Salidroside

Salidroside: A Comprehensive Reference Article

1. Identity and Chemical Characterization

1.1 Nomenclature and Chemical Structure

Salidroside is chemically named 2-(4-hydroxyphenyl)ethyl-beta-D-glucoside, with the molecular formula C₁₇H₂₀O₇ and a relative molecular mass of 300.3. It is classified as a phenolic glycoside widely found in Rhodiola plants. The compound is also known in the scientific literature by several synonyms, including p-hydroxyphenylethyl-O-β-D-glucopyranoside and rhodioloside. Salidroside (p-hydroxyphenylethyl-O-β-D-glucopyranoside) and its aglycone metabolite p-tyrosol are two major phenols found in the genus Rhodiola.

The chemical structure of salidroside, as one of the main bioactive compounds in Rhodiola rosea extracts, contains phenolic hydroxyl groups and unsaturated bonds. Salidroside, a phenylpropanoid glycoside, is the main active component found in all species of Rhodiola.

1.2 Botanical Sources

Rhodiola is a genus of a perennial succulent plant in the Crassulaceae family that produces flowers ranging in color from yellow to red. Having more than two hundred species in total, Rhodiola is widespread in high-altitude places, such as mountainous regions in Asian and European countries. Its habitat includes the southwestern part of China, India, Pakistan and North Korea, as well as Russia, Europe (especially the Alps), and America.

The main sources of salidroside in Rhodiola plants are Rhodiola sachalinensis, Rhodiola rosea, Rhodiola tibetica, and large Rhodiola. Ligustrum lucidum has also been found to contain a large amount of salidroside. In addition, salidroside has been identified in the leaves of Salix triandra L. and willow bark, Vaccinium vitis-idaea L. leaves, and Veronica minor.

A key practical distinction is that salidroside is found across many Rhodiola species, but rosavins are unique to Rhodiola rosea. Salidroside can be found in all Rhodiola species with concentrations ranging from 1.3 to 11.1 mg/g.

Salidroside's biosynthetic origin is well characterized at the molecular level. The salidroside biosynthetic pathway in Rhodiola rosea was described in 2018. Rhodiola contains a pyridoxal phosphate-dependent 4-hydroxyphenylacetaldehyde (4-HPAA) synthase that converts tyrosine to 4-HPAA, which is further reduced to tyrosol by 4-HPAA reductase. Subsequent glycosylation of tyrosol yields salidroside.

1.3 Other Key Constituents of Rhodiola

Salidroside is one of several recognized bioactive markers in Rhodiola rosea. The samples from Rhodiola rosea underground organs have been evaluated in terms of the content of tyrosol derivatives (salidroside and its aglycone tyrosol) as well as rosavins (trans-cinnamic alcohol derivatives, including rosavin, rosarin, rosin, and trans-cinnamic alcohol). The broad spectrum of biological activity of R. rosea is attributed to its major phenyletanes and phenylpropanoids: rosavin, salidroside, rosin, cinnamyl alcohol, and tyrosol.

1.4 Common Forms and Preparations

Extracts of R. rosea roots and rhizomes are mostly sold in the form of tablets or capsules for oral administration. In Europe, the Committee on Herbal Medicinal Products (HMPC) provides a monograph for R. rosea that requires a drug-to-extract ratio of 1.5–5:1, using 67–70% ethanol as extraction solvent. Products are standardized to salidroside and rosavin content to ensure therapeutic efficacy.

An important development in the production of salidroside is the emergence of bioengineered or fermentation-derived forms. In vitro research has examined bioengineered, nature-identical salidroside for its drug interaction potential. Studies utilizing Rhodiola rosea, which contains a complex mixture of phytochemicals, reported some drug–drug interaction (DDI) findings, and the variation in and multiplicity of constituents present in Rhodiola products is a cause for concern for accurately evaluating DDI risk. The effects of bioengineered salidroside were examined on the inhibition potential against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 using human liver microsomes, the induction potential on CYP enzymes in cryopreserved human hepatocytes, the inhibitory potential against human MAO-A and MAO-B, and the OATP uptake transport inhibitory potential using transfected HEK293 cells.

Source material from cultivated plants is recommended — wild-harvested material is covered by CITES Appendix II since 2023.

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2. Traditional and Historical Use

2.1 Cross-Cultural Ethnopharmacological Record

From empirical belief to research studies, Rhodiola has undergone a long history of discovery, and has been used as traditional medicine in many countries and regions for treating high-altitude sickness, anoxia, resisting stress or fatigue, and for promoting longevity.

As early as 200 A.D., Rhodiola was documented as a medicinal botanical drug in both Tibetan and Chinese medical texts for treating cardiovascular diseases. Salidroside has been identified as one of the most potent compounds isolated from various Rhodiola plants, which have been used for a long time as adaptogens in traditional Chinese medicine.

Rhodiola rosea (Crassulaceae), which is widely growing in Northern Europe, North America, and Siberia, has been used since ancient times to alleviate stress, fatigue, and mental and physical disorders.

2.2 Preparations and Purposes in Traditional Systems

The Rhodiola species have been known as a traditional medicine in Asian and eastern European countries to maintain overall health and are considered to be a source of adaptation to environmental challenges. It has been used as an adaptogen in people with high-intensity work, as well as in some special professions including athletes, mountaineers, pilots, and astronauts, to improve the body's ability to adapt to adverse circumstances.

Rhodiola is a perennial flowering herb, which grows mainly in the Himalayas, Northwest Asia, North America, and other alpine regions. It is known as 'plateau Panax ginseng' for its tenacious vitality and resistance to hypoxic conditions.

Salidroside is a constituent of the traditional medicinal plant Rhodiola rosea L., which has been used to increase physical endurance and resistance to depression, among others.

2.3 Regulatory Recognition of Traditional Use

Based on accumulated studies and clinical data, the EMA's Community Herbal Monograph on Rhodiola rosea L. rhizoma et radix (EMA/HMPC/232091/2011) approved its use for the temporary relief of symptoms associated with stress, such as fatigue, exhaustion, and mild anxiety, for traditional use only. The European Medicines Agency issued a revised herbal monograph on Rhodiola rosea rhizome and root in March 2024 (EMA/HMPC/24177/2023), reflecting the most comprehensive regulatory evaluation of this plant in Europe.

Rhodiola rosea L. is officially listed in the United States Pharmacopeia and is included in the pharmacopoeias of several countries in the Eurasian Economic Union, such as Russia and Belarus, where it is used in officinal medicine.

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3. Key Constituents and Mechanisms of Action

3.1 Antioxidant Activity

The chemical structure of salidroside, containing phenolic hydroxyl groups and unsaturated bonds, allows these compounds to be effective at scavenging reactive oxygen species (ROS). Salidroside is able to increase the expression of antioxidant enzymes (e.g., glutathione peroxidase, GPx) and activate the nuclear erythroid 2-related factor 2 (Nrf2) pathways in rats to protect against bleomycin-induced pulmonary fibrosis and to reverse ultraviolet B-induced DNA damage in HaCaT cells.

3.2 AMPK Pathway Activation

Salidroside has been shown to stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). A study reported that salidroside ameliorated insulin resistance through activation of an AMPK/PI3K/AKT/GSK3β pathway. Under diabetic stimuli, salidroside suppressed reactive oxygen species production and restored mitochondrial membrane potential via reducing NOX2 expression and inhibiting the JNK–caspase 3 apoptotic cascade to protect β-cell survival. Diabetes-associated oxidative stress also activated FOXO1 and triggered nuclear exclusion of PDX1, resulting in β-cell dysfunction. This was reversed by salidroside by activating AMPK-AKT to inhibit FOXO1 and recover PDX1 nuclear localization.

3.3 HIF-1α and Hypoxia Pathways

Salidroside can stimulate the accumulation of hypoxia-inducible factor (HIF)-1α under hypoxia conditions, decrease hypoxia-induced injury of cells, and protect cardiomyocytes from hypoxia/reoxygenation injury, indicating the potential of salidroside in combating hypoxia injury. Salidroside is a phenolic compound widely found and extracted from the rhizomes and tubers of Rhodiola plants. Compared with other adaptogens in traditional medicine, salidroside has unique value in anti-hypoxia, antioxidation, and anti-inflammation. For example, Astragaloside and Ginsenoside indirectly play an anti-hypoxia role by enhancing the body's immune function and improving cardiac function. Salidroside can directly stimulate the production of erythropoietin, thereby improving the oxygen-carrying capacity of blood and effectively alleviating hypoxia damage.

3.4 Neuroprotective Signaling

Salidroside not only inhibits oxidative damage in the brain and alleviates neuroinflammation, but also reduces Aβ production and aggregation and attenuates Aβ-induced neurotoxicity and cell death, thus ameliorating learning, memory, and cognitive deficits. The underlying mechanisms may involve the IR-AMPK-AKT/CREB, MAPK, PI3K-AKT, Nrf2/HO-1, NAMPT-NAD+-SIRT1, TLR4/AKT, NLRP3-ASC-Caspase-1, SIRT1-NF-κB, BACE1, and Caspase-3/Caspase-9 signaling pathways.

In Parkinson's disease models, salidroside markedly attenuated MPP+/MPTP-induced declines in cell viability, accompanied by decreases in reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxy-deoxyguanosine (8-OHdG) contents, and increases in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione (GSH) levels. It greatly improved behavioral performance and prevented the severe reduction of TH-positive neuron numbers in the substantia nigra. Salidroside increased the nuclear translocation of DJ-1 and Nrf2 and the mitochondrial translocation of DJ-1, accompanied by activating complex I.

3.5 Anti-Inflammatory and Anti-Apoptotic Mechanisms

Salidroside can enhance cell survival and angiogenesis while suppressing oxidative stress and inflammation, and thereby has been considered a potential compound for treating ischemia and ischemic injury.

Salidroside has beneficial effects on atherosclerosis through multiple pathways. These include the regulatory effect of salidroside on atherosclerosis through protecting against atherosclerosis by ameliorating endothelial dysfunction, suppressing macrophage activation and polarization, inhibiting vascular smooth muscle cell (VSMC) proliferation, adjusting lipid metabolism, attenuating platelet aggregation, and modulating the gut microbiota.

3.6 SIRT1 and Mitochondrial Function

In neuroscience, salidroside demonstrates neuroprotective, antioxidant, anti-apoptotic, and anti-inflammatory effects, which are associated with improved learning and memory functions, protection of damaged synapses, reduction of neuronal apoptosis, and preservation of mitochondrial function.

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4. Scientific Evidence by Area of Use

4.1 Stress Adaptation and Anti-Fatigue Effects

Traditional / regulatory status: As noted above, the EMA HMPC has recognized Rhodiola rosea (the primary source of salidroside) for the traditional use indication of temporary relief of stress-related fatigue, exhaustion, and mild anxiety. This classification reflects a traditional use designation rather than a well-established medicinal use, meaning that supporting clinical data, while present, are not yet considered sufficient for the latter category under European pharmaceutical law.

Human evidence: Although Rhodiola rosea extract and its key constituent salidroside have been researched, data in humans are limited. Salidroside has demonstrated neuroprotective and anticancer effects in vitro. Animal data suggest benefits on cognitive function, but most studies were determined to have a high risk of bias. In humans, preliminary data suggest rhodiola supplementation may improve physical endurance and mental performance, and reduce fatigue and stress. Other small studies suggest it may improve symptoms of generalized anxiety disorder and mild to moderate depression.

In 2000, V. Darbinyan et al. conducted a double-blind crossover study to investigate the effects of a standardized extract of R. rosea (SHR-5) administered as a repeated low-dose treatment on the mental performance of healthy doctors during night shifts. The experiment lasted two weeks. The results showed that fatigue scores were reduced and cognitive ability and overall mental performance were enhanced compared to placebo.

In an endurance exercise performance test, 24 healthy volunteers who were treated with 100 mg of R. rosea extract (containing 3% rosavin + 1% salidroside) exhibited significant increases in time to exhaustion, VO₂, VCO₂, peak O₂ output, and peak CO₂ output.

Limitation note: Most human evidence still comes from Rhodiola extracts, not salidroside alone. This is a critical distinction: the clinical evidence for the parent plant extract — which contains salidroside along with rosavins and other compounds — cannot be straightforwardly attributed to salidroside as an isolated compound. The prevailing view is that Rhodiola's effects arise from a multi-compound synergy rather than a single "active ingredient." Whole Rhodiola rosea extracts likely better reflect the combined effects of both compounds, whereas isolated salidroside may act through narrower mechanisms.

4.2 Cognitive Function and Mental Fatigue

Salidroside from Rhodiolae Crenulatae Radix Et Rhizoma is used as an adaptogen in Northern Europe and Russia and as a traditional herb in China. Studies have shown that it can improve attention in cognitive function during fatigue.

A number of studies have revealed that salidroside exhibits neuroprotective activities, including anti-Alzheimer's disease, anti-Parkinson's disease, anti-Huntington's disease, anti-stroke, and anti-depressive effects; it is also useful for improving cognitive function, treating addiction, and preventing epilepsy.

Evidence strength: There have been few clinical trials on the beneficial effect of salidroside in the general population, and the most effective clinical dose is unclear. Most available findings regarding cognitive protection derive from preclinical (in vitro and animal) models. Extrapolation to human outcomes requires further prospective, randomized, controlled trials with salidroside as the isolated intervention.

4.3 Mood and Depression

Small studies suggest that Rhodiola preparations may improve symptoms of generalized anxiety disorder and mild to moderate depression. The EMA monograph cites the traditional use for stress-related fatigue and mild anxiety.

Emerging evidence indicates that salidroside possesses a wide spectrum of pharmacological properties, including activities on the cardiovascular system and central nervous system, anti-hypoxia, anti-fatigue and anti-aging activities, anticancer activity, anti-inflammatory activity, antioxidant activity, antivirus and immune stimulation activities, antidiabetic activity, and anti-osteoporotic activity.

Evidence strength: Evidence for depression and anxiety is still preliminary. Most available data are from studies of Rhodiola rosea standardized extracts in small populations, or from animal models. Human data specifically on isolated salidroside in mood disorders are sparse.

4.4 Cardiovascular System

According to Modern Practical Materia Medica, R. rosea L. has the following effects: central inhibitory effect, antifatigue effect, promotion of cardiovascular function, anti-inflammatory effect, hypoglycemic effect, antiperoxidation effect, and antiradiation effect.

Accumulating studies show that salidroside plays a protective role by suppressing cardiovascular risk factors and the development of coronary heart disease, heart failure, stroke, and pulmonary hypertension.

Atherosclerotic cardiovascular disease is currently the leading cause of death worldwide. Its pathophysiological basis includes endothelial dysfunction, macrophage activation, vascular smooth muscle cell (VSMC) proliferation, lipid metabolism, platelet aggregation, and changes in the gut microbiota. Salidroside has beneficial effects on atherosclerosis through multiple pathways.

Salidroside has the ability to directly reshape the gut microbiota and also indirectly influences it through reducing inflammation, enhancing gut and mucus layer integrity, promoting appropriate immune responses, and increasing antimicrobial peptide production.

Evidence strength: The body of cardiovascular evidence for salidroside is extensive but consists overwhelmingly of in vitro cell-culture and animal model data. There are currently no large randomized human clinical trials demonstrating reduced cardiovascular events with salidroside supplementation. In animal models, salidroside has shown protective effects in ischemic heart disease, atherosclerosis, and pulmonary hypertension. It appears to reduce oxidative stress in blood vessels, improve endothelial function, and limit cell death after restricted blood flow. These actions may help preserve heart tissue after ischemia and slow plaque development in arteries. So far, there are no large clinical trials proving cardiovascular event reduction.

4.5 Neuroprotection: Alzheimer's and Parkinson's Disease

Salidroside not only inhibits oxidative damage in the brain and alleviates neuroinflammation but also reduces Aβ production and aggregation and attenuates Aβ-induced neurotoxicity and cell death, thus ameliorating learning, memory, and cognitive deficits. The underlying mechanisms may involve multiple signaling pathways. Salidroside has shown great promise as an adjunctive agent for the treatment of Alzheimer's disease (AD) and cognitive impairment, and thus it may be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

Regulation of the microbiota-gut-brain axis by salidroside has been observed in the context of the Alzheimer's disease model. It has shown efficacy in models of neurodegenerative diseases and cognitive impairment, including Alzheimer's disease and Parkinson's disease, as well as in models of depression and anxiety.

Future research should focus on optimizing delivery methods to enhance central nervous system bioavailability, further elucidating molecular mechanisms, and conducting well-designed clinical trials to confirm therapeutic efficacy and safety in neurodegenerative and neuropsychiatric disorders.

Evidence strength: Neuroprotective data for salidroside in Alzheimer's and Parkinson's disease exist primarily in preclinical (cell culture and rodent) models. No human clinical trials have yet confirmed these effects for salidroside specifically as an isolated compound in diagnosed patients.

4.6 Ischemic Disease (Stroke, Cardiac Ischemia)

Salidroside can enhance cell survival and angiogenesis while suppressing oxidative stress and inflammation, and thereby has been considered a potential compound for treating ischemia and ischemic injury. Research highlights advances in salidroside in treating ischemic diseases, such as cerebral ischemia, ischemic heart disease, liver ischemia, ischemic acute kidney injury, and lower limb ischemia.

Salidroside has shown potential as a neuroprotective agent for the treatment of ischemic stroke. It has been found to reduce cerebral infarction, prevent cerebral edema, and improve neurological function. Salidroside's neuroprotective effects are attributed to its ability to inhibit excitotoxicity, oxidative stress, inflammation, apoptosis, and damage to the blood-brain barrier.

Salidroside exerts powerful therapeutic effects on ischemic stroke in experimental models, both in vitro and in vivo, due to its neuroprotection, significantly diminishing infarct size, preventing cerebral edema, and improving neurological function. The underlying mechanisms involve anti-oxidation, anti-inflammation, and anti-apoptosis by regulating multiple signaling pathways and key molecules, such as NF-κB, TNF-α, and the PI3K/Akt pathway.

Evidence strength: Confined to preclinical models. No human clinical trials specifically for salidroside in ischemic stroke or cardiac ischemia have been published as of the most recent literature.

4.7 Diabetes and Metabolic Disease

There are only a few reports about hypoglycemic effects of salidroside, which are focused on improving insulin sensitivity. For example, salidroside has been shown to stimulate glucose uptake in skeletal muscle cells by activating AMP-activated protein kinase (AMPK). A study reported that salidroside ameliorated insulin resistance through activation of an AMPK/PI3K/AKT/GSK3β pathway.

In animal model studies, salidroside dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Salidroside has also been shown to protect cardiomyocytes from oxidative injury by activating the PI3K/Akt pathway and to stimulate glucose uptake in skeletal muscle cells by activating AMPK.

Evidence strength: As with cardiovascular evidence, antidiabetic effects of salidroside are established at the preclinical level (cell culture and rodent models). There are no published large-scale human trials demonstrating glycemic efficacy for salidroside as an isolated compound.

4.8 Physical Performance and Exercise

A recent human study using isolated salidroside examined endurance and high-intensity exercise performance. In that trial, healthy active adults took 60 mg/day of bioengineered salidroside for a short period. The results suggested improved oxygen utilization and reduced markers of exercise-induced muscle damage, with no serious adverse events reported. While promising, one trial is not enough to define broad clinical benefits.

In a separately designed endurance exercise performance test, 24 healthy volunteers who were treated with 100 mg of R. rosea extract (containing 3% rosavin + 1% salidroside) exhibited significant increases in time to exhaustion, VO₂, VCO₂, peak O₂ output, and peak CO₂ output.

In humans, preliminary data suggest rhodiola supplementation may improve physical endurance and mental performance, and reduce fatigue and stress.

Evidence strength: Preliminary in humans. Exercise-related evidence exists for standardized Rhodiola extracts (which contain salidroside among other compounds) at small-trial level. Studies using isolated salidroside in humans are very limited in number and scale.

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5. Body Systems and Health Areas

Based on published preclinical and, to a lesser extent, clinical research, the body systems and health areas most investigated in relation to salidroside include:

• Central nervous system: Neuroprotection, anti-fatigue, anti-depressive effects, cognitive function, anti-Alzheimer's, anti-Parkinson's, anti-stroke.
• Cardiovascular system: Cardioprotection in ischemia, anti-atherosclerosis, antihypertensive effects in pulmonary hypertension models, endothelial protection.
• Endocrine and metabolic: Insulin sensitization, glucose metabolism, antidiabetic effects in preclinical models.
• Musculoskeletal: Anti-fatigue in exercise, reduction of exercise-induced oxidative damage.
• Immune system: Immunostimulating and anti-inflammatory activity.
• Oncology (preclinical): Anticancer activity documented in vitro.
• Respiratory: Pulmonary fibrosis protection (animal model), pulmonary hypertension.
• Gut microbiota: Emerging evidence for modulation of gut microbial composition with downstream systemic effects.

Several molecular mechanisms potentially responsible for the observed stress resistance, anti-aging, and anti-cancer effects of Rhodiola rosea extracts and its active compounds have been identified in in vitro cell culture systems and in vivo animal models. The biological mechanisms of the individual active compounds have both similarities to and differences from those of whole Rhodiola rosea extracts. Rhodiola rosea extracts and the main bioactive compound salidroside appear to have multi-targeted effects.

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6. Pharmacokinetics

In the plain environment, salidroside is rapidly absorbed after oral administration, reaching the maximum concentration within 0.5–1 hour, and it is widely distributed in various organs of the human body, mainly metabolized in the liver, and finally excreted through the kidneys. Tyrosol is the primary metabolite of salidroside in the human body, with pharmacological activities such as anti-inflammation, immune regulation, anti-cancer, and neuroprotection.

Salidroside is rapidly absorbed after oral administration. However, due to rapid metabolism and clearance, its oral bioavailability is only about 20%, which limits its druggability.

Salidroside's absorption is influenced by transport pathways, including the involvement of sodium-dependent glucose cotransporter (SGLT1) in active transport. Competitive inhibition during transport may limit absorption. It is primarily distributed in the liver and organs with rich blood flow. Efficient distribution is also observed in tissues such as fat, skeletal muscle, ovary, and testis. The liver is the main site of salidroside metabolism, involving phase I and phase II reactions.

Phenol glycosides have the potential for deglycosylation, resulting in aglycone metabolites in vivo. The glycoside forms are hydrolyzed by β-glucosidases to the aglycone forms in the jejunum, and the released aglycone forms are either absorbed intact by the intestine or further metabolized by intestinal microflora into several other products before absorption.

In pharmacokinetics, although showing rapid absorption and elimination, the bioavailability of salidroside is elevated under some non-physiological conditions. The compound and its metabolite (tyrosol) are capable of distributing to brain tissue, and tyrosol maintains a higher level of concentration there.

Rat pharmacokinetic studies have found short plasma elimination half-lives for salidroside. Following intravenous dosing at 7.5, 15, and 30 mg/kg in rats, the plasma concentration declined rapidly with a short half-life time of about 1 hour, and the data suggested linear pharmacokinetics between the three doses.

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7. Dosage Forms and Reported Dosages

It is important to note that the large majority of clinical dosage evidence involves Rhodiola rosea standardized extracts (which are standardized for salidroside content) rather than isolated salidroside. Dosages for isolated salidroside in human studies are very limited.

• Per the EMA/HMPC Community Herbal Monograph, the specified herbal preparation for Rhodiola rosea is a dry extract with a drug-to-extract ratio of 1.5–5:1 using ethanol 67–70% v/v as extraction solvent, formulated as solid dosage forms for oral use.
• In one human exercise study, 100 mg of R. rosea extract standardized to contain 3% rosavin and 1% salidroside was administered to healthy volunteers.
• In one human trial using isolated salidroside, healthy active adults received 60 mg/day of bioengineered salidroside.
• A manufacturer-reported recommended dose of pure salidroside (bioengineered form) is 60 mg/day.
• The salidroside content may vary according to the type of Rhodiola-based supplement (between 0.5 and 3%).
• Recovery after exercise was examined following treatment of untrained subjects with 340 mg RHODAX (a preparation containing 30 mg of the active substances of R. rosea extract) twice a day for 30 days before and 6 days after exhausting physical exercise.

The EMA monograph applies to standardized extracts for traditional use; no official therapeutic dose for salidroside as a single isolated compound has been established by a major regulatory body. Dosing regimens identified in human research remain based on small or preliminary trials.

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8. Safety Considerations and Drug Interactions

8.1 General Safety Profile

Emerging evidence indicates that salidroside is a promising environmentally-adapted drug with low toxicity and few side effects.

The safety of R. rosea extract has been tested in rats, mice, dogs, and humans. Rhodiola rosea has a very low level of toxicity. The LD50 after intraperitoneal injection of the liquid extract in mice was found to be 28.6 mL/kg, equivalent to approximately 3,360 mg/kg, and the equivalent dosage in a 70 kg human would be approximately 235 g.

Studies indicate that salidroside is a safe substance, with no obvious adverse reactions reported in preclinical and clinical trials.

8.2 Drug–Drug Interactions via CYP Enzyme Modulation

A rat study using a five-probe drug cocktail showed that salidroside had no significant effect on the activity of CYP2D6, but it could induce the activities of CYP1A2, CYP2B6, CYP2C9, and CYP3A4. This suggests that salidroside may accelerate biotransformation rates of CYP1A2, CYP2B6, CYP2C9, and CYP3A4 probe drugs, and reduce their pharmaceutical plasma concentration and clinical effects.

CYP enzyme-mediated (CYP1A2, CYP2B6, CYP2C9, and CYP3A4) herb-drug interactions between salidroside and other drugs must be given high priority to avoid the occurrence of adverse reactions. It is of interest to further investigate the clinical significance in future studies.

However, a more recent in vitro study using bioengineered salidroside at clinically relevant concentrations came to a different conclusion: at concentrations of <2 µM (based on a 60 mg oral dose), salidroside showed no risk for drug–drug interaction due to CYP450 enzymes, MAO enzymes, or OATP drug transport proteins.

Variation in and multiplicity of constituents present in Rhodiola products is a cause for concern for accurately evaluating drug–drug interaction (DDI) risk. This caveat is important: the DDI risk seen in complex Rhodiola extracts may not be attributable to salidroside specifically.

8.3 Pharmacokinetic Interactions in Hypoxic Conditions

There is still a lack of clear research conclusions on whether the hypoxic environment (relevant given salidroside's traditional use at altitude) will further affect the absorption, distribution, metabolism, and excretion processes of salidroside by altering pathways such as the activity of metabolic enzymes in the body, organ blood flow, or the expression of membrane transporters.

8.4 Specific Population Considerations

Salidroside is generally considered safe, but caution is advised during pregnancy and when used alongside other medications due to potential drug–drug interactions. The EMA HMPC monograph restricts the traditional-use indication to adults 18 and over, given the lack of clinical data in pediatric populations.

8.5 Conservation and Adulteration Risks

Global demand for medicinal plants such as R. rosea rootstock and its compound salidroside has contributed to the species becoming rare and threatened in some regions, depleting a natural resource important for human health. Faced with resource depletion and environmental destruction, R. rosea and R. crenulata are becoming endangered, making them more economically valuable to collectors and middlemen, and also increasing the risk of adulteration and low quality. Rhodiola products have been subject to adulteration. Adulteration and species substitution in commercial products mean that stated salidroside content may not reflect actual content in all preparations.

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9. Summary of Evidence Strength

• Stress and fatigue (via Rhodiola extracts): Moderate human evidence at the small-trial level; recognized as traditional use by EMA. Evidence for salidroside specifically as the active principle is inferential, not directly demonstrated by isolated compound trials.
• Cognitive performance under fatigue: Preliminary human evidence from standardized extract trials; preclinical data for isolated salidroside are extensive but not validated in large human trials.
• Neuroprotection (Alzheimer's, Parkinson's): Preclinical evidence only; no confirmatory human RCTs.
• Cardiovascular and ischemic disease: Strong preclinical (cell and animal) evidence; no large human clinical trial evidence.
• Diabetes/metabolic disease: Preclinical evidence (cell culture and rodent); no large human clinical trial evidence.
• Physical performance: Preliminary and small-scale human evidence from extract trials; one small human study with isolated salidroside at 60 mg/day.
• Anti-cancer: In vitro and early animal evidence only; no clinical trial data.

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