Red Clover

Summary and Pharmaceutical Comment

The chemistry of red clover is well documented. Limited information is available on the pharmacological properties and no documented scientific evidence was found to justify the herbal uses. Robust clinical research assessing the efficacy and safety of red clover is limited. Reported oestrogenic sideeffects in grazing animals have been attributed to the isoflavone constituents. Few toxicity data are available for red clover. In view of this and the isoflavone and coumarin components, excessive use and use during pregnancy and lactation should be avoided.

Species (Family)

Trifolium pratense L. (Leguminosae)

Synonym(s)

Cow Clover, Meadow Clover, Purple Clover, Trefoil, Trifolium borysthenicum Gruner, T. bracteatum Schousb., T. lenkoranicum

(Grossh.) Rosk., T. pratense L. var. lenkoranicum Grossh., T. ukrainicum Opp.

Part(s) Used

Flowerhead

Pharmacopoeial and Other Monographs

BHC 1992(G6)

BHP 1996(G9)

Martindale 35th edition(G85)

Legal Category (Licensed Products)

GSL(G37)

RConstituents

The following is compiled from several sources, including General Reference G6.

Carbohydrates Arabinose, glucose, glucuronic acid, rhamnose, xylose (following hydrolysis of saponin glycosides); polysaccharide (a galactoglucomannan).

Coumarins Coumarin, medicagol.

Figure 1 Selected constituents of red clover.

Isoflavonoids Biochanin A, daidzein, formononetin, genistein, pratensin, trifoside, calycosine galactoside(1) and pectolinarin.

Flavonoids Isorhamnetin, kaempferol, quercetin, and their glycosides.(2)

Saponins Soyasapogenols B–F (C–F artefacts) and carbohydrates (see above) yielded by acid hydrolysis.(3)

Other constituents Coumaric acid, phaseolic acid, salicylic acid, transand cis-clovamide (L-dopa conjugated with transand ciscaffeic acids), resin, volatile oil (containing furfural),(4) fats, vitamins and minerals. Cyanogenetic glycosides have been documented for a related species, Trifolium repens.(G33)

Food Use

Red clover is listed by the Council of Europe as a natural source of food flavouring (category N2). This category indicates that it can be added to foodstuffs in small quantities, with a possible limitation of an active principle (as yet unspecified) in the final

product.(G16) Previously, red clover has been listed as GRAS (Generally Recognised As Safe).(G65)

Herbal Use

Red clover is stated to act as a dermatological agent, and to possess mildly antispasmodic and expectorant properties. Tannins are known to possess astringent properties. Traditionally red

clover has been used for chronic skin disease, whooping cough, and specifically for eczema and psoriasis.(G6, G7, G8, G64)

Dosage

Dosages for oral administration (adults) for traditional uses recommended in standard herbal reference texts are given below.

Dried flowerhead 4 g as an infusion three times daily.(G6, G7)

Liquid extract 1.5–3.0 mL (1 : 1 in 25% alcohol) three times

daily.(G6, G7)

Tincture 1–2 mL (1 : 10 in 45% alcohol) three times daily.(G6, G7)

Figure 2 Red clover (Trifolium pratense).

Figure 3 Red clover – dried drug substance (flowerhead).

Pharmacological Actions

In vitro and animal studies

Biochanin A, formononetin and genistein (isoflavones) are known to possess oestrogenic properties.(5) The saponin constituents are reported to lack any haemolytic or fungistatic activity.(3) A possible chemoprotective effect has been documented for biochanin A, which has been reported to inhibit carcinogenic activity in cell culture.(6)

Clinical studies

A systematic review of randomised clinical trials assessing the efficacy of products containing T. pratense isoflavones in reducing the frequency of hot flushes in menopausal women identified 17 articles of which five were suitable for inclusion into a metaanalysis.(7) The five studies assessed the effects of T. pratense isoflavones administered in doses ranging from 40–82 mg daily. Meta-analysis of data from these trials indicated that the frequency of hot flushes was lower for red clover, compared with placebo (weighted mean difference (95% confidence interval): 1.5 ( 2.94 to 0.03); p = 0.05). The clinical relevance, if any, of this finding is unclear. Another systematic review, which assessed the efficacy of phytoestrogens for treatment of menopausal symptoms, also included five trials that examined the effects of red clover extracts on frequency of hot flushes for red clover preparations, compared with control groups (weighted

mean difference (95% confidence interval): 0.60 ( 1.71 to 0.51)).(8)

Side-effects, Toxicity

Clinical data

There is a lack of clinical and toxicity data for red clover and further investigation of these aspects is required.

Urticarial reactions have been documented.(G51)

Preclinical data

Infertility and growth disorders have been reported in grazing animals.(G33) These effects have been attributed to the oestrogenic isoflavone constituents, in particular to formononetin.(5)

Contra-indications, Warnings

In view of the oestrogenic constituents, excessive ingestion should be avoided.

Drug interactions None documented. However, the potential for preparations of red clover to interact with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered. There is evidence that constituents of red clover have oestrogenic effects and the possibility that this could interfere with the activity of hormonal therapies taken concurrently should be considered.

Pregnancy and lactation In view of the oestrogenic components the use of red clover during pregnancy and lactation should be avoided.

Preparations

Proprietary single-ingredient preparations

Australia: Promensil; Trinovin. Brazil: Climadil. UK: Menoflavon.

Proprietary multi-ingredient preparations

Australia: Bioglan Mens Super Soy/Clover; Bioglan Soy Power Plus; Lifechange Menopause Formula; Trifolium Complex. Canada: Natural HRT. Malaysia: Cleansa Plus. USA: Women's Menopause Formula.

References

1Saxena VK, Jain AK. A new isoflavone glycoside from Trifolium pratense. Fitoterapia 1987; 58: 262–263.

5Kelly RW et al. Formononetin content of 'Grasslands Pawera' red clover and its oestrogenic activity to sheep. NZ J Exp Agric 1979; 7:

131–134.

6Cassady JM et al. Use of a mammalian cell culture benzo(a)pyrene metabolism assay for the detection of potential anticarcinogens from natural products: inhibition of metabolism by biochanin A, an isoflavone from Trifolium pratense L. Cancer Res 1988; 48: 6257–6261.

7Coon JT, et al. Trifolium pratense isoflavones in the treatment of menopausal hot flushes: a systematic review and meta-analysis. Phytomedicine 2007; 14(2–3): 158–159.

8Krebs EE, et al. Phytoestrogens for treatment of menopausal symptoms: a systematic review. Obstet Gynecol 2004; 104(4): 824–836.

Summary and Pharmaceutical Comment

The chemistry of Rhodiola rosea root and rhizome is well documented. The precise chemical constituents responsible for the documented pharmacological activities are not fully understood, although tyrosol and salidroside (rhodioloside) and the phenylpropanoid glycoside constituents (rosin, rosavin, rosarin) (see Constituents) are believed to be important for certain activities.

Over 200 other Rhodiola species have been described, and several of these are used as local medicines in China. Certain constituents of R. rosea have also been reported for other Rhodiola species. For example, salidroside has been documented for extracts of R. crenulata, R. quadrifida and R. sachalinensis root.

A substantial body of research investigating the pharmacological and clinical properties of R. rosea has been undertaken, although much of this work has been published in the Russian scientific literature, making it difficult to access. A limited number of reports of in vitro and animal studies published in the English scientific literature have described certain adaptogenic and other effects, such as antitumour and antimetastatic activities, for extracts of R. rosea, although further investigation is required to confirm these findings. Well-designed clinical trials of R. rosea root/rhizome extracts published in the English (or other European language) scientific literature are lacking. To date, clinical investigations are limited to a small number of single-dose or short-term trials (lasting less than three weeks) involving small numbers of healthy volunteers.

In view of the lack of safety and toxicity data, excessive use (higher than recommended dosages and/or for long periods of time) of R. rosea should be avoided.

Pharmacists and other healthcare professionals should be aware that herbal products containing rhodiola are readily

Rproducts are often promoted as being beneficial in supporting mental and physical performance, emotional balance, cardiovascular health, resistance to infection, male sexual function and in increasing ability to cope with stressful situations. There are no licensed rhodiola products available in

the UK, so the quality of commercially available products is not assured.available over the internet and from retail outlets; such

Species (Family)

Rhodiola rosea L. (Crassulaceae)

Synonym(s)

Arctic root, Golden root, Hong Jing Tian, Rhodiola, Rodiola, Rose root, Sedum rosea (L.) Scop., Sedum roseum Scop.

Rhodiola rosea and several other Rhodiola species are used as local medicines in China.(1)

Part(s) Used

Rhizome and root

Pharmacopoeial and Other Monographs

None

Legal category (Licensed Products)

Rhodiola is not on the GSL. There are no licensed products containing rhodiola available in the UK.

Constituents

Flavonoids Herbacetin, gossypetin, kaempferol and their glycosides rhodionin, rhodionidin, rhodiolgin, rhodiolgidin, rhodalin,

rhodalidin, rhodiosin and kaempferol-7-O-a-L-rhamnopyrano- side.(2)

Phenylethanoids Hydroxyphenylethyl tyrosol (p-tyrosol) and its glycoside salidroside (rhodioloside; p-hydroxyphenylethyl-O-b-D- glucopyranoside).(3)

Phenylpropanoids Rosin (cinnamyl-O-b-D-glucopyranoside), rosarin (cinnamyl-(60-O-a-L-arabinofuranosyl)-O-b-D-glucopyra- noside), rosavin (cinnamyl-(60-O-a-L-arabinopyranosyl)-O-b-D- glucopyranoside),(4) sachaliside 1 (4-hydroxy-cinnamyl-O-b-D- glucopyranoside), vimalin (4-methoxy-cinnamyl-O-b-D-glucopyr- anoside), cinnamyl-(60-O-b-xylopyranosyl)-O-b-glucopyranoside, 4-methoxy-cinnamyl-(60-O-a-arabinopyranosyl)-O-b-glucopyra- noside(4) and cinnamyl alcohol.(2)

Volatile oils 0.05% (1% has been documented for Russian material) of dry weight of crude rhizome, containing monoterpene hydrocarbons, monoterpene alcohols and straight-chain aliphatic alcohols as major components; major compounds (>3%) include geraniol, 1,4-p-menthadien-7-ol, limonene, a- pinene (monoterpenes), and decanol and dodecanol (aliphatic alcohols).(5) The monoterpenes rosiridol(2) and rosiridin(6) are also present.

Other constituents Picein ((4-O-b-D-glucopyranosyl)-acetophe- none), benzyl-O-b-D-glucopyranoside,(4) sterols (b-sitosterol, daucosterol),(2) tannins,(7) gallic acid and its esters.(8)

Quality

As with other herbal medicines, there can be qualitative and quantitative variation in the profile of constituents present in crude rhodiola material and in marketed products. Content of salidroside and tyrosol in samples of R. rosea root obtained from different outlets in the Yanbian area of China has been reported to vary up to ten-fold (range: 1.3–11.1 and 0.3–2.2 mg/g for salidroside and tyrosol, respectively).(9)

Standardisation of commercial extracts of R. rosea may be for content of 'salidrosides' and 'rosavins', although the precise composition of these groups may not always be stated.(6) For example, one commercial product available in the UK is described as containing 3% 'rosavins', 1% 'salidrosides' and 24% polyphenols per 100 mg capsule of rhodiola. Several other rhodiola products are stated to contain 1% 'salidrozid' and 40% polyphenols. The quality of these products is not assured as they are not licensed products.

Figure 1 Selected constituents of rhodiola.

An extract of R. rosea (SHR-5) tested in clinical trials was standardised for salidroside content (170 mg(10) or 185 mg(11)

extract provided approximately 4.5 mg salidroside).(10, 11) Analysis of 19 samples of dried rhizome from 10 Rhodiola

species other than R. rosea, obtained in the east of Qinghai province in China, found that all species contained salidroside, although only five species had a content greater than 0.3%.(12) Five species also contained lotaustralin, a cyanoglucoside which is toxic to humans following oral administration.

Food Use

Rhodiola root and rhizome are not used in foods, although the aerial parts of R. rosea are used as a food ingredient.(10)

Herbal Use

Rhodiola has a long history of use as a medicinal plant in several traditional systems. It is reported to have been used as a 'brain

tonic', to treat headache and lung disorders,(10) and to eliminate fatigue and improve work capacity.(13) It is also stated to have

stimulant properties, and to prevent stress.(10)

Modern interest in rhodiola is focused on its adaptogenic properties. (Adaptogens increase an organism's resistance to physical, chemical and biological stressors, and have a normalising influence on bodily systems.)

Figure 2 Selected constituents of rhodiola.

Figure 3 Selected constituents of rhodiola.

R

502 Rhodiola

Figure 4 Rhodiola (Rhodiola rosea).

Dosage

Authoritative guidance on dosages of R. rosea preparations for adults and children hitherto is lacking. Given the intended uses of R. rosea, it is not suitable for use in children.

In clinical trials involving young adults, dosages used have ranged from R. rosea root extract (SHR-5) 50 mg twice daily (salidroside content not stated)(14) to 170 mg daily (equivalent to approximately 4.5 mg salidroside) for two weeks.(10) In another study investigating the effects of R. rosea on fatigue and stress, participants took a single dose of two or three capsules (total

daily doses of 370 mg and 555 mg R. rosea extract, respectively).(11)

Other dosages have been suggested, although data supporting these regimens are not available. For example, for long-term use as an adaptogen (up to four months) daily doses of R. rosea extract standardised for 1% rosavin of 360–600 mg (equivalent to 3.6–

R6 mg rosavin daily), initiated several weeks before an anticipated period of increased stress and continued for its duration, have been stated.(15) For use as an adaptogen in acute stressful situations, such as taking an examination, a dose three times that suggested for longer term administration, taken as a single

dose (i.e. 1080–1800 mg R. rosea extract standardised for 1% rosavin, equivalent to 10.8–18 mg rosavin), has been advised.(15)

Pharmacological Actions

A substantial body of research investigating the pharmacological and clinical properties of R. rosea has been undertaken, although much of this work has been published in the Russian scientific literature, making it difficult to access. The following represents a summary of some of this literature, together with that published in English. Where papers published in Russian or Ukrainian are cited, information has been taken from the English abstract and/ or previous authoritative reviews only, thus the data and methods have not been scrutinised here. The information is included here to guide the interested reader to the original literature, and should not be taken as confirmation of the effects described.

Several activities, including various adaptogenic effects, as well as anti-arrhythmic, cardioprotective, antimutagenic and antitumour properties, have been described for R. rosea following preclinical and/or clinical studies. Several of these more specific activities are often considered as part of the overall profile of adaptogenic activity of R. rosea. The precise chemical constituents responsible for the documented pharmacological activities of R. rosea root and rhizome are not fully understood, although tyrosol and salidroside (rhodioloside) and the cinnamyl (phenylpropanoid) glycoside constituents (rosin, rosavin, rosarin) (see Constituents) are believed to be important for certain activities.(3, 4, 16)

In vitro and animal studies

Adaptogenic effects Several adaptogenic properties have been described for R. rosea extracts following preclinical studies.

The effects of R. rosea extract on erythropoiesis and granulocytopoiesis following paradoxical sleep deprivation (which leads to behavioural disorders and changes in haematopoiesis, for example, suppression of bone marrow erythropoiesis and activa-

tion of granulocytopoiesis) have been explored in experiments in mice.(17, 18) In one study, mice were given R. rosea extract (no

further details given) 1 ml/kg once daily by gastric lavage for five days before sleep deprivation.(17) Measurement of peripheral blood reticulocytes over days 1–7 following treatment indicated that R. rosea, compared with control, stimulated erythropoiesis during the early stage (days 1–3) but inhibited accumulation of erythroid cells in the bone marrow during days 4–7. In contrast, in a similar experiment using the same dosage regimen, administration of R. rosea before sleep deprivation did not modulate granulocytopoiesis as demonstrated by bone marrow content of neutrophilic granulocytes.(18)

A protective effect against various stress conditions was shown for an aqueous extract of R. rosea (SHR-5; containing rosavin 3.6%, salidroside 1.6% and p-tyrosol <0.1%) when applied to preparations of three-day-old larvae of the freshwater snail Lymnaea stagnalis before they were exposed to stressors.(19) Preincubation of larvae with increasing concentrations of R. rosea extract (ranging from 4.05 to 40.5 mg/mL) for 20 hours resulted in a concentration-dependent protective effect against exposure to lethal heat shock (438C for 4 minutes) for concentrations above 4.05 mg/mL. A protective effect of R. rosea was also demonstrated against other stressors (menadione, copper and cadmium) although the effect was less marked than against lethal heat shock. Further investigations, involving incubation of larvae with

Figure 5 Rhodiola – dried drug substance (rhizome).

R. rosea extract at a concentration of 40.5 mg/mL for 20 hours, ruled out induction of the synthesis of heat shock proteins by R. rosea extract as a possible mechanism of action for its protective effect against stressors.(19)

Cognitive effects The effects of a 40% ethanol extract of R. rosea root on learning and memory were investigated in rats in a battery of tests, including those involving passive avoidance and active avoidance with negative or positive reinforcement.(13) The results of these studies were conflicting. A single oral dose of R. rosea root extract of 0.1 mL given 30 minutes before maze training significantly facilitated learning and improved memory at 24 hours after administration (p < 0.01 compared with control), whereas doses of 0.02 and 1 mL had no demonstrable effect. In other tests using the staircase method (which trains animals to retrieve food from the top stair), oral administration of R. rosea extract 0.1 mL daily for 10 days before training resulted in a significantly greater proportion of trained rats, compared with control (92.3% versus 61.5%, respectively; p < 0.05). However, in other tests (including passive avoidance and active avoidance with negative reinforcement methods), this dosage regimen of R. rosea root extract had no significant effects on learning and memory.(13) Oral administration of a 40% ethanol extract of R. rosea rhizome 0.1 mL daily for 10 days before training also had no effect on electroconvulsive shock-impaired learning and memory in rats.(20)

The CNS depressant effects of a 50% ethanol extract (said to be of Sedum rosea; plant part not stated) at doses of 10, 30 and 100 mg/kg body weight intraperitoneally were investigated in mice.(21) Animals were given a single dose of sodium pentobarbital (50 mg/kg body weight, intraperitoneally) 30 minutes after S. rosea, and the narcosis time (time between loss and recovery of the righting reflex; the righting reflex is any one of the neuromuscular responses that restore the body to its upright position when it has been displaced) was measured by a blinded observer. It was reported that S. rosea extract potentiated the effects of pentobarbital, since the time to recovery of the righting reflex was significantly longer for treated mice than for controls. However, this finding is questionable since numerical data and a precise p-value were not reported (the p-value was given as p 4 0.05).

Antitumour activities Antitumour and antimetastatic effects have been reported for an extract of R. rosea (no further details given) following in vivo experiments. In one study, mice transplanted with Ehrlich adenocarcinoma were treated with R. rosea extract 0.5 mL/kg body weight orally daily from day 4 posttransplantation until day 13 or 15 post-transplantation when the animals were sacrificed.(22) It was reported that tumour growth was significantly inhibited in treated mice, compared with controls. However, the findings of this study are questionable since the p-value given for this finding was p = 0.05, and the number of animals involved in the experiment was not stated. A similar experiment involved rats transplanted with metastasising Pliss lymphosarcoma and treated with R. rosea extract according to the same regimen. In this study, the extent of metastasis in treated rats was reported to be 50% that in control animals (p < 0.01) and the mass of metastases was significantly less than that in control animals (mean (standard deviation): 142.5 (23.0) and

203.3 (27.0), for treated and control groups, respectively; p < 0.05).(22) However, again, the sample size for this study was not

stated.

In another in vivo study, an extract of R. rosea root was tested for its effects on the haematotoxicity of cyclophosphamide in mice transplanted with Ehrlich ascites tumour and Lewis lung

Rhodiola 503

carcinoma. After transplantation, mice were treated with cyclophosphamide (100 mg/kg body weight), R. rosea root extract (0.5 mL/kg orally on days 2–8 following transplantation), or both substances.(23) Cyclophosphamide, but not R. rosea extract, reduced the numbers of leukocytes and myelokaryocytes to 40– 50%, compared with control (p < 0.05); when the two substances were given in combination, the numbers of leukocytes and myelokaryocytes were reported to increase by 30% and 16–18%, respectively, although only the change in the former parameter was reported to be statistically significant (p < 0.05). R. rosea extract was also reported to have no effect on the colony-forming activity of myelokaryocytes, whereas cyclophosphamide inhibited the proliferation of these cells. In mice given a combination of the two substances, no inhibition of colony-forming activity was observed; this was stated to be statistically significant, compared with values for mice treated with cyclophosphamide alone, although no p-value was given.(23)

Antimutagenic activities Antimutagenic activity has been described for extracts of R. rosea. Ethanol extracts (20% and 40%) of R. rosea were reported to counteract gene mutations induced by various chemical mutagens in the Ames test (Salmonella typhimurium).(24) In another in vitro experiment, R. rosea extract (no further details given) was reported to reduce the yield of bone marrow cells with chromosome aberrations induced in vivo (mice) by cyclophosphamide. It is postulated in abstracts of the Russian and Ukrainian literature that R. rosea acts as an antimutagen by increasing the efficiency of intracellular DNA repair mechanisms.(25) Since this information is taken from abstracts, confirmation is required.

Clinical studies

Mental performance Several clinical trials, with reports published in the English scientific literature, have investigated the effects of preparations containing a dry extract of R. rosea rhizome (SHR-5; Swedish Herbal Institute) on stress-induced fatigue and on mental work capacity.

In a randomised, double-blind, placebo-controlled, parallelgroup trial, 40 healthy male Indian medical students took tablets containing R. rosea dry extract 50 mg, orally twice daily, or placebo, for 20 days during an examination period.(14) At the end of the study, statistically significant improvements in self-assessed mental fatigue, self-assessed general well-being and in one of the psychomotor tests (accuracy of movement versus speed in a maze test) were reported for the treated group, compared with the placebo group (p < 0.01, 0.05 and 0.01, respectively). Statistically non-significant differences were reported in several other tests, including another psychomotor test (tapping test) and two mental capacity tests. The findings of the study are limited since no

described in a report of the study is inadequate and, additionally, the no-treatment control group was not randomly allocated at all but simply comprised the last 20 cadets to be enrolled into the study.

Other conditions In a double-blind, placebo-controlled, crossover study designed to assess the effects of R. rosea on hypoxia and oxidative stress, 15 healthy volunteers aged 20–33 years received capsules each containing R. rosea 447 mg (no further details given), four daily for seven days, or placebo, before

undergoing hypoxic exposure (to simulate conditions at an elevation of 4600 m).(28) (The study also assessed the effects of a

supplement claimed to contain dissolved oxygen, although these results are not reported here.) Fourteen participants completed the study. There were no statistically significant differences between R. rosea and placebo recipients in any of the outcome measures, including arterial capillary blood oxygen (concentration – PcO2), blood oxyhaemoglobin saturation as assessed using a pulse oximeter on an index finger, and serum lipid peroxide and urine malondialdehyde concentrations (as markers of oxidative stress).(28) However, given the small sample size for this study, further investigation into the effects of R. rosea preparations in hypoxia is warranted.

Preliminary studies conducted in China and involving men living and working at high altitude have compared the effects of a multiherbal product containing the related species Rhodiola kirilowii (Regel) Maxim. with those of acetazolamide.(29, 30)

Side-effects, Toxicity

Clinical data

There is a lack of reliable, accessible information relating to the safety and toxicity of preparations of R. rosea. Data from clinical trials of R. rosea are extremely limited, and no postmarketing surveillance or other pharmacoepidemiological studies have been identified.

Clinical trials involving small numbers of healthy young (<35

years) volunteers who received R. rosea extract (SHR-5) 100 mg for 20 days,(14) or 170 mg for 14 days(10) (see Pharmacological

Actions, Clinical studies for further details), have reported that no adverse effects or events were observed during the studies.(10, 14) Another study in which healthy young (19–21 years) volunteers received R. rosea extract (SHR-5) 370 mg (containing 9 mg salidroside) or 555 mg (containing 13.5 mg salidroside) as a single dose also reported that no adverse effects or events were observed.(11)

Preclinical data

In vitro experiments have investigated the effects of incubation of three-day-old larvae of the freshwater snail Lymnaea stagnalis with different concentrations of an aqueous extract of R. rosea (SHR-5; containing rosavin 3.6%, salidroside 1.6% and p-tyrosol <0.1%) for 24 hours. At a concentration of R. rosea extract of

1.35 mg/mL, all larvae were killed; at 405 mg/mL, around 80% were killed.(19) With a longer period of exposure (up to four days),

R. rosea extract 81.2 mg/mL did not induce death of exposed larvae, but their development appeared to be retarded: specimens hatched later and were smaller than control specimens, yet no deformations or other abnormalities were observed. Exposure of larvae to R. rosea 40.5 mg/mL for up to four days was not associated with any slowing down of growth or development.

Abstracts of papers published in Russian or Ukrainian have described antimutagenic activity for R. rosea extracts, although confirmation of these data is required. Antimutagenic activity has

been reported for ethanol extracts (20% and 40%) of R. rosea in the Ames test (Salmonella typhimurium).(24) A reduction in the

yield of bone marrow cells with chromosome aberrations induced

in vivo (mice) by cyclophosphamide has also been described for an extract of R. rosea.(25)

Contra-indications, Warnings

None documented. In view of the lack of safety data, use of R. rosea extracts at dosages higher than those recommended (see Dosage) and/or for longer periods should be avoided.

Drug interactions No interactions have been documented for R. rosea. However, in view of the documented pharmacological effects, whether or not there is potential for clinically important interactions with other medicines with similar or opposing effects should be considered.

Pregnancy and lactation The safety of R. rosea has not been established. In view of the lack of information on the use of R. rosea during pregnancy and lactation, its use should be avoided during these periods.

References

1Yoshikawa M et al. Bioactive constituents of Chinese natural medicines. II. Rhodiolae radix. (1). Chemical structures and antiallergic activity of rhodiocyanosides A and B from the

underground part of Rhodiola quadrifida (Pall.) Fisch et Mey. (Crassulaceae). Chem Pharm Bull 1996; 44: 2086–2091.

2Tolonen A. Analysis of secondary metabolites in plant and cell culture tissue of Hypericum perforatum L. and Rhodiola rosea L. Oulu, Finland: University of Oulu, 2003; (PhD thesis). Available at http:// herkules.oulu.fi/isbn9514271610/index.html?lang=en (accessed 16 July

2004).

3Ssaratikov SA et al. [Rhodioloside, a new glycoside from Rhodiola rosea and its pharmacological properties]. Pharmazie 1968; 23: 392– 395 [German].

4Tolonen A et al. Phenylpropanoid glycosides from Rhodiola rosea. Chem Pharm Bull 2003; 51: 467–470.

5 Rohloff J. Volatiles from rhizomes of Rhodiola rosea L. Phytochemistry 2002; 59: 955–661.

6Ganzera M et al. Analysis of the marker compounds of Rhodiola rosea L. (golden root) by reversed phase high performance liquid chromatography. Chem Pharm Bull 2001; 49: 465–467.

7Nekratova NA et al. [Changes of quantitative contents of salidroside and tannins in underground organs of Rhodiola rosea L. in its natural

habitats in Altai]. Rastit Resur 1992; 28: 40–48 [Russian].

8Dubichev AG et al. [HPLC study of the composition of Rhodiola rosea rhizomes]. Khim Prir Soedin 1991; 2: 188–193 [Russian].

9Linh PT et al. Quantitiative determination of salidroside and tyrosol from the underground part of Rhodiola rosea by high performance

liquid chromatography. Arch Pharm Res 2000; 23: 349–352.

10Darbinyan V 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.

Rhodiola 505

11Shetsov VA et al. A randomized trial of two different doses of a SHR-5 Rhodiola rosea extract versus placebo and control of capacity for mental work. Phytomedicine 2003; 10: 95–105.

12Kang S, Wang J. [Comparative study of the constituents from 10 rhodiola plants]. Zhong Yao Cai 1997; 20: 616–618 [Chinese].

13Petkov VD et al. Effects of alcohol aqueous extract from Rhodiola rosea L. roots on learning and memory. Acta Physiol Pharmacol Bulg

1986; 12: 3–15.

14Spasov AA 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.

15Anon. Rhodiola rosea. Altern Med Rev 2002; 7: 421–423.

16Sokolov S et al. [Studies of neurotropic activity of new compounds isolated from Rhodiola rosea L.]. Khim Farm Zh 1985; 19: 1367–1371 [Russian].

17Provalova NV et al. Mechanisms underling the effects of adaptogens on erythropoiesis during paradoxical sleep deprivation. Bull Exp Biol Med 2002; 133: 428–432.

18Provalova NV et al. Effects of adaptogens on granulocytopoiesis during paradoxical sleep deprivation. Bull Exp Biol Med 2002; 3: 261– 264.

19Boon-Niermeijer EK et al. Phyto-adaptogens protect against environmental stress-induced death of embryos from the freshwater snail Lymnaea stagnalis. Phytomedicine 2000; 7: 389–399.

20Lazarova MB et al. Effects of meclofenoxate and extr. Rhodiolae roseae L. on electroconvulsive shock-impaired learning and memory in rats. Meth Find Exp Clin Pharmacol 1986; 8: 547–552.

21Ahumada F et al. Effect of certain adaptogenic plant extracts on druginduced narcosis in female and male mice. Phytother Res 1991; 5: 29– 31.

22Udintsev 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.

23Udintsev SN, Schakhov VP. Decrease of cyclophosphamide haematotoxicity by Rhodiola rosea root extract in mice with Ehrlich and Lewis transplantable tumours. Eur J Cancer 1991; 27: 1182.

24Duhan OM et al. [The antimutagenic activity of biomass extracts from the cultured cells of medicinal plants in the Ames test]. Tsitol Genet 1999; 33: 19–25.

25Salikhova RA et al. [Effect of Rhodiola rosea on the yield of mutation alterations and DNA repair in bone marrow cells]. Patol Fiziol Eksp Ter 1997; 4: 22–22 [Russian].

26Maimeskulova LA et al. [The participation of the mu-, deltaand

kappa-opioid receptors in the realization of the anti-arrhythmia effect of Rhodiola rosea]. Eksp Klin Farmakol 1997; 60: 38–39.

27 Lishmanov IuB et al. [Contribution of the opioid system to realization R of inotropic effects of Rhodiola rosea extracts in ischemic and

reperfusion heart damage in vitro]. Eksp Klin Farmakol 1997; 60: 34– 36.

28Wing SL et al. Lack of effect of rhodiola or oxygenated water supplementation on hypoxemia and oxidative stress. Wilderness Environ Med 2003; 14: 9–16.

29Ha Z et al. [The effect of rhodiola and acetazolamide on the sleep architecture and blood oxygen saturation in men living at high altitude]. Chin J Tuberc Respir Dis 2002; 25: 527–530 [Chinese].

30Ma Y et al. [Effect of rhodiola and acetazolamide in improving hypoxia at high altitude]. Chin Ment Health J 2001; 15: 117–118 [Chinese].