Rhodiola
rosea L. Crassulaceae has been used for centuries in folk medicines of
Between
1749 and 1961 medicinal applications of Rhodiola rosea appeared in the
scientific literature of
This review
provides an introduction to some of the traditional uses of Rhodiola rosea, its biochemistry, and the scientific studies exploring its diverse
physiological effects. It includes material based on the personal experiences
of Dr. Ramazanov who was commissioned to develop a hydroponic system for
growing Rhodiola rosea for the East European Agricultural Program.
Dr. Ramazanov grew up in the Russian Province of Georgia where Rhodiola rosea, Rhododendron caucasicum and Caucasian blueberry (Vaccinium arctostaphylos) are believed to contribute to the renowned
longevity of those Georgians who live at the highest altitudes. The discussion
of Rhodiola rosea in modern medical practice draws upon the
scientific literature and the practical clinical experiences of Dr. Brown and
Dr. Gerbarg.
In
In 1961, Krylov led an expedition to
the cedar taiga in the
Taxonomy
and Standardization of Rhodiola rosea Extract
Komorov described 20 species of the
Rhodiola genus 8. Numerous Rhodiola species have been reported to contain
antioxidant compounds of medicinal interest including Rhodiola rosea, R. sacchalinensis, R.
kirilowii, R. coccinea, R. sacra,
and others. Their pharmacological properties are species dependent. Rhodiola rosea is by far the most extensively researched in biochemical, animal, and
human studies 9, 10. Investigations of the phytochemicals in
Rhodiola rhizomes reveal the presence of organic acids, polyphenols and
phenylpropanoids. The most crucial active constituents specific to Rhodiola rosea include rosavin, rosin, rosarin (see figures 1-3), and related
cinnamyl alcohol glycosides. Compounds with less powerful adaptogenic properties
include tyrosol and salidroside (see figures 4-5). However, numerous other
phyto-active components remain to be more fully researched: rhodiolin,
kaempherol, tricin-5 and -7-ortho-glycosides, caffeic acid, gallic acid, and
beta-sistosterol. The phytochemistry of the leaves and stems has not been the
subject of as much research. These aerial parts have a high content of
salidroside, hydroxycinnamic acid 11, and caffeic acid. The most important
adaptogenic compounds are not found in significant amounts in the leaves and
stems or in plant tissue culture.
Standardization of Rhodiola
rosea extract has undergone
considerable evolution. In the 1970s it was thought that the medicinal
properties were derived from salidroside and tyrosol 12. The Russian Pharmacopoeia Committee originally
standardized Rhodiola rosea to a minimum 0.8% salidroside. However, by
the late 1980s the growing demand for Rhodiola rosea root
exceeded the supply of wild crafted material, leading to a decline in quality
and effectiveness. Investigation showed that the raw material was being diluted
with other Rhodiola species that also contained salidroside. Further research
using high pressure liquid chromatography (HLPC) showed that the cinnamyl
alcohol beta-vicianides, particularly rosavin, rosin, and rosarin were specific
to Rhodiola rosea, i.e. not found in other Rhodiola species
or other salidroside containing plants 9, 13, 14. The whole Rhodiola rosea extract
possessed superior physiological activity compared with individual components.
The Russian Pharmacopoeia 15 adopted a new standard for Rhodiola rosea using rosavin, rosin, rosarin and salidrosides as markers 9, 16.
R.
rosea extracts used in the
clinical studies in this review were standardized to 1% salidroside and 3%
rosavin. It is important to note that the naturally occurring ratio of
salidroside to rosavin is approximately 1:3. A natural balance of
phytochemicals can be achieved by growing plants under controlled conditions
free of pesticides and herbicides. However, the correct balance in
phyto-medicinal extracts is not sufficient to guarantee pharmacological effect.
The presence of maltodexrine or other large polymeric molecules (used by some
manufacturers as spray drying agents or carriers) dramatically reduces the
bioavailability of phyto-active constituents. Therefore, the best
pharmacological effect requires standardized R. rosea extract free of
maltodexrine and other carriers.
Introduction of Rhodiola rosea into the
The traditional use of Rhodiola rosea as a tonic in Siberian and Russian medicine stimulated extensive research leading to its identification as an adaptogen, a substance which nonspecifically increases the resistance of an organism and does not disturb normal biological parameters. Studies in cell cultures, animals, and humans have revealed antihypoxic, antifatigue, antiradiation, anticancer, immune enhancing and sexual stimulating effects. 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 PhD theses. This summary relies heavily on monographs by Kurkin and Zapesochnaya 1986; Saratikov and Krasnov 1987; and Saratikov and Marina 1987. The research data contained in these documents is helpful in understanding recent human studies in normal and pathological conditions.
Central Nervous System Effects
The systematic study of pharmacological effects of Rhodiola rosea begun in 1965 found that small and medium doses had a simulating effect such as lengthening the time mice swim and remain on vertical perches to the limit of their abilities. On the other hand larger doses were found to have more sedative effects. Small doses increased the bioelectrical activity of the brain, presumably by a direct effect on the brainstem reticular formation, both ascending and descending. In contrast, large doses led to suppression of bioelectrical activity. Further studies showed that medium range doses, unlike tranquilizers, enhanced the development of conditioned avoidance reflexes in rats and facilitating learning based on emotionally positive reinforcement. Overall, in small and medium doses, Rhodiola rosea stimulated norepinephrine (NE), dopamine (DA), serotonin (5-HT), and nicotinic cholinergic effects in the central nervous system (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.
In comparing studies of Rhodiola
rosea, Panax ginseng,
meclofenoxate, piracetam, citicholine, and other nootropics (agents that
enhance cognition, 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 serotonin levels in the frontal
cerebral cortex 17. Rhodiola
rosea activates multiple neuronal
pathways by increasing NE and DA in the hypothalamus and increasing NE, DA and
5-HT in the brainstem reticular formation and cerebral hemispheres. These
neuronal systems deteriorate with age. Rhodiola activation may exert a
neuroprotective effect. Cholinergic blocking agents are known to suppress the
activity of the ascending pathways of the posterior hypothalamus and the limbic
system where memories are processed. Rhodiola
rosea reverses this blockade. As a
nicotinic cholinergic stimulator, Rhodiola
rosea probably protects the brain
memory systems.
The complex effects of Rhodiola rosea on the brain can be summarized as both cognitively stimulating and emotionally calming. This may account for its abilities to enhance learning, memory, and resistance to emotional stresses. By increasing DA, it can reverse the Parkinsonian side effects of dopamine antagonists, and by increasing 5-HT, NE and DA, it can augment the action of antidepressants.
The psychostimulant effects of Rhodiola were studied in apparently
healthy individuals who had a tendency to asthenia in the course of intense
intellectual work 18. Symptoms of asthenia (decline in work
capacity, trouble falling asleep, poor appetite, irritability, and headaches)
responded favorably to Rhodiola. It is difficult to say how many of the
asthenics in Russian clinical studies of inpatients and outpatients would meet
current DSM (Diagnostic and Statistical Manual) criteria for major depression.
The asthenic states included both psychiatric and physical causes (for example
following influenza or other physical illness). In one study of 128 patients
aged 17 to 55 Rhodiola rosea alleviated fatigue, irritability,
distractibility, headache, weakness and other vegetative symptoms in 2/3 cases.
Improvement was confirmed by psychological testing and work productivity.
In another study 27 healthy students, physicians, and scientists aged
19 to 46 were given Rhodiola 150 mg once or twice a day for 3 weeks before
anticipated intense intellectual work, such as final exams. Rhodiola improved
the amount and quality of work. A series of studies using a proofreading test
showed that a one time dose of Rhodiola
rosea did not significantly
increase the number of symbols corrected, but very significantly decreased the
percent of errors made, particularly over an 8 hour period 19, 20. Rhodiola increased intellectual capacity
to a greater degree than Siberian Ginseng, particularly by improving perception
and processing of information 2, 21. The decrease in physical and mental
performance on prolonged night call is well known to physicians. In a
double-blind placebo-controlled crossover study low dose Rhodiola rosea was given to physicians on night call. A significant improvement in
cognition was noted during the first 2-week period. However, at 6 weeks the
effect appeared to be lost. It is difficult to interpret this study due to the
low dose used and the crossover design 2.
Spasov and colleagues gave 100 mg/day of standardized extract of Rhodiola rosea for 20 days to Indian medical students studying in Russia during their
final exam period. They found significant improvements in general well being,
physical fitness, mental fatigue, and coordination, but not in some aspects of
cognitive functioning compared to placebo. Despite the low dosage, the
investigators noted improvement in exam grades in the group on Rhodiola
compared to placebo 22. Positive results found in the studies of
proofreading tests noted above were based on 300 mg/day or more. In medical treatments
the usual doses are 200 to 600 mg/day. Rhodiola rosea extracts
given to foreign students during study at a Russian high school resulted in an
increase in physical work capacity, coordination, sensitivity, and general well
being along with a decrease in psychic fatigue and situational anxiety 23. In studies related to the Russian space
program an herbal adaptogen preparation with Rhodiola rosea as its
primary component was given to subjects during 24-hour periods of extremely
difficult and tedious mental work. Compared to placebo, the herbal adaptogen
improved wakefulness, attention, memory, energy levels, abstract thinking and
reaction time, while it decreased the number of errors, and reduced eye
irritation 4.
Rhodiola
rosea was beneficial in post
traumatic and vascular lesions of the brain. It was especially effective in
combination with piracetam for patients with marked cognitive dysfunction.
However, it did not reduce manic symptoms and could worsen paranoid states. In
one study of more clearly depressed patients Rhodiola in combination with
tricyclic antidepressants (TCAs) produced significant improvement in the
majority of cases and decreased side effects of the TCAs. Ultimately, some
patients were able to respond to Rhodiola alone 24. It was also used to correct the
Parkinsonian side effects caused by antipsychotics used to treat schizophrenia
in patients whose anticholinergic medications had failed to relieve
extrapyramidal symptoms 18.
Rhodiola may affect emotional tone
by changing monoamine levels in the amygdala, hippocampus, hypothalamus, and
midbrain. The stimulation of nicotinic cholinergic activity with concurrent
blocking of muscarinic cholinergic activity may also contribute to these
effects. Alterations in monoamine levels underlie this complex spectrum of
psychotropic activity: stimulating, tranquilizing, antidepressant, and
anti-stress. The authors have found
that Rhodiola rosea can help patients with neurasthenia or
depressive syndromes as the following cases indicate. All patients were treated
with Rosavin 100 mg capsules from Ameriden, P.O. Box 1870, Fallbrook, CA 92088.
Ms W., a 45-year old writer never quite finished her PhD thesis. A block prevented her from completing any manuscripts for publication. Seven years of psychotherapy did not alleviate the problem. After drifting for years and being terrified of taking any more prescription antidepressants, she tried Rhodiola rosea 100 mg twice a day. Although she had not considered herself to be depressed (nor would she meet criteria for dysthymic disorder), within 6 weeks, she experienced a new sense of enthusiasm and increased productivity. She became able to complete writing projects and to feel happy with herself for the first time in her life. She has been well for over two years on Rhodiola rosea. However, feeling recovered and happily married, she decided on her own to stop the Rhodiola and gradually relapsed over 6 months. Upon resuming the Rhodiola, she again improved with full recovery.
Ms. P., a 50-year old computer analyst complained of constant fatigue, dragging herself out of bed every morning, and dreading encounters at work. Because she was highly sensitive to side effects of any psychotropic medication, she began with one pinch of Rhodiola rosea in her morning tea (equivalent to 50 mg). Within a few days her fatigue was gone. She had the energy and confidence to deal more effectively with the inevitable conflicts at work.
Mr. M, a 53-year old psychologist suffering most of his life from major depression, had only partially responded to antidepressant medications and had complained of numerous side effects. He responded to a combination of phototherapy and Rhodiola rosea extract 100 mg twice a day. As his depression lifted, he recovered his energy, motivation, interest in his family, and ability to concentrate at work. He remained well without antidepressant medications. To his wifes delight, coincidentally, his libido returned after 10 years of disinterest.
Ms. B, a 45-year old mental health professional had refractory depression and fibromyalgia for 5 years that were completely unresponsive to multiple trials of psychotropic medication. She had a partial response to sertraline, but this was not adequate for her to do more than carry out her daily job. The addition of Rhodiola rosea 600 mg/day enabled her to return to normal enjoyment and full productivity in life. It took about 2 months to see these effects. After 6 months, the patient began to doubt that she needed the Rhodiola and discontinued it on her own, only to relapse over the next 3 weeks. Upon reinstitution of the Rhodiola she returned to full remission and remains well 2 years later on sertraline and Rhodiola rosea.
Overall, Rhodiola rosea has very few side effects. Most people find that it improves their mood, energy level, and mental clarity. Some individuals, particularly those who tend to be anxious, may feel overly activated, jittery, or agitated. If this occurs, then a smaller dose with very gradual increases may be needed. Rhodiola should be taken early in the day because it can interfere with sleep or cause intense dreaming during the first few weeks. People with bipolar disorder may become manic when given the extract. Rhodiola does not appear to interact with other medications, though it may have additive effects with other stimulants. Rhodiola is best absorbed when taken on an empty stomach 30 minutes before breakfast and lunch. Consumers may need professional guidance to avoid purchasing inferior brands.
A number of large studies showed that Rhodiola increased physical work capacity and dramatically shortened the recovery time between bouts of high intensity exercise. These studies included normal individuals exposed to maximal work on a bicycle ergometer and Olympic level cross country skiers and biathletes. Rhodiola was compared to Siberian ginseng and piridrol (a stimulating psychotropic similar to methylphenidate). Rhodiola rosea improved recovery time, strength, endurance, cardiovascular measures and coordination 25. Animal studies suggest mechanisms that may be involved in these effects. Rhodiola increased ATP and creatine phosphate in the muscle and brain mitochondria in mice made to swim to the limit 26. It may also enhance the ammonia cycle and energy metabolism of the cell by increasing ATP, RNA, protein synthesis, glutamine and glutamic acid 27. In animal studies Rhodiola rosea increased metabolism of fats twice as much as Siberian ginseng 28 and improved energy metabolism in the brain during intensive muscular workloads 29.
In their classic paper Breckhman and Dardymov described a number of plants that increase nonspecific resistance in animal models 30. They used 3 major criteria to define an adaptogen:
1. It would increase resistance against multiple stressors including biological, chemical, or physical insults
2. It would normalize physiology: if a body parameter was high the adaptogen would bring it down toward normal; if a parameter was low, the adaptogen would bring it up toward normal.
3. It would not perturb normal body functions more than necessary to improve resistance.
A recent study showed that Rhodiola and another plant adaptogen protected fresh water snails from a variety of environmental stressors 31. The mechanisms of this nonspecific resistance are not entirely clear. They probably involve improvements in cellular energy metabolism. In higher animals and humans, nonspecific resistance is also enhanced by improvements in the neurological mechanisms of dealing with stress (catecholamines and serotonin) and changes in the endorphin system. A body of Russian research had shown that serotonin systems are crucial for the anti-stress effect. The swimming test, originally used to measure nonspecific resistance to stress, subsequently became a screening test for antidepressant agents by pharmaceutical companies in the West. The serotonin system is necessary for the stress response reaction, adaptation to new environmental conditions, and tolerance of hypoxia. Numerous stressors decrease serotonin in the hypothalamus. The ability of Rhodiola rosea to increase the nonspecific resistance of animals is probably related to its capacity to increase serotonin in the hypothalamus and midbrain. Additional research showed that an intact hypothalamic pituitary adrenal axis and participation of the gonads and thymus were necessary for this anti-stress effect. Furthermore, Rhodiola reduces the activation of several components of the stress response system. For example, it modestly increased serum beta-endorphin which protected rats against subsequent stress induced excess endorphin elevation (Lishmanov et al 1987). In addition, Rhodiola moderates the release of opioid peptides that occurs as part of the pituitary adrenal axis response to stress. This reduced release protects against sudden excess opioid and catecholamine (NE and DA) levels (that interfere with normal brain functions and can lead to heart damage) while allowing a more moderate release that increases stress tolerance without damaging the central nervous system or the cardiovascular system. Rhodiola rosea extracts also protect the brain and heart by reducing the secretion of corticotrophin releasing factor (CRF) under stress (Ramazanov et al, personal communication December 2001).
Neuroendocrine animal studies showed that Rhodiola rosea, like other adaptogens, enhanced thyroid function without causing hyperthyroidism. The thymus gland functioned better and was protected from the involution that occurs with aging. The adrenal glands functioned with better reserve and without the kind of hypertrophy caused by other psychostimulants. Egg maturation was enhanced in rats and an anabolic effect in males was observed in a number of species. These pre-clinical investigations led to studies of Rhodiola rosea for the treatment of women suffering from amenorrhea (loss of menstrual cycles). Out of 40 women with amenorrhea Rhodiola rosea restored normal menses to 25 women, 11 of whom became pregnant 32. One of the authors (Dr. Brown) has treated several women in his practice who had failed to conceive with standard fertility drugs and who become pregnant within several months of beginning Rhodiola rosea extract. Using the in vitro estrogen receptor competition assay, Dr. Patricia Eagon recently found that Rhodiola extract showed strong estrogen binding properties which require further characterization (personal communication, Dr. PK Eagon, December 2001). In another study, 26 out of 35 men with erectile dysfunction and premature ejaculation responded to Rhodiola rosea with concomitant normalization of prostatic fluid and an increase in 17-ketosteroids in urine. These preliminary observations warrant controlled follow up clinical trials 33.
Another traditional use of Rhodiola in Siberia and China is to protect against high altitude pulmonary edema or high altitude mountain sickness. Rhodiola kirilowii protected villagers from high altitude sickness when they moved from 2500 to 4475 meters 34. A proanthocyanodin (very similar to a phenylpropanoid found in Rhodiola rosea) had a pronounced antihypoxic effect in different models of hypoxia 25, 35. This may in part be due to the induction of nitric oxide synthase 36 and is similar to ginkgo (also used to prevent high altitude sickness). Rhodiolas beneficial effects on the heart may also contribute to protection at high altitudes. Cardioprotective effects include: prevention of stress induced cardiac damage (assessed by Technetium accumulation) 37; reduction of myocardial catecholamines and cyclic adenosine monophosphate (cAMP) levels; and reduced adrenal catecholamine release 38. Furthermore, activation of mu opiate receptors in heart muscle prevented reperfusion arrhythmias in animal hearts. This effect could be blocked by naloxone injection 39.
Swedish and Russian studies randomized subjects to Rhodiola or placebo for 6 weeks. Completely sedentary subjects given Rhodiola were able to perform in the lower level of trained athletes without any exercise training. Their heart variability and inotropic functions improved. Both the sympathetic and parasympathetic input to the heart were enhanced such that the heart showed increased reserves under stress of greater intensity 4.
Studies of numerous Rhodiola species show strong antioxidant effects. Rhodiola sacra extract contained the most powerful antioxidant activity of 70 herbal medicines from the orient, with a particularly strong capacity to neutralize superoxide and hydroxide free radicals 40. Several studies found extremely high antioxidant activity in Rhodiola rosea extract 40, 41. By preventing lipid peroxidation, Rhodiola rosea protected the mucosa of rat small intestines subjected to acute x-ray irradiation 42.
An extensive literature documents studies on Rhodiolas abilities to prevent mutations in bacteria and bone marrow cells and to enhance cancer survival in animals and humans 43-46, 46. Rhodiola seems to decrease toxicity from cyclophosphamide, rubomycin, and adriamycin (agents used to fight cancers) as well as to enhance their anticarcinogenic effects 47, 48.
Rhodiola rosea and Aging
Repeated activation of the stress response system, deficits in cellular energy, and oxidative free radical damage are likely to be major factors in the premature aging of humans. Rhodiola rosea improves cellular (particularly mitochondria) energy metabolism, protects catecholamine, serotonin, cholinergic, and possibly opioid systems of the brain from stress, and exhibits antioxidant and stress resistance properties. It would require a 20-year placebo controlled study to prove unequivocally that Rhodiola rosea increases longevity, and such a study is unlikely to be funded. Nevertheless, it is intriguing that Rhodiola is taken regularly by the most long-lived people in the world who live in high mountainous regions of the Republic of Georgia 49-51.
Scientific research is needed to establish the preventive and curative
benefits of Rhodiola rosea.
Controlled studies are warranted to explore its use in antidepressant
augmentation, attention deficit disorder (in combination with ginkgo and
ginseng), traumatic brain injury (TBI) and Parkinsons disease, protection
against arrhythmias, sports performance, prevention of high altitude mountain
sickness, military aviation and space medicine (enhancing physical and mental
performance while reducing stress reactions), endocrine disorders (fertility,
premenstrual disorder, menopause, and sexual dysfunction), and disorders of the
stress response system (fibromyalgia, chronic fatigue syndrome, and post
traumatic stress disorder), and enhancement of chemotherapy/radiation with
amelioration of toxicity.
In the course of evolution, Rhodiola has adapted to the harsh conditions of high altitude (extreme cold, low oxygen, little rainfall, and intense irradiation from the sun) by producing a group of powerful compounds that have diverse beneficial effects in animals and humans. One is struck by the versatility of Rhodiola rosea from its description in Greek medicine 2000 years ago to its use in 20th century cosmonauts. It is time for Western medicine to seriously study this unique adaptogen.
Richard P. Brown, MD is Associate
Clinical Professor of Psychiatry at Columbia University College of Physicians
and Surgeons in New York City. He
received his M.D. in 1977 from Columbia University College of Physicians and
Surgeons in New York. Dr. Brown completed his Residency in Psychiatry and a
Fellowship in Psychobiology and Psychopharmacology at New York Hospital. Dr.
Brown is the recipient of numerous awards, including a Mead-Johnson
Neuropsychopharmacology Travel Fellowship, a Mallinckrodt Scholar award, and a
Fellowship in Neurosciences and
Brain Imaging from the Dana Foundation.
He has had a longstanding interest in herbal and complementary medicine,
especially as relevant to psychiatry. In 2000, he coauthored the book, Stop
Depression Now, which presents a holistic approach to the treatment of
depression, including SAM-e. Since 1999, Dr. Brown has taught a full day course
on Herbs and Nutrients in Psychiatry at the annual meetings of the American
Psychiatric Association.
Patricia L.
Gerbarg, MD is Assistant Clinical Professor in Psychiatry at New York Medical
Center. She graduated from Harvard Medical School in 1975 and completed her
Psychiatry Residency at Beth Israel Hospital in Boston in 1979. She finished
psychoanalytic training at the Boston Psychoanalytic Society and Institute in
1992 and has maintained a private psychiatric practice for 23 years. Dr.
Gerbarg has taught and lectured on a range of topics in psychiatry and
psychoanalysis. Over the past six years she has been increasingly involved in
research and writing about alternative and complementary medicine in psychiatry
and has co-authored numerous articles and book chapters with Dr. Brown. Dr.
Gerbarg and Dr. Brown can be reached by Fax: 845-331-3562.
Dr. Zakir Ramazanov is Professor of
Biochemistry at Las Palmas Technological Institute, Spain. In 1978 he received
a bachelors degree with a double major in biochemistry and plant physiology
from North Caucasian State University and in 1981 a PhD in Plant Physiology and
Biochemistry from the Soviet Academy of Sciences. He has served as Senior
Scientist and Chief of the Department of Biotechnology at the Soviet Academy of
Science and as Chairman of Algal Biotechnology Development. In 1991 He accepted
a research fellowship at Louisiana State University. The recipient of numerous
research grants, Dr. Ramazanov is know for his work in space biology, the
cultivation of photosynthetic organisms in space stations, and the development
of marine natural products from sea vegetables. He has published over 140
scientific studies and co-authored two books: Arctic Root (Rhodiola rosea) The
powerful new Ginseng Alternative (1998) and Effective Natural Stress
and Weight Management Using Rhodiola Rosea and Rhododendron Caucasicum (1999).
Dr. Ramazanov is President and CEO of National Biosciences Corporation.
Address: 193 Black Meadow Rd., Chester, NY 10918. Phone: 845-469-6143. Fax:
845-469-1983. E-mail: Medicine@warwick.net.
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