Summary of Rhaponticum carthamoides
Primary Information, Benefits, Effects, and Important Facts
Rhaponticum carthamoides (Russian Leuzea or Maral Root) is an herb used in traditional Siberian and Russian medicine to bolster physical performance particularly after illness, in addition to being used as a general physical enhancement and male sexual enhancement aid. It is a source of molecules known as ecdysteroids which are hormones involved in the molting and maturation process in insects but have different actions when ingested by non-insect organisms. Despite being an 'insect steroid' of sorts, ecdysteroids have not been found to interact with estrogen or androgen receptors nor influence levels of these hormones in the body.
The major claim associated with Rhaponticum carthamoides is the enhancement of physical strength and muscle protein synthesis. The evidence to support these claims are limited to rodent evidence at this point in time and focuses mostly on the ecdysteroid known as 20-hydroxyecdysone (also known as ecdysterone). However, the limited evidence does suggest potential for oral supplementation to aid in both of these claims.
A major limitation of orally supplemented Rhaponticum carthamoides and 20-hydroxyecdysone, however, is rapid metabolism of 20-hydroxyecdysone in serum (with an 8 minute half-life or less) which results in limited amounts of the molecule reaching skeletal muscle. This has been circumvented in some animal studies where 20-hydroxyecdysone has been administered directly to the muscular area via injections, and it appears that in this manner it causes time-dependent increases in the size of the muscle in the applied area with limited peripheral actions (ie. other muscle groups may not experience muscle protein synthesis nor do organs appear to be affected).
Human studies are nonexistent at this point in time, but there does appear to be potential for this herb and the 20-hydroxyecdysone content to be an ergogenic aid pending future research, including research into preserving its stability in serum (to allow more to reach the target tissues).
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Scientific Research on Rhaponticum carthamoides
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Rhaponticum carthamoides (of the family Asteraceae) is a plant more commonly referred to as either Maral root or Russian Leuzea, which has traditional usage in Russian/Siberian medicine for overcoming fatigue (particularly after illness) and for male sexual and physical enhancement. In Traditional Chinese Medicine there is limited usage for the herb in decreasing body fat, increasing immunity, and reducing atherosclerosis. The common name of Maral root comes from observations that a species of deer (Cervus elaphus sibiricus or 'Maral' deer) seems to be invigorated by feeding on the roots.
The Rhaponticum genus itself comprises approximately 40 species, of which Rhanponticum leuzea (synonymous with Rhanponticum carthamoides) appears to be the only one with traditional medicinal usage although uniflorum is also investigated. Although Rhanponticum carthamoides is legitimately synonymous with Rhanponticum leuzea, at times other herbal species in the genera of Centaurea, Cnicus, Fornicium, Leuzea, Serratula, and Stemmacantha have been used synonymously (which is less common as well as less accepted).
Rhaponticum carthamoides is an herb used traditionally in Russian and Siberian medicine mostly for the purposes of immune support and physical enhancement.
The Rhaponticum carthamoides plant contains:
20-hydroxyecdysone (one of the major ecdysteroids) which can reach 2.2% with an ethanol extraction although they are normally found at 0.81% (dry root weight), 1.22% (aerial parts), and 1.51% (seeds). Although less prominent, other ecdysteroids such as 23ε-ethylecdysterone (Rhapisterone C), Inokosterone, Carthamosterone A and B, Rubrosterone and Dihydrorubrosterone, Posterone, Turkesterone, and (20R)-1α,20-Dihydroecdysone (Integristerone B) are present in the roots
Triterpenoids named Rhaponticosides A-H
(E)-3,3'-dimethoxy-4, 4'-dihydroxystilbene (Stilbene)
Ellagic acid (tannin) in the underground and aerial parts
N-feruloylserotonin isomers (seed) mostly consisting of N-(E)-isoferuloylserotonin (67.4% total isomers), N-(E)-feruloylserotonin (18.3%), N-(Z)-isoferuloylserotonin (8.2%), and N-(Z)-feruloylserotonin (6.1%)
(Triterpenoid) α-Amyrin (597.55+/-38.2µg/g leaf dry weight)
There appears to be an essential oil content of up to 0.2% in the underground parts of the plant, ranging from 0.07-0.11% and 0.08-0.09% in the dried underground organs and leaves respectively. The roots primarily comprise geraniol (17.04–18.27%) and linalool (8.88–12.07%) whereas the leaves contain mostly β-caryophylline (24.65–32.30%) and neeral (8.12–10.22%). One other study, in contrast to the former, suggests a high concentration of 13-norcypera-1(5),11(12)-diene, cyperene and aplotaxene in the roots.
When looking at the composition of Rhaponticum carthamoides, most attention is paid to the ecdysteroid content. While there are abundant ecdysteroids in this plant, the most researched one appears to be 20-hydroxyecdysone (ecdysterone). Some other small molecules, such as the N-feruloylserotonin isomers and flavonoids, are also included in this plant although their role in supplementation is unknown.
Ecdysone is known as an insect steroid hormone acting via the ecdysone receptor present in insects but not in humans and other primates, although these receptors are orthologs of mammalian farnesoid X receptors (FXR) and liver X receptors (LXR). Due to the structual similarity, these receptors are thought to be the mammalian targets of ecdysones.
Some nuclear receptors in humans which are orthologs (structurally similar) to the receptors ecdysteroids act on in insects are thought to be molecular targets for the ecdysteroids, although the exact insect hormone receptors for ecdysteroids are not present in humans.
In isolated HeLa cells 20-hydroxyecdysone was able to inhibit NF-kB activation (assessed by IL-6 transcription) with an IC50 of 31.8µM, a potency significantly less than other tested herbal agents such as Withaferin A (from Ashwagandha) at 1.4µM and less than the overall Rhaponticum carthamoides plant extract itself (3.5-6.2µg/mL).
While high concentrations (25µM) of 20-hydroxyecdysone are able to enhance the NF-kB inhibitory effects of the glucocorticoid dexamethasone in vitro, using Rhaponticum carthamoides extracts showed unreliable interactions.
While the overall herb has been implicated in inhibiting NF-kB (an anti-inflammatory mechanism), this does not appear to be associated with the 20-hydroxyecdysone content. The molecules mediating this effect and its practical significance are uncertain.
Pharmacokinetic studies in white mice have shown that 20-hydroxyecdysone is mostly distributed to the kidneys, liver, and blood plasma, with relatively little distributed to muscle. Intracellularly, the compound distributes mostly to the cytoplasm and microsomes following administration whereas less was detected in mitochondria and nuclei of mouse liver cells.
An intravenous injection of 20-hydroxyecdysone at a dose of 50 mg/kg was rapidly eliminated from the blood of mice, within 30 minutes, with a half-life of 8.15 minutes.
20-hydroxyecdysone is mostly distributed to the liver, kindneys, and serum, with relatively little reaching the peripheral tissues. It has a very rapid serum half-life.
Intraperitoneal injections of N-feruloylserotonin isomers (a substance isolated from Rhaponticum carthamoides seeds) at 10mg/kg in rats reduced anxiety in animals with high pain thresholds (which were also more anxious) but not in those with low pain thresholds (which exhibited lower baseline anxiety). No studies have been conducted to date, however, to confirm that these findings hold for oral adminstration.
Injections of components from a Rhaponticum carthamoides extract may lower anxiety in anxiety-prone rats, but there are no studies to date confirming these results for oral supplementation.
At concentrations of 10μM, 20-hydroxyecdysone was able to inhibit glucose production in vitro in serum-starved H4IIE hepatoma rat cells with similar potency to physiologically relevant concentrations of insulin (10nM), with concentrations as low as 100nM having minor efficacy. The inhibition of glucose production was dependent on PI3K activation. This inhibition of glucose production was associated with suppressing activation of Glucose-6-Phosphatase (G6Pase) and Phosphoenolpyruvate Carboxykinase (PEPCK), which are two rate limiting glucogenic enzymes under the regulation of insulin, as well as inducing phosphorylation of Akt2 at Ser473; these actions are all secondary to PI3K and not affected by AMP-activated Protein Kinase (AMPK) inhibition. Reduced expression of PEPCK and G6Pase has been noted in mice following oral administration of 10mg/kg 20-hydroxyecdysone.
Also similar to the functions of insulin, 1-100µM of 20-hydroxyecdysone was able to increase the rate of glucose consumption at high glucose concetrations by 44% in HepG2 cells in a manner not dependent on insulin.
At concentrations of 2.5-50μM, 20-hydroxyecdysone activated AMPKα1 in a concentration dependent manner by 4-32%, although AMPKα2, the main catalytic unit, was unaffected, suggesting that the effect 20-hydroxyecdysone has on glucose metabolism is due to the PI3K pathway and not through AMPK. As 20-hydroxyecdysterone has also been noted to increase circulating adiponectin at the doses it takes to suppresses PEPCK and G6Pase in high-fat fed rats, and adiponectin may suppress these two enzymes via an AMPK dependent mechanism, a possible indirect role for 20-hydroxyecdysterone affecting glucose metabolism exists.
In vitro, 20-hydroxyecdysone appears to have properties on a cellular level similar to that of insulin as it activates PI3K and the target genes that are downstream of PI3K.
Basal glucose concentrations in rats given a high-fat diet (20% relative to normal chow control) was noted to be reduced up to 19.4% with eight weeks supplementation of 300mg/kg Rhaponticum carthamoides extract (2.2% 20-hydroxyecdysone).
The increase in blood glucose levels seen with an oral glucose tolerance test in rats following eight weeks supplementation with 300mg/kg Rhaponticum carthamoides (2.2% 20-hydroxyecdysone) on a high-fat diet was reduced relative to both the high fat control as well as the normal diet control. A similar improved glucose tolerance has been noted in rats given a high fat diet supplemented with pure 20-hydroxyecdysone (10mg/kg) orally.
Oral ingestion of 10mg/kg 20-hydroxyecdysone in rats given a high-fat diet for 13 weeks resulted in elevated adiponectin concentrations in visceral adipose tissue relative to high fat control, and raised plasma adiponectin to a level comparable with that of normal chow-fed rats (when expressed against total body weight, which was ultimately lower in the normal chow group). Adiponectin is known to be reduced in obese and diabetic subjects, suggesting a therapeutic role of 20-hydroxyecdysone.
In regards to leptin, one study in ovarectomized rats given 20-hydroxyecdysone (18-115mg/kg orally for three months) noted that supplementation reduced the elevations in leptin seen in ovariectomized control but not to the degree of estrogen therapy.
Two studies have noted beneficial influences in adipokines (namely adiponectin and leptin) but neither used a standard rodent model, instead using a high-fat fed model and an ovariectomized model respectively. Thus the effect of 20-hydroxyecdysone on the adipokine levels of normal rats on a normal diet remains uncertain.
Oral ingestion of 10mg/kg 20-hydroxyecdysone for 13 weeks in mice fed a high-fat diet was able to attenuate weight gain by 18% (41% less adipose, 5% less lean mass) relative to a high-fat control, although 20-hydroxyecdysone fed rats were still heavier than the normal chow control. When assessed at the end of the experiment, there were no noticeable differences in heat production between groups.
A study in ovarectomized rats given 20-hydroxyecdysone at 18, 56, and 115mg/kg for three months failed to find any significant alteration in weight relative to ovarectomized control (despite estrogen therapy reducing weight as expected).
A possible mild antiobese property may be present with isolated 20-hydroxyecdysone, perhaps due to its effects on adiponectin levels. No human studies have been conducted to confirm this effect, however.
Ecdysteroids, including 20-hydroxyecdysone, have been implicated in promoting muscle protein synthesis (MPS) in isolated muscle cells via a mechanism dependent upon Phosphoinositide-3-Kinase (PI3K); a concentration of 40nM increased protein synthesis by 10%, and peaking at 100nM-1,000nM (20% increase) although lower concentrations (10nM) caused a minor inhibition of protein synthesis. It is thought that the activation of Akt/PI3K leads to 20-hydroxyecdysone-induced muscle synthesis, which occurs downstream of increased intracellular calcium levels caused by a putative G-Protein Coupled Receptor (GPCR) linked to the Phospholipase C (PLC)/inositol 3-phosphate (IP3) pathway.
In assessing genes possibly involved in 20-hydroxyecdysone-induced muscle protein synthesis in the mouse, sixteen genes were deemed most probable (such as GDFS, GDF5, CCL24, and SOCS1), including ACVR2A, which was a gene already implicated in MPS.
While the exact mechanisms of 20-hydroxyecdysone on muscle protein synthesis are not fully elucidated, it appears to involve a rapid increase in calcium in the cell (cytosol) causing activation of Akt/PI3K signalling. This activation then induces muscle protein synthesis.
The increase in MPS seen in vitro may persist for up to 24 hours if the concentration of 20-hydroxyecdysone is controlled, and if 20-hydroxyecdysone is continuously administered at a therapeutic dose subcutaneously via an osmotic pump then it can increase local muscle mass in the mouse in vivo by 30% over the course of five days. Despite the increase in weight of the local muscle, no significant influence was noted on whole-body muscle mass which disagrees with other research using injections of 20-hydroxyecdysone. Other muscle tissues or organs where the agent was not administered locally were unaffected in this study, and no 20-hydroxyecdysone could be detected in plasma. Increases in local muscle mass production (relative to whole body) with injections of 20-hydroxyecdysone have been noted elsewhere in rats given once daily injections of 5mg/kg over eight days, where less apparent effects were noted the further away from the injection site.
If a steady concentration of 20-hydroxyecdysone can be attained in muscle tissue, usually seen in experiments with osmotic pump implants, then muscle mass can be increased to a large degree in a time-dependent manner. These studies may not reflect oral supplementation of 20-hydroxyecdysone due to rapid metabolism of 20-hydroxyecdysone in serum leading to little to none of it reaching muscle tissue.
One study in puberal rats using peroral administration of 5mg/kg 20-hydroxyecdysterone (an estimated human dose of 0.8mg/kg based on body surface area) daily for ten days noted that supplementation was associated with a weight gain rate 51.9% greater than that of control, a level comparable to the reference drug methylandrostenediol and slightly lesser than turkesterone (63.5%). Ecdysterone triacetate and tetraacetate were also effective (30.8-36.5% greater than control), and the effects of 20-hydroxyecdysone appeared to be heavily reliant on the hormonal status of the rats since hypophysectomized and impuberal rats experienced little to no growth rate enhancement with 20-hydroxyecdysterone (yet they did with methylandrostenediol and nerobol; the androgenic controls).
In ovarectomized rats (a model for menopause) given 20-hydroxyecdysone at three doses (18mg/kg, 56mg/kg, and 115mg/kg) over three months following ovarectomy, it was noted that despite not influencing overall body weight, all three doses were equipotent in increasing muscle mass relative to control, but less than the estrogen control group.
Although animal evidence is very limited for orally supplemented Rhaponticum carthamoides or its putative active components, there may be some activity seen via this route associated with the ecdysteroid content.
50mg/kg 20-hydroxyecdysone fed to rats (estimated human dose 8mg/kg based on body surface area scaling) over the course of 28 days has been noted to increase grip strength by 18% relative to untreated control, with similar increases seen in the groups given 20-hydroxyecdysone via spinach extract (24%) and the reference drug methandrostenolone (21% with 10mg/kg); this has been noted previously with orally supplemented 20-hydroxyecdysone.
Limited evidence has associated orally supplemented 20-hydroxyecdysone (estimated human dose of 8mg/kg) with an increase in power output in the rat; currently no human studies assessing this property of supplementation.
A Rhaponticum carthamoides extract has been noted to suppress the secretion of inflammatory cytokines, including TNF-α, from HeLa cells transfected with IL-6 genes in vitro. Whole plant extract was more potent in this suppression (IC50 of 3.5-6.2µg/mL) than pure 20-hydroxyecdysone (IC50 of 31.8µM).
In rats, an increase in TNF-α (2.7-fold) and IL-6 (3.1-fold) due to being fed a high-fat diet for eight weeks was attenuated by 61.6% and 48.4% respectively with coingestion of a Rhaponticum carthamoides extract (300mg/kg of 2.2% 20-hydroxyecdysone); the reduction in IL-6 was comparable to similar doses of pomegranate extract as well as that of licorice, but the reduction in TNF-α was slightly greater with Rhaponticum carthamoides.
A mild antiinflammatory effect may be present with oral supplementation of Rhaponticum carthamoides in rats fed a high fat diet, although the whole herb extract appears more effective than isolated 20-hydroxyecdysone.
When various ecdysteroids from Rhaponticum carthamoides, including 20-hydroxyecdysone, were tested in a macrophage activation assay (stimulating macrophages with IFN-γ and LPS and assessing nitric oxide production), all tested ecdysteroids failed to influence nitric oxide production.
Ecdysteroids may not affect the immunologic activity of macrophages.
N-feruloylserotonin isomers in concentrations ranging from 10-100µM isolated from the seeds of Rhaponticum carthamoides and incubated wtih neutrophils isolated from human serum were able to strongly suppress activation from phorbol-myristate-acetate (PMA), with 1µM having minor effects and lower concentrations ineffective, and less markedly suppress neutrophil activation from A23187 and OpZ. The inhibition appears in part to be due to inhibiting PKC phosphorylation and affects the oxidative burst response of the neutrophil.
The N-feruloylserotonin isomers can suppress neutrophil function in vitro, although whole animal or human studies do not currently exist.
The increase in corticosterone seen in rats given a high fat diet appears to be attenuated by up to 27% when given Rhaponticum carthamoides (300mg/kg of a 2.2% 20-hydroxyecdysone extract) for eight weeks, a reduction that was comparable in magnitude to a similar dose of pomegranate extract containing 40% ellagic acid. Rhaponticum carthamoides was also able to restore corticosterone concentrations in the adrenal glands by 25%, as they were depleted 2.15-fold in the high fat control group, despite pomegranate not having this effect.
Rhaponticum carthamoides may attenuate a rise in serum corticosterone levels while restoring adrenal levels in rats fed a high-fat diet. No data currently exists to confirm this effect in humans.
In ovarectomized rats given 20-hydroxyecdysone in their feed (1, 3, of 6g/kg feed; drug intake ranging from 18-115mg/kg bodyweight) for three months failed to influence TSH, T3, of T4 concentrations relative to control.
No known interation of 20-hydroxyecdysone with thyroid hormones exists in ovarectomized rat models, although no human evidence currently exists.
Ovarectomized rats given 20-hydroxyecdysone ranging from 18-115mg/kg bodyweight failed to experience any gains in uterine weight or serum estradiol concentrations, suggesting no significant estrogenic effect. A lack of estrogenic effects have been noted elsewhere and this is in accordance with research showing that tested ecdysteroids (β-Ecdysone in this study) do not have any affinity for estrogen receptors.
Ecdysteroids do not appear to interact with the estrogen receptor, and alterations in serum estrogens has not been demonstrated in rats orally supplementated with 20-hydroxyecdysone.
20-hydroxyecdysone has failed to bind to the androgen receptor at concentrations between 1-100µM, a concentration range where protein synthesis was observed to be enhanced. Oral ingestion of 5mg/kg daily for ten days failed to cause any alterations in ventral prostate or seminal vesicle weight suggesting no androgenic activity.
Supplementation of 20-hydroxyecdysone does not appear to cause androgenic effects in the rat nor does it appear to have affinity for the androgen receptor.
In isolated βTC3 cells, ecdysterone failed to stimulate insulin secretion in the concentration range of 1-100µM.
Rats subject to eight weeks of a high-fat diet are known to have a reduction in PPARα binding activity in liver tissue concomitant with an increase in triglyceride content of this tissue. Oral supplementation of 300mg/kg Rhaponticum carthamoides (2.2% 20-hydroxyecdysone) during this time is able to mostly abrogate the reduction, increasing PPARα-binding activity by 48.5% and nearing activity seen in the normal chow control.
When assessing Sterol Regulatory Element-Binding Protein-1 (SREBP-1) activity, no differences have been noted between a high-fat diet group and the same group given 10mg/kg 20-hydroxyecdysone over 13 weeks,suggesting no effect on hepatic lipogenesis.
At least one study has noted a preservation of PPARα activity in the liver of rats fed a high-fat diet, while leaving fat synthesis in the liver unaffected. No human data are currently available.
In women with ovarian cancer assigned to take an adaptogenic herb mixture containing Rhaponticum carthamoides as well as rhodiola rosea, eleutherococcus senticosus, and schisandra chinensis (270mg collectively under the brand name AdMax; extractions not specified) alongside their assigned chemotherapy for four weeks, there were minor increases in IgG (12.5%) and IgM (7.9%) concentrations with no influence on IgA, along wtih with slight increased T-cell count in certain subclasses (CD3, 4, 5, and 8). Side-effects of fatigue and depressive symptoms seen in control did not appear to occur in the treated group.
Rhaponticum carthamoides may contribute to a reduction in fatigue and depression as an adjunct to chemotherapy for ovarian cancer patients alongside slight increaes in some indicators of immune function. These results are confounded, however, by the addition of other herbs to the mixture. Also, the sample size of the study was small. Further research would be needed on the herb in isolation to confirm what role it plays, if it alone is active or not.
One study in boars testing fertility and libido in response to supplementation of Rhaponticum carthamoides mixed with other agents (eurycoma longifolia jack and tribulus terrestris) using 6.66mg/kg of the herb (0.1mg/kg 20-hydroxyecdysone) daily noted an increase in sperm concentration per volume ejaculate, although this conclusion was confounded by a reduction in total ejaculate volume. There was no apparent influence on libido relative to control, although libido was enhanced 20% relative to the baseline values in the experimental group.
No evidence exists for Rhaponticum carthamoides enhancing libido in isolation. One lone animal study was confounded with other known libido-enhancing herbs, and had no influence on libido relative to control.
When looked at alone, 20-hydroxyecdysone appears to have a large therapeutic window as the acute LD50 in rats via intraperitoneal injections is 6.4g/kg whereas for oral ingestion it is greater than 9g/kg.
In isolation, 20-hydroxyecdysone appears to have a large therapeutic index and low risk for acute toxicity. Neither studies on Rhaponticum carthamoides nor chronic toxicity studies have been conducted at this time.
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