times.20 Administration of Rhodiola rosea extract also directly suppressed the growth of and the extent of metastasis from transplanted Lewis lung carcinomas.21 When Rhodiola rosea extract was combined with the antitumor agent cyclophosphamide in these same tumor models, the antitumor and antimetastatic efficacy of drug treatment was enhanced. The authors also commented that, "complete abrogation of the haematotoxicity of cyclophosphamide" was observed.21 The chemotherapeutic drug Adriamycin is known to induce pronounced liver dysfunction, generally reflected by an increase in transaminase levels. In animal experiments, adding Rhodiola rosea extract to a protocol with Adriamycin resulted in an improved inhibition of tumor dissemination (as compared to that found with Adriamycin alone), and the combined protocol prevented liver toxicity.22

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Clinical Studies

Although Rhodiola rosea has been studied in the former Soviet Union for more than 35 years, this research is presently unavailable for review. This makes it impossible to verify the Russian claims of its antidepressant, anticancer, cardioprotective, and central nervous system enhancing properties.23 Available animal evidence seems supportive of a possible role for this plant adaptogen in many of these conditions. Table 2 outlines the conditions suggested to benefit from Rhodiola supplementation.

TABLE 2

*

amenorrhea
*

asthenia
*

cancer
*

colds and flu
*

depression
*

fatigue
*

headaches
*

hypertension
*

insomnia
*

schizophrenia
*

sexual dysfunction (male)

There have also been claims that this plant has great utility as a therapy in asthenic conditions (decline in work performance, sleep disturbances, poor appetite, irritability, hypertension, headaches, and fatigue) developing subsequent to intense physical or intellectual strain, influenza and other viral exposures, and other illness. 23 Two randomized, double-blind, placebo-controlled trials of the standardized extract of Rhodiola rosea root (SHR-5) provide a degree of support for these claimed adaptogenic properties and indicate possible utility in asthenic conditions induced by overwork or over study. SHR-5 is standardized to contain rosavin (3.6%), salidroside (1.6%), and p-tyrosol (<0.1%).10

Darbinyan et al evaluated the effect of chronic administration of 170 mg of SHR-5 for 14 days on aspects of mental performance and fatigue on 56 healthy male and female physicians (age 24-35) on night duty. Mental performance was evaluated using tests to determine speed of visual and auditory perception, attention capacity, and short-term memory. Based on the results of the battery of tests used, a Fatigue Index was calculated. The trial was divided into three periods: (1) a two-week test period of one SHR-5 or placebo tablet daily; (2) a two-week washout period; and (3) a third two-week cross-over period of one placebo or SHR-5 tablet daily. A statistically significant improvement in Fatigue Index was observed during the first two-week period in the SHR-5 group, and the improved mental performance reverted toward baseline values during the washout period. Administration of SHR-5 for the final two weeks of the six-week night duty period was unable to significantly offset declines in mental performance.24

Spasov et al investigated the effects of SHR-5 on male medical students during an exam period. Forty students were randomized to receive either 50 mg SHR-5 or placebo twice daily for a period of 20 days. The students receiving the standardized extract of Rhodiola rosea demonstrated significant improvements in physical fitness, psychomotor function, mental performance, and general wellbeing. Subjects receiving the Rhodiola rosea extract also reported statistically significant reductions in mental fatigue, improved sleep patterns, a reduced need for sleep, greater mood stability, and a greater motivation to study. The average exam scores between students receiving the Rhodiola rosea extract and placebo were 3.47 and 3.20, respectively. 25

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Dosage and Toxicity

In the two double-blind clinical trials, the dose of a standardized Rhodiola rosea extract ranged from 100-170 mg per day. The content of rosavin consumed in these daily doses is approximately 3.6-6.14 mg. The therapeutic dose of available Rhodiola rosea preparations will vary depending on degree of standardization; however, for chronic administration rosavin content within the above range seems prudent. This would suggest a dose of approximately 360-600 mg Rhodiola rosea daily of an extract standardized for one-percent rosavin, 180-300 mg of an extract standardized for two-percent rosavin, or the dose of between 100-170 mg for an extract standardized for 3.6-percent rosavin. As an adaptogen, chronic administration is normally begun several weeks prior to a period of expected increased physiological, chemical, or biological strain, and continued throughout the duration of the challenging event or activity. When using Rhodiola rosea as a single dose for acute purposes (e.g., for an exam or athletic competition), the suggested dose is three times the dose used for chronic supplementation.

The Russian approach to long-term supplementation with adaptogens generally calls for repeating cycles characterized by short periods of adaptogen administration, followed by an interval with no supplementation.26 Rhodiola rosea has been administered for periods ranging from as little as one day (acute administration) up to four months. Until more specific information is available, a dosing regime following the established patterns used with other plant adaptogens, with periodic intervals of abstinence, seems warranted when Rhodiola rosea is being used chronically.

At the doses administered in the clinical trials, a complete absence of all side effects has been reported. However, preliminary clinical feedback indicates that at doses of 1.5-2.0 grams and above of Rhodiola rosea extract standardized for two-percent rosavin, some individuals might experience an increase in irritability and insomnia within several days. It is possible that other physiological parameters that benefit from a lower dose of Rhodiola rosea extract might be exacerbated by a dose that is inappropriately high and/or sustained for prolonged periods of time.

Evidence on the safety and appropriateness of Rhodiola rosea supplementation during pregnancy and lactation is currently unavailable.

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Conclusion

Consistent with benefits found with other adaptogenic substances, Rhodiola rosea appears to offer generalized resistance to physical, chemical, and biological stressors. Available evidence suggests it can be a suitable substitute in conditions where other adaptogens might be considered. However, Rhodiola rosea also appears to be unique among the currently available adaptogenic herbs and might offer an advantage in some clinical conditions and stressful circumstances. Unlike Korean and Siberian ginseng, which are thought to exert their adaptogenic activity primarily at the level of HPA function,27-29 Rhodiola rosea appears to exert its adaptogenic effects by working centrally and peripherally on monoamine and opioid synthesis, transport, and receptor activity. If this is in fact the case in humans, it suggests the potential for therapeutic utility of Rhodiola rosea in conditions not particularly responsive to administration of ginseng products. It also suggests the possibility of potential synergistic interactions among Rhodiola rosea and other plant adaptogens.

Based on the proposed mechanism of action and available experimental data, Rhodiola rosea appears to offer an advantage over other adaptogens in circumstances of acute stress. A single dose of Rhodiola rosea prior to acute stress produces favorable results and prevents stress-induced disruptions in function and performance. Acute stress tends to initially impact monoamine levels and endorphins, while chronic stress places greater demands on the HPA axis. While this is a generalization and there is obvious overlap in the stress response, Rhodiola does seem to exert a pronounced effect on aspects of the acute stress response. Since many stressful situations are acute in nature, and sometimes unexpected, an adaptogen that can be taken acutely in these circumstances, rather than requiring chronic advance supplementation, could be very useful.

Rhodiola rosea also offers some cardioprotective benefits not associated with other adaptogens. Its proposed ability to moderate stress-induced damage and dysfunction in cardiovascular tissue might make Rhodiola rosea the adaptogen of choice among patients at higher risk for cardiovascular disease.

Since Rhodiola rosea administration appears to impact central monoamine levels, it might also provide benefits and be the adaptogen of choice in clinical conditions characterized by an imbalance of central nervous system monoamines. This is consistent with Russian claims for improvements in depression and schizophrenia. It also suggests that research in areas such as seasonal affective disorder, fibromyalgia, and chronic fatigue syndrome, to name a few clinical conditions, is warranted.

Administration of Rhodiola rosea appears to have potential as an anticancer agent, and might be useful in conjunction with some pharmaceutical antitumor agents. While available evidence is limited to animal models, results appear promising. This is an area that would benefit from additional research.

The clearest indication for Rhodiola rosea administration is for the asthenic condition resulting from acute or chronic overwork, which may manifest as decline in work performance, sleep disturbances, poor appetite, irritability, hypertension, headaches, and fatigue.

Some animal and preliminary clinical evidence suggests the need for a narrow range of therapeutic dosage of Rhodiola rosea, above and below which beneficial physiological effects might be less likely. Because of this, it seems prudent to keep doses at a moderate level both in terms of the quantity and duration of supplementation. While Rhodiola rosea appears to be a promising plant medicine, and has been investigated intensively in Russia, additional research is required before any conclusions with respect to its therapeutic utility can be made.


References

1. Petkov VD, Yonkov D, Mosharoff A, et al. Effects of alcohol aqueous extract from Rhodiola rosea L. roots on learning and memory. Acta Physiol Pharmacol Bulg 1986;12:3-16.

2. Brekhman II, Dardymov IV. New substances of plant origin which increase nonspecific resistance. Ann Rev Pharmacol 1969;9:419-430.

3. Lishmanov IB, Trifonova ZV, Tsibin AN, et al. Plasma beta-endorphin and stress hormones in stress and adaptation. Biull Eksp Biol Med 1987;103:422-424. [Article in Russian]

4. Linh PT, Kim YH, Hong SP, et al. Quantitative determination of salidroside and tyrosol from the underground part of Rhodiola rosea by high performance liquid chromatography. Arch Pharm Res 2000;23:349-352.

5. Lee MW, Lee YA, Park HM, et al. Antioxidative phenolic compounds from the roots of Rhodiola sachalinensis A. Bor. Arch Pharm Res 2000;23:455-458.

6. Ohsugi M, Fan W, Hase K, et al. Active-oxygen scavenging activity of traditional nourishing-tonic herbal medicines and active constituents of Rhodiola sacra. J Ethnopharmacol 1999;67:111-119.

7. Visioli F, Galli C, Bornet F, et al. Olive oil phenolics are dose-dependently absorbed in humans. FEBS Lett 2000;468:159-160.

8. Bonanome A, Pagnan A, Caruso D, et al. Evidence of postprandial absorption of olive oil phenols in humans. Nutr Metab Cardiovasc Dis 2000;10:111-120.

9. de la Puerta R, Ruiz Gutierrez V, Hoult JR. Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochem Pharmacol 1999;57:445-449.

10. Boon-Niermeijer EK, van den Berg A, Wikman G, Wiegant FA. Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis. Phytomedicine 2000;7:389-399.

11. Stancheva SL, Mosharrof A. Effect of the extract of Rhodiola rosea L. on the content of the brain biogenic monamines. Med Physiol 1987;40:85-87.

12. Maslova LV, Kondrat'ev BI, Maslov LN, Lishmanov IB. The cardioprotective and antiadrenergic activity of an extract of Rhodiola rosea in stress. Eksp Klin Farmakol 1994;57:61-63. [Article in Russian]

13. Lishmanov IB, Maslova LV, Maslov LN, Dan'shina EN. The anti-arrhythmia effect of Rhodiola rosea and its possible mechanism. Biull Eksp Biol Med 1993;116:175-176. [Article in Russian]

14. Maimeskulova LA, Maslov LN, Lishmanov IB, Krasnov EA. The participation of the mu-, delta- and kappa-opioid receptors in the realization of the anti-arrhythmia effect of Rhodiola rosea. Eksp Klin Farmakol 1997;60:38-39. [Article in Russian]

15. Lishmanov IB, Naumova AV, Afanas'ev SA, Maslov LN. Contribution of the opioid system to realization of inotropic effects of Rhodiola rosea extracts in ischemic and reperfusion heart damage in vitro. Eksp Klin Farmakol 1997;60:34-36. [Article in Russian]

16. Azizov AP, Seifulla RD. The effect of elton, leveton, fitoton and adapton on the work capacity of experimental animals. Eksp Klin Farmakol 1998;61:61-63. [Article in Russian]

17. Lazarova MB, Petkov VD, Markovska VL, et al. Effects of meclofenoxate and Extr. Rhodiolae roseae L. on electroconvulsive shock-impaired learning and memory in rats. Methods Find Exp Clin Pharmacol 1986;8:547-552.

18. Afanas'ev SA, Alekseeva ED, Bardamova IB, et al. Cardiac contractile function following acute cooling of the body and the adaptogenic correction of its disorders. Biull Eksp Biol Med 1993;116:480-483. [Article in Russian]

19. Maimeskulova LA, Maslov LN. The anti-arrhythmia action of an extract of Rhodiola rosea and of n-tyrosol in models of experimental arrhythmias. Eksp Klin Farmakol 1998;61:37-40. [Article in Russian]

20. Udintsev SN, Shakhov VP. The role of humoral factors of regenerating liver in the development of experimental tumors and the effect of Rhodiola rosea extract on this process. Neoplasma 1991;38:323-331.

21. Udintsev SN, Schakhov VP. Decrease of cyclophosphamide haematotoxicity by Rhodiola rosea root extract in mice with Ehrlich and Lewis transplantable tumors. Eur J Cancer 1991;27:1182.

22. Udintsev SN, Krylova SG, Fomina TI. The enhancement of the efficacy of adriamycin by using hepatoprotectors of plant origin in metastases of Ehrlich's adenocarcinoma to the liver in mice. Vopr Onkol 1992;38:1217-1222. [Article in Russian]

23. Germano C, Ramazanov Z, Bernal Suarez M. Arctic Root (Rhodiola Rosea): The Powerful New Ginseng Alternative. New York, NY: Kensington Publishing Corp; 1999.

24. Darbinyan V, Kteyan A, Panossian A, et al. Rhodiola rosea in stress induced fatigue ­ a double blind cross-over study of a standardized extract SHR-5 with a repeated low-dose regimen on the mental performance of healthy physicians during night duty. Phytomedicine 2000;7:365-371.

25. Spasov AA, Wikman GK, Mandrikov VB, et al. A double-blind, placebo-controlled pilot study of the stimulating and adaptogenic effect of Rhodiola rosea SHR-5 extract on the fatigue of students caused by stress during an examination period with a repeated low-dose regimen. Phytomedicine 2000;7:85-89.

26. Baranov AI. Medicinal uses of ginseng and related plants in the Soviet Union: recent trends in the Soviet literature. J Ethnopharmacol 1982;6:339-353.

27. Hiai S, Yokoyama H, Oura H, Yano S. Stimulation of pituitary-adrenocortical system by ginseng saponin. Endocrinol Jpn 1979;26:661-665.

28. Fulder SJ. Ginseng and the hypothalamic-pituitary control of stress. Am J Chin Med 1981;9:112-118.

29. Golotin VG, Gonenko VA, Zimina VV, et al. Effect of ionol and eleutherococcus on changes of the hypophyseo-adrenal system in rats under extreme conditions. Vopr Med Khim 1989;35:35-37. [Article in Russian]

Rhodiola and used thereof

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions, articles of manufacture, extracts, compounds, methods of use, methods of treatment, methods of preparation, etc., which relate to plants of the genus Rhodiola, preferably Rhodiola crenulata, which have a variety of useful and beneficial effects, including, e.g., to enhance blood oxygen and nutrients levels, e.g., through enhancing oxygen transport, to enhance working capacity and endurance, to reduce muscle fatigue, to enhance memory and concentration, to reduce stress, to enhance cardiac and cardiovascular function, to provide antioxidant effects, to protect against oxidation, to provide anti-cancer effects, to promote DNA repair, to provide anti-radiation effects, to protect against radiation, to reduce inflammation, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, preferably, to modulate testosterone levels, and to modulate sleep, especially to promote sleep, to modulate blood lipids, preferably, e.g., to lower cholesterol levels, to promote weight loss, and to enhance sexuability, such as improve sexual performance.

Rhodiola crenulata is a species of Rhodiola which grows mostly in Tibet and south west of China on the altitude between 3400 meters to 5600 meters. It has been used in Tibetan medicine for more than 1000 years for uses that have been limited to curing lung inflammation and cough, for stopping and activating blood, and for treating external wounds and burns. It has been discovered herein that Rhodiola crenulata has other beneficial properties that make it useful for a variety of conditions and diseases, as mentioned above and below.

Rhodiola is a diverse genus of plants which includes more than 50 different species, including, e.g., algida, arctica, crenulata, elongata, gelida, imbricataishidae, iremelica, kirilowii, linearifolia, phariensis, pinnatifida, quadrifida, aff. quadrifida, rosea, sachalinensis, and wolongensis. These species vary from each other widely, differing in, e.g., chromosome number (e.g., Makoto et al., Journal of Japanese Botany, 70(6):334-338, 1995), chemical composition, morphology, medicinal properties, developmental stages (e.g., Ishmuratatova and Satsyperova, Rastitel'nye Resursy., 34(1):3-11, 1998), geographical distribution, etc. Scientific studies (e.g. Peng et al, Chinese Herb Medicine (1995), 26(4): 177-179, and Wang et al, Acta Phrmaceutica Sinica(1992), 27(2): 117-120) indicate constituents of Rhodiola crenulata include, e.g., salidroside, tyrosol, β-sitosterol, gallic acid, pyrogallol, crentulatin, rhodionin, rhodiosin, among which, crenulatin, e.g., is found only in R. crenulata and has not been found in any other Rhodiola species. Rhodiosin and rhodionin exists in some, but not all, Rhodiola species.

The term "plant" as used herein refers to seeds, leaves, stems, flowers, roots, berries, bark, or any other plant parts that are useful for the purposes described. For certain uses, it is preferred that the underground portion of the plant, such as the root and rhizoma, be utilized. The leaves, stems, seeds, flowers, berries, bark, or other plant parts, also have medicinal effects and can be used for preparing tea and other beverages, cream, and in food preparation.

Rhodiola of the present invention can be in any form which is effective, including, but not limited to dry powders, grounds, emulsions, extracts, and other conventional compositions. To extract or concentrate the effective ingredients of Rhodiola, typically the plant part is contacted with a suitable solvent, such as water, alcohol, methanol, or any other solvents, or mixed solvents. The choice of the solvent can be made routinely, e.g., based on the properties of the active ingredient that is to be extracted or concentrated by the solvent. Preferred active ingredients of Rhodiola crenulata include, but are not limited to, salidroside, tyrosol, β-sitosterol, gallic acid, pyrogallol, crenulatin, rhodionin, and/or rhodiosin. These ingredients can be extracted in the same step, e.g., using an alcoholic solvent, or they may be extracted individually, each time using a solvent which is especially effective for extracting the particular target ingredient from the plant. In certain embodiments, extraction can be performed by the following process: Milling the selected part, preferably root, to powder. The powder can be soaked in a desired solvent for an amount of time effective to extract the active agents from the Rhodiola. The solution can be filtered and concentrated to produce a paste that contains a high concentration of the constituents extracted by the solvent. In some cases, the paste can be dried to produce a powder extract of Rhodiola crenulata. The content of active ingredient in the extract can be measured using HPLC, UV and other spectrometry methods.

A Rhodiola of the present invention can be administered in any form by any effective route, including, e.g., oral, parenteral, enteral, intraperitoneal, topical, transdermal (e.g., using any standard patch), ophthalmic, nasally, local, non-oral, such as aerosal, inhalation, subcutaneous, intramuscular, buccal, sublingual, rectal, vaginal, intra-arterial, and intrathecal, etc. It can be administered alone, or in combination with any ingredient(s), active or inactive, including in a medicinal form, or as a food or beverage additive.

In preferred embodiments of the invention, Rhodiola is administered orally in any suitable form, including, e.g., whole plant, powdered or pulverized plant material, extract, pill, capsule, granule, tablet or a suspension.

Rhodiola can be combined with any pharmaceutically acceptable carrier. By the phrase, "pharmaceutically acceptable carriers," it is meant any pharmaceutical carrier, such as the standard carriers described, e.g., Remington's Pharmaceutical Science, Eighteenth Edition, Mack Publishing company, 1990. Examples of suitable carriers are well known in the art and can include, but are not limited to, any of the standard pharmaceutical carriers such as a phosphate buffered saline solutions, phosphate buffered saline containing Polysorb 80, water, emulsions such as oil/water emulsion and various type of wetting agents. Other carriers may also include sterile solutions, tablets, coated tablets pharmaceutical and capsules. Typically such carriers contain excipients such as such as starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums, glycols. Such carriers can also include flavor and color additives or other ingredients. Compositions comprising such carriers are formulated by well known conventional methods. Generally excipients formulated with Rhodiola are suitable for oral administration and do not deleteriously react with it, or other active components.

Suitable pharmaceutically acceptable carriers include but are not limited to water, salt solutions, alcohols, gum arabic, vegetable oils, benzyl alcohols, gelatin, carbohydrates such as lactose, amylose or starch, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxy methylcellulose and the like. Other additives include, e.g., antioxidants and preservatives, coloring, flavoring and diluting agents, emulsifying and suspending agents, such as acacia, agar, alginic acid, sodium alginate, bentonite, carbomer, carrageenan, carboxymethylcellulose, cellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxppropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, octoxynol 9, oleyl alcohol, povidone, propylene glycol monostearate, sodium lauryl sulfate, sorbitan esters, stearyl alcohol, tragacanth, xanthan gum, and derivatives thereof, solvents, and miscellaneous ingredients such as microcrystalline cellulose, citric acid, dextrin, dextrose, liquid glucose, lactic acid, lactose, magnesium chloride, potassium metaphosphate, starch, and the like.

Rhodiola can also be formulated with other active ingredients, such as anti-oxidants, vitamins (A, C, ascorbic acid, B's, such as B1, thiamine, B6, pyridoxine, B complex, biotin, choline, nicotinic acid, pantothenic acid, B12, cyanocobalamin, and/or B2, D, D2, D3, calciferol, E, such as tocopherol, riboflavin, K, K1, K2). Preferred compounds, include, e.g creatine monohydrate, pyruvate, L-Carnitine, α-lipoic acid, Phytin or Phytic acid, Co Enzyme Q10, NADH, NAD, D-ribose, amino acids such as L-Glutamine, Lysine, chrysin; pre-hormones such as 4-drostenedione, 5-androstenedione, 4(or 5-)androstenediol, 19-nor-4 (or 5-)-drostenedione, 19-nor-4 (or 5-)-androstenediol, Beta-ecdysterone, and 5-Methyl-7-Methoxy Isoflavone. Preferred active ingredients include, e.g., pine pollen, fructus lycii, hippophae rhamnoides, Salvia Miltiorrhiza, Ligusticum, Acanthopanax, Astragalus, Ephedra, codonopsis, polygola tenuifolia Willd, Lilium, Sparganium, ginseng, panax notogiseng, Garcinia, Guggle, Grape Seed Extract or powder, and/or Ginkgo Biloba.

Other plants and herbs which can be formulated with a Rhodiola of the present invention includes those mentioned in various text and publications, e.g., ES Ayensu, Medicinal Plants of West Africa, Reference Publications, Algonac, Mich. (1978); P. Back, The Illustrated Herbal 1987, Hamlyn Publishers, distributed by Octopus Books, Printed in Hong Kong by Mandarin, ISBN 0-600 553 361; F. Bianchini and F. Corbetta, The Fruits of the Earth, translated from Italian by A. Mancinelli, Bloomsbury Books, London, ISBN 1-870630-10-6; H. M. Burkill, The Useful plants of West Tropical Africa, Ed. 2, V. I, Royal Botanic Gardens Kew, ISBN 0-947643-01-X (1985); L. Boulos, Medicinal Plants of North Africa, Reference Publications Inc., Algonac, Mich. (1983); and N. C. Shah, Herbal Folk Medicines in Northern India, J. Ethnopharm, 6:294-295 (1982).

Other active agents include, e.g., antioxidants, anti-carcinogens, anti-inflammatory agents, hormones and hormone antagonists, antibiotics (e.g., amoxicillin) and other bacterial agents, and other medically useful drugs such as those identified in, e.g., Remington's Pharmaceutical Sciences, Eighteenth Edition, Mack Publishing Company, 1990. A preferred composition of the present invention comprises, about 1%-100%, preferably about 20-70% Rhodiola crenulata extract, more preferably about 60%, said extract having about 0.5-10% salidroside content; 10-45% 5:1 extracted fructus lycii powder (5 kilograms of the herb is used to produce 1 kg of herb powder); 1-20% of hippophae rhamnoides powder; and, optionally, a pharmaceutically-acceptable excipient.

The present invention relates to methods of administering Rhodiola, especially Rhodiola crenulata, e.g., to enhance blood oxygen levels, to enhance working capacity and endurance, to reduce muscle fatigue, to enhance memory and concentration, to reduce stress, to enhance cardiac and cardiovascular function, to improve sexual ability, to provide antioxidant effects, to protect against oxidation, to provide anti-cancer effects, to promote DNA repair, to provide anti-radiation effects, to protect against radiation, to reduce inflammation, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, preferably, to modulate testosterone levels, to increase male virality, to modulate sleep, especially to promote sleep. to modulate blood lipids, preferably, e.g., to lower cholesterol levels, to promote weight loss, to increase estradiol levels, etc., and other conditions and diseases as mentioned above and below.

By the term "administering," it is meant that Rhodiola is delivered to the host in such a manner that it can achieve the desired purpose. As mentioned Rhodiola can be administered by an effective route, such as orally, topically, rectally, etc. Rhodiola can be administered to any host in need of treatment, e.g., vertebrates, such as mammals, including humans, male humans, female humans, primates, pets, such as cats and dogs, livestock, such as cows, horses, birds, chickens, etc.

An effective amount of Rhodiola is administered to such a host. Effective amounts are such amounts which are useful to achieve the desired effect, preferably a beneficial or therapeutic effect as described above. Such amount can be determined routinely, e.g., by performing a dose-response experiment in which varying doses are administered to cells, tissues, animal models (such as rats or mice in maze-testing, swimming tests, toxicity tests, memory tests as performed by standard psychological testing, etc.) to determine an effective amount in achieving an effect. Amounts are selected based on various factors, including the milieu to which the virus is administered (e.g., a patient with cancer, animal model, tissue culture cells, etc.), the site of the cells to be treated, the age, health, gender, and weight of a patient or animal to be treated, etc. Useful amounts include, 10 milligrams-100 grams, preferably, e.g., 100 milligrams-10 grams, 250 milligrams-2.5 grams, 1 gm, 2 gm, 3 gm, 500 milligrams-1.25 grams. etc., per dosage of different forms of Rhodiola crenulata such as the herbal powder, herbal extract paste or powder, tea and beverages prepared to contain the effective ingredients of Rhodiola, injections, depending upon the need of the recipients and the method of preparation.

In preferred embodiments, the present invention relates to a method of increasing testosterone levels in a host in need thereof, comprising, administering an effective amount of a Rhodiola to said host. Testosterone, principal male hormone, or androgen, is produced mainly in the Leydig cells in the male testes. The Leydig cells also produce two other androgens of less potency and in much smaller quantities. Testosterone stimulates the development of the male secondary sex characteristics after puberty, causing growth of the beard and pubic hair, development of the penis, and change of voice. The hormone also aids in growth, muscular development, and masculine body contour of the adult male.

Testosterone is considered to be a male virilizing hormone. Its effects include maintenance of muscle and bone mass, improving and/or enhancing sexual function and psychological well being among others. As males grow older, especially after the age of 35, a slow decline in testosterone levels is observed which is accompanied by symptoms that have been associated with the condition known as "andropause". Symptoms of andropause include lethargy, depression, lack of sexual desire and function, and loss of muscle mass and strength. Increasing testosterone levels therefore can be useful to treat any of the mentioned conditions. Additionally, increasing testosterone levels can be useful in treating certain types of breast cancer in women.

Testosterone levels refer to the amounts of testosterone which are circulating in the blood, e.g., as measured using enzyme-linked immunosorbent assay, HPLC, or any other suitable detection method.

Any effective amount of Rhodiola crenulata can be administered. In accordance with present invention, it has been demonstrated that intake of a standardized Rhodiola crenulata extract (e.g., having 0.1-10%. Preferably 1-6%) salidroside by total weight of composition) produced a significant increase in total testosterone as compared to placebo. For example, after taking 2 grams of standardized rhodiola extract with 2% salidroside, once a day for a month, subjects showed about a 76% increase in total testosterone in the blood as compared to the 6.0% increase in total testosterone level after taking placebo for a month. These amounts, however, can be increased by any value, e.g., at least about 5%, 10%, 15%, 20%, 50%, 60% 70%, 75%, 100%, 2-fold, 5-fold, etc., over amounts which are present in the blood prior to administration.

The present invention also relates to a method of increasing estradiol levels in a host in need thereof, comprising, administering an effective amount of a Rhodiola to said host.

Estradiol is a female sex hormone that stimulates the appearance of secondary female sex characteristics in girls at puberty. Estradiol controls growth of the lining of the uterus during the first part of the menstrual cycle, cause changes in the breast during pregnancy, and regulate various metabolic processes. Increasing estradiol can treat various conditions, including menopausal symptoms, estrogen deficiencies in women (most commonly after menopause; low eight; etc) and inflammation of the vagina. It can also stimulate lactation following childbirth and in the treatment, but not cure, advanced and even disseminated cancer of the prostate gland in men. Amounts of estradiol can be increased by any value, e.g., 5%, 6%, 8%, 10%, 15%, 20%, 30%, 50%, 75%, 100%, 2-fold, 5-fold, etc., over amounts which are present in the blood prior to administration. For example, in Example 10, Rhodiola as effective in increasing estradiol levels by about 12% as compared to only 3% in controls. Thus, Rhodiola can used to treat conditions associated with estrogen deficiency, such as menopuse, perimenopause, low-weight, etc.

Rhodiola can be combined with any agent which raises testosterone and/or estradiol levels. For example, testosterone precursors, such as those disclosed in U.S. Pat. Nos. 5,880,117 and 6,011,027, e.g., 4-androstenediol and 19-nor-4-androstenediol, can be utilized in combination with Rhodiola as a means of increasing testosterone levels in human. Currently, 4-androstenedione, 5-androstenedione, 4-androstenediol, 5-androstenediol, 19-nor-4-androstenedione, 19-nor-5-androstenedione, 19-nor-4-androstenediol, and 19-nor-5-androstenediol, Beta-ecdysterone, and 5-Methyl-7-Methoxy Isoflavone are being used to increase the testosterone level in humans. Rhodiola crenulata can be used with these ingredients to enhance their effects of boosting the testosterone level, other hormones, such as estradiol. Rhodiola crenulata can also be formulated to boost hormonal levels with other herbs, such as wild yam, Epimedium (including all Epimedium species), Angelica, Lycium, panex ginseng, Ganoderma lucidum, Codonopsis, Eleutherococcus, Schisandra chinensis, Atractylodes, and Ligustrum lucidum.

The present invention also relates methods of improving sleep in a host in need thereof, comprising administering an effective amount of a Rhodiola to said host. By the phrase "improving sleep," it meant bringing about a beneficial effect on sleep, including, e.g., prolonging sleep time (e.g., as measured in animal models by administering Rhodiola in the presence or absence of a barbiturate, or other sleep-promoting agent, and determining the sleep-prolongation time produced by Rhodiola), increasing time spent in REM-sleep, reducing sleep apnea and other sleep disorders, decreasing insomnia, decreasing amount of time to fall asleep, etc.

Rhodiola can also be formulated with other agents which promote sleep, such as Valerian, Melatonin, Kava Kava, St. John's Wort, Tryptophan and 5-Hydroxytryptophan, Astragalus, Hops, Passionflower, Skullcap, Chamomile, He Shou Wu, Ashwaganda, and Lady's Slipper.

The present invention also relates to methods of treating impotence, comprising administering an effective amount of Rhodiola, preferable Rhodiola crenulata. Impotency, or erectile dysfunction, is the inability to achieve an erection. The ability of Rhodiola crenulata to increase the blood oxygen transportation and testosterone level can enhance male sexual ability and performance in some cases. The Rhodiola can be administered immediately prior to performance, or more preferably, on a daily basis according to the regime mentioned above to increase testosterone levels. Rhodiola can also be administered in combination with agents which are used for treating impotency, including, e.g., vasodilators, phosphodiesterase inhibitors, stimulators of NO release, alpha-adrenergic agents, etc.

Administration of Rhodiola crenulata can also be used to enhance blood oxygen levels and transport to body tissues; to enhance working capacity and endurance. By "working capacity and endurance," it preferably meant that the effective amount increases the ability to perform a physical task, such as in exercise, physical labor, or sports activity, even before fatigue would normally occur; thus, enhanced working capacity and endurance is defined herein not to mean "fatigue," which simply indicates that the performer does not tire. Associated with enhanced working capacity and endurance can be an increase in muscle ATP levels and a reduction in circulating lactic acid levels (see, Examples 2 and 3). Thus, the present invention also relates to methods of increasing muscle ATP levels and/or reducing lactic acid in blood, thereby enhancing working capacity and endurance, improving sexual performance, etc.

As shown in the Example 2, Rhodiola crenulata reduces blood lactic acid (lactate) levels. Such reduction in lactic acid levels indicates that muscle fatigue is reduced. By "muscle fatigue," it is meant that the muscle cells carry out anaerobic respiration because of lack of oxygen. Reducing muscle fatigue therefore means, e.g., that fewer muscle cells become anaerobic. The present invention therefore also relates to a method of reducing muscle fatigue comprising administering an effective amount of Rhodiola crenulata. Lactic acid can be reduced by an effective amount in ameliorating fatigue, such as at least 10%, 15%, 20%, 25%, 30%, 35%, etc.

As shown in Example 3, Rhodiola crenulata increases the ATP available to muscle, e.g., by increasing aerobic respiration, by increasing oxygen transport, etc. Amounts of ATP can be increased by an effective amount in reducing muscle fatigue, such as 20%, 25%, 30%, 35%, 37%, 40%, 40%, 45%, 50%, etc.

Rhodiola can also be used to enhance or improved memory and concentration (such improved functions are to be distinguished from the more general brain stimulation which indicates increased non-selective neuronal activity, whereas the mentioned improved functions are selective, e.g., by stimulating specific parts of the brain or other organs, or by stimulating specific neural and hormonal systems); to reduce stress, e.g., lower blood pressure, reduce anxiety, promote calmness; to enhance cardiac and cardiovascular function (including, e.g., to protect against heart disease); to provide antioxidant effects and protect against oxidation; to provide anti-cancer effects, e.g., promote cessation of cell growth; to promote DNA repair; to provide anti-radiation effects and to protect against radiation, e.g., as a sun-screen when applied topically to the skin; to reduce inflammation, e.g., systemic inflammation, skin inflammation (where Rhodiola can be administered topically), but with the proviso that it is not lung-inflammation, coughing, or bleeding associated with lung-inflammation and coughing, to increase insulin, to decrease levels of glucagon, to reduce histamine release, to reduce allergic reactions, to enhance sexual ability. Rhodiola crenulata in accordance with the present invention is preferably not used to treat external wounds, external burns, lung inflammation, and coughing.

EXAMPLES

Method of Examples One, Two, and Three

20 Kunming-species mice (10 males and 10 females), weighing approximately 18-22 grams each, were randomly divided into experimental and control groups, with each group containing 10 mice. Mice in the experimental group were provided with food containing about 50 mg (0.05 gram, about 0.25 gram every 1 kilogram body weight) Rhodiola crenulata per day for 3 days. Mice in the control group were fed with the same food but without Rhodiola crenulata.

Example One

After 3 days of consuming food containing Rhodiola crenulata, the mice were subjected to a swimming test. A lead weight that comprised about 6% of the mice's body weight was attached to each mouse prior to placing it in a water-filled receptacle. The average survival time for experimental group was 92.85±5.20 minutes while for the control group it was 69.89±5.10 minutes. This represents a 33% improvement in the endurance of mice fed Rhodiola crenulata as compared to controls.

Example Two

After one hour of swimming, the blood lactate levels were assayed as a measure of fatigue. The average blood lactate level for the experimental group was 14.50±1.41 mmol/L while the control group was 19.30±1.80 mmol/L. Thus, muscle fatigue levels were reduced by 25% in mice fed Rhodiola crenulata.

Example Three

After one hour of swimming, the levels of skeletal muscle ATP level were measured. The average skeletal ATP level for the experimental group was 210.45±14.88 mg/100 g while for the control group it was 153.88±20.67 mg/100 g. ATP levels were increased by 37% in mice fed Rhodiola crenulata, indicating that the herb enhanced energy levels.

Method for Example Four, Five, Six, Seven, Eight, Nine, Ten, Eleven

40 volunteers are divided into two groups, each comprising 20 people. The test group was administered 2 grams of Rhodiola crenulata standardized extract (with 2% salidroside), once a day for one month. The control group received a placebo. After one month, each participant was required to assess improvement of their memory, sleep, physical strength, and sexual performance. Blood samples were collected prior to taking any Rhodiola and after the one-month period.

Example Four

Using a blood oxygen analyzer, the blood oxygen pressure of each participant before and after taking rhodiola crenulata extract and placebo was tested. The average of the blood oxygen pressure of the test group before and after taking rhodiola crenulata for a month was 6.97±0.64 and 7.86±0.90 respectively. For the control group, the average testosterone level before and after taking placebo for a month was 6.87±0.66 and is 7.04±0.95 respectively. These results show after taking Rhodiola crenulata for one month, the oxygen transport and supply in the human body is enhanced by about 12.6%.

Example Five

The test subjects were asked whether their memory was improved during the course of the test. In the test group, 45% stated that their memory was improved after one month of the medication. In the control group, only 21% reported memory improvement after one month of the placebo.

Example Six

The test subjects were asked whether their physical strength was improved. In the test group, 81% reported improvements in physical strength after one month of the medication as compared to only 38% in the control group.

Example Seven

Test subjects were asked whether their sexual performance was improved. In the test group, 75% described improved sexual performance after one month of the Rhodiola extract. In the control group, only 28.9% said their sexual performance was improved.

Example Eight

Test subjects were asked whether their sleep is improved. In the test group, 83% of the subjects their sleep was improved after one month of the Rhodiola. In the control group, 41% said their sleep is improved after one month medication.

Example Nine

Using an enzyme-linked immunosorbent assay, the blood testosterone levels of each participant was tested. The average of testosterone level of the test group before and after taking Rhodiola crenulata, once a day, for a month was 17.68±5.6 mmol/L and 31.12±10.6 mmol/L, respectively. For the control group, the average testosterone level before and after taking placebo for a month was 18.02±6.0 mmol/L and 19.10±7.6 mmol/L respectively. The Rhodiola increased testosterone levels by 76%, while in controls the increase was only 6%.

Example Ten

Using an enzyme-linked immunosorbent assay, the blood estradiol levels of each participant before and after taking rhodiola crenulata extract and placebo were tested. The average of estradiol level of the test group before and after taking Rhodiola crenulata for a month was 163.56±33.9 mmol/L and 182.93±107.34 mmol/L respectively. For the control group, the average estradiol level before and after taking placebo for a month was 164.5±34.43 mmol/L and 169.30±40.02 mmol/L respectively. Rhodiola increased estradiol levels by about 12% whereas in control the increase was only about 3%.

Example Eleven

The blood content of superoxide dismutase (SOD) levels of each participant was tested using the method of pyrogallol auto-oxidization before and after taking Rhodiola crenulata extract and placebo. The average of SOD level of the test group before and after taking Rhodiola crenulata for a month was 1173.8±122.2 U/g.Hb and 1296.7±157.3 U/g.Hb respectively. For the comparison group, the average testosterone level before and after taking placebo for a month was 1173.4±121.5 U/g.Hb and 1205.8±147.40 U/g.Hb respectively. This test indicates that Rhodiola crenulata has antioxidant effects.

Example Twelve

A composition comprising effective amounts of Rhodiola crenulata can be administered to subjects to enhance levels of blood oxygen, to enhance working capacity and endurance, to enhance memory and concentration, to reduce stress, to enhance cardiac and cardiovascular function, to provide antioxidant effects, to modulate testosterone levels, to modulate sleep, and to improve sexual performance. to increase energy level, and to enhance memory and concentration. Such a composition can comprise, by weight:

60% Rhodiola crenulata, having 2% salidroside content; and

30% of a 5:1 extracted fructus lycii powder; and

10% of hippophae rhamnoides powder.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limiting the remainder of the disclosure in any way whatsoever. The entire disclosure of all applications, patents and publications, cited above and in the figures are hereby incorporated by reference in their entirety.

health4ni wrote:@Bison:
1. what's your dosage?
2. when do you take it?
3. with food or on empty stomach?

kp1512 wrote:Bison

Which ratio are you using?

KP

Orinoco wrote:It seems that Rhodiola crenulata has differing levels of active ingredients compared to rosea....all the commercially available supplements I've seen have been rosea and not crenulata.

Bison wrote:

health4ni wrote:@Bison:
1. what's your dosage?
2. when do you take it?
3. with food or on empty stomach?

I usually have 500mg in the morning. Sometimes before breakfast and sometimes just after, depends how I wake up lol. If I'm going through a stressful time or at the business end of a routine and lifting heavy and going for PB's then I'll double up to 1000mg by having an extra 500mg in the afternoon.

health4ni wrote:

Bison wrote:I usually have 500mg in the morning. Sometimes before breakfast and sometimes just after, depends how I wake up lol. If I'm going through a stressful time or at the business end of a routine and lifting heavy and going for PB's then I'll double up to 1000mg by having an extra 500mg in the afternoon.

woah, that's a big dose dude. Esp at 3% rosavin. How heavy are you?

Try taking 250mg 30mins b4 breakfast and another 250mg 30mins b4 lunch. See how you get on.

standardized amount of 3 percent rosavins and 0.8-1 percent salidroside because the naturally occurring ratio of these compounds in Rhodiola rosea root is approximately 3:1.

Rilla wrote:Link to your source Bison?
I'm using MP as well...

Bison wrote:

kp1512 wrote:Bison

Which ratio are you using?

KP

Currently I'm using this http://www.bulknutrition.com/?products_ ... dvr0oq9bd6 but it's the first time I've used this, only been taking for about 10 days and I've just had a long break from it. Haven't really felt any effects yet.

kp1512 wrote:

standardized amount of 3 percent rosavins and 0.8-1 percent salidroside because the naturally occurring ratio of these compounds in Rhodiola rosea root is approximately 3:1.

this should be the ideal ratio, right?

health4ni wrote:From what I have gleaned the following is recommended:

300-600 mg if extract standardized for 1 % rosavin or
180-300 mg if 2% rosavin or
100-170 mg if 3.6 % rosavin

Treatment resistant depression and certain neurological disorders may require 600 mg a day or more

Bison wrote:

kp1512 wrote:

standardized amount of 3 percent rosavins and 0.8-1 percent salidroside because the naturally occurring ratio of these compounds in Rhodiola rosea root is approximately 3:1.

this should be the ideal ratio, right?

Sounds good to me

Has anyone tried looking into the Rhodiola crenulata? I haven't had time yet, hoping to this week though!

Effect of Rhodiola rosea and Rhodiola crenulata (Crassulaceae) root extracts on ATP content in Muscle Mitochondria
Abidoff Musa, Center of Modern Medicine, Russian Ministry of Defense Industries, Moscow-121351, Russia.
Krendal Felix & Grachev Sergey, IM Sechenev Medical Academy, Bolshaya Pirogovskaya, 2/6, Moscow, Russia.
Seifulla Roshen, Russian Center for Higher Sport Education, Moscow.
Tim Ziegenfuss, Pinnacle Institute of Health & Human Performance, Wadsworth Medical Center, STE 103 323 High Street, Wadsworth, OH 44281
Abstract

We investigated the effect of oral Rhodiola rosea and Rhodiola crenulata root extract supplementation on swimming time to exhaustion and concentrations of adenosine 5'-triphosphate (ATP) in muscle mitochondria of rats. Animals received either 50mg/kg R.rosea extract (standardized to 3% rosavins and 0.8% salidroside) or 50 mg/kg R.crenulata (standardized to 2% salidroside) 30-minutes prior to completing an exhaustive swimming test conducted over 6-days. R.rosea increased swim time to exhaustion by 24.6% compared to control (0% change) and R.crenulata (4.3% change, P<0.05). There were no statistically significant differences between the control and R.crenulata extract-treated groups, despite the latter animals receiving salidroside in a dosage 2.5 times greater than the R.rosea. The exercise test reduced the content of mitochondrial ATP from 5.46±0.3 to 3.8±0.2 mmol/g protein (31.5±2.2%) in both the control and R.crenulata extract-treated groups, while its level in the R.rosea extract-treated group decreased to 22.02±1.6%, from 5.51±0.4 to 4.85±0.2 mmol/g. In addition, after 24 h resting levels of ATP in the R.rosea-extract treated group had recovered to 5.42±0.3mmol/g, while its content in both control and R.crenulata-extract treated groups were significantly (P<0.05) lower (4.26±0.2 and 4.46±0.3 mmol/g, respectively). These results indicate that R.rosea extract increases the synthesis or re-synthesis of ATP in mitochondria, and stimulates energetic recovery processes after intensive muscular work. Results of this study provide strong evidence that R.rosea and R.crenulata possess significantly different pharmacological properties, and that R.rosea is superior in terms of enhancing physical performance.

Introduction

Rhodiola rosea (Crassulaceae) or “golden root” is a plant indigenous to the high altitude Arctic Regions and is considered a phytomedicine in Russia, Scandinavia and Asia (Saratikov and Krasnov 1987, Brown et al. 2002). Extensive animal and human research has revealed that the R.rosea root extract possesses anti-stress and anti-depression properties, alleviates emotional, mental, and physical disorders (Saratikov and Krasnov 1987; Spasov et al. 2000; Shevtsov et al. 2003), and reduces exhaustion after intensive training workloads (Dambueva 1968; Adamchuk 1969; Salnik 1970, Lapaev, 1982; Azizov and Seifulla 1998). It was also demonstrated that R. rosea root extract increases the level of brain norepinephrine (NE), dopamine (DA), serotonin (5-HT), and has nicotinic cholinergic effects in the central nervous system (Saratikov et al. 1978, Stancheva et al. 1987; Lazarova et al. 1986; Petkov et al. 1986).

Animal studies have revealed that R.rosea stabilizes the ultrastructure of mitochondria during exhaustive swimming (Salnik 1970; Saratikov and Krasnov, 1987), stimulates the release fatty acids from adipose tissue (Dambueva 1968), and enhances creatine phosphate synthesis in muscle and brain, and muscle protein synthesis (Adamchuk 1969; Revina 1969; Saratikov et al. 1971). It has also been reported that professional athletes have used R.rosea to enhance physical performance, promote anabolism in muscle, prolong stamina during peak periods of physical stress, and enhance cardiovascular recovery time after intense training (Fulder 1980; Saratikov et al. 1968; Azizov & Seifulla, 1998; Seifulla, 1999).

There are about 20 species of the genus Rhodiola, and the phytochemistry and pharmacological properties of these plants seem to depend entirely upon which species is being used (Komarov, 1939; Saratikov 1974; Kurkin and Zapesochnaya 1986). Principal constituents in R.rosea are cinnamyl alcohol vicyanoside rosavin, rosin, rosarin, (collectively the rosavins) and hydroxyphenylethanol-2-D-glucopyranoside (salidroside, also known as rhodioloside) (Saratikov et al. 1968; Kurkin and Zapesochnaya 1986a,b). The presence of rosavins seems to be specific to R.rosea only (Kurkin and Zapesochnaya, 1996a,b; Dubichev et al. 1991), while the presence of salidroside was shown in all plant species of the genus Rhodiola (Barnaulov et al. 1965; Wang et al. 1992a,b; Kang et al. 1992; Yoshikawa et al. 1996; Linh et a. 2000). In contrast, R. crenulata is medicinal plant in Uzbekistan, China and other Asian countries (Wang et al. 1992b; Cui S et al 2003). It is believed that R.crenulata possesses notifying properties, and that salidroside is responsible for this effect, although it has not yet been clinically evaluated (Xiu 2002).

In this study, we investigated the effect of R. rosea and R. crenulata root extracts on the concentration of ATP in rat muscle mitochondria before and after a swimming test to exhaustion. Results of this study demonstrate that administration of R.rosea root extract increased the time to exhaustion and the content of mitochondrial ATP compared with compare to controls and the R.crenulata extract-treated group.

Materials and Methods

Plant material

Underground parts of R. rosea were collected in Eastern Siberia (Russia), and R. crenulata Fish et Mey root and rhizome was received as a gift from the Uzbekistan Academy of Science. Voucher samples from each original lot were retained in our laboratory. Plant material was collected in the late flowering period, separated from soil residues, and carefully sliced into 1-3cm cuts and dried under continuous airflow chambers at 30oC. When the moisture content was reduced to 5-6%, plant material was milled to 2mm particles size and used in extract preparations.

Powdered plant materials were extracted with an ethanol: water mixture (60:40, v/v) in 100 L extraction vessels at 45-55oC for 12 h with continuous agitation. The crude extracts were separated from cell-wall debris by centrifugation at 2000 rpm, alcohol removed following distillation under reduced pressure and the liquid alcohol-free extract was freeze dried.

HPLC analysis of rosavins and salidroside

The content of rosavins and salidroside were determined using a Waters System HPLC equipped with 996 Photodiode Array Detector, two model 515 Pumps, a Gradient Mixer Kit 051518, a Pump Control Module, a Bus SAT/IN Module, a model 7725I Injector with 20 ml loop, and a Millenium32 Chromatography Manager (Version 3.0). For all separations a RP-C18 analytical column C-18, 3.9 x 150 mm, 5 mm particle size was used (Symmetry, WATO27324, Waters Associates, Inc.). Two mobile solvents were used to develop a binary gradient, phase A: 0.16 M ammonium acetate solution in water (w/v) (pH is adjusted to 5.5 with acetic acid) and, phase B: methanol. The mobile phase flow rate was adjusted to 1.0 ml/min, and UV detection wavelength was set at 2 different wavelengths, 254 for rosavin, rosin and rosarin, and 280 nm for salidroside (Dubichev et al. 1991; Kurkin et al. 1986a; Ramazanov & Bernal Suarez, 1999). After 5 min holding the initial solvent mix, 66:34 (A: B, v/v), a linear ramp up to 60:40 (A: B, v/v) over 17 min was developed, followed by a return to the initial conditions over 5 min, and 5 min equilibration before the next analysis.

The HPLC reference standards of rosavin, rosin, rosarin and salidroside were received as gifts from the Russian Institute of medicinal Plants (VILAR), Moscow. Stock standard solutions were prepared in ethanol: water (85:15, v/v) to a concentration of 1 mg/ml. Four standard solutions containing both components in different concentrations, between 0.01 and 0.3 mg/ml, were injected. The calibration curve for each standard was linear in the described range with correlation coefficients of 0.99.

Animals

Twenty-four adult Sprague-Dawley rats (250±20g) housed in temperature (20±2 °C) and light (08:00h-20.00h) controlled cages were used in this study. Food and water were made available ad libitum. The animals were divided into three groups; control (n=8), the 50mg/kg R.rosea extract-treated group (n=8) and the 50mg/kg R.crenulata extract-treated group (n=8).

Exercise Protocols

A swim test was used to measure the time to exhaustion and to determine the effects of plant extracts on ATP content in muscle mitochondria. The animals were made to swim to exhaustion in a tank filled with water at room temperature. Normally, rats are able to swim for 10–14 hours without rest, but with additional weight attached, exhaustion occurred within 5 hours. The animals were forced to swim for as long as possible over a six day period. They were subjected to two swimming sessions per day until exhaustion, with 30-minutes rest between sessions. Plant extracts (50mg/kg) were administered by oral gavage 30-minutes before each exercise bout. Time to exhaustion was defined as the time between the commencement of exercise and the first occurrence of the animal failing to swim. Immediately after determination of the time to exhaustion, 50% of the rats in each group were sacrificed with an IP injection of sodium pentobarbital (5 mg/100 g body weight) while the other 50% were killed 24 h after the last treatment.

Mitochondrial isolation

Muscle mitochondria were isolated following the method described by Tonkonogi and Sahlin (1999). Muscle specimens were disintegrated with scissors, homogenized in the presence of proteinase and resuspended in an ice-cold isolation medium containing 70mM sucrose, 220mM mannitol, 5mM HEPES (pH 7.2), 0.5mM EDTA. The homogenate was centrifuged at 600 X g for 10 minutes. Supernatant was decanted, re-diluted with the isolation medium, and centrifuged again at 12,000 X g for 10 minutes to obtain the mitochondrial fraction. The final mitochondrial pellet was resuspended in a buffer (pH 7.40) consisting of 225mM mannitol, 75mM sucrose, 10mM Tris, and 0.1mM EDTA. An aliquot of the suspension and muscle were taken for measurements of protein content and citrate synthase activity as a mitochondrial marker to estimate the percentage of mitochondria freed from the muscle (Tonkonogi et al. 1997). The protein concentration was determined by the method of Bradford using nitrogen-calibrated bovine serum albumin as the standard (Marshall and Williams, 1992).

ATP analysis

The content of ATP in muscle and isolated mitochondria was determined using the bioluminescence method described by Drew and Leeuwenburgh (2003) with a commercial ATP kit. This assay is based on the reaction of ATP with firefly luciferase and its substrate luciferin. Measurements of ATP content were made immediately after isolation of the mitochondria to improve the accuracy of the measurements and reduce any inherent errors associated with the luminescent decay or reduced viability of the isolated mitochondria (Drew and Leeuwenburgh, 2003). All mitochondrial samples were performed in triplicate and an average of these results was used in the quantification of ATP content.

Chemicals

The ATP determination kit (A-22066) by Molecular Probes (Eugene, OR) contains D-luciferin, luciferase (40 III of a 5 mg/ml solution in 25 mM Tris-acetase, pH 7.8, 0.2 M ammonium sulfate, 15% (v/v) glycerol and 30% (v/v) ethylene glycol), dithiothreitol (DTT), adenosine 5'-triphosphate (ATP), and a Reaction Buffer (10 ml of 500 mM Tricine buffer, pH 7.8, 100 mM MgSO4, 2mM EDTA and 2 mM sodium azide). The reagents and reaction mixture were combined according to the protocol provided by the manufacturer.

Statistical analysis

All values reported are means ± SE. Differences between means were tested for statistical significance by single-factor analysis of variance (ANOVA) with a repeated-measure design. P< 0.05 was considered as an indicator of significant differences.

Results and discussion

Rhodiola rosea (Crassulaceae) root extract is a phytomedicine used to reduce chronic stress and promote mental and physical performance. The phytoactive compounds responsible for its pharmacological effects are a complex of cinnamyl alcohol vicyanosides rosavin, rosin, rosarin, (the rosavins) and hydroxyphenylethanol-2-D-glucopyranoside (salidroside). Rhodiola crenulata also belongs to the genus Rhodiola and is used as general tonic. It has been speculated that R.crenulata possesses pharmacological properties similar to R.rosea, even though it does not contain the complex of rosavins.

Figure 1 shows the HPLC chromatograms of R.rosea and R.crenulata root extracts used in this study. These results indicate that the HPLC fingerprint of these two plant extracts is very different. R.rosea root extract contains the complex rosavins and salidroside, while R.crenulata root extract contain salidroside only. This is in agreement with previous data obtained by other laboratories (Kurkin and Zapesochnaya 1986a; Dubichev et al. 1991). Using corresponding HPLC reference standards, the content of rosavins in R.rosea root extract was calculated as 3.02% dry weight and salidroside 0.89% dry weight. In contrast, the content of salidroside in the R.crenulata root extract was calculate as 2.05% dry weight. Therefore, the ratio of rosavins to salidroside in true R.rosea root extract is about 3:1, which is in agreement with Kurkin and Zapesochnaya (1996a,b).

Table 1 summarizes the effect of R. rosea and R.crenulata root extracts on time to exhaustion for the swim test. The mean time to exhaustion was 34.2±2.5, 35.5±3.1 and 44.9±2.1 minutes in control, R.crenulata and R.rosea extract-treated groups, respectively. The mean time to exhaustion of animals in R.crenulata extract-treated group was no different from that in control group (p>0.05). These results indicate that R.crenulata root extract does not enhance physical performance compared with R.rosea extract, despite on fact that R.crenulata root extract used in this study contain 2.5 times higher salidroside content. Therefore, the complex of rosavins and or its combination with salidroside might be responsible for the observed effects in this study, although the role of other yet to be identified yet compounds cannot be excluded.

More evidence supporting distinct pharmacological differences between these two plants of the genus Rhodiola can be gleaned from their effects on mitochondrial ATP content. Table 2 shows that the swim exercise significantly reduced the content of ATP in muscle mitochondria from 5.38±0.3 mmol/g protein to 3.86±0.4 mmol/g in the control group and from 5.48±0.5 to 3.81±0.5 mmol/g protein in the R.crenulata extract-treated group. However, the reduction in ATP content was substantially lower in the R.rosea extract treated-group, from 5.41±0.4 to 4.85±0.3 mmol/g protein (P<0.05). These results indicate that R.rosea extract appears to enhance the synthesis/re-synthesis of mitochondrial ATP in exercised muscle.

The current findings agree with previous reports demonstrating that R.rosea root extract can enhance mitochondrial levels of high energy phosphates. Revina investigated the effect of R.rosea extract on the level of brain ATP and CP in rats under experimental conditions similar to described above (Revina 1969). The results of that study revealed that administration of R. rosea (1:1 liquid tincture in 40% ethanol) before exhaustion swimming exercise extract increased the level of both ATP and CP in the brain at the same time that these decreased in the control group (Revina 1969; Saratikov and Krasnov 1987). Results of this study suggest that stimulation of synthesis of ATP and CP in brain might contribute to endurance or stamina during physical exertion, simultaneously reducing the recovery time after intensive physical workloads. Similar results have been reported by other researchers (Adamchuk 1969; Adamchuk and Salnik 1970; Saratikov and Krasnov 1987; Salnik, 1970).

The anabolic properties of R. rosea root extract were first studied in mice (Salnik et al. 1968; Adamchuk 1969; Saratikov et al. 1971). Concentrations of RNA and DNA, activity of aminoacyl-t-RNA synthetase and ATP in muscle were analyzed before and after exhaustive swimming exercise. Results indicated that the activity of aminoacyl-t-RNA-synthetase, and the concentration of RNA and ATP were significantly higher in muscle of animals received R.rosea extract. In addition to indicating a potential anabolic effect from R. rosea root extract, data from Adamchuk and other authors suggest that the anabolic activity of whole extract of R.rosea root is superior to that of isolated individual compound salidroside.

Intramuscular lactic acidosis and ammonia are other metabolic factors that can cause fatigue during resistance exercise and reduce the rate of synthesis of ATP and CP in mitochondria (Seifulla 1999; Lambert and Flynn, 2002). High levels of lactic acid that accumulate during intensive muscular exercise impair the respiratory function of skeletal muscle mitochondria and induce reorganization of the ultrastructure of the mitochondria. Notably, at least one study has reported that mice receiving R. rosea have reduced muscle ammonia concentrations. Since ammonia metabolism is fundamental to muscle function, this effect may explain how R. rosea accelerates muscle recovery after intensive muscular workloads (Saratikov and Krasnov 1987).

Research on the effects of R. rosea on athletes and others performing maximum physical and mental workloads has confirmed the same pattern of improved performance demonstrated in animal studies (Revina 1969; Saratikov and Krasnov 1987). Human test subjects taking R. rosea showed more robust pulse rates, greater back muscle strength and hand endurance under static tension, better coordination, and reduced recovery times. Extensive experiments on skiers and other athletes have reliably demonstrated the significant and unique value of R. rosea tincture for increasing stamina and accelerating recovery from physical exertion (Saratikov and Krasnov 1987). Based on the multitude of Russian studies beginning with 35 years ago, Soviet scientists and trainers have recommend R. rosea with increased frequency in many arenas of athletic performance to improve speed and strength, stamina, energy reserves, and short recovery time between competitions (Lapaev 1982; Saratikov et al. 1968; Saratikov and Krasnov 1987; Seifulla 1999).

In summary, these results indicate that R.rosea root extract possesses pharmacological properties unique to this plant species. Aside from the positive effects on mitochondrial ATP synthesis we observed that animals treated with R.rosea root extract increase the time to exhaustion and reduce their recovery time after intense exercise. Our results also suggest that the complex of rosavins might be responsible for the beneficial effects observed in this study, however, the role of other yet to be identified compounds in R.rosea cannot be ruled out.