Rhodiola Rosea

Rhodiola Rosea (of the family Crassulaceae; henceforth Rhodiola) is a herb traditionally used as an adaptogen compound and is synonymous with common names such as Arctic root, Rose root/Rosenroot, Orpin Rose, or Golden root.^[1][2] The adaptogenic effects have traditionally been referred to as inducing a 'nonspecific immunity' and normalizing effect,^[1] and traditional usage seems to be localized to around Europe and sometimes spreading east into Asia (with usage reported in Mongolia^[1] and Siberia^[2]) and is commonly reported to have traditionally been used by scandinavian Vikings to preserve physical robustness (this may be speculative^[2]). It has extended far enough into Asia to be incorporated into traditional chinese medicine (under the name Hong Jing Tian)^[3] where it is recommended to take 3-6g of the root daily for vitality and longevity.

Rhodiola is common to northern Europe and Russia at altitudes between 1000-5000m, and can be found on some North American coastlines.^[1] The main commercial source of Rhodiola appears to be Mountain Altai and in south region of foothill Altai, mainly in Ust-Kanski, Ust-Koksinski, Charishki regions.^[2]

Rhodiola (rosea as the most common species) is a nordic/russian herb that has traditionally been used as a vitality enhancing and physical preserving agent. It has also sometimes been used for cognitive decline and the connection between cognition and physical fatigue

The root of rhodiola (main segment that is used medicinally) contains:

• Tyrosol,^[4] sometimes seen as one of the main bioactives, and its glucoside known as Salidroside^[4] (chemically p-hydroxyphenylethyl-O-ß-D-glucopyranoside and synonymous with Rhodioloside or Rhodosin^[5]) as the other main bioactive
• The 'Rosavins' (Rosin,^[6][4] Rosarin,^[4] and Rosavin^[4][7] are the main rosavins. Other molecules that can possible be called rosavins include rosaridin,^[6][7] but this molecule is structurally different)
• Viridoside^[4] (structurally Salidroside that is methylated)
• Lotaustralin (Cyanogenic glycoside)^[7]
• Gossypetin (as 7-O-L-rhamnopyranoside)^[8] and Rhodioflavonoside (Gossypetin diglycoside)^[8]
• Benzyl-O-β-glycopyranoside^[6]
• Procyanidins built off of EGCG (from green tea catechins)^[4][9] at up to 35% of a 70% aqueous acetone extract by weight.^[4] Procyanidins appear to consist of up to 3.6-5.43% of the weight of the dry root dependeing on growing conditions^[10] which places it lower than grapes (7.8%) and sea buckthorn (8.14%) but higher than crataegus pinnatifida (2.7%).^[9]
• Small phenolics including gallic acid,^[8] cinnamic acid,^[8]
• β-sitosterol^[7]

The tyrosol and salidroside molecules as well as the rosavins are known as phenylpropanoid compounds.^[6][11]

On a molecular basis, the main active ingredients appear to be Tyrosol and its glucoside known as Salidroside. When consuming the root, there are other structurally related bioactive (the rosavins) that may play a role. Rhodiola is a surprisingly high source of procyanidins (same molecules as those in Pycnogenol) built of EGCG, the catechin thought to be somewhat unique to green tea

The clear and colorless essential oil (0.05% of the root by dry weight,^[1] it has been reported to be lower) contains mostly:

• n-Decanol (30.38%^[1])
• Gerianol (12.49%^[1])
• 1,4-p-menthadien-7-ol (5.10%^[1])
• Limonene (4.91%^[1])
• α-Pinene (4.69%^[1])
• β-pinene (1.47%^[1])
• sabinene (1.45%^[1])
• β-Myrcene (2.25%^[1])
• 3-Carene (2.04%^[1])
• β-Phellandrene (2.31%^[1])
• p-Cymene (2.97%^[1])
• n-Octanol (2.77%^[1])
• Linalool (2.31%^[1])
• Dodecanol (3.67%^[1])
• Cumin alcohol (2.66%^[1])

Due to the remarkably low level of overall essential oils in rhodiola root, these molecules are unlikely to play a significant role in the body following supplementation

Isolated salidroside and tyrosol appear to be stable in solution at 2 hours at room temperature and 30 days at either 4°C or -20°C.^[12]

SHR-5 is a standardized extract of rhodiola that is used in many human studies^[13][14] and is the extract used in the formulation ADAPT-232 (a combination of rhodiola, schisandra chinensis, and eleutherococcus senticosus).

The SHR-5 extract is standardized for rhodioloside (4mg per 144mg tablet)^[15] and appears to be a 70% ethanolic extract with a 4:1 drug:extract ratio,^[15] thus 200mg of SHR-5 is claimed to be bioequivalent to 800mg of the dry herb.

As for ADAPT-232, the 70% ethanolic extract is used in a drug:extract concentration of 2.8:1 while schisandra chinensis and eleutherococcus senticosus are used as a 95% ethanolic extract (fruits) and 70% ethanolic extract (roots) respectively and in a 1.2:1 and 10.5:1 herb:drug concentration.^[16] Adapt-232 appears to be standardized to 0.5% rosavin, 0.32% rhodioloside, 0.05% tyrosol, 0.37% schisandrin, 0.25% γ-schisandrin, and 0.15% eleutherosides B and E.^[16]

Salidroside appears to be absorbed in the intestines via the SGLT1 transporter^[17] (which is similar to other glucoside compounds as the glucoside is sensed by the transpoter^[18] and this has shown efficacy in increasing absorption of Quercetin glucosides relative to free quercetin^[19]) and oral ingestion of 48mg/kg does not appear to confer any additional advantage relative to 24mg/kg (exact same serum concentration) although 24mg/kg outperformed 12mg/kg.^[17]

The bioavailability of salidroside has been detected to be 32.1% (12mg/kg oral intake),^[20] 98.1% (25mg/kg),^[21] and 51.97% (100mg/kg);^[12] it is not currently known why there is inconsistencies in these results.

Following oral ingestion of salidroside in rats, the half-life of salidroside appears to be around 40-46 minutes^[17] with a T_max of 25 minutes and a C_max of 10.47+/-1.08µg/mL (240 minute AUC of (695.62+/-95.39µg/h/mL).^[17] Another study using oral ingestion of 100mg/kg salidroside noted a C_max of 3,716.73+/-860.13ng/mL, a T_max of 0.30+/-0.1 hours, and a half-life of 1.32+/-0.22 hours with an AUC_0–∞ of 7,724.52+/-446.62h/ng/mL.^[12]

In investigating whether salidroside in isolation can increase serum p-tyrosol, one study has failed to find such an effect following 100mg/kg salidroside to rats, but suggested that further metabolism was possible.^[12]

In vitro, rhodiola appears to inhibit the CYP3A4 enzyme with an IC₅₀ in the range of 1.7-3.1mcg/mL and has been noted to inhibit P-glycoprotein with an IC₅₀ in the range of 16.7-51.7mcg/ML.^[22] Despite the possible influences on CYP3A4, rhodiola has been noted to not adversely interact with Warfarin pharmacokinetics in rats.^[23]

May possibly interact with CYP3A4 and P-gp, although there is not enough evidence to come to a conclusion

Rhodiola (10-25ug/mL of feed) given to nematodes (C. Elegans) for their lifetime was able to delay aging in the whole population (extending the time required for the first deaths to occur) and extend life to around 10-20%; this study also noted efficacy of eleutherococcus senticosus at 10-fold the concentration, suggesting common mechanisms.^[24] Higher doses of rhodiola (50-100ug/mL) had the opposing effect (reducing lifespan) and adding the adaptogens later in life (50% through the lifecyle) still exerted anti-aging effects but to a lower degree (11.7% rather than 17.8% in a particular set of experiments).^[24]

The mechanism is thought to be secondary to DAF-16 nuclear translocation,^[24] as DAF-16 is vital for improving heat tolerance in nematodes^[25] which was also observed following dietary intake of rhodiola.^[24] DAF-16 translocation is generally thought to be related to longevity and stress resistance^[26][27] and the effects of rhodiola on DAF-16 is thought to be related to a hormetic mimicking of stress.^[28]

A subsequent study on drosophilia using Rhodiola at 15-200mg/mL noted significant reductions in mortality (with only the higher doses reducing fecundity) and promoted longevity in these flies by 3.2-3.5 days,^[3] which has been replicated twice elsewhere with an enhancement of life by 24%.^[29][30] Longevity has also been noted to occur in yeast,^[31] and when comparing the two fly studies the one that had a higher concentration of salidroside and rosavins^[29] appeared to outperform the one with standard concentrations, suggesting they are the bioactive components.^[3]

Adaptogens in general, but particularly rhodiola, appear to be involved with promoting longevity. A bell curve has been noted in nematodes, and the mechanism is thought to be from inducing nuclear translocation of DAF-16 (a response to stress)

Ex vivo, 100μg/mL of the methanolic and water extracts can inhibit MAOA (92.5% and 84.3%) and MAOB (81.8% and 88.9%) whereas the dichloromethane extract appears to be less potent (50.5% and 66.9%).^[32] When looking at causative compounds, it appears Rosiridin appears to potently inhibit MAOB (83.8+/-1.1% at 10μM) but not MAOA (16.2+/-2.3%) whereas salidroside was weakly effective on MAOB only (35.8+/-2.5% at 10μM).^[32] This study is duplicated elsewhere,^[33] where an inhibitory effect on acetylcholinesterase was also noted to be and attributed to hydroquinone, rhodiolgin, and rhodioflavonoside (although IC₅₀ values were not calculated).

The influence on monoamine oxidase has been brought into question as it has been found that oral Rhodiola ingestion failed to modify the 5-HT/5-HIAA ratio.^[34]

It has been said rhodiola also has the ability to inhibit the COMT (Catechol-o-methyltransferase) enzyme^[35] although the evidence this is based on does not appear to be publicly available.

Appears to have mechanisms to inhibit MAO enzymes, and appears to be potent in vitro. This may not apply following oral ingestion of rhodiola supplements. COMT interactions have been mentioned, but there does not appear to be evidence for this claim

Rhodiola has been implicated in inducing the activity of Neuropeptide Y and subsequent release of Hsp72 (seen using the mixture of ADAPT-232 as well as isolated salidroside^[13]) via HSP1 dependent mechanisms and ADAPT-232 appears synergistic in this regard, as the amount of salidroside in ADAPT-323 at the EC₅₀ concentration was equivalent to 5.5nM while in isolation salidroside needed to be present at concentrations of 5μM (5000nM).^[13] It has been hypothesized, but not established, that these effects may underlie the stress reducing effects of rhodiola supplementation^[36] as increases in serum Hsp72 have been seen with ADAPT-323 in rats.^[37]

Appears to influence Neuropeptide Y activity, which then increases Hsp72 levels via HSP1 transcription; thought to underlie the anti-stress effects

A psychostimulatory effect has been noted to last for 4 hours or so following oral ingestion of 2.5mg salidroside (around 250mg rhodiola) according to one review^[38] (main article, Aksenova 1968, not detectable online).

May have a small psychostimulatory effect

Salidroside at 5-10mg/kg (intraperitoneal injections) to rats following a sciatic nerve injury has been noted to accelerate the rate of nerve healing.^[39] This has been noted with other adaptogens such as Panax Ginseng (via Ginsenoside Rg1^[40]) and may be related to the anti-degenerative effects of Hsp70 on neurons.^[41][42]

Requires more evidence, but has mechanisms to accelerate the rate of nerve healing

Salidroside has been noted to improve neurogenesis rates in the diabetic rat hippocampus (thought to be from reducing oxidative stress, which may impair neurogenesis in diabetic mammals)^[43] and has been replicated with intracerebral injections of rhodiola.^[44] In vitro, salidroside also appears to preserve stem cell differentiation rates in the presence of streptozotocin (diabetic toxin used in the aforemented studies) without significantly affecting viability up to 2mM.^[43]

As a side note, it was recorded that salidroside incubation with neurons increased the average length of cellular processes in NF150 positive cells suggesting that salidroside may enhance the extension of cellular processes in differentiating cells.^[43]

Neurogenesis may be implicated with rhodiola, but most practically this appears to be secondary to reducing oxidation in stem cells and preserving normal neurogenesis rates (with research toxins that are oxidative in nature reducing neurogenesis rates). Practical significance of the above unknown

In rats given a passive avoidance task, rhodiola at 50-100mg/kg for 9 days was able to enhance memory in a dose and time dependent manner in otherwise normal and healthy rats.^[45] Not many other studies assess cognitive enhancement in non-stressed and healthy rats, with one suggesting efficacy with 0.10mL of a 1:1 aqueous alcoholic extract of rhodiola^[46] and the same dose showing inefficacy elsewhere.^[47]

50-100mg/kg rhodiola is able to abolish the memory impairing effects of scopolamine over 9 days of oral supplementation.^[45] The memory impairing effects from β-amyloid injections has also been noted to be abolished with 50-75mg/kg isolated salidroside^[48] and the impairments in both neurogenesis^[43][44] and cognitive function^[49] seen in diabetic rats is abolished.

Memory improvements have been noted in persons with cognitive impairment (not pathological) given a formulation known as Vigodana^[50] but the results are confounded with Magnesium and B-vitamins.

Rhodiola has outright abolished the effects of scopolamine, suggesting it is a potent anti-amnesian agent. May also improve memory slightly independent of stress (although in practical situations, the reduction of stress and fatigue and preservation of cognition is likely to be the most noticeable)

Salidroside has shown protective effects in neurons exposed to hypoglycemia and serum starvation,^[51] with pretreatment of 80-320µg/mL preserving as many neurons as the active control of adenosine (250µg/mL), the protective effects mediated via stabilizing the mitochondria and thought to be related to preventing the increase in ROS (reactive oxygen species) seen in cell pretreated with rhodiola.^[51] These possibly antioxidative effects may also extend to protection from the oxidative stress from β-amyloid protein (reduced with salidroside at 10-100µM) and subsequently reduced JNK activation and apoptosis from these proteins^[52] which has been shown to be biologically relevant at an oral intake of 50-75mg/kg in rats.^[48]

General antioxidative effects are noted with salidroside in response to hydrogen peroxide (H₂O₂)^[53] which has also been noted with isolated tyrosol galactoside.^[54]

Salidroside has been noted to induce levels of the mRNA of the antioxidative enzymes heme-oxygenase 1 (HO-1), thioredoxin, and peroxiredoxin-I^[52] and thus enzymatic induction may underlie the protective effects observed with salidroside.

Salidroside, and thus rhodiola, appear to have antioxidative protective effects in isolated neurons. The mechanisms appear to be from inducing levels of antioxidative enzymes or otherwise exerting antioxidative effects

Salidroside has also shown protective effects against excitotoxicity induced by glutamate or intracellular calcium in neurons.^[55][56][57]

Possible protective against excitotoxicity

One study assessing the interactions of rhodiola and nicotine withdrawal noted that rhodiola was able to increase neural serotonin and 5-HIAA concentrations independent of nicotine dependency, with dose-dependent increases in serotonin at 5-40mg/kg rhodiola in control (13-183%) and nicotine dependent (11-262%) rats, with more effects in the latter due to a relative serotonin insufficiency.^[34] This study did not note any alterations in the 5-HT/5-HIAA ratio nor in levels of tryptophan,^[34]

One other study has noted that the decreased levels of serotonin found in depressive rat hippocampus' was normalized with rhodiola ingestion (1.5-6g/kg of rhodiola with 4% salidroside), with 1.5g/kg actually being most effective (serotonin increasing 20% higher than nonstressed control) although not as effective as fluoxetine (2.2mg/kg; reached 48% of control).^[58]

Rhodiola appears to be serotonergic, and increases serotonin levels in the brain and hippocampus. This appears to be general rather than context-specific

Rhodiola has also been found to increase the protein content of the 5-HT_1A receptor in both control and nicotine dependent rats (although much more profoundly in the latter)^[34] and ADAPT-232 has been implicated in downregulating the 5-HT₃ receptor of serotonin, which is due to suppressing expression of the gene HTR1A via tyrosol and salidroside at 3μM (6.3 and 6.6-fold downregulation).^[59] This is hypothesized to be related to anxiolysis, as activation of the 5-HT₃ receptor induces anxiety.^[60]

Rhodiola has been shown to alter expression of serotonin receptors, with more of the 5-HT_1A subset and possibly suppressive effects on 5-HT₃ subsets

One meta-analysis investigating fatigue in academic settings^[61] assessing the following studies with students given 100mg SHR-5 for 20 days,^[62] 660mg of a product called Rhodaxon (rhodiola root extract, unspecified) for 20 days,^[63] 100mg Rhodiola for 2 days,^[64] 170mg SHR-5 for 42 days,^[65] and 370-555mg SHR-5 for a single dose (work related stress).^[66] Overall, these studies suggest that usage of rhodiola is associated with improvements in cognitive fatigue,^{[65][62][63][66]} PWC exercise scores,^[62] neuro-motoric fitness (maze drawing),^[62] reductions in processing errors,^[63] sustained attention,^[64] reaction time,^[64] general well-being,^[62][63] and a reduction in pulse rate^[62] relative to placebo treatment. Although the reduction in fatigue perception appears to be reliable, the improvement in both sustained attention and improved visual reaction speeds appears to be less reliable.^[61]

Other trials conducted after this date and not included in the meta-analysis include an open-label trial with rhodiola extract (WS1375; a 1.5-5:1 concentration) at 400mg daily (200mg twice daily) for 4 weeks showed general benefits on perceived stress (questionnaire), improvements in stress-induced social and work dysfunction, and reductions in fatigue^[67] and one in nursing students where a mandatory 384mg (2.8% rosavins) each morning with an optional halfdose four hours later failed to influence fatigue scores each week over 35 days and even increased fatigue relative to placebo at study day 42.^[68]

Appears to be effective, either acutely or with daily supplementation, for reducing perceived fatigue and the subsequent impairment to cognition that results from fatigue in otherwise healthy persons subject to stress or a high workload. One study has shown an increase in fatigue which needs to be expanded upon

One trial in persons with chronic fatigue related to stress (not necessarily 'chronic fatigue syndrome') was able to find a significant protective effect of rhodiola (576mg SHR-5 for 28 days) against stress as assessed by the Pines’ burnout score.^[15]

In chronically fatigued people, rhodiola may have some efficacy in attenuating fatigue

In female rats conditioned to binge eat to highly palatable foods in response to stress, rhodiola (3% rosavins and 3.12% salidroside) one hour prior to binge eating there appeared to be a significant reduction in binge eating with 10mg/kg and 20mg/kg abolished the binge eating.^[69] This was apparently due to the salidroside content, and rhodiola did not have any apparent effect on eating patterns that weren't stress induced binge eating.^[69] Another study that noted anorectic (appetite suppressing) effects of stress has also noted normalization with rhodiola.^[70] These bidirectional effects are similar to those seen with Panax ginseng and suggest a common mechanism, and one study has noted that the reduction in binge eating seen with salidroside is synergistic with Hypericum perforatum.^[71]

This is thought to be more due to the adaptogenic effects of rhodiola rather than the serotonergic effects, as serotonergic drugs (fluoxetine, sibutramine) reduce food intake universally.^[72]

Rhodiola appears to regulate the interaction between stress and appetite, and although human evidence is lacking animal evidence suggests it can attenuate or otherwise abolish both binge eating and appetite suppression from stress. These effects may merely be from reducing the effects of stress rather than per se influences on appetite, and although there is serotonergic actions of rhodiola there is no evidence to suggest it can reduce appetite like 5-HTP supplementation

In animal models, rhodiola has been noted to exert anti-depressive effects in a forced swim test at 10-20mg/kg bodyweight (3% rosavins and 1% salidroside content).^[73]

Rhodiola has been reported to reduce the side-effect profile of tricyclic antidepressants when taken alongside the TCA pharmaceutical, which appears to also apply to eleutherococcus senticosus.^[74]

In persons with mild to moderate depression given either 340mg or 680mg of rhodiola (SHR-5) daily for 42 days noted that treatment reduced total symptoms of depression as assessed by the BDI and HAMD rating scales (no dose-dependence noted on HAMD and a trend for dose-dependence on BDI, symptoms being reduced to 65-70% of baseline value on HAMD and halved with the higher dose according to BDI) with improvements in insomnia and emotional instability, and only the higher dose being associated with improved sense of well being.^[14]

Appears to reduce depressive symptoms when taken as a daily supplement, and the degree of improvement in the prelimianry evidence appears to be quite large

It is thought that rhodiola may aid anxiety secondary to its adaptogenic abilities, with the increase in serotonin seen with rhodiola^[34][58] not likely a concern for anxiogenic effects as the receptor that mediates anxiety from serotonin (5-HT₃) appears to be downregulated by rhodiola.^[60]

10-20mg/kg of rhodiola (3% rosavins and 1% salidroside) one hour prior to a light/dark exploration test has been found to have some minor anxiolytic effects with no apparent dose-dependency.^[73] In humans, there appears to be improvements in generalized anxiety disorder with rhodiola supplementation at 340mg over 10 weeks; this study was open-label.^[75]

Rhodiola is suspected to have anxiolytic effects, but currently there is insufficient evidence to support it. Preliminary evidence looks promising

A study assessing the nocioreceptive interactions with rhodiola failed to find a significant reduction in pain as assessed by a tail-flick test in animals given an active dose of rhodiola.^[73]

In cardiac muscle cells (H9c2 cell line) subject to ischemia/reperfusion injury, both salidroside (50-200μM) and tyrosol (125-500μM) or their combination were able to greatly reduce the damage to the cells as measured by apoptosis rates, which was attributed to inhibition of JNK activation where tyrosol and salidroside was additive (a reference drug for JNK inhibition also mimicked the cardioprotective effects).^[76] This inhibition may account for results seen elsewhere where salidroside protected cardiomyocytes from ischemia via inhibiting mitochondrial-dependent apoptosis^[77] (JNK acts on the mitochondria to induce apoptosis^[78][79]). This inhibition of JNK may come secondary to antioxidant effects, since ROS activates JNK in this cell line (H9c2)^[80] and salidroside confers and antioxidative potential,^[81] and the antioxidative effects may also underlie less N-acetylglucosamine linkages^[82] (an alternate theory of cardioprotection from salidroside).

Elsewhere, salidroside has been noted to protect the heart from cell death induced by hypoxia,^[83] and oxidative damage by H₂O₂.^[84]

Appears to have cardioprotective effects at the level of the heart tissue in vitro which appears to mostly be related to antioxidative effects of the active compounds (tyrosol and salidroside)

In diabetic rats showing signs of heart failure, 75mg/kg of a 95% ethanolic extract of rhodiola for 21 days was able to preserve blood pressure (reduced in diabetic rats with heart failure) and improve cardiac output via PPARδ dependent mechanisms.^[85] The level of PPARδ protein and mRNA levels in the hearts of diabetic rats were reduced compared to control, and rhodiola ingestion normalized these parameters.^[85] PPARδ is a receptor that is known to regulate ionotrophic function when expressed in cardiomyocytes (heart muscle cells).^[86][87][88]

Has been noted to have some bioactivity following oral ingestion and is dependent on the actions of PPARδ

One study using isolated salidroside at 600mg daily in breast cancer patients started 1 week prior to chemotherapy noted that the reduction in systolic function (as assessed by Strain Rate Imaging) induced by epirubicin (a cardiotoxic anthracycline that is highly effective in breast cancer^[89][90]) was abolished by salidroside, and the increase in plasma ROS found with placebo did not significantly occur with salidroside.^[91]

May have cardioprotective effects against anthracycline drugs similar to CoQ10, although protection from rhodiola occurs at a large dose of isolated salidroside

Hematopoietic stem cells (a self-renewing source of pluripotent stem cells in bone marrow^[92]) experience an increase in DNA synthesis after incubation with salidroside (secondary to stimulating PARP-1 activity)^[93] and red blood cells experience protection form oxidative damage (from inducing thioredoxin and glutathione peroxidase) and appeared to augment the efficacy of erythropoeitin in vitro.^[94] The induction of PARP-1 appears to also occur in lymphocytes, and has been confirmed in mice at an oral dose of 75mg/kg; this PARP-1 activity appeared to be vital for antioxidative effects.^[93]

Elsewhere, the mRNA expression of erythropoietin (EPO) has been found to be induced in liver and kidney cells via isolated salidroside, which was thought to be due to HIF-1α accumulation within the cell.^[95]

Rhodiola water extract appears to have ACE inhibiting effects with around 30% inhibition of 100-200µg/mL in vitro and 50% at 500µg/mL.^[96] This ACE inhibitory effect has been noted elsewhere with a 12% ethanolic extract of rhodiola with 38.5% inhibition.^[97]

Rhodiola water extracts appear to have α-glucoside inhibitory potential, where 100-200µg/mL reached absolute in vitro inhibition and 50µg/mL inhibited just under 50% of enzyme activity; this inhibitory effect was synergistic with cranberry extract, as the inhibitory effects of rhodiola were preserved when in a 3:1 mixture with cranberry water extract.^[96] Rhodiola was determined to have an IC₈₀ of 93µg/mL on α-glucoside and an IC₈₀ of 100µg/mL on α-amylase.^[96] This inhibition has been replicated elsewhere with IC₅₀ values for α-glucoside (44.7-52.3µg/mL) and α-amylase (173.4µg/mL) which is thought to be linked to tyrosol (IC₅₀ of 70.8µg/mL)^[97] and the salidroside content.^[98]

Appears to have mechanisms to reduce carbohydrate absorption, but does not appear to be overly potent in this regard. Currently no studies assessing carbohydrate absorption in a living model

Salidroside appears to reduce advanced glycemic end product (AGE) formation in mice injected with D-galactosamine (an accelerated aging model^[99][100] that is at least partially due to the AGE production^[101]) where high doses of 1,000mg/kg salidroside reduced the AGE content in serum to 62% of galactosamine control yet fully preserved motor function.^[102]

Salidroside has shown hypoglycemic activity in alloxan-induced diabetic rats at 50, 100, and 200mg/kg oral intake for 28 days in a time and dose depedent manner (with no significant differences between doses).^[103] The highest dose of salidroside at 28 days was able to normalize blood glucose levels similar to non-diabetic control.^[103] Another study using db/db diabetic rats and 200mg/kg of rhodiola for 12 weeks noted that rhodiola was effective as 200mg/kg cinnamon in reducing blood glucose (51.4-54.2% lower than control) and no time dependence was noted.^[104]

The age-related suppression in T-lymphocyte proliferation and IL-2 secretion (from a mitogen) appears to be abolished with ingestion of 1,000mg/kg salidroside in mice^[102] which has been noted in rats.^[105]

Salidroside has been noted to activate AMPK in skeletal muscle cells and increased glucose uptake in a concentration dependent manner between 1.25-80µM with no dose outperforming the active control (insulin at 100nM).^[106] This study also noted that insulin-induced glucose uptake was slightly enhanced with salidroside.^[106]

One study using rhodiola supplementation (170mg daily for 4 weeks) noted a reduced fatty acid circulating level during a VO₂ max test (from 12.86+/-1.62mg/dL to 7.31+/-1.31mg/dL) without significantly affecting glucose, which was associated with increased antioxidative parameters in serum and less biomarkers of muscle damage.^[107] Lactate levels were also reduced after exercise when measured at 3 minutes into recovery (50% lower than control), 6 minutes (42%), and 9 minutes (33%).^[107]

In studies assessing blood oxygenation, Rhodiola has twice failed to significantly influnce this parameter relative to placebo.^[108][109]

Currently, one meta-analysis has assessed the interaction of rhodiola supplementation on physical performance or physical fatigue.^[61] Of the 7 trials included in this analysis, they have used 660mg of rhodiola root extract (Rhodaxon) for 30 days prior to exercise,^[110] 100mg of rhodiola for 4 days,^[64] 250mg for 15-22 days preceding the test (1,000mg on the day of),^[109] 447mg acutely,^[108] 288mg of SHR-5 for 5 days,^[111] 100mg SHR-5 for 20 days,^[62] and 660mg of a product called Rhodaxon (rhodiola root extract, unspecified) for 20 days.^[63] Most of the trials assessed in this meta-analysis were relatively minor in regards to physical capacity, and the observed benefits seem to be related to reducing the neural sensation of fatigue and allowing more physical work to be conducted (effective in cycling tests^[62][63] but ineffective in hypoxia^[108] and photon emission^[111]).

In regards to physical fatigue not related to exercise, rhodiola appears to have a significant protective and rehabilitative effect. This has been tested in moderate to high stress situations such as in physicians (doing rounds) or students during exam periods

Rhodiola has been associated with an increased VO₂ max and time to exhaustion on a cycling test^[64] with another study performing a VO₂ max test (and not reporting on the outcome of said test) noting a reduction creatine kinase and C-reactive protein release from the test relative to placebo.^[110] In other studies merely assessing cardiovascular output on a cycling test (in part of a battery of tests on fatigue) there does appear to be benefit with rhodiola relative to placebo,^[62][63] which has been tested in one study (acute dose of 3mg/kg SHR-5) which noted that rhodiola taken prior to a 10k bicycle ride showed significantly reduced time to complete the ride (25.4 minutes relative to 25.8 minutes) and reduced heart rate during the warmup (136+/-17 relative to placebo's 140+/-17) but not during exericse, which alongside average power output and cadence only trended towards improvement.^[112] This study was conducted in recreationally fit women, and the subjects reported less subjective fatigue after consumption of Rhodiola Rosea,^[112] and is duplicated in Medline.^[113]

Some other studies are confounded with Cordyceps sinensis (no significant effect of supplementation with 300mg rhodiola with 2.5% salidroside on VO₂ max of trained cyclists),^[114] Cordyceps and minerals (same dose of rhodiola and again a failure of 2 weeks of supplementation to improve performance),^[115] or 5mg zinc with 200mg rhodiola in elite rowers, where despite increasing plasma anti-oxidant capacity there was no effect on power output or time to complete a 2,000m rowing test.^[116] Other studies using trained or elite athletes note that 170mg of rhodiola for 4 weeks trended to but failed to significantly increase VO₂ max.^[107]

Mixed effects when looking at the interaction of rhodiola and physical exercise, with some benefit seen with higher doses in untrained persons but more moderate doses in trained athletes not having a significant ergogenic effect. Studies are a bit too hetereogeneous to compare (studies in elite athletes are confounded with inclusion of other nutrients, and it is unclear if the benefit seen in the other studies is due to higher dosages or due to training status)

Rhodiola appears to be able to prevent accumulation of lipids during adipocyte differentiation in vitro at 1mg/mL (with Tyrosol inhibiting lipid accumulation at 0.1-1mg/mL) with lower concentrations not highly effective.^[81]

Salidroside in MC3T3-E1 cells (bone) at 0.1-10µM concentration is able to reduce the oxidative damage done by H₂O₂, with 0.1µM of salidroside being as effective as the other concentrations and as effective as the active control of N-Acetylcysteine (10mM).^[117] The mechanisms that normally proceeded following oxidative damage were thus inhibited.^[117]

When supplementing salidroside (5-20mg/kg) to ovarectomized rats, there was a dose-dependent increase in bone mineral density with the higher dose preserving 55% of bone mass of true control (relative to ovarectomized control femur).^[117]

May be able to attenuate the rate of bone loss via antioxidative effects

Rhodiola, via the salidroside component, appears to induce PARP-1 activity which appears crucial for in vivo protection of DNA from H₂O₂,^[93] which has been noted in red and white blood cells as well as fibroblasts.^[93] PARP-1 is an NAD(+) dependent enzyme that is activated by damaged DNA and acts to preserve DNA integrity and induce repair^[118] which has been noted with salidroside in mice.^[93]

Salidroside is known to increase protein levels of the antioxidant enzymes thioredoxin-1^[52][94] and glutathione peroxidase^[119][94] with heme oxygenase-1 (HO-1)^[52] (contested^[120]), peroxiredoxin-I,^[52] catalase,^[119] and superoxide dismutase^[119] having been implicated. As many of these enzymes tend to be catered towards hydrogen peroxide (H₂O₂) that radical seems to be where most antioxidative defense comes from salidroside in vitro in bone,^[117] red blood cells,^[121][93] neurons,^{[122][53][57]} fibroblasts,^[123] and liver cells.^[124]

One study has concluded, however, that antioxidative effects cannot fully explain cytoprotective effects of rhodiola.^[120]

Salidroside appears to both activate antioxidant enzymes and to also act upon PARP-1 and induce DNA repair machinery. The antioxidative effects seem to be best demonstrated with hydrogen peroxide

A standardized extract of rhodiola (3% rosavins and 1% salidroside) is able to competitively inhibit estrogen binding to the receptor in a concentration dependent manner^[125] and when given to ovarectomized rats fails to show estrogenic effects (and instead caused a nonsignificant anti-estrogenic trend in some rats due to increasing the metabolism of estradiol).^[125]

Preliminary evidence suggests that Rhodiola Rosea is anti-estrogenic

One study has noted that salidroside is able to induce mesenchymal cell division towards hepatocytes and, when assessing biomarker proteins (EROD, PROD, and LDL uptake) salidroside at 2µM appears to be as effective as hepatocyte growth factor (HGF; 20ng/mL) for inducing mesenchymal division over 4 weeks.^[126]

Appears to induce proliferation of liver cells from a common stem cell precursor, practical significance of these results currently unknown

Salidroside (25-100mg/kg) has been noted to reduce oxidative stress in the liver that is the result of exhaustive exercise^[119] which has also been noted with p-tyrosol, rosavin, and rosidrin (as well as rhodiola extract consumption).^[127]

A small trial (n=12) has associated rhodiola supplementation with half the risk for bladder cancer relapse^[128] and a later in vitro test noted that salidroside had suppressive effects on p53 deficient cells which was partly dependent on TSC2 expression; there was ultimately an activation of AMPK and suppression of mTOR signalling and its downstream targets (S6 and 4E-BP1) resulting in autophagic cell death.^[129] Concentrations as low as 5μg/mL were active on cancer cells, and 25μg/mL was unable to suppress noncancerous cells.^[129]

Salidroside has been noted to induce apoptosis in breast cancer cells on both MDA-MB-231 and MCF-7 cells, with an IC₅₀ of 10μM and 20μM respectively.^[130] Salidroside was confirmed in this study to not be an estrogen receptor antagonist (which can induce apoptosis in MCF-7 cells) and was noted to induce apoptosis in both cell lines in a concentration dependent manner.^[130] Elsewhere, the IC₅₀ for salidroside in inhibiting proliferation was calculated at 3.2μg/mL (MDA-MB-231) and 6.5μg/mL (MCF-7).^[131]

Salidroside has also noted protection against the cardiotoxic effects of a common breast cancer chemotherapeutic known as epirubicin.^[91]

Salidroside has shown inhibitory effects on the gastric cancer cell line SGC-7901 with an IC₅₀ value for inhibiting cell proliferation of 6.1μg/mL.^[131]

Nicotine is the primary stimulatory alkaloid in cigarettes and some smoking aids. In mice conditioned to nicotine via injections who exhibited withdrawal behaviours (anxiety and locomotor changes) noted that oral ingestion of Rhodiola at 10-20mg/kg during nicotine therapy reduced anxiety by more than 50% (appeared to be dose dependent, but 10mg/kg was not significantly different than 20mg/kg) with similar effects seen with acute usage of Rhodiola (20mg/kg) after nicotine was ceased.^[132] This study also noted that Rhodiola was able to abolish all somatic symptoms of withdrawal in these mice.^[132] A later study in rats with similar methodlogy confirmed these effects^[34] and noted that the mechanisms appear to be serotonergic in nature as the serotonin receptor antagonist (WAY 100635) abolished the effects and nicotine treated animals appeared to have lower levels of serotonin in their brain (which Rhodiola normalized).^[34]

Limited evidence, but rhodiola at fairly reasonable oral doses (20mg/kg in mice and 40mg/kg in rats correlates to a human estimated dose of 1.2mg/kg or 80mg for a 150lb person) can greatly suppress or eliminate physical symptoms of smoking cessation (nicotine withdrawal). Cognitive symptoms (anxiety being measured) are somewhat less affected

Weikang Keli is a traditional chinese medicine for gastric cancer which consists of Atractylodis macrocephalae, Curcumae Aeruginosae, the rhizome of Pinelliae, codonopsis pilosula, rhodiola rosea, and Actinidia chinensis (1:1:1:2:2:2 ratio). It has been demonstrated in SGC-7901 stomach cancer cells to inhibit proliferation in a concentration and time dependent manner with an IC₅₀ of 0.2g/mL via autophagic mechanisms.^[133] In mice implanted with tumors, 2,400-9,600mg/kg of the herbal therapy was able to reduce tumor mass by 43%, 55%, and 57% respectively with the active control of 5-fluorouracil (15mg/kg) reducing tumor size by 51%.^[133]

A study investigating the influence of hypericum perforatum on binge eating noted that 250-500mg/kg (but not 125mg/kg) of this herb was able to reduce binge eating episodes in female rates conditioned to hyperpalatable foods. The addition of 312mcg/kg salidroside to the ineffective dose of St.John's wort (125mg/kg) was able to synergistically enhance the anti-binge eating effect.^[71] It should be noted that higher doses of salidroside (20mg/kg or a 3.12% extract; or 624mcg/kg) are able to abolish binge eating in this model.^[69]

Salidroside (from rhodiola) can make subeffective doses of St.John's wort more effective in aiding binge eating. Although synergistic, the practical implications of this are limited as rhodiola in isolation is effective in abolishing binge eating in this rat model

One study found issues involving possible inaccurate labeling of Rhodiola supplements^[134]. On study examined 39 Rhodiola products obtained through various UK consumer outlets found that 23% of them contained no detectable levels of rosavin, which is a key marker that distinguishes Rhodiola rosea from other species of Rhodiola. Two of the products did not contain any salidroside, either, which is found in other species of Rhodiola, including Rhodiola rosea, indicating not Rhodiola product was present at all. Furthermore, 80% of the samples that did contain rosavin had levels lower than a traditional herbal registration sample that was used as a reference. Finally, one supplement had 5-HTP, which is normally not found in Rhodiola, and is used for antidepressive or weight loss purposes.^[134]

One study has found that some commercial Rhodiola rosea supplements may be adulterated.

In human trials that use Rhodiola supplementation, there do not tend to be side effects associated with treatment that are deemed to be clinically relevant.^[61]