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40 | HerbalGram 56 2002 www.herbalgram.org hodiola rosea, also known as “golden root” or “roseroot” belongs to the plant family Crassulaceae.1 R. rosea grows pri- marily in dry sandy ground at high alti- tudes in the arctic areas of Europe and Asia.2 The plant reaches a height of 12 to 30 inches (70cm) and produces yel- low blossoms. It is a perennial with a thick rhizome, fragrant when cut. The Greek physician, Dioscorides, first recorded medicinal applications of rodia riza in 77 C.E. in De Materia Medica.3 Lin- naeus renamed it Rhodiola rosea referring to the rose-like attar (fragrance) of the fresh cut rootstock.4 For centuries, R. rosea has been used in the traditional medicine of Russia, Scandi- navia, and other countries. Between 1748 and 1961 various medicinal applications of R. rosea appeared in the scientific literature of Sweden, Norway, France, Germany, the Soviet Union, and Iceland.2,4-12 Since 1961, more than 180 pharmacological, phyto- chemical and clinical studies have been published. Although R. rosea has been exten- sively studied as an adaptogen with various health-promoting effects, its properties remain largely unknown in the West. In part this may be due to the fact that the bulk of research has been published in Slavic and Scandinavian languages. This review pro- by Richard P. Brown, M.D., Patricia L. Gerbarg, M.D., and Zakir Ramazanov, Ph.D., D.S. R Rhodiola rosea A Phytomedicinal Overview Top photos: ©2002 Zakir Ramazonov; Bottom photo:©2002 Patricia Gerbarg vides an introduction to some of the traditional uses of R. rosea, its phytochemistry, scientific studies exploring its diverse physiologi- cal effects, and its current and future medical applications. Rhodiola rosea in Traditional Medicine Traditional folk medicine used R. rosea to increase physical endurance, work productivity, longevity, resistance to high altitude sickness, and to treat fatigue, depression, anemia, impotence, gas- trointestinal ailments, infections, and nervous system disorders. In mountain villages of the Republic of Georgia, a bouquet of roots is still given to couples prior to marriage to enhance fertility and assure the birth of healthy children.2 In Middle Asia, R. rosea tea was the most effective treatment for cold and flu during severe Asian winters. Mongolian doctors prescribed it for tuberculosis and cancer.13 For centuries, only family members knew where to harvest the wild “golden roots” and the methods of extraction.2 Siberians secretly transported the herb down ancient trails to the Caucasian Mountains where it was traded for Georgian wines, fruits, garlic, and honey. Chinese emperors sent expeditions to Siberia to bring back the “golden root” for medicinal preparations. Linnaeus wrote of R. rosea as an astringent and for the treatment of hernia, leucorrhoea (vaginal discharge), hysteria, and headache.4,7 In 1755 R. rosea was included in the first Swedish Pharmacopoeia. Vikings used the herb to enhance their phys- ical strength and endurance.14 German researchers described the benefits of R. rosea for pain, headache, scurvy, hemor- rhoids, as a stimulant, and as an anti-inflammatory.15,16 In 1961, G.V. Krylov, a Russian botanist and taxonomist in the Department of Botany at the Novosibirsk Branch of the Russ- ian Academy of Sciences, led an expedition to the cedar taiga in the Altai Mountains of southern Siberia where he located and identified the “golden root” as Rhodiola rosea.17 Extracts of the R. rosea root were found to contain powerful adaptogens. Research revealed that it protected animals and humans from mental and physical stress, toxins, and cold.2,17 The quest for new medicines to treat diseases such as cancer and radiation sickness, and to enhance physical and mental performance, led to the dis- covery of a group of phenylpropanoids that are specific to R. rosea. (See Phytochemistry section below.) Geographical Distribution and Taxonomy of Rhodiola rosea While Rhodiola as a genus may have originated in the moun- tainous regions of Southwest China and the Himalayas,18 botanists have established that various species of the genus Rhodiola natural- ly display a circumpolar distribution in mountainous regions in the higher latitudes and eleva- tions of the Northern Hemisphere. In Central and Northern Asia, the genus is distributed from the Altai Moun- tains across Mongolia into many parts of Siberia.19 According to Hegi, its distribution in Europe extends from Iceland and the British Isles across Scandinavia as far south as the Pyrenees, the Alps, the Carpathian Mountains and other mountainous Balkan regions. Several varieties of Rhodiola species have also been identi- fied across Alaska, Canada, and the northern mountains of the continental United States.20 In fact, the world database of botani- cal literature shows many citations identifying a broad range of species of the genus Rhodiola, in some cases including R. rosea, in many diverse locations in northern latitudes (see Table 1). The current taxonomical status of the genus Rhodiola has become quite complex. Before World War II, some taxono- mists separated different species of Rhodiola into an independent genus, belonging to the sub- family Sedoidae.20 Then Rhodiola was reclassified as a sub- genus of the larger genus Sedum, which contained about 10 species. In 1963 Hegi identified more than 50 species of Rhodiola and re-established them as a separate genus.20 Due to their morphological similarities, they form a distinct Rhodiola group.21 There are still differing opinions among specialists about which new species should or should not be included in the genus Rhodiola. The rationale and defining criteria for the boundaries of the genus remain somewhat controversial. This is not, in itself, necessarily counterproductive, since the acquisition of botanical knowledge inevitably stimulates new understanding and insight, creat- ing the need for revised systems of classification. In the case of R. rosea, however, this taxonomic ambiguity may have unexpected and potentially negative consequences. Popularizing a phytomedicinal plant like R. rosea can create confusion when the public is offered a variety of “Rhodiola” products using the general plant family name instead of the full botanical name of the particular species. For example, products called “Rhodiola spp., Tibetan Rhodiola or Indian Rhodiola” may incorrectly imply equivalence with R. rosea extract. Because of significant species-dependent variation in phytochemistry and pharmacology, the use of “Rhodiola” as a general term is inaccurate and misleading. The correct identification of all Rhodiola species according to precise and generally accepted botani- cal, phytochemical, and genetic taxonomic criteria is not merely an abstract intellectual exercise. It is critical for both scientific and phytopharmacological accuracy, as well as for product labeling for the public. Consumers may need pro- fessional guidance to avoid purchasing ineffective brands, partic- ularly those that do not provide full information, including the complete botanical name of the plant species. Companies may change their suppliers over time. Therefore, consumers should periodically check independent sources of product evaluation, as well as requesting information about quality control and content from manufacturers. The pharmacological and medicinal properties www.herbalgram.org 2002 HerbalGram 56 | 41 Rhodiola rosea A Phytomedicinal Overview Rhodiola rosea Baxter, William. British phaenogamous botany. Oxford, published by the author, sold by J. H. Parker [etc.], 1834-1843, vol. 5, plate 391. Coutesy of The Hunt Institute for Botanical Documentation. of Rhodiola are species- dependent phenome- na.22 Of all the Rhodiola species, R. rosea has been the predominant subject of phytochemical, animal, and human studies.2,18,23,24 Table 2 compares the research record of R. rosea with all other species of the genus Rhodiola. Approximately 51 percent of all animal studies and 94 percent of all human studies conduct- ed on plants in the genus Rhodiola are on the species R. rosea. Only R. rosea has passed extensive toxicological studies and has been cer- tified safe for both animals and humans.25 Phytochemistry of Rhodiola rosea The investigation of the phytochemistry of R. rosea root has revealed the presence of six distinct groups of chemical com- pounds: • Phenylpropanoids: rosavin, rosin, rosarin (specific to R. rosea); • Phenylethanol derivatives: salidroside (rhodioloside), tyrosol; • Flavanoids: rodiolin, rodionin, rodiosin, acetylrodalgin, tricin; • Monoterpernes: rosiridol, rosaridin; • Triterpenes: daucosterol, beta-sitosterol; • Phenolic acids: chlorogenic and hydroxycinnamic, gallic acids. The standardization of R. rosea root extracts has gone through two distinct phases. Initially, in the 1970s, the compound respon- sible for its unique pharmacological properties was believed to be salidroside (rhodioloside).2,23,24,26,27 Therefore, the first generation of R. rosea tincture/extracts approved by the Russian Pharmacopoeia Committee was standardized to a minimum of 0.8 percent salidro- side content.25 In late 1980s, demand for R. rosea-based phytomedicines dra- matically increased. The wild-crafted raw material was over-har- vested, resulting in a steady decline in the quality and effectiveness of “Rhodiola” preparations. Scientific investigation revealed that other species of genus Rhodiola (which also contained salidroside) were being substituted for R. rosea. While some of these mixed batches were highly variable in quality, others had no pharmaco- logical effect. Logically, the suspicion arose that the salidroside standard was inadequate. Based on comparative analysis, the obvi- ous hypothesis was that the original high potency product con- tained other active compounds specific to R. rosea that had not yet been identified. Specific compounds set Rhodiola rosea apart from other Rhodiola species After more than a decade of research, Kurkin and colleagues pre- sented evidence in 1986 that the chemical composition of R. rosea root is, in fact, different from the other species of genus Rhodiola.23 Using newly developed methods of analysis, Dubichev and col- leagues demonstrated that R. rosea root contains three cinnamyl alcohol-vicianosides — rosavin, rosin and rosarin — that are spe- cific to this species.28,29 The term rosavins can be used to include rosavin, rosin, and rosarin (see chemical figures). It became evident that salidroside is present in all chemically analyzed plants in the genus Rhodiola, and in a wide variety of species outside the genus.2,25-34 The term salidroside is derived from Salix, the genus name for the willows. Salidroside was first isolated in 1926 from Salix triandra L. (Salicaceae).33 Since then it has been detected in Vaccinium vitis-idaea L. (Ericaceae) and in Rhododen- dron35,36 (plants not belonging to the genus Rhodiola) in concentra- tions that can be higher than levels found in Rhodiola species, including R. rosea. Therefore, salidroside alone is not a useful marker compound for differentiating true R. rosea from other Rho- diola species; nor should it be used as the only marker compound for the standardization of R. rosea root extracts. According to the revised 1989 Soviet Pharmacopeia,37 the extracts of R. rosea — primarily in the form of water/alcohol tinc- tures or dried root extract — are now standardized for both rosavins and salidroside. Although rosavins are now the accepted marker for genetically pure R. rosea (and its extracts), they are not necessarily the only pharmacologically active ingredients responsi- ble for the efficacy observed in clinical studies. In fact, precise identification of the compounds responsible for the numerous health benefits of R. rosea remains to be confirmed. R. rosea extracts used in most human clinical studies were stan- dardized to minimum 3 percent rosavins and 0.8–1 percent salidroside because the naturally occurring ratio of these com- pounds in R. rosea root is approximately 3:1. 42 | HerbalGram 56 2002 www.herbalgram.org Rhodiola rosea A Phytomedicinal Overview Table 1. Distribution of plants in the genus Rhodiola Asia: China (Gansu, Hebei, Jilin, Shanxi, Sichuan, Xinjiang); Kaza- khstan and Uzbekistan; Mongolia; Russian Federation (Altai, Eastern Siberia, Kamchatka, Khabarovsk, Magadan) Europe: Austria; Bulgaria; Czechoslovakia; Finland; France; Green- land; Iceland; Ireland; Italy; Norway; Poland; Romania; Russian Feder- ation (European part); Spain; Sweden; United Kingdom; Yugoslavia North America: Canada (British Columbia, Northwest Territory, Yukon Territory); United States (Alaska, California, Colorado, Idaho, Minnesota, Montana, Nevada, New Mexico, New York, Oregon, Ten- nessee, Utah, Virginia, Washington, Wyoming) Table 2. Comparison of human and animal studies of plants in the genus Rhodiola * Species name Animal Studies Human Studies R. rosea 32 17 R. alterna 0 0 R. brevipetiolata 0 0 R. coccinea 1 0 R. crenulata 4 1 R. ellipticum 0 0 R. fastigita 2 0 R. gelida 0 0 R. henryi 0 0 R. heterodonta 1 0 R. kirilowii 6 0 R. pinnatifida 1 0 R. quadrifidia 1 0 R. sachalinensis 6 0 R. sacra 5 0 R. wolongensis 1 0 R. yunnanensis 0 0 *NOTE: Numbers in this Table indicate the number of animal and human studies on each plant species of the genus Rhodiola, according to a Copernic on-line database search, 2001. This article reviews many additional studies not listed in online databases. Rhodiola rosea in Modern Medicine Since 1969, R. rosea has been included in official Russian medi- cine. The Pharmacological and Pharmacopoeia Committee of the Soviet Ministry of Health recommended medicinal use and indus- trial production of liquid R. rosea extract. In 1975, the Soviet Min- istry of Health approved and registered preparation No. 75/933/14 as a medicine and tonic, allowing large-scale production under the name Rhodiola Extract Liquid, an alcohol-based extract (40 per- cent ethyl alcohol). Medical and pharmacological texts describe its use as a stimulant for asthenia (fatigue), for somatic and infectious illnesses, in psychiatric and neurological conditions, and in healthy individuals to relieve fatigue and to increase attention span, mem- ory, and work productivity. The common dose is 5–10 drops 2–3 times a day, 15–30 minutes before eating for a period of 10–20 days. In psychiatric disorders with fatigue, a starting dose of 10 drops 2–3 times a day is gradually increased up to 30–40 drops for 1–2 months. In Sweden R. rosea was recognized as an Herbal Medicinal Prod- uct in 1985 and has been described as an antifatigue agent in the Textbook of Phytomedicine for Pharmacists.9 In the textbook of phar- macology for dispenser training in Sweden, R. rosea is mentioned as a plant with a stimulant action. Also the Pharmaceutical Book (Läkemedelsboken 97/98) mentions R. rosea as one of the most commonly used psychostimulants in the group of officially regis- tered herbal medicinal products.11 In Denmark, R. rosea is regis- tered as a medical product in the category of botanical drugs. Reg- istered preparations are extensively used in Sweden and other Scan- dinavian countries to increase mental work capacity during stress, as a psychostimulant, and as a general strengthener. Pharmacological and Clinical Studies The traditional use of R. rosea as a tonic in Siberian and Russian medicine stimulated extensive research leading to identification of R. rosea as an adaptogen, a substance that nonspecifically increas- es the resistance of an organism and does not disturb normal bio- logical parameters. Studies in cell cultures, animals, and humans have revealed antifatigue, anti-stress, antihypoxic (protection against damaging effects of oxygen deprivation), anticancer, antioxidant, immune enhancing and sexual stimulating effects.2,18,24,38-40 Since the Russian and Bulgarian literature is so extensive, this discussion will highlight seminal studies and major reviews. The authors were fortunate to gain access to original reviews, articles, and doctoral theses. This overview relies heavily on monographs and peer-reviewed publications. The research data contained in these documents is helpful in understanding recent human studies in normal and pathological conditions. Effects upon the Central Nervous System The systematic study of pharmacological effects of R. rosea, begun in 1965, found that small and medium doses had a simu- lating effect, such as lengthening the time mice swim and remain on vertical perches to the limit of their abilities. In contrast, larger doses were found to have more sedative effects. Small doses increased the bioelectrical activity of the brain, presumably by direct effects on the brainstem ascending and descending reticular formation.23-26,38,39,41 Further studies showed that medium range doses, unlike tranquilizers, enhanced the development of condi- tioned avoidance reflexes in rats and facilitated learning based on emotionally positive reinforcement.18,42-46 Overall, in small and medium doses, R. rosea stimulated nor- epinephrine (NE), dopamine (DA), serotonin (5-HT), and nicotinic cholin- ergic effects in the central nervous sys- tem (CNS). It also enhanced the effects of these neurotransmitters on the brain by increasing the permeability of the blood brain barrier to precursors of DA and 5-HT.2,23,42,46-48,49 In comparing studies of R. rosea, Asian ginseng (Panax ginseng C.A. Mey., Arali- aceae), meclofenoxate (centrophenox- ine), piracetam, citicholine, and other nootropics (substances that enhance cog- nition, protect the brain, and have low toxicity and few side effects), Petkov and colleagues noted that all of these agents enhance learning and memory in animal models and increase 5-HT levels in the frontal cerebral cortex.46-50 Diagram 1 illustrates the possible effects of R. rosea on neurotransmitters in multiple neu- ronal pathways.51 Starting in the brain stem, R. rosea promotes release of NE, 5- HT, and DA in ascending pathways that activate the cerebral cortex and the lim- bic system.2,49,50 Consequently, the cogni- tive (thinking, analyzing, evaluating, cal- culating, and planning) functions of the www.herbalgram.org 2002 HerbalGram 56 | 43 Rhodiola rosea A Phytomedicinal Overview cerebral cortex and the attention, memory, and learning functions of the prefrontal and frontal cortex are enhanced. Other neuronal systems also contribute to the many aspects of memory: encoding, sorting, storage, and retrieval. For example, the cholinergic system uses the neurotransmitter acetylcholine (Ach) and contributes to memory function via path- ways ascending from the memory storage systems of the limbic sys- tem to various areas of the cerebral cortex (memory retrieval). Agents that block Ach suppress the activity of these ascending pathways and interfere with memory. R. rosea reverses this block- ade.49,50 The deterioration of these systems with age results in age- associated memory loss.52 R. rosea may prevent or ameliorate some age related dysfunction in these neuronal systems. As an antioxidant,53-55 R. rosea may help protect the nervous sys- tem from oxidative damage by free radicals. Stress interferes with memory functions and, over time, causes deterioration in memory systems. In addition to enhancing cognitive functions, learning, and memory by stimulating NE, DA, 5-HT, and Ach neuronal systems, R. rosea may exert positive effects on memory and cogni- tion by improving resistance to physical and emotional stress. Thus, the dual action of cognitive stimulation and emotional calming creates benefits for both immediate cognitive and memo- ry performance and for the long-term preservation of brain func- tions. The psychostimulant effects of R. rosea were studied in 53 healthy subjects and 412 patients wit