By Sanem Hosbas Coskun, PhDa and Josef Brinckmannb
aAmerican Botanical Council, PO Box 144345, Austin, TX 78714
bTraditional Medicinals, 4515 Ross Road, Sebastopol, CA 95472
Citation (JAMA style): Hosbas Coskun S, Brinckmann J. Adulteration of eleuthero (Eleutherococcus senticosus) root and its extracts. Botanical Adulterants Prevention Bulletin. Austin, TX: ABC-AHP-NCNPR Botanical Adulterants Prevention Program; 2022.
Keywords: Acanthopanax senticosus, adulteration, adulterant, eleuthero, Eleutherococcus senticosus, Eleutherococcus spp., Periploca sepium, Siberian ginseng
Goal: This bulletin aims to provide timely information and/or updates on the adulteration of the root and root extracts of eleuthero (Eleutherococcus senticosus [Rupr. & Maxim.] Maxim.) to the international herbal industry and the extended natural products and natural health communities in general. It may be used as guidance for quality control personnel and members of the international phytomedicine, botanical supplement, and the extended natural products community in general. This bulletin is intended to provide a summary of the scientific data regarding the occurrence of eleuthero adulteration. In addition, information on the market situation, laboratory methods to detect adulteration, and economic and safety consequences for the consumer and the industry will be presented.
1 General Information
1.1 Common names: "Eleuthero" is the currently accepted common name for the plant in the United States1 and various other countries. However, even in recent publications, the common name "Siberian ginseng" is still broadly used.2 As required by the passage of the Farm Security and Rural Investment Act of 2002, signed into law in the United States on May 13, 2002, only roots of Panax species (Araliaceae) may be legitimately termed "ginseng".3 In a later amendment, that legal definition extended to the Food, Drug, and Cosmetic Act.4,5 The American Herbal Products Association's Herbs of Commerce (1992) and the International Code of Botanical Nomenclature (Tokyo Code) 1994 are the codified sources of common names used on dietary supplement product labels, establishing the name "Asian ginseng" for P. ginseng, "American ginseng" for P. quinquefolius, and "eleuthero" for E. senticosus.5-7 The name Siberian ginseng was first applied to eleuthero upon its introduction to the North American herbal market. "Siberian" comes from its primary area of distribution. Like the species of the Panax genus, it is a member of the Araliaceae family. Its earlier botanical name was Acanthopanax senticosus, which means thorny ginseng, a name that continues to persist in Asian literature.8 Its actions are considered similar to P. ginseng (section 1.7).
1.2 Common names in other languages9-13
Bulgarian: eleuterokok (елеутерокок)
Chinese: ci wu jia (刺五加)
Croatian: Sibirski ginsenga
Danish: Russisk rod
Dutch: Siberische/Russische ginseng
English: devil's shrub, eleuthero, Russian pepper bush, Siberian ginseng (see section 1.1)
Estonian: harilik eleuterokokk
French: eleuthérocoque, ginseng Sibérien
German: Eleutherococcus, Sibirischer Ginseng, Stachelpanax, Taigawurzel
Greek: píza eleftherokókkou (Pίζα Eλευθεροκόκκου)
Hungarian: Szibériai ginszeng, tajga gyökér
Icelandic: Síberíu ginseng
Japanese: shigoka (シゴカ), ezokogi (エゾウコギ)
Korean: gasiogapi (가시오갈피)
Lithuanian: juodasis eleuterokokas
Norwegian: Russisk rot
Romanian: ginseng Siberian
Russian: Элеутероко́кк колю́чий, Свободноя́годник колючий
Swedish: Rysk rot
Turkish: Sibirya ginsengi
1.3 Accepted Latin binomial:
Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.
1.4 Synonyms: The taxonomic resources of the Royal Botanical Garden at Kew include 11 scientific synonym(s) for this plant:14
Acanthopanax senticosus (Rupr. & Maxim.) Harms, Eleutherococcus senticosus f. subinermis Regel, Acanthopanax asperatus Franch. & Sav., Eleutherococcus senticosus f. inermis Kom., Acanthopanax senticosus f. inermis (Kom.) Harms, Acanthopanax senticosus f. subinermis (Regel) Harms, Eleutherococcus koreanus Nakai, Eleutherococcus asperatus (Franch. & Sav.) Koidz., Acanthopanax senticosus var. subinermis (Regel) Kitag., Acanthopanax senticosus var. brevistamineus S.F.Gu, Hedera senticosa Rupr. & Maxim.
1.5 Botanical family: Araliaceae
The genus Eleutherococcus has nearly 40 species, with 14 endemic to the People's Republic of China (PRC), and is naturally distributed in northeast Asia, Korea, Japan, and the southeastern part of Russia.15 Eleutherococcus senticosus is one of the well documented species with quality monographs published in several textbooks and national pharmacopeias.15-20 Eleuthero grows as a spiny-stemmed shrub with numerous stalks arising from the root, reaching a height of up to 9 feet in broadleaf and mixed broadleaf/conifer forests, especially in northern Asia. It usually grows in forests or thickets, elevated from hundreds to above 2000 m in altitude in the PRC.21,22 In the PRC, it is indigenous to Heilongjiang, Jilin, Liaoning, Inner Mongolia, Hebei, and Shanxi provinces. In Japan, the shrub occurs spontaneously on the northern island of Hokkaido. In Russia, the plant's distribution includes most of the Far East regions, extending to the Middle Amur region north to Sakhalin, and is most abundant in the Khabrarosvk and Primorsk districts. In the Amur region in Russia, the plant grows in Selemdzhinsky, Svobodnensky, Blagoveshchensky, Mazanovsky, Belogorsky, Romnensky, Bureysky, and Arkharinsky districts. The species can be found outside the region only in the south of the Far East (including Sakhalin). It is widely cultivated in private plots in the Far East and beyond.23
1.7 General use[s]:
Eleuthero is a typical adaptogen known to increase the ability to resist and cope with stress and is considered safe in long-term use at the appropriate dose level.24-27 Indications in traditional Chinese Medicine (TCM) for the use of E. senticosus include benefiting "qi" (vital energy), treating a deficiency of "yang" in the spleen and kidney, and normalizing body functions.28 Rejcek mentioned eleuthero as an adaptogen particularly prized for its energy-boosting properties.29 For use as an active ingredient of over-the-counter (OTC) registered Traditional Herbal Medicinal Products (THMPs) in the European Union (EU), the authorized indications are "for symptoms of asthenia such as fatigue and weakness."12 In Russian official medicine, eleuthero is considered an adaptogen and tonic. Liquid extracts of eleuthero (40% aqueous ethanol; 1:1) and coated tablets (100 mg dry extract) are available in Russia in pharmacies as an OTC medicine.30
1.8 Historical use[s]:
Eleuthero species have over 2000 years of use in TCM. However, the identification of the use of E. senticosus in TCM has been challenging. The confusion arises from the lack of definitive botanical identities and shared common names in historical documents. Su Song mentioned the concern about Cortex Acanthopanacis (wu jia pi in pinyin) identification in his book Tu Jing Ben Cao (Illustrated Herbs, 1062 CE).31 Records indicate that wu jia pi was initially obtained from several different species of the genus Acanthopanax, as well as from plants of other genera. Eleutherococcus senticosus was believed to be one of those species, later named as ci wu jia to prevent any further confusion.28 In the Ben Cao Gang Mu (Compendium of Materia Medica, printed in 1596), Li Shizhen noted the presence of spines on some regional forms of the medicinal material (referred to as ci wu jia) and listed these forms as a particular wu jia pi.32 He classified the plant in a group called Superior Herbs based on the earlier text Shen Nong Ben Cao Jing, in which these herbs are considered to be tonics and can be used for long periods of time in Chinese medicine.33 In current TCM wu jia pi and ci wu jia are considered two different drugs, the former is used for arthritis and the latter as a tonic.
2.1 Importance in the trade:
Eleutherococcus senticosus roots have been used for medicinal purposes for centuries by Chinese practitioners, and utilized in other Asian systems of medicine, such as traditional Japanese Kampo medicine and traditional Korean medicine. Harvest and trade of eleuthero raw materials to satisfy domestic demand requirements for medicines in hospitals and pharmacies in the PRC, Japan, Korea, and the Russian Federation are important factors followed by export trade, for example, to the European Union where eleuthero products are registered as THMPs and the United States where the same products are marketed as dietary supplements. It is not possible to quantify the export trade because no country has assigned a species-specific harmonized system tariff code (HS Code), necessary to track the value and volume of eleuthero shipments. It can be ascertained, however, from other sources of data, that the main eleuthero producing and exporting countries are the PRC and the Russian Federation. Relatively small amounts are harvested and traded in the Republic of Korea (South Korea) and Democratic People's Republic of Korea (DPR; North Korea).
A 2007 eleuthero raw material demand survey in the PRC estimated that the global annual requirement at that time was about 5,000 tons, 1,200 tons of which could be fulfilled from harvests in the PRC, meaning that approximately 3,800 additional tons originated outside of the country.34 The balance was likely wild collected in parts of the Russian Federation's Far Eastern Federal District. Estimates of annual quantities of eleuthero root that can be sustainably harvested in the Russian Far East (RFE) range from 1,655 tons to 2,900 tons.35,36
In the United States and European countries, market demand for eleuthero products, then marketed and labeled as Siberian ginseng began to increase in the late 1990s. In the United States, in 1996 and 1997, eleuthero was ranked 9th, and 10th on the top ten bestselling list for health remedies, respectively, and imported products of this plant had a market share of 3.1% of the $12 billion medicinal herbal industry in the United States.24,37,38
In the top-selling herbal dietary supplements list in the US Food, Drug, and Mass Market (FDM) retail channels in 2004, eleuthero ranked the 19th best-selling supplement.39 In 2008 and 2010, eleuthero was no longer among the 20 top-selling herbal dietary supplements in the FDM channel40,41 and had dropped to rank number 36 in the US FDM channel in 2011.42 This decline coincided with the prohibition of the use of the more familiar name Siberian ginseng in favor of the relatively unknown eleuthero and the inability of marketers to rebuild familiarity with the new standardized common name (R. Upton [AHP] email communication to S. Gafner, October 5, 2021).
While retail sales of herbal and botanical dietary supplements in the United States increased an estimated 5.5% in 2012, eleuthero supplements had decreased in popularity and were no longer ranked among the list of 40 top-selling herbal dietary supplements in the FDM in the years after 2011.43,44 From 2013 through 2017, eleuthero dietary supplement sales in the United States were between US $178,000–$227,000 in the natural channel, and between $975,000–$1,450,000 in the multi-outlet channel (formerly known as the FDM channel).
2.2 Supply sources:
Eleuthero root is wild collected for commercial trade in parts of the RFE, mainly in the Primorsky Territory,45,46 in the PRC's northeastern provinces of Heilongjiang, Jilin, and Liaoning, followed by the PRC's northern provinces of Inner Mongolia, Hebei, and Shanxi,34 and parts of North Korea.47 Due to rapidly declining wild populations, in recent years, the supply is increasingly sourced from semi-wild or natural fostering (replenishment planting in natural habitat) type cultivation sites in the PRC and South Korea. Because eleuthero root is slow growing and can take up to five years to develop high-quality roots, many farmers grow it instead for annual harvesting of its fresh aerial parts (fruits, leaves, stems), which can be more profitable.34,48 The dried ripe fruits are also used in TCM in northeastern China.49 The harvest (of roots, rhizomes, and stems) generally begins around mid-September, depending on the weather.
Roots of wild E. senticocus, P. ginseng, and Rhodiola rosea (Crassulaceae), rank among the most common wild-collected medicinal plants by hunters in the RFE for additional income.50 Since 2012, permits issued by the Ministry of Industry and Trade of the Russian Federation have been required for the legal harvest of wild eleuthero roots from the RFE for export across customs borders.36 A 2020 survey of rural residents in the Primorsky Territory found that wild collection of eleuthero root from September to November, for supplemental household income, is commonplace.51 It is also possible that some quantities of wild eleuthero are exported from North Korea into the PRC. North Korea lists E. senticosus as a wild plant species of high economic value in its national biodiversity action plan.52 While South Korea is a major market, with about 100 companies manufacturing eleuthero-containing products, about 95% of the raw material supply is imported from the PRC and the Russian Federation. That is because the wild populations in South Korea are rapidly declining, and commercial cultivation is still at a small scale. South Korea reportedly imports hundreds of tons of legally harvested eleuthero root each year, but the actual number is believed to be much higher if the quantity of illegally harvested wild eleuthero were calculated.53 The most recent survey of the Japan Kampo Medicine Manufacturers Association showed that in the five-year period between 2012 to 2016, about 505,628 kg of dried eleuthero root (about 101,126 kg annually) were used in Kampo medicines, the raw material imported almost entirely from the PRC.54
In a report published in 2005, Ball writes that most eleuthero root material is of Russian origin. According to the report, much of the eleuthero habitat in the PRC is lost, and Chinese harvesters are allowed to collect only the branches of the plant without a harvesting license.55 This has led to a situation in which much of the material sold in the PRC is smuggled in from Russia over the Amur River border. The eleuthero root from Russia was expensive (above US $2.00/kg in 2005) since buyers must pay certification fees and administration fees to the Russian harvesting co-operative. Material from Chinese traders can be purchased at a price that is more than 30% lower than the price of Russian roots.
The high demand in the PRC for wild eleuthero root, coupled with chronic poverty and high unemployment on the Russian side of the border, are drivers of illegal logging and poaching of wild eleuthero and wild ginseng as well as of endangered Siberian (Amur) tigers (Panthera tigris altaica).56 A survey of illegally trafficked plants seized by the Far Eastern Customs Administration of the Russian Federation over the period of 1999 to 2009 found that up to about 10 tons of poached eleuthero roots are seized annually at the border of the Primorsky Territory attempting to enter the northeastern PRC.57 The officially reported legal export trade levels of eleuthero root from the Primorsky Territory range in the tens of tons annually, but it is believed that the volume of illegally exported poached roots is much higher.58 A survey of border seizures since the onset of COVID-19 indicates that the highest volume of illegally harvested wild plants in the RFE were those with high demand in Chinese markets for use in TCM formulations for the treatment of viral and infectious diseases and as immunostimulant drugs, namely E. senticosus, P. ginseng, R. rosea, and Scutellaria baicalensis (Lamiaceae), among others.59
Wild eleuthero resources have been necessary enough for medicine and trade to warrant periodic population surveys in the PRC and Russia since the late 20th century. Until the 1980s, the estimated reserve in the PRC's three northeastern provinces (Heilongjiang, Jilin, and Liaoning), where eleuthero is mainly wild collected, was about 10,000 tons. Due to continuous destructive harvesting coupled with deforestation and land use changes, the annual yield from the three northeastern provinces dropped to about 3,000 tons by the end of the 1990s. By 2006, the total output from the region was 1,000 tons, and only 700 tons by 2007.34 In 2021, the total wild area of eleuthero in Heilongjiang was estimated at about 125,200 acres.60 In the former Soviet Union, in the 1970s, it was estimated that the biological reserve of eleuthero thickets covered about 16 million hectares (about 39.5 million acres), equating to approximately 85,000 tons of root, which meant that about 2,900 tons could be sustainably harvested annually in order to enable regeneration in the harvested plots. Plots need four to seven years to regenerate before harvesting can occur again.61 It is estimated that about 100 to 170 kg of roots can be harvested from each hectare (ha) of eleuthero thickets in humid forests and, in some cases, up to one ton/ha, but only about 10 to 12 kg/ha can be harvested in dry forest areas.36 The RFE Forest Management Plan estimated in 2012 that about 1,655 tons of eleuthero root were harvested in a year, with an estimated additional five tons of eleuthero leaves per year.35 According to data from the Wildlife Conservation Society's Tiger Friendly initiative, at least 20 tons of eleuthero roots and about five tons of leaves are harvested annually within the habitat of the endangered Siberian (Amur) tiger in the Primorsky and Khabarovsky territories of the RFE.62 There is some evidence of sustainable wild collection of eleuthero in the PRC. In 2013, an estimated 112,990 kg were harvested and traded from the PRC with organic wild crop certification.63
Regarding supply sources originating from cultivation, there are an estimated 60 hectares (about 148 acres) of eleuthero cultivation in South Korea, of which 22 hectares (about 54 acres) are in the mountainous, forested Gangwon Province. However, most of this is for seedling production, with a minor amount of harvested roots used domestically in herbal medicinal and health products.64 Cultivation efforts also began in the PRC in the late 20th century. A 2000 survey found about 824 acres of eleuthero cultivation area in the three northeastern provinces of the PRC. A 2006 survey found only about 500 acres of eleuthero farm area. It is grown as a three-to-five-year root crop that is not as profitable for farmers as other possible crops in the region. Much of the eleuthero is grown for harvest and trade of the fresh berries,48 or fresh leaves and tender stems that are supplied to farmers' markets and restaurants,34 as well as dried leaves for the growing eleuthero leaf herbal tea market.65 In 2021, announcements of significant government support to develop eleuthero industry clusters (including farm production bases, post-harvest processing facilities, and eleuthero product manufacturing sites) were made for both Heilongjiang Province and Jilin Province.60,65
In North America, seeds have become available in recent years, and experimental plots have been established in Montana, Oregon, and other states.66
2.3 Market dynamics:
The market dynamics of eleuthero production and trade, affecting access and commercial availability, pricing, quality, and authenticity or adulteration, are impacted because the wild genetic resource has been overexploited for several decades in its limited geographic range. As noted, the plants take up to seven years to regenerate after clearing, and commercial cultivation is only recently scaling up. To date, the slow-growing 3-5-year root crop has not yet been very profitable for farmers. More is earned from growing the crop for annual harvests of fresh aerial parts (berries and leaves). In the meantime, evidence shows (section 2.2) that some of the commercial supply originates from unpermitted illegal wild collection (poaching) smuggled across borders, undocumented and unquantified. The primary market for eleuthero raw materials is the PRC, where it is used in traditional Chinese medicines but is also valued added into extracts for the export market. Demand (in the PRC and the export market) is apparently increasing, which suggests that, until commercial cultivation can sufficiently scale up to surpass the demand for wild-collected eleuthero, a market for poached eleuthero will continue to exist and, furthermore, predictable shortage conditions may invite adulteration or substitution. The provincial governments of Heilongjiang and Jilin are both initiating large projects to develop and scale-up eleuthero production bases. As a multi-year root crop, it may take another decade to stabilize the production scenario to match market demand.
Where dried eleuthero root is traded at the big TCM materials markets, the average market price has been relatively stable over the period of 2016–2021. Figure 1 shows the average market price [Chinese yuan (CNY) per kg; 1 USD = 6.46 CNY on July 29, 2021] from January 2016 through July 2021 at three major TCM markets, averaging around 28 CNY/kg at Anguo TCM Market (Hebei), 24 CNY/kg at Bozhou TCM Market (Anhui), and 30 to 32 CNY/kg at Yulin TCM Market (Guangxi).67 The prices paid to producers at origin can be about one-third of the market price. For example, the average price paid for eleuthero roots to producers in Dunhua, Jilin province, remained stable from 2020 to 2021 at about 9 CNY/kg. Similarly, Shangzhi, Heilongjiang province prices have ranged between 9 to 10 CNY/kg.
Besides related species from the genus Eleutherococcus, eleuthero root is also adulterated with Periploca sepium, also known as Chinese silk vine, a member of the family Apocynaceae. Additionally, reports of an increase in the harvest of eleuthero fruits, leaves, and stems (sections 2.2 and 2.3) suggest a higher likelihood that some of these aerial parts may be used to prepare extracts and sold as eleuthero root extracts. Eleuthero root has also been used as an adulterant for Panax species. However, the admixture to or substitution of Panax spp. with eleuthero is not further discussed in this review.
3.1 Known adulterants:
In 1990 a "hairy baby" case report was published by the Journal of the American Medical Association, claiming association of neonatal androgenization with maternal "ginseng" use in Canada.68 Follow-up research by the Natural Products Section, Bureau of Drug Research, Health and Welfare Canada, pointed out the egregious errors in the report and revealed that the product in question did not contain eleuthero, but instead contained Periploca sepium.69 However, the particular P. sepium constituents responsible for the androgenization effects and the mechanism by which they were produced have not been elucidated.68,70
The literature points to confusion among the vernacular names of Eleutherococcus species and regional differences in using various Eleutherococcus species as sources for Chinese medicine.71 In the Chinese Pharmacopoeia, ci wu jia is the root, rhizome, or stem of E. senticosus (Radix et Rhizoma seu Caulis Acanthopanacis senticosi), while wu jia pi is the root bark of E. nodiflorus (syn. E. gracilistylus, Acanthopanax gracilistylus, Cortex Acanthopanacis).8,72 Another common name for eleuthero, wu jia shen, is quite popular in usage (W. Lau [NuHerbs] email to S. Gafner, October 11, 2021). Chinese herbal literature refers to both E. senticosus and E. nodiflorus as "Eleutherococcus"—suggesting both can be used interchangeably—but making it somewhat confusing to distinguish the two related species based on their names. Additionally, 80 percent of Cortex Acanthopanacis in the Chinese domestic market is estimated to be a plant from a distinctly different plant taxon, P. sepium. In TCM, P. sepium is referred to by its pinyin name of xiang jia pi or northern wu jia pi,73 a species whose bark also has a long history of use in TCM and is recognized as containing cardiac glycosides. The taxonomy of Acanthopanax is based mainly on morphological characteristics.74 However, their characteristics sometimes are of limited use in species identification, and therefore, ingredients may be unintentionally used interchangeably. In fact, two species, E. nodiflorus and P. sepium are mentioned as a common adulterant for Cortex Acanthopanacis in A Materia Medica for Chinese Medicine.75
To summarize the plants known to be adulterants of E. senticosus, the Latin and vernacular names of the plants are given in Table 1.76
3.2 Sources of information supporting the confirmation of adulteration:
Numerous publications report on the adulteration of eleuthero and the confusion and interchangeable use with other Eleutherococcus species in TCM. In an authenticity study for herbal medicines from Chinese markets using DNA barcoding, of the two Acanthopanacis Senticosi Radix et Rhizoma Seu Caulis (ci wu jia) samples, one was identified as Alangium chinense (Cornaceae) and the other was another undisclosed plant from the genus Aralia. In the same study, E. giraldii and P. sepium parts were found to be the adulterants of Acanthopanacis Cortex (wu jia pi).77 In a PhD thesis study, mislabeled material bought as E. senticosus at a market in Kunming was found to be dried cortex of P. sepium.78 A survey of Japanese and Chinese products published in 2017 reported that E. sessiliflorus was found in nine of 25 (36%) supplements labeled as E. senticosus.79 DNA sequencing and chemical analyses were used to determine the correct species and chemical constituents of 22 commercial products sold as E. senticosus rhizome in Japanese markets. Results showed that one-third of the products originated from the incorrect species. Eleutheroside B and isofraxidin were recognized as marker substances to distinguish eleuthero from its adulterants by chemical analysis.10 In 2019, Wang et al. published the results from an evaluation of the authenticity of commercial products sold in the PRC as ci wu jia tea. Out of the 11 commercial products, three products were discovered to contain green tea (Camellia sinensis, Theaceae) that was considered an adulterant since it was not an ingredient declared on the labels.22
Confusion among Eleutherococcus species is also evident from papers investigating the authenticity of E. nodiflorus. Brand et al. noted the frequent confusion between E. nodiflorus root bark and Periploca root bark.76 There are two other species mentioned in this paper that can be confused with E. nodiflorus, i.e., Hedyotis hedyotidea (Rubiaceae) and E. giraldii. A review of misidentified ingredients used in TCM by the Taiwan Food and Drug Administration included testing results from five samples, all of which were found to contain P. sepium.80 In the Hooper Collection (HC, a collection of drugs acquired from Chinese herbal pharmacies in Malaysia around 1924) with the holdings relevant to Chinese medicine, a specimen of H. hedyotidea was labeled as wu jia pi where a specimen of E. giraldii was labeled as chuan jia pi (wu jia pi from Sichuan province), providing a bit of historical context to the nomenclatural issues surrounding the genus Eleutherococcus. The HC also contained a comparison specimen that was consistent with P. sepium, and a specimen of E. henryi that could not be botanically identified. Thus, the samples derived from several different species were grouped under the name wu jia pi.76
3.3 Accidental or intentional adulteration:
In most cases, adulteration occurs because of insufficient identification and similarities in Chinese names. Traditional Chinese herbal drug names often represent "plant complexes" that include more than one species. In PRC, Latin scientific names (the binomial method) began to be systematically applied for the botanical identification of Chinese medicinal materials (CMM) only in the early 20th century. Significant research is needed to identify which species were in use during different historical periods. Eleutherococcus nodiflorus, known in Chinese as wu jia pi, is translated as "Eleutherococcus" in some of the herbal literature, making it prone to confusion with its closely related species, E. senticosus.
On the other hand, Leon and Lin note that the root bark of periploca is a frequent substitute of E. nodiflorus.81 According to these authors, the reasons for this substiution could be the legacy from former editions of the Pharmacopoeia of the PRC, where periploca was permitted to be used as wu jia pi, but also the wide geographical distribution and easy access to periploca in many areas of the PCR, making it a more affordable (i.e., lower cost) ingredient compared to E. nodiflorus. The same argument for economically motivated adulteration can be made for E. senticosus as the average market price of xiang jia pi (approximately 13 CNY/kg in 2020 and 2021) is much lower than the average market prices of ci wu jia (approximately 28 CNY/kg in 2021, Figure 1).82,83
3.4 Frequency of occurrence:
While data from large-scale investigations are missing, the available reports suggest that admixture or substitution with other Eleutherococcus species and confusion with P. sepium are common.
3.5 Possible safety/therapeutic issues:
In general, only a small number of minor adverse events have been reported with eleuthero dietary supplementation. There has been one call or suggestion that more systematic studies are needed.84 A few case studies report adverse events linked to eleuthero intake, although the authenticity of the products involved was never verified. One such case involves a 70-year-old woman taking one capsule daily of a food supplement labeled to contain 400 mg of the root of E. senticosus and vitamins for 16 years, who was found to have hypertension (170 mmHg systolic/100 mmHg diastolic). Her blood pressure returned to normal when she stopped taking the supplement. Re-exposure caused a rise in blood pressure. There have been other case reports with patients taking products labeled as containing eleuthero having elevated blood pressure.85 On the other hand, the clinical trials reviewed led to the conclusion that the "arterial hypertension" contraindication for eleuthero is not evidence based. Nevertheless, the European Community Herbal Monograph states "arterial hypertension" as a contraindication.12 As reported in 1996,86 a 74-year-old man who had been taking digoxin for many years to treat his atrial fibrillation had an unexplained rise in serum digoxin level. Even after digoxin therapy was stopped, the digoxin level remained high. The patient then revealed that he was taking a product labeled to be eleuthero as a dietary supplement. After he stopped taking the supplement, the serum digoxin level returned to an acceptable level. It is not clear in the report whether the patient took a product possibly adulterated with P. sepium, a plant that contains cardiac glycosides. There was no testing for eleutherosides to authenticate the product.87
A few other cases of herb-drug interactions have been mistakenly linked to products labeled as containing eleuthero. In these cases, the herb P. sepium was accidentally mistaken for eleuthero.88 As mentioned in section 3.1, one case report of substitution of eleuthero with P. sepium has been linked to androgenization. Additionally, Leon and Lin note that due to the presence of cardiac glycosides, ingestion of periploca rootbark represents a safety risk.81
3.6 Analytical methods to detect adulteration:
Macroscopic characteristics for E. senticosus, E. nodiflorus, and P. sepium are provided in the Flora of China.21 Additionally, identification of easily-confused species of eleuthero by macroscopic and microscopic characteristics are illustrated on the webpage of the Chinese Medicine Regulatory Office.89 Microscopic differentiation between dried root bark of E. senticosus and whole root bark of P. sepium can be observed by differences in the oxalate crystals. In the root bark of Periploca, calcium oxalate prisms appear in conspicuous axial rows and can be observed in longitudinal sections, whereas in the root bark of Eleutherococcus the prisms are accumulated in clusters.78
The main constituents of E. senticosus roots are lignans (eleutherosides B, E), coumarins (isofraxidin), and phenol carboxylic acids (e.g., phenylpropanoic acids and caffeoylquinic acid derivatives).90 According to the European Pharmacopoeia monograph, dried whole or cut underground organs of E. senticosus should contain a minimum of 0.08% for the sum of eleutherosides B (syn. syringin) and eleutheroside E.20 Determination of the eleutherosides B, E, and E1 in the aerial parts of the different Eleutherococcus species was made by HPTLC using the Liebermann-Burchard reagent for the first time to search for these glycosides in the other parts of the plant.91 Where E. senticosus aerial parts (leaves and fruits) contained all three eleutherosides, aerial parts of E. sessiliflorus (eleutherosides E and E1), E. gracilistylus (eleutherosides B and E1), and E. divaricatus (eleutherosides E and E1) contain only two of these compounds each. Another phytochemical study on E. senticosus leaves revealed triterpene saponins, flavonoids, lignans, coumarins, polysaccharides and other compounds.22,92 Xu et al. investigated changes in eleutherosides B and E, isofraxidin, hyperoside, rutin, and kaempferol levels in three parts of eleuthero under drought stress.93 The results showed that the content of eleutherosides B and E, and isofraxidin was higher in roots and stems, the flavonoid concentration was higher in the leaves. In the control samples (i.e., eleuthero plants that were not grown under drought conditions), rutin and hyperoside contents were below 0.001 mg/g dry weight in the root, but approximately 0.025 and 0.030 mg/g, respectively, in the stem, and 0.313 and 0.073, respectively, in the leaf. As such, amounts of these flavonoids above 0.001 mg/g dried root could indicate adulteration with aerial parts.
The Chinese Pharmacopoeia suggests either TLC or HPLC for the identification of lignans, coumarins, and other phenylpropane derivatives. Eleutheroside B and chlorogenic acid were observed as the dominant and characteristic peaks in the HPLC analysis.8
In a PhD thesis, the best results for detecting adulteration of Eleutherococcus spp. root bark with Periploca root bark were obtained with the Kedde reagent to indicate the presence of cardiac glycosides.78,94 The HPTLC assay for authentication in the US Pharmacopeia (USP) for eleuthero root and its extracts describes the method by using eleutherosides B and E as marker compounds.95 This allows the detection of ≥ 5% Chinese silk vine root in eleuthero root. Wagner tested different HPTLC systems with eleutherosides E, B, E1, esculin, and catalpol as chemical markers for Eleutherococcus plant materials to minimize misidentification and detect adulterations of E. senticosus.26 HPTLC Association gathered useful resources for identification of marker compounds by HPTLC on their website.96
The high-performance liquid chromatography (HPLC) analysis by Hempen and Fischer showed the dominant and characteristic peaks in eleuthero as eleutheroside B and chlorogenic acid.90A number of other HPLC-UV methods have been published over the years for quality control of eleuthero.95,97-100 Among them, Apers et al. published a validated HPLC-UV method to determine eleutherosides B and E.100 The method was later adapted as an official method by the European Pharmacopoeia.20
DNA barcoding and other genetic methods have been used to identify plant species. The authenticity of two popular herbal supplements, E. senticosus, and R. rosea, was investigated using DNA barcoding. The analysis revealed that 36% of the products contained an Eleutherococcus species other than E. senticosus. ITS2 sequences of adulterated samples matched the sequences of E. sessiliflorus, E. divaricatus, and E. seoulensis accessions in GenBank.79 In a study with microscopic and chromatographic techniques, in which the odor compounds 2-hydroxy-4-methoxybenzaldehyde, vanillin, borneol, thymol, and linalool, and eleutherosides B, E, and E1 were used as chemical markers, the results weren't adequately distinct. To ensure the results, DNA sequence analysis of the nuclear ribosomal internal transcribed spacer (ITS) of the raw materials was used. ITS sequence analysis allowed clear discrimination of the two genera Periploca and Eleutherococcus.73
The ITS region of commercial eleuthero preparations (shigoka) available on the Japanese and Chinese crude drug markets was sequenced to identify the source plant of the Medicine. Results showed that E. senticosus is distinguishable from other Eleutherococcus species based on its sequence. In addition, the quantitative determination of three marker compounds, eleutheroside B, syringaresinol diglucoside, and isofraxidin by UPLC-MS was performed for these commercial eleuthero preparations to clarify the relationship between the ITS genotypes and the contents of the marker compounds.101
Eleutherococcus senticosus roots are well characterized herbal materials which have a long history of medicinal usage. Importantly, eleuthero is considered a safe plant when taken at suggested doses. However, standardization and quality control of the plant material in the marketed products are needed to avoid misidentification or adulteration with other herbal supplements. The use of vernacular names may result in the interchanging or substitution of raw materials, which poses a challenge for quality control. Specifying the Latin name, collecting plants with proper identification, and testing using authenticated botanical reference materials can reduce the potential for unintentional adulteration with closely related species. Additionally, validated analytical methods (DNA barcoding, HPLC with a combination of UV and tandem mass spectrometry, HPTLC) are available to authenticate the eleuthero products in the market.
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