Rhodiola species: A comprehensive review of traditional use, phytochemistry, pharmacology, toxicity, and clinical study

Abstract

Rhodiola species, belonging to the family Crassulaceae, have long been used as an adaptogen, tonic, antidepressant, and antistress medicine or functional food in Asia and Europe. Due to the valuable application, the growing demand of Rhodiola species has led to a rapid decrease in resource content. This review aims to summarize the integrated research progress of seven mainstream Rhodiola species. We first outline both traditional and current use of Rhodiola for the treatment of various diseases. A detailed summary and comparison of chemical, pharmacological, toxicological, and clinical studies of various Rhodiola species highlight recent scientific advances and gaps, which gives insights into the understanding of Rhodiola application and would be helpful to improve the situation of biological resources and diversities of Rhodiola plants.

Full text

Received: 9 July 2018
|
Revised: 23 November 2018
|
Accepted: 31 December 2018
DOI: 10.1002/med.21564
REVIEW ARTICLE
Rhodiola species: A comprehensive review of
traditional use, phytochemistry, pharmacology,
toxicity, and clinical study
Hongxun Tao
1
|
Xu Wu
2
|
Jiliang Cao
1
|
Yu Peng
1
|
Anqi Wang
1
|
Jin Pei
3
|
Jianbo Xiao
1
|
Shengpeng Wang
1
|
Yitao Wang
1
1
State Key Laboratory of Quality Research in
Chinese Medicine, Institute of Chinese
Medical Sciences, University of Macau,
Macao, China
2
Laboratory of Molecular Pharmacology,
Department of Pharmacology, School of
Pharmacy, Southwest Medical University,
Luzhou, Sichuan, China
3
State Key Laboratory Breeding Base of
Systematic Research, Development and
Utilization of Chinese Medicine Resources,
Development and Utilization of Chinese
Medicine Resources, College of Pharmacy,
Chengdu University of Traditional Chinese
Medicine, Chengdu, Sichuan, China
Correspondence
Yitao Wang and Shengpeng Wang, Institute of
Chinese Medical Sciences, University of
Macau, Avenida da Universidade, Taipa,
Macau 999078, China.
Email: sxwsp@163.com (SW);
ytwang@umac.mo (YW)
Funding information
Macau Science and Technology Development
Fund, Grant/Award Number: 071/2017/A2;
Research Fund of the University of Macau,
Grant/Award Number: MYRG2016‐00143‐
ICMS‐QRCM
Abstract
Rhodiola species, belonging to the family Crassulaceae, have
long been used as an adaptogen, tonic, antidepressant, and
antistress medicine or functional food in Asia and Europe.
Due to the valuable application, the growing demand of
Rhodiola species has led to a rapid decrease in resource
content. This review aims to summarize the integrated
research progress of seven mainstream Rhodiola species. We
first outline both traditional and current use of Rhodiola for
the treatment of various diseases. A detailed summary and
comparison of chemical, pharmacological, toxicological, and
clinical studies of various Rhodiola species highlight recent
scientific advances and gaps, which gives insights into the
understanding of Rhodiola application and would be helpful
to improve the situation of biological resources and
diversities of Rhodiola plants.
KEYWORDS
Bioactivity, chemical constituents, Rhodiola species, toxicology,
traditional use
1
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INTRODUCTION
The genus Rhodiola, belonging to the family of Crassulaceae, comprises more than 100 perennial plants, which
resembles Sedum and its genus members. Generally, the Rhodiola species are called stonecrops that have nearly
discrete petals, stout roots, short root neck, and a basal rosette of leaves. The only species of Crassulaceae that
Med Res Rev. 2019;1–72. wileyonlinelibrary.com/journal/med © 2019 Wiley Periodicals, Inc.
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1
Hongxun Tao and Xu Wu contributed equally to this work.

have unisexual flowers are contained in this genus. Many species, especially the R. crenulata (Hook. f. & Thomson)
H. Ohba and R. rosea L., have been widely used as traditional medicines in both Asia and Europe for their beneficial
functions, such as antioxidation, anti‐inflammation, antimountain sickness, antifatigue, and immune enhancement.
1
Considering both edible and medicinal value, Rhodiola plants are also regarded as a functional food. In addition,
Rhodiola shows potential to be used as an additive of cosmetics.
The differences in folk application habits of Rhodiola might mostly depend on their geographical distributions.
The Rhodiola species grow in high‐altitude and other cold areas of the northern hemisphere, including Tibet, Altai
Mountains, Far East area, Scandinavia countries, Iceland, the British Isles, and Alaska.
2–4
A total of 73 Rhodiola
species, two subspecies and seven variants are documented in the Flora of China.
5
In addition, according to the
database of Global Biodiversity Information Facility (https://www.gbif.org/), 136 Rhodiola species are recorded. As
shown in Figure 1, R. crenulata (Hook. f. & Thomson) H. Ohba, R. sacra (Prain ex Raym.‐Hamet) S.H. Fu, R. kirilowii
(Regel) Maxim., R. quadrifida (Pall.) Fisch. & C. A. Mey., and R. dumulosa (Franch.) S. H. Fu show distributions in the
southwestern area of China, while R. rosea L. and R. sachalinensis Boriss. distribute widely across Europe to North
America, showing significant regional distribution.
Due to the pollen abortion of genus Rhodiola, as well as the adverse environment and its large‐scale manual
excavation, its overall resources are on the verge of extinction. This has made Rhodiola, especially the R. rosea and
FIGURE 1 Geographical distribution of Rhodiola species. Data from the Global Biodiversity Information Facility
[Color figure can be viewed at wileyonlinelibrary.com]
2
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TAO ET AL.

R. crenulata, of the great value of collection and economy. Unsurprisingly, in the market, increasing adulteration, and
low‐quality and related undesirable products are frequently reported.
6
Therefore, there is an urgent need to
analyze the specific differences in chemistry, pharmacology, and clinical relevance among the various Rhodiola
species, To determine whether the resource shortages for the particular Rhodiola species can be replaced by other
species and whether endangered species conservation areas need to be established to protect their natural
resources and genetic diversity. Although some Rhodiola species, especially the R. rosea, have been reviewed
previously,
7–9
studies on Rhodiola have made great progress in recent years. This review thus aims to summarize
the leading‐edge understandings in traditional and modern use, chemical constituents, bioactivities, and clinical
studies of Rhodiola plants. Scientific gaps in current knowledge is also discussed, highlighting future research
directions.
2
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TRADITIONAL AND CURRENT USE
The Rhodiola plants have been used as medicinal and edible plants in Europe and Asia for a long time. Perhaps the
most famous species of Rhodiola is R. rosea (also known as roseroot, rosenroot, golden root, and arctic root). R. rosea
has been used for traditional medicine of Russia, Scandinavia, and other countries for centuries, and appeared in
the Materia Medica of many countries. The first recordation of R. rosea for medicinal use can be traced back to
Dioscorides in 77ADs.
10
It has been recognized as a botanical adaptogen with antifatigue, antistress, and
antidepressant properties.
11
In 1969, it had already been approved and registered by the Soviet Ministry of Health
for medical use. Ever since 1985, R. rosea has been recorded in Herbal Medicinal Product in Sweden.
10
R. rosea has
now been documented by European Medicines Agency for temporary relief of symptoms of stress (http://www.
ema.europa.eu/ema/). In addition to R. rosea,R. crenulata has been received by US Pharmacopeial Convention.
In China, Rhodiola was widely used to eliminate fatigue, improve physical activity, and alleviate altitude sickness
in the high‐altitude area in the form of decoction or alcohol.
12
The first appearance of Rhodiola in traditional
Tibetan medicine can be dated back to 1000 years ago. In the Tibetan monographs, such as “Four Medical Code”
(rGyud‐bzhi in Tibetan, Si Bu Yi Dian in Chinese, 800AD)
13
“Jing Zhu Materia Medica”(Shel Gong Shel Phreng in
Tibetan, Jing Zhu Ben Cao in Chinese, 1745‐1840AD),
14
Rhodiola was described as a folk medicine to treat
hemoptysis, pneumonia, cough, and leucorrhea.
Rhodiola was first listed in China Pharmacopoeia in 1977. From 1977 to 1985 version, two species were
documented, namely R. kirilowii and R. algida. Nevertheless, R. kirilowii did not match with its Chinese name.
Actually, the Chinese name of this species, Dazhu, should be matched with R. wallichiana. From 2005 to 2015
version, only R. crenulata has been documented by China Pharmacopoeia.
15
This phenomenon reflects the complexity
of Rhodiola species. Thus, one of this review’s goals is to compare both the similarities and differences of
mainstream species like R. crenulata and R. rosea with others. Moreover, modern pharmacological research have
revealed multiple bioactivities of Rhodiola plants, such as antioxidative,
16–18
immunomodulatory,
19,20
anti‐
inflammatory,
21,22
antidiabetic,
23–26
antihypertensive and neuroprotective,
27–29
antistress and antidepressant,
30–34
antialtitude sickness,
35–37
antifatigue,
38–41
and anticancer
42–45
activities. The relationship between the chemical
profile and bioactivities of Rhodiola should be established.
3
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CHEMISTRY AND QUALITY CONTROL
Volatile ingredients identified by gas chromatography‐mass spectrometry are not included in this review. Among all
Rhodiola species, the phytochemistry of R. crenulata and R. rosea have been mostly investigated. A total of 160 and
109 compounds have been found from R. crenulata and R. rosea, respectively. All the compounds can be divided into
the following subgroups: acyclic alcohol derivatives, benzyl and phenol derivatives, phenylethane derivatives, gallic
TAO ET AL.
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3

acid and its derivatives, phenylpropanoid derivatives, flavonoids and their glycosides, nitrile derivatives, and several
other compounds. Notably, tyrosol and its derivatives (including salidrosides), together with gallic acid and its
derivatives, are regarded as characteristic chemical constituents of Rhodiola species. The reported compounds are
summarized in Table 1 according to their chemical name, molecular formula, chemical type, and their original plant
source. Their molecular structures are shown in Figures 2–6.
3.1
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Chemical constituents
3.1.1 |Acyclic alcohol derivatives
A total of 35 acyclic alcohol and their derivatives have been found in Rhodiola plants. Compounds 1‐30 contain at
least one carbon‐carbon double‐bond in their structure. Among them, Compounds 17‐28 and 30
52,53
have two
carbon‐carbon double‐bond structures. Compounds 1
46
and 6‐9
47,48
possess a carbonyl group in their structures.
For Compounds 31‐32,
47
33,
50,56
34,
47,57,59,66,71
and 35,
56
their straight chains are saturated, which consist of six
carbons and eight carbons for Compounds 31‐32 and Compounds 33‐35, respectively. In the structures of
Compounds 1,2‐3,
47,48
5,
47
7,9,11,
49
12,
47
14,
52,54
15,
47,49,52,55
16,
49
and 17‐35, there are different glycosyl
substitutions. A common disaccharide of arabinopyranose(1→6)glucopyranose is shared among compound 12,15,
18,
47,51,56,59
28,
59,68
29,
55
32, and 34. Compound 30 contains a glucopyranose(1→3)glucopyranose group, while
Compound 35 has an arabinofuranose(1→6)glucopyranose. In addition, the glycosyl substitution of Compounds
24
51,56
and 25
60
is arabinofuranose. Notably, 15 acyclic alcohol derivatives are found in R. crenulata, including
Compounds 2,5,9,12,14‐15,18‐19,
54
21,
53,54
22,
53,54
28,30‐32, and 34; from R. rosea, 17 acyclic alcohol
derivatives are identified, including Compound 2‐3,4,
48
6‐9,13,
51
14‐15,
92
18,19,
52
21,
51,62,65
22,
52,67
23,
51
24,
and 30; 14 acyclic alcohol derivatives, 10,
49
11,13,
50
15‐16,17,
56
18,20,
60
21,
50,60
24‐26,
60
33, and 35, are isolated
from R. sachalinensis; from R. kirilowii, only five acyclic alcohol derivatives, Compounds 1,17,27,31, and 34,
57
are
found; five acyclic alcohol derivatives, Compounds 15,18,28,29, and 34, are isolated from R. sacra; only Compound
31 and 34 are found in R. quadrifida; none of these compounds have been reported in R. dumulosa yet. As acyclic
alcohol derivatives are universal natural products, it is difficult to identify chemical specificity across various
Rhodiola species simply based on this type of compounds. However, as these compounds contain several reactive
chemical groups in their structures, such as carbon‐carbon double‐bond, hydroxyl, and carbonyl, they might
contribute to the biological activities of Rhodiola plants.
3.1.2 |Benzyl and phenol derivatives
The structures of benzyl and phenol derivatives are shown in Figure 2. Benzyl β‐D‐glucopyranoside (Compound
36) is found in R. crenulata,R. rosea,andR. sachalinensis.
50,56,58,73,74
Two other benzene methane derivatives,
phenylmethyl 6‐O‐α‐L‐arabinopyranosyl‐β‐D‐glucopyranoside (Compound 41)
51,56
and phenylmethyl 6‐O‐α‐L‐
arabinofuranosyl‐β‐D‐glucopyranoside (Compound 42),
56,78
are isolated from both R. rosea and R. sachalinensis.
Hydroquinone (Compound 37) is found in both R. rosea and R. sacra.
69,70,75
Meanwhile, two hydroquinone
derivatives, α‐arbutin (Compound 38)
70
and hydroquinone glucose (Compound 39),
69,70,76,77
are isolated from
R. sacra. Compound 39 is from R. kirilowii.Ap‐hydroxyphenylmethane derivative, 4‐hydroxybenzyl β‐D‐
glucopyranoside (Compound 40), is isolated from R. crenulate.
47
A trihydroxyphenol derivative, tachioside
(Compound 43),
73
isolated from R. crenulate is found to contain a glucopyranose substitute in its structure. 4‐
Hydroxybenzaldehyde (Compound 44)and4‐acetophenol (Compound 45) are found in R. kirilowii,
46
which
share a same p‐hydroxybenzene group, with the carbonyl group on the side chain different from each other.
Compound 45 also appears in R. crenulata.
79
Compounds 46‐54 share a common mother nucleus of p‐
hydroxybenzoic acid. The carboxyl group on the side chain of compound 46,
46,55,69,80
49,
80
51,
69,70,80
and 52‐
53
80
is retained, indicating the capability of acidification of environment pH. For Compounds 51‐53,theyhave
ameta‐hydroxy derivatization in the structure. Compounds 46,49,and51‐54 are found in R. crenulata;
4
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TAO ET AL.

TABLE 1 Chemical compositions of Rhodiola species
No Compounds
Molecular
formula Type Source of species References
11‐(2‐Hydroxy‐2‐
methylbutanoate)
β‐D‐glucopyranose
C
11
H
20
O
8
Acyclic acid glycoside Rhodiola kirilowii
46
22‐Methyl‐3‐buten‐2‐yl
β‐D‐glucopyranoside
C
11
H
20
O
6
Acyclic alcohol
glycoside
Rhodiola crenulata;
Rhodiola rosea
47,48
33‐Methyl‐2‐buten‐1‐yl
β‐D‐glucopyranoside
C
11
H
20
O
6
Acyclic alcohol
glycoside
R. rosea
48
42‐Methylhept‐2‐ene‐1,6‐diol C
8
H
16
O
2
Acyclic alcohol R. rosea
48
5Creoside II C
14
H
26
O
7
Acyclic alcohol
glycoside
R. crenulata
47
6(E)‐2‐Methyl‐6‐oxo‐2‐hepten‐
1‐ol
C
8
H
14
O
2
Acyclic alcohol R. rosea
48
7(E)‐Creoside I C
14
H
2
4O
7
Acyclic alcohol
glycoside
R. rosea
48
8(Z)‐2‐Methyl‐6‐oxo‐2‐hepten‐
1‐ol
C
8
H
14
O
2
Acyclic alcohol R. rosea
48
9Creoside I C
14
H
24
O
7
Acyclic alcohol
glycoside
R. crenulata;R.
rosea
47,48
10 Sachalol C
10
H
20
O
2
Acyclic alcohol Rhodiola
sachalinensis
49
11 Sachaloside VI C
16
H
30
O
7
Acyclic alcohol
glycoside
R. sachalinensis
49
12 Creoside V C
21
H
38
O
10
Acyclic alcohol
glycoside
R. crenulata
47
13 Sachalinol A C
10
H
20
O
3
Acyclic alcohol R. rosea;R.
sachalinensis
50,51
14 Rhodioloside D C
16
H
30
O
8
Acyclic alcohol
glycoside
R. crenulata;R.
rosea
51–54
15 Rhodioloside E C
21
H
38
O
11
Acyclic alcohol
glycoside
R. crenulata;R.
rosea;R.
sachalinensis;
Rhodiola sacra
47,49,52,55
16 Sachaloside VII C
16
H
30
O
8
Acyclic alcohol
glycoside
R. sachalinensis
49
17 Geraniol glucoside C
16
H
28
O
6
Acyclic alcohol
glycoside
R. sachalinensis;R.
kirilowii
56,57
18 Kenposide A C
21
H
36
O
10
Acyclic alcohol
glycoside
R. crenulata;R.
rosea;R.
sachalinensis;R.
sacra
47,51,56,58,59
19 Rhodioloside A C
16
H
28
O
8
Acyclic alcohol
glycoside
R. crenulata;R.
rosea
52–54
20 Rosiridosides A C
15
H
26
O
6
Acyclic alcohol
glycoside
R. sachalinensis
60
21 (−)‐Rosiridin C
16
H
28
O
7
Acyclic alcohol
glycoside
R. crenulata;R.
rosea;R.
sachalinensis
50,51,53,54,58,60–67
(Continues)
TAO ET AL.
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5

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
22 Rhodioloside B C
22
H
38
O
12
Acyclic alcohol
glycoside
R. crenulata;R.
rosea
52–54,67
23 Rhodioloside F C
21
H
36
O
11
Acyclic alcohol
glycoside
R. rosea
51
24 Geranyl 6‐O‐α‐L‐
arabinofuranosyl‐β‐D‐
glucopyranoside
C
21
H
36
O
10
Acyclic alcohol
glycoside
R. rosea;R.
sachalinensis
51,56
25 Rosiridosides B C
21
H
36
O
11
Acyclic alcohol
glycoside
R. sachalinensis
60
26 Rosiridosides C C
18
H
30
O
8
Acyclic alcohol
glycoside
R. sachalinensis
60
27 Neryl glucoside C
16
H
28
O
6
Acyclic alcohol
glycoside
R. kirilowii
57
28 Sacranoside B C
21
H
36
O
10
Acyclic alcohol
glycoside
R. crenulata;R.
sacra
57,59,68
29 Rhodioloside G C
21
H
38
O
11
Acyclic alcohol
glycoside
R. sacra
55
30 Rhodioloside C C
22
H
38
O
12
Acyclic alcohol
glycoside
R. crenulata;R.
rosea
52–54,67
31 1‐Hexyl β‐D‐glucoside C
12
H
24
O
6
Acyclic alcohol
glycoside
R. crenulata;R.
kirilowii;R.
quadrifida
47
32 Creoside IV C
17
H
32
O
10
Acyclic alcohol
glycoside
R. crenulata
47
33 Octyl glucoside C
14
H
28
O
6
Acyclic alcohol
glycoside
R. sachalinensis
50,56
34 Rhodiooctanoside C
19
H
36
O
10
Acyclic alcohol
glycoside
R. crenulata;R.
kirilowii;R. sacra;
R. quadrifida
47,57,59,66,69–72
35 Octyl 6‐O‐α‐D‐
arabinofuranosyl‐β‐D‐
glucopyranoside
C
19
H
36
O
10
Acyclic alcohol
glycoside
R. sachalinensis
56
36 Benzyl β‐D‐glucopyranoside C
13
H
18
O
6
Benzyl derivative R. crenulata;R.
rosea;R.
sachalinensis
50,56,58,73,74
37 Hydroquinone C
6
H
6
O
2
Phenol R. rosea;R. sacra
69,70,75
38 α‐Arbutin C
12
H
16
O
7
Phenol glycoside R. sacra
70
39 Hydroquinone glucose C
12
H
16
O
7
Phenol glycoside R. kirilowii;R. sacra
69,70,76,77
40 4‐Hydroxybenzyl β‐D‐
glucopyranoside
C
13
H
18
O
7
Phenol glycoside R. crenulata
47
41 Phenylmethyl 6‐O‐α‐L‐
arabinopyranosyl‐β‐D‐
glucopyranoside
C
18
H
26
O
10
Benzidine glycoside R. rosea;R.
sachalinensis
51,56
42 Phenylmethyl 6‐O‐α‐L‐
arabinofuranosyl‐β‐D‐
glucopyranoside
C
18
H
26
O
10
Benzidine glycoside R. rosea;R.
sachalinensis
56,78
(Continues)
6
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TAO ET AL.

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
43 Tachioside C
13
H
18
O
8
Phenol glycoside R. crenulata
73
44 4‐Hydroxybenzaldehyde C
7
H
6
O
2
Phenol R. kirilowii
46
45 4‐Acetophenol C
8
H
8
O
2
Phenol R. crenulata;R.
kirilowii
46,79
46 4‐Hydroxybenzoic acid C
7
H
6
O
3
Benzoic acid
derivative
R. crenulata;R.
kirilowii;R. sacra
46,55,69,70,80
47 4‐Hydroxymethyl benzoate C
8
H
8
O
3
Benzoic acid
derivative
R. rosea
48
48 p‐Hydroxy‐benzoic acid ethyl
ester
C
9
H
10
O
3
Benzoic acid
derivative
R. kirilowii
46
49 4‐Hydroxybenzoic acid 4‐O‐β‐D‐
glucopyranoside
C
13
H
16
O
8
Benzoic acid
derivative
R. crenulata
80
50 4‐Hydroxybenzoic acid β‐D‐
glucosyl ester
C
13
H
16
O
8
Benzoic acid
derivative
R. sacra
55,69
51 Protocatechuic acid C
7
H
6
O
4
Benzoic acid
derivative
R. crenulata;R.
sacra
69,70,80
52 Vanillic acid C
8
H
8
O
4
Benzoic acid
derivative
R. crenulata
80
53 Vanillic acid 4‐O‐β‐D‐
glucopyranoside
C
14
H
18
O
9
Benzoic acid
derivative
R. crenulata
80
54 Creoside III C
18
H
24
O
9
Phenol derivative R. crenulata;R.
rosea
47,48
55 Phenethyl β‐D‐glucopyranoside C
14
H
20
O
6
Phenylethane
glycoside
R. crenulata;R.
sachalinensis;R.
sacra
47,50,56,69,70
56 Phenethanol β‐vicianoside C
19
H
28
O
10
Phenylethane
glycoside
R. crenulata;R.
rosea;R. sacra
47,51,69,70
57 Phenethyl β‐primeveroside C
19
H
28
O
10
Phenylethane
glycoside
R. crenulata
73
58 2‐Phenylethyl 6‐O‐α‐L‐
arabinofuranosyl‐β‐D‐
glucopyranoside
C
19
H
28
O
10
Phenylethane
glycoside
R. crenulata;R.
rosea
51,73
59 Tyrosol C
8
H
10
O
2
Phenylethane R. crenulata;R.
rosea;R.
sachalinensis;R.
kirilowii;R. sacra;
R. quadrifida
47,48,50,56,57,67
74,79–98
60 2‐(4‐Methoxyphenyl)‐1‐ethanol C
9
H
12
O
2
Phenylethane
derivative
R. kirilowii
46
61 4‐Hydroxyphenyl‐2‐ethyl
β‐D‐glucopyranoside
C
14
H
20
O
7
Phenylethane
glycoside
R. rosea
48
62 Salidroside C
14
H
20
O
7
Phenylethane
glycoside
R. crenulata;R.
rosea;R.
sachalinensis;R.
kirilowii;R. sacra;
R. quadrifida
47,48,50,51,55,56
58,61,63–67,71
72,74,76,80,82
84–90,92,94–102
(Continues)
TAO ET AL.
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7

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
63 2‐(4‐Hydroxyphenyl)ethyl
6‐O‐β‐D‐glucopyranosyl‐β‐D‐
glucopyranoside
C
20
H
30
O
12
Phenylethane
glycoside
R. crenulata
85
64 Icariside D2 C
14
H
20
O
7
Phenylethane
glycoside
R. crenulata;R.
rosea;R. kirilowii
47,48,55,85
65 Viridoside C
15
H
22
O
7
Phenylethane
glycoside
R. crenulata;R.
rosea;R.
sachalinensis
51,53,54,56
66 Mongrhoside C
20
H
30
O
11
Phenylethane
glycoside
R. rosea
51
67 4‐Methylsalidroside‐6‐O‐β‐D‐
arabinopyranoside
C
20
H
30
O
11
Phenylethane
glycoside
R. quadrifida
66
68 2‐(4‐Hydroxyphenyl)ethyl 4‐
methoxybenzoate
C
16
H
16
O
4
Phenylethane
derivative
R. sachalinensis
56
69 4‐[2‐[2‐(4‐Methoxyphenyl)
ethoxy]ethyl]‐phenol
C
17
H
20
O
3
Phenylethane
derivative
R. kirilowii
46
70 Aspergillol B C
16
H
16
O
4
Phenylethane
derivative
R. rosea
48
71 4‐Ethoxy‐benzeneethanol‐1‐
acetate
C
12
H
16
O
3
Phenylethane
derivative
R. kirilowii
46
72 Crenulatanoside C C
14
H
20
O
7
Phenylethane
glycoside
R. crenulata
103
73 2‐(β‐D‐Glucopyranosyloxy)‐1‐
(4‐hydroxyphenyl)ethanone
C
14
H
18
O
8
Phenylethane
glycoside
R. crenulata
85
74 Picein C
14
H
18
O
7
Phenylethane
glycoside
R. crenulata;R.
rosea
74,85
75 Rodiolinozide C
15
H
20
O
9
Phenylethane
glycoside
R. kirilowii
97
76 Domesticoside C
15
H
20
O
9
Phenylethane
glycoside
R. crenulata
54
77 Gallic acid C
7
H
6
O
5
Gallic acid R. crenulata;R.
rosea;R.
sachalinensis;R.
kirilowii;R. sacra;
R. dumulosa
48,50,55,5 7,63,64
69,70,80–83,86,91
92,94,97–99
104,105
78 3‐O‐Methylgallic acid C
8
H
8
O
5
Gallic acid derivative R. crenulata
80
79 Methyl gallate C
8
H
8
O
5
Gallic acid derivative R. crenulata;R.
rosea;R. kirilowii
46,48,92,106,107
80 Gallic acid ethyl ester C
9
H
10
O
5
Gallic acid derivative R. crenulata;R.
sacra
94,99
81 Gallic acid 4‐O‐β‐D‐
glucopyranoside
C
13
H
16
O
10
Gallic acid glycoside R. sacra
69,70
82 4‐O‐β‐D‐Glucopyranosyloxy‐
3,5‐dimethoxybenzoic acid
C
15
H
20
O
10
Gallic acid derivative R. crenulata
80
83 1,2,6‐Tri‐O‐galloyl‐β‐D‐
glucoside
C
27
H
24
O
18
Gallic acid derivative R. rosea
48
(Continues)
8
|
TAO ET AL.

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
84 1,2,3,6‐Tetra‐O‐galloyl‐β‐D‐
glucopyranose
C
34
H
28
O
22
Gallic acid derivative R. rosea;R.
sachalinensis
48,50
85 1,2,3,4,6‐Penta‐O‐
galloylglucose
C
41
H
32
O
26
Gallic acid derivative R. crenulata;R.
sachalinensis
50,81
86 1,2,3,6‐tetra‐O‐galloyl‐4‐O‐p‐
hydroxybenzoyl‐β‐D‐
glucopyranoside
C
41
H
32
O
24
Gallic acid derivative R. rosea
48
87 Phenethyl gallate C
15
H
14
O
5
Gallic acid derivative R. sacra
55
88 2‐(4‐Hydroxyphenyl)ethyl
ester‐3,4,5‐trihydroxy‐
benzoic acid
C
15
H
14
O
6
Gallic acid derivative R. crenulata
106,108
89 6‐O‐Galloylsalidroside C
21
H
24
O
11
Gallic acid derivative R. crenulata;R.
rosea;R.
sachalinensis
47,48,50,81,83
90 Benzoic acid, 3,4,5‐trihydroxy‐
2‐[3‐hydroxy‐3‐methyl‐2‐[[6‐
O‐(3,4,5‐trihydroxybenzoyl)‐β‐
D‐glucopyranosyl]oxy]butyl]‐,
1,1‐dimethyl‐2‐propen‐1‐yl
ester
C
30
H
38
O
16
Gallic acid derivative R. crenulata
83,109
91 Sachalinoside A C
23
H
32
O
11
Gallic acid derivative R. crenulata;R.
sachalinensis
50,53,54
92 Rhodiocyanoside B C
18
H
21
NO
11
Gallic acid derivative
(nitrile)
R. sacra;R.
quadrifida
55,71,72
93 Cinnamyl alcohol C
9
H
10
O Phenylpropanoid
(cinnamic alcohol)
R. rosea;R.
sachalinensis
66,67,92,100
94 trans‐Cinnamic alcohol C
9
H
10
O Phenylpropanoid
(cinnamic alcohol)
R. rosea;R.
sachalinensis
56,64
95 Rosavin C
20
H
28
O
10
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. crenulata;R.
rosea;R.
sachalinensis;R.
quadrifida
51,53,56,58,61
63–68,74,92,101
110,111
96 Rosin C
15
H
20
O
6
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. crenulata;R.
rosea;R.
sachalinensis
50,51,53,56,58,61
63–65,67,74,92
110,111
97 Rosarin C
20
H
28
O
10
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. crenulata;R.
rosea;R.
sachalinensis;R.
quadrifida
50,51,56,58,61
63–65,67,74,92
110,111
98 3‐Phenyl‐2‐propenyl
6‐O‐β‐D‐xylopyranosyl‐β‐D‐
glucopyranoside
C
20
H
28
O
10
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. rosea
112
99 (2E)‐3‐Phenyl‐2‐propen‐1‐yl
6‐O‐β‐D‐xylopyranosyl‐β‐D‐
glucopyranoside
C
20
H
28
O
1
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. rosea
51,111,113
100 Triandrin C
15
H
20
O
7
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. crenulata;R.
rosea
47,67,101
(Continues)
TAO ET AL.
|
9

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
101 Vimalin C
16
H
22
O
7
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. crenulata;R.
rosea
47,112
102 Coniferoside C
16
H
22
O
8
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. crenulata
47
103 Sachaliside 1 C
15
H
20
O
7
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. rosea
74
104 (2E)‐3‐(4‐Methoxyphenyl)‐2‐
propen‐1‐yl β‐D‐
glucopyranoside
C
16
H
22
O
7
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. rosea
74
105 (2E)‐3‐(4‐Methoxyphenyl)‐2‐
propen‐1‐yl 6‐O‐α‐L‐
arabinopyranosyl‐β‐D‐
glucopyranoside
C
21
H
30
O
11
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. rosea
113
106 3‐(4‐Methoxyphenyl)‐2‐
propenyl 6‐O‐α‐D‐
arabinofuranosyl‐β‐D‐
glucopyranoside
C
21
H
30
O
11
Phenylpropanoid
(cinnamic alcohol
glycoside)
R. rosea
112
107 p‐Coumaric acid C
9
H
8
O
3
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata;R.
rosea;R. sacra
48,55,69,73
108 trans‐p‐Hydroxycinnamic acid C
9
H
8
O
3
Phenylpropanoid
(cinnamic acid
derivative)
R. rosea;R.
sachalinensis;R.
sacra
50,56,70,91
109 Caffeic acid C
9
H
8
O
4
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata; R.
rosea;R. sacra
48,53,54,69,70,94
101,114
110 trans‐Caffeic acid C
9
H
8
O
4
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata;R.
sachalinensis
47,56
111 Ferulaic acid C
10
H
10
O
4
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata
53
112 p‐Coumaric acid 4‐O‐β‐D‐
glucopyranoside
C
15
H
18
O
8
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata
73
113 Rhodiolate C
17
H
22
O
6
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata
106
114 Octacosyl ferulate C
38
H
66
O
4
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata
86
115 Chlorogenic acid C
16
H
18
O
9
Phenylpropanoid
(cinnamic acid
derivative glycoside)
R. rosea;R.
quadrifida
66
(Continues)
10
|
TAO ET AL.

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
116 Caffeic acid phenethyl ester C
17
H
16
O
4
Phenylpropanoid
(cinnamic acid
derivative)
R. sacra
115
117 Rosmarinci acid C
18
H
16
O
8
Phenylpropanoid
(cinnamic acid
derivative)
R. rosea
116
118 3‐[(2R,3R)‐2,3‐Dihydro‐3‐(4‐
hydroxy‐3‐methoxyphenyl)‐2‐
(hydroxymethyl)‐1,4‐
benzodioxin‐6‐yl]‐2‐
propenoic acid
C
19
H
18
O
7
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata
106
119 Arteminorin D C
19
H
18
O
7
Phenylpropanoid
(cinnamic acid
derivative)
R. crenulata
106
120 Umbelliferone C
9
H
6
O
3
Phenylpropanoid
(coumarin
derivative)
R. sacra
94,117
121 (−)‐Mellein C
10
H
10
O
3
Phenylpropanoid
(coumarin
derivative)
R. kirilowii
46
122 Scopoletine C
10
H
8
O
4
Phenylpropanoid
(coumarin
derivative)
R. quadrifida
117
123 7‐Methoxycoumarin‐6‐
aldehyde
C
11
H
8
O
4
Phenylpropanoid
(coumarin
derivative)
R. crenulata;R.
rosea
82,86,93
124 Ellagic acid C
14
H
6
O
8
Phenol R. crenulata
99
125 Nodakenin C
20
H
24
O
9
Phenylpropanoid
(coumarin derivative
glycoside)
R. sachalinensis
56
126 Thunberginol C C
15
H
12
O
5
Phenylpropanoid
(coumarin
derivative)
R. sacra
55
127 trans‐Coumaric acid C
9
H
8
O
3
Phenylpropanoid
(coumaric acid
derivative)
R. kirilowii
57
128 (2S,3R)‐
Dihydrodehydroconiferyl
alcohol
C
20
H
24
O
6
Phenylpropanoid
(lignin)
R. crenulata
106
129 Clemastanin A C
25
H
32
O
11
Phenylpropanoid
(lignin glycoside)
R. crenulata
47,80
130 (7S,8R)‐
Dihydrodehydrodiconiferyl
alcohol 9‐O‐α‐L‐
rhamnopyranoside
C
25
H
32
O
10
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
131 (7R,8S)‐
Dihydrodehydrodiconiferyl
alcohol 3′‐O‐β‐D‐
glucopyranoside
C
25
H
32
O
11
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
(Continues)
TAO ET AL.
|
11

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
132 4‐[(2R,3S)‐2,3‐Dihydro‐7‐
hydroxy‐3‐(hydroxymethyl)‐5‐
(3‐hydroxypropyl)‐2‐
benzofuranyl]‐2‐
methoxyphenyl β‐D‐
glucopyranoside
C
25
H
32
O
11
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
133 (7R,8S)‐
Dihydrodehydrodiconiferyl
alcohol 3′‐O‐α‐L‐
rhamnopyranosyl‐4‐O‐β‐D‐
glucopyranoside
C
31
H
42
O
15
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
134 3‐Phenyl‐1‐propanol glucoside C
15
H
22
O
6
Phenylpropanoid
(lignin glycoside)
R. sachalinensis
56
135 Dihydroconiferin C
16
H
24
O
8
Phenylpropanoid
(lignin glycoside)
R. crenulata
47,73
136 (7R,8R)‐Threo‐4,7,9,9′‐
tetrahydroxy‐3,3′‐dimethoxy‐
8‐O‐4′‐neolignan 4‐O‐β‐D‐
glucopyranoside
C
26
H
36
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
137 (7R,8R)‐4,7,9,3′,9′‐
Pentahydroxy‐3‐methoxy‐8,4′‐
oxyneolignan 4‐O‐β‐D‐
glucopyranoside
C
25
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
138 (7S,8R)‐4,7,9,3′,9′‐
Pentahydroxy‐3‐methoxy‐8,4′‐
oxyneolignan 4‐O‐β‐D‐
glucopyranoside
C
25
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
139 (7S,8S)‐4,7,9,3′,9′‐
Pentahydroxy‐3‐methoxy‐8,4′‐
oxyneolignan 4‐O‐β‐D‐
glucopyranoside
C
25
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
140 (7R,8R)‐4,7,9,3′,9′‐
Pentahydroxy‐3‐methoxy‐8,4′‐
oxyneolignan 3′‐O‐β‐D‐
glucopyranoside
C
25
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
141 (7R,8S)‐4,7,9,3′,9′‐
Pentahydroxy‐3‐methoxy‐8,4′‐
oxyneolignan 3′‐O‐β‐D‐
glucopyranoside
C
25
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
142 (7S,8R)‐4,7,9,3′,9′‐
Pentahydroxy‐3‐methoxy‐8,4′‐
oxyneolignan 3′‐O‐β‐D‐
glucopyranoside
C
25
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
143 (7S,8S)‐4,7,9,3′,9′‐
Pentahydroxy‐3‐methoxy‐8,4′‐
oxyneolignan 3′‐O‐β‐D‐
glucopyranoside
C
25
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
144 (+)‐Isolariciresinol C
20
H
24
O
6
Phenylpropanoid
(lignin)
R. crenulata
80,106
(Continues)
12
|
TAO ET AL.

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
145 (+)‐Isolarisiresinol 4′‐O‐β‐D‐
glucopyranoside
C
26
H
34
O
11
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
146 5′‐Methoxy‐(+)‐isolariciresinol
4′‐O‐β‐D‐glucopyranoside
C
27
H
36
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
147 5‐Methoxy‐(+)‐isolariciresinol
4′‐O‐β‐D‐glucopyranoside
C
27
H
36
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
148 (+)‐Isolarisiresinol 4‐O‐β‐D‐
glucopyranoside
C
26
H
34
O
11
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
149 (+)‐Isolarisiresinol 9‐O‐β‐D‐
xylopyranoside
C
25
H
32
O
10
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
150 Isolariciresinol 9‐O‐β‐D‐
glucopyranoside
C
26
H
34
O
11
Phenylpropanoid
(lignin glycoside)
R. kirilowii
57
151 (+)‐Isolariciresinol‐3α‐O‐β‐D‐
glucopyranoside
C
26
H
34
O
11
Phenylpropanoid
(lignin glycoside)
R. dumulosa
105
152 (−)‐Isolariciresinol‐3α‐O‐β‐D‐
glucopyranoside
C
26
H
34
O
11
Phenylpropanoid
(lignin glycoside)
R. dumulosa
105
153 5′‐Methoxy‐8′‐hydroxy‐(+)‐
isolariciresinol 4′‐O‐β‐D‐
glucopyranoside
C
27
H
36
O
13
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
154 (+)‐Cycloolivil 4′‐O‐β‐D‐
glucopyranoside
C
26
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
155 8′‐Hydroxy‐(+)‐isolariciresinol
9‐O‐β‐D‐xylopyranoside
C
25
H
32
O
11
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
156 (−)‐Cycloolivil‐9‐O‐β‐D‐
glucopyranoside
C
26
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. sacra
55
157 Olivil 4′‐O‐β‐D‐glucopyranoside C
26
H
34
O
12
Phenylpropanoid
(lignin glycoside)
R. crenulata
80
158 2‐Methoxy‐4‐(2‐propen‐1‐yl)
phenyl 6‐O‐D‐apio‐β‐D‐
furanosyl‐β‐D‐glucopyranoside
C
21
H
30
O
11
Other
phenylpropanoid
glycoside
R. sachalinensis
56
159 Gein C
21
H
30
O
11
Other
phenylpropanoid
glycoside
R. sachalinensis
56
160 Syzygiresinol A C
19
H
18
O
7
Other
phenylpropanoid
R. crenulata
106
161 (5αR,6S,11αR)‐1,5,5α,6,11,11α‐
Hexahydro‐6‐(4‐hydroxy‐3‐
methoxyphenyl)‐9‐methoxy‐
3,3‐dimethyl‐naphtho[2,3‐e]
[1,3]dioxepin‐8‐ol
C
23
H
28
O
6
Other
phenylpropanoid
R. crenulata
73
162 3,5,7,3′‐Tetrahydroxyflavone C
15
H
10
O
6
Flavonole R. crenulata
118
163 Kaempferol C
15
H
10
O
6
Flavonole (Kae.) R. crenulata;R.
rosea;R.
sachalinensis;R.
quadrifida;R.
dumulosa
47,50,55,56,87,93
94,99,100,104–107
116–123
(Continues)
TAO ET AL.
|
13

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
164 Herbacetin
(8‐hydroxykaempferol)
C
15
H
10
O
7
Flavonole (Kae. Der.) R. crenulata;R.
rosea
53,121,122,124
165 Pollenitin (3,4′,5,8‐
tetrahydroxy‐7‐methoxy‐
flavone)
C
16
H
12
O
7
Flavonole (Kae. Der.) R. crenulata
47,106
166 Herbacetin‐8‐methyl ether C
16
H
12
O
7
Flavonole (Kae. Der.) R. crenulata;R.
dumulosa
53,123
167 Kaempferide (kaempferol 4′‐O‐
methyl ether)
C
16
H
12
O
6
Flavonole (Kae. Der.) R. dumulosa
125
168 Kaempferin (kaempferol‐3‐O‐α‐
L‐rhamnopyranoside)
C
21
H
20
O
10
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
sachalinensis
87,126
169 Kaemnpferol‐3‐O‐α‐L‐
rhamnopyranoside
C
21
H
20
O
10
Flavonole glycoside
(Kae. Der.)
R. crenulata
118
170 Kaempferol‐3‐O‐α‐L‐
rhammopyranoside
C
21
H
20
O
10
Flavonole glycoside
(Kae. Der.)
R. rosea
48
171 Astragalin (kaempferol‐3‐O‐
glucopyranoside)
C
21
H
20
O
11
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
rosea;R.
sachalinensis
100,118,127
172 Herbacetin‐3‐O‐glucoside C
21
H
20
O
12
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
sachalinensis
100,118
173 Kaempferol 7‐O‐α‐L‐
rhamnopyranoside
C
21
H
20
O
10
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
rosea;R.
sachalinensis;R.
dumulosa
99,102,104,106,107
116,119,120
123,128
174 Rhodionin (herbacetin‐7‐O‐α‐L‐
rhamnopyranoside)
C
21
H
20
O
11
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
rosea;R.
sachalinensis;R.
sacra;R. dumulosa
48,50,55,63,64
81,83,86,87,98
99,102,104,106
107,114,116,118
119,121–123,125
128–131
175 Kaempferide‐7‐O‐α‐L‐
rhamnoside
C
22
H
22
O
10
Flavonole glycoside
(Kae. Der.)
R. dumulosa
125
176 Isoarticulatin (herbacetin‐7‐O‐
glucoside)
C
21
H
20
O
12
Flavonole glycoside
(Kae. Der.)
R. crenulata
118
177 Rhodalin (herbacetin‐8‐O‐β‐D‐
xylopyranoside)
C
20
H
18
O
11
Flavonole glycoside
(Kae. Der.)
R. rosea
114
178 Herbacetin‐8‐glucoside C
21
H
20
O
12
Flavonole glycoside
(Kae. Der.)
R. rosea
132
179 Leucoside (kaempferol‐3‐
sambubioside)
C
26
H
28
O
15
Flavonole glycoside
(Kae. Der.)
R. rosea;R.
sachalinensis
51,56,132
180 Kaempferol‐3‐O‐β‐D‐
xylopyranosyl‐(1→2)‐O‐β‐D‐
galactopyranoside
C
26
H
28
O
15
Flavonole glycoside
(Kae. Der.)
R. sachalinensis
50
181 Kaempferol‐3‐xylosylglucoside C
26
H
28
O
15
Flavonole glycoside
(Kae. Der.)
R. rosea
127
182 Kaempferol‐3‐O‐α‐L‐
rhamnopyranosyl (1→3) ‐O‐β‐
D‐glucopyranoside
C
27
H
30
O
15
Flavonole glycoside
(Kae. Der.)
R. crenulata
126
(Continues)
14
|
TAO ET AL.

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
183 3‐[[4‐O‐(6‐Deoxy‐α‐L‐
mannopyranosyl)‐β‐D‐
glucopyranosyl]oxy]‐5,7‐
dihydroxy‐2‐(4‐
hydroxyphenyl)‐4H‐1‐
benzopyran‐4‐one
C
27
H
30
O
15
Flavonole glycoside
(Kae. Der.)
R. crenulata
126
184 Ternatumoside II (kaempferol‐
3‐O‐β‐D‐glucopyranosyl‐
(1→2)‐α‐L‐mannopyranoside)
C
27
H
30
O
15
Flavonole glycoside
(Kae. Der.)
R. crenulata
106
185 Multiflorin B (kaempferol‐3‐O‐
β‐D‐glucopyranosyl‐(1→4)‐α‐L‐
rhamnopyranoside)
C
27
H
30
O
15
Flavonole glycoside
(Kae. Der.)
R. sachalinensis
87
186 Kaempferol‐3‐sophoroside C
27
H
30
O
16
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
sachalinensis
50,126,133
187 Kaempferol 7‐
neohesperidoside
C
27
H
30
O
15
Flavonole glycoside
(Kae. Der.)
R. rosea
124
188 Crenuloside (kaempferol 7‐O‐β‐
D‐glucopyranosyl‐(1→3)‐α‐L‐
rhamnopyranoside)
C
27
H
30
O
15
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
dumulosa
99,106,119,131
189 Rhodiosin (herbacetin‐7‐O‐β‐D‐
glucopyranosyl‐(1→3)‐α‐L‐
rhamnopyranoside)
C
27
H
30
O
16
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
rosea;R.
sachalinensis;R.
quadrifida
63,64,66,87,104
121,126,134
190 Kaempferol‐3‐glucoside‐7‐
rhamnoside
C
27
H
30
O
15
Flavonole glycoside
(Kae. Der.)
R. rosea;R.
dumulosa
105,132
191 Sinocrassoside C1 (herbacetin‐
3‐glucoside‐7‐rhamnoside)
C
27
H
30
O
16
Flavonole glycoside
(Kae. Der.)
R. rosea
132
192 Sachaloside III (kaempferol‐3‐
O‐β‐D‐xylopyranosyl‐(1→2)‐β‐
D‐glucopyranosyl‐7‐O‐α‐L‐
rhamnopyranoside)
C
32
H
38
O
19
Flavonole glycoside
(Kae. Der.)
R. sachalinensis
56
193 Robinin (kaempferol‐3‐
robinoside‐7‐rhamnoside)
C
33
H
40
O
19
Flavonole glycoside
(Kae. Der.)
R. rosea
124
194 Sachaloside IV (8‐
hydroxykaempferol 3‐O‐β‐D‐
glucopyranosyl‐7‐O‐β‐D‐
glucopyranosyl(1→3)‐α‐L‐
rhamnopyranoside)
C
33
H
40
O
21
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
sachalinensis
53,56
195 Rhodalidin (herbacetin‐3‐O‐β‐D‐
glucopyranosyl‐8‐O‐β‐D‐
xylopyranoside)
C
26
H
28
O
16
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
rosea
53,54,114,135
196 Rhodionidin (herbacetin‐8‐O‐β‐
D‐glucopyranosol‐7‐O‐α‐L‐
rhamnopyranoside)
C
27
H
30
O
16
Flavonole glycoside
(Kae. Der.)
R. rosea
114,135
197 Kaempferol 4′‐rhamnoside C
21
H
20
O
10
Flavonole glycoside
(Kae. Der.)
R. crenulata
126
198 Rhodiolatuntoside (herbacetin
4′‐O‐α‐L‐rhamnopyranoside)
C
21
H
20
O
11
Flavonole glycoside
(Kae. Der.)
R. crenulata;R.
sachalinensis
84,120
(Continues)
TAO ET AL.
|
15

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
199 Rhodalide (herbacetin 4‐
xylopyranoside‐8‐
arabinopyranoside)
C
25
H
26
O
15
Flavonole glycoside
(Kae. Der.)
R. crenulata
68
200 Allivicin (kaempferol‐3,4′‐O‐di‐
glucopyranoside)
C
27
H
30
O
16
Flavonole glycoside
(Kae. Der.)
R. sachalinensis
87
201 Alginin (herbacetin 4′‐β‐D‐
glucopyranuronic acid)
C
21
H
18
O
13
Flavonole glycoside
(Kae. Der.)
R. crenulata
68
202 Quercetin C
15
H
10
O
7
Flavonole (Que.) R. crenulata;R.
rosea;R.
sachalinensis;R.
quadrifida;R.
dumulosa
53,105,116–118
120,124
203 Gossypetin (8‐
hydroxyquercetin)
C
15
H
10
O
8
Flavonole (Que. Der.) R. rosea
124
204 Corniculatusin (8‐methoxy‐
quercetin)
C
16
H
12
O
8
Flavonole (Que. Der.) R. rosea
107
205 Ayanin (3,7,4′‐
trimethylquercetin)
C
18
H
16
O
7
Flavonole (Que. Der.) R. crenulata
118
206 Quercitrin (quercetin‐3‐O‐
rhamnoside)
C
21
H
20
O
11
Flavonole glycoside
(Que. Der.)
R. crenulata;R.
rosea
53,54,118,124
207 Isoquercitrin (quercetin‐3‐O‐β‐
glucoside)
C
21
H
20
O
12
Flavonole glycoside
(Que. Der.)
R. crenulata
53,118
208 Rhodiolgin (gossypetin‐7‐O‐L‐
rhamnopyranoside)
C
21
H
20
O
12
Flavonole glycoside
(Que. Der.)
R. crenulata;R.
rosea;R. kirilowii;
R. quadrifida
4,53,54,57,71,72
91,114,135
209 Gossypin (gossypetin 8‐
glucoside)
C
21
H
20
O
13
Flavonole glycoside
(Que. Der.)
R. rosea
124
210 Spiraeoside (quercetin‐4′‐
glucoside)
C
21
H
20
O
12
Flavonole glycoside
(Que. Der.)
R. rosea
124
211 Rutin (quercetin‐3‐O‐rutoside) C
27
H
30
O
16
Flavonole glycoside
(Que. Der.)
R. crenulata;R.
rosea;R.
sachalinensis;R.
dumulosa
77,105,116,120,124
212 Rhodioflavonoside (gossypetin‐
7‐O‐β‐D‐glucopyranosyl‐
(1→3)‐α‐L‐rhamnopyranoside)
C
27
H
30
O
17
Flavonole glycoside
(Que. Der.)
R. rosea;R.
quadrifida
4,71,72,91
213 Isoquercitrin‐7‐O‐gentiobioside C
33
H
40
O
22
Flavonole glycoside
(Que. Der.)
R. crenulata
53,54
214 Rhodiolgidin (gossypetin‐7‐O‐α‐
L‐rhamnopyranose‐8‐O‐β‐D‐
glucopyranoside)
C
27
H
30
O
17
Flavonole glycoside
(Que. Der.)
R. crenulata;R.
rosea
53,54,114,135
215 Crenulatin A C
25
H
20
O
10
Flavonole (Kae. Der.) R. crenulata
99
216 Crenulatin B C
25
H
20
O
10
Flavonole (Kae. Der.) R. crenulata
99
217 Rhodiolin C
25
H
20
O
10
Flavonole (Kae. Der.) R. crenulata;R.
rosea;R.
sachalinensis;R.
quadrifida
56,63,66,87,104
121,126,134
(Continues)
16
|
TAO ET AL.

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
218 Luteolin C
15
H
10
O
6
Flavone R. crenulata;R.
sachalinensis;R.
kirilowii
56,97,106
219 3′,4′‐Dimethoxyluteolin C
17
H
14
O
6
Flavone R. crenulata
118
220 Tricetin C
15
H
10
O
7
Flavone R. kirilowii;R.
quadrifida
71,72,97
221 Tricin (3′,5′‐O‐dimethyltricetin) C
17
H
14
O
7
Flavone R. crenulata;R.
rosea;R.
sachalinensis;R.
sacra
55,56,63,118,136
222 Luteolin‐7‐O‐α‐L‐rhamnoside C
21
H
20
O
10
Flavone glycoside R. crenulata
53
223 Tricin 5‐O‐glucoside C
23
H
24
O
12
Flavone glycoside R. rosea
63,136
224 Tricin‐7‐O‐β‐D‐glucoside C
23
H
24
O
12
Flavone glycoside R. crenulata;R.
rosea
63,68,118,136
225 Acetylrhodalgin (herbacetin‐3‐
acetate‐α‐L‐
arabinopyranoside)
C
22
H
20
O
12
Flavone glycoside
(Kae. Der.)
R. rosea
107
226 5,7,3′,5′‐Tetrahydroxy‐
flavanone
C
15
H
12
O
6
Flavanone R. rosea
102
227 Eriodictyol (3′,4′,5,7‐
tetrahydroxy‐flavanone)
C
15
H
12
O
6
Flavanone R. crenulata;R.
sachalinensis
53,54,56
228 (2S)‐5,7,3′,5′‐Tetrahydroxy‐
flavanone
C
15
H
12
O
6
Flavanone R. crenulata;R.
sacra
55,106
229 Naringenin C
15
H
12
O
5
Flavanone R. sacra
55
230 Dihydrokaempferol C
15
H
12
O
6
Flavanonole R. rosea;R. sacra
48,55
231 (+)‐Catechin C
15
H
14
O
6
Flavanole R. crenulata;R.
sachalinensis
53,54,137,138
232 (−)‐Catechin C
15
H
14
O
6
Flavanole R. rosea;R. kirilowii
139
233 Epicatechin C
15
H
14
O
6
Flavanole R. crenulata;R.
rosea;R. kirilowii
77,97,108,139
234 (−)‐Epigallocatechin C
15
H
14
O
7
Flavanole R. rosea;R.
sachalinensis;R.
kirilowii
50,97,139
235 Epicatechin‐3‐O‐gallate C
22
H
18
O
10
Flavanole R. rosea
48
236 Epicatechin gallate C
22
H
18
O
10
Flavanole R. crenulata;R.
kirilowii
108,138
237 (−)‐Epicatechin‐3‐O‐gallate C
22
H
18
O
10
Flavanole R. rosea;R. kirilowii
97,139
238 Epigallocatechin 3‐gallate C
22
H
18
O
11
Flavanole R. crenulata;R.
rosea;R.
sachalinensis;R.
kirilowii;R. sacra
57,69,70,76,80,97
104,127
239 (−)‐Epiafzelechin‐(4β‐8)‐(−)‐
epigallocatech
C
30
H
26
O
12
Dimeric
proanthocyanidin
R. crenulata
54
240 Procyanidin B 2 3′‐O‐gallate C
37
H
30
O
16
Dimeric
proanthocyanidin
R. crenulata
79,108
(Continues)
TAO ET AL.
|
17

TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
241 3,3′‐Digalloylprocyanidin B2 C
44
H
34
O
20
Dimeric
proanthocyanidin
R. kirilowii
97
242 Rhodisin (3,3′‐di‐O‐
galloylprodelphinidin B 2)
C
44
H
34
O
22
Dimeric
proanthocyanidin
R. kirilowii;R. sacra
69,70,97
243 3‐O‐Galloylepigallocatechin‐
(4→8)‐epigallocatechin
3‐O‐gallate
C
44
H
40
O
19
Dimeric
proanthocyanidin
R. sachalinensis
50
244 Dimeric procyanidin C
30
H
26
O
12
Dimeric
proanthocyanidin
R. crenulata
53
245 Epigallocatechin gallate dimer C
44
H
34
O
22
Dimeric
proanthocyanidin
R. rosea
67
246 3‐O‐Galloylepigallocatechin‐
epigallocatechin‐3‐O‐gallate
C
44
H
34
O
22
Dimeric
proanthocyanidin
R. crenulata
68
247 4H‐1‐Benzopyran‐4‐one, 2‐(3,
4‐dihydroxyphenyl)‐3,5,7,8‐
tetrahydroxy‐,di‐β‐D‐
glucopyranoside
C
27
H
30
O
18
Flavonoid R. rosea
124
248 4H‐1‐Benzopyran‐4‐one,
3,5,7,8‐tetrahydroxy‐2‐(4‐
hydroxyphenyl)‐,di‐β‐D‐
glucopyranoside
C
27
H
30
O
17
Flavonoid R. rosea
124
249 Sarmentosin C
11
H
17
NO
7
Acyclic alcohol nitrile
glycoside
R. crenulata;R.
sacra
69,70,80
250 Rhodiocyanoside A C
11
H
17
NO
6
Acyclic alcohol nitrile
glycoside
R. crenulata;R.
rosea;R.
sachalinensis;R.
kirilowii;R. sacra;
R. quadrifida
50,56,67,69–72,76,80
251 Rhodiocyanoside F C
16
H
25
NO
10
Acyclic alcohol nitrile
glycoside
R. sacra
55
252 Rhodiocyanoside D C
11
H
17
NO
6
Acyclic alcohol nitrile
glycoside
R. crenulata;R.
sacra
59,73
253 Heterodendrin C
11
H
19
NO
6
Acyclic alcohol nitrile
glycoside
R. crenulata;R.
sachalinensis;R.
sacra
53,54,56,59,69,70
254 Sachaloside V C
11
H
19
NO
7
Acyclic alcohol nitrile
glycoside
R. sachalinensis
56
255 4‐(β‐D‐Glucopyranosyloxy)‐3‐
hydroxy‐2‐(hydroxymethyl)‐
butanenitrile
C
11
H
19
NO
8
Acyclic alcohol nitrile
glycoside
R. kirilowii
77
256 Lotaustralin C
11
H
19
NO
6
Acyclic alcohol nitrile
glycoside
R. rosea;R.
sachalinensis;R.
kirilowii;R. sacra
50,56,59,65,76
96,140
257 (S)‐Lotaustralin C
11
H
19
NO
6
Acyclic alcohol nitrile
glycoside
R. rosea
65
258 Crenulatanoside A C
15
H
19
NO
7
Benzonitrile glycoside R. crenulata
80
259 Pyrogallol C
6
H
6
O
3
Polyphenol R. crenulata
82,83
(Continues)
18
|
TAO ET AL.

Compound 47
48
is from R. rosea; Compounds 46,48
46
are found in R. kirilowii; and Compounds 46,50
55,69
‐51
are in R. sacra. In summary, a total of 18 benzyl and phenol derivatives are found in Rhodiola plants. As this
group of compounds are quite reactive, they might be potentially bioactive. Their scientific significances need
further investigation.
TABLE 1 (Continued)
No Compounds
Molecular
formula Type Source of species References
260 Chrysophanol‐8‐O‐β‐D‐
glucopyranoside
C
21
H
20
O
9
Anthraquinone
glycoside
R. dumulosa
131
261 β‐Sitosterol C
29
H
50
O Sterol R. crenulata;R.
rosea;R. kirilowii;
R. sacra;R.
dumulosa
48,57,62,64,65,82
86,93–95,123
262 Stigmasterol C
29
H
48
O Sterol R. kirilowii
46
263 Daucosterol C
35
H
60
O
6
Sterol glycoside R. crenulata;R.
rosea;R.
sachalinensis;R.
kirilowii;R. sacra;
R. dumulosa
64,86,94,96,100,123
128,131
264 Nonadecane C
19
H
40
Alkane R. crenulata
47,86
265 n‐Hexacosanol C
26
H
54
O Alkanol R. crenulata
86
266 Rosiridol C
10
H
18
O
2
Alkene alkene R. rosea
51,62,64,93
267 Octadecanoic acid C
18
H
36
O
2
Fatty acid R. crenulata
86
268 Hexacosanoic acid C
26
H
52
O
2
Fatty acid R. crenulata
86
269 Suberic acid C
8
H
14
O
4
Fatty acid R. sacra
69,70
270 Alginoside C
13
H
22
O
8
Furanone glycoside R. rosea
61
271 Sachalinol B C
10
H
18
O
3
Furanol derivative R. sachalinensis
50
272 Sachalinol C C
10
H
18
O
3
Furanol derivative R. sachalinensis
50
273 Sachalinoside B C
16
H
28
O
7
Furancyclo glycoside R. crenulata;R.
sachalinensis
50,53
274 Sacranoside D C
21
H
36
O
11
Cyclo glycoside R. sacra
55
275 Crenulatanoside B C
24
H
38
O
12
Cyclo glycoside R. crenulata
103
276 Sacranoside A C
21
H
34
O
10
Bicyclo[3.1.1]
glycoside
R. sacra
70
277 Sacranoside C C
21
H
34
O
11
Bicyclo[3.1.1]
glycoside
R. sacra
55
278 Sachaloside I C
21
H
36
O
10
Bicyclo[3.1.1]
glycoside
R. sachalinensis
56
279 (−)‐Myrtenyl β‐D‐
glucopyranoside
C
16
H
26
O
6
Bicyclo[3.1.1]
glycoside
R. sachalinensis
56
280 Sacranoside A C
21
H
34
O
10
Bicyclo[3.1.1]
glycoside
R. crenulata;R.
sachalinensis;R.
sacra
53,59,69
281 Sachaloside II C
21
H
34
O
10
Bicyclo[3.1.1]
glycoside
R. crenulata;R.
sachalinensis
53,54
282 Thiouracil C
4
H
4
N
2
OS Pyrimidinone R. rosea
64
TAO ET AL.
|
19

FIGURE 2 Benzyl, phenol, phenylethane, and gallic acid derivatives present in Rhodiola species. a, R. crenulata;b,
R. rosea;c,R. sachalinensis;d,R. kirilowii;e,R. sacra;f,R. quadrifida;g,R. dumulosa
20
|
TAO ET AL.

3.1.3 |Phenylethane derivatives
Phenylethane derivatives are important chemical constituents of Rhodiola plants. Four phenylethanol compounds
are isolated. Two phenylethylglycosides (Compounds 56
47,51,69,70
and 58
51,73
) are found in R. rosea. All the five
phenylethylglycosides (Compounds 55‐58, and 73) have been isolated from R. crenulata. Compound 55 coexists in R.
sachalinensis and R. sacra.
47,56,70
Compound 56 is also found in R. sacra.
47,51,70
Compound 73 has a carbonyl group
on the side chain of tyrosol group, which differs it from other phenylethylglycosides.
85
Notably, these compounds
could release a fragrance similar to flowers, which might be the material basis for fragrance. Two most important
ingredients, namely tyrosol (Compound 59) and its derivative salidroside (Compound 62), belong to this
class.
47,50,51,55,56,65,66,71,72,74,76,80,88,90,94,97,99
Actually, they are p‐hydroxyl derivatives of phenylethyl alcohol, which
appear frequently in many Rhodiola species, such as R. crenulata,R. rosea,R. sachalinensis,R. sacra,R. kirilowii, and
R. quadrifida.2‐(4‐Methoxyphenyl)‐1‐ethanol (Compound 60) is a tyrosol methyl substituent isolated from
R. kirilowii.
46
Other tyrosol glycosides are 4‐hydroxyphenyl‐2‐ethyl β‐D‐glucopyranoside (Compound 61) isolated
FIGURE 3 Cinnamaldehyde and coumarin derivatives present in Rhodiola species. a, R. crenulata;b,R. rosea;c,R.
sachalinensis;d,R. kirilowii;e, R. sacra;f,R. quadrifida;g,R. dumulosa
TAO ET AL.
|
21

from R. rosea,
48
2‐(4‐hydroxyphenyl)ethyl 6‐O‐β‐D‐glucopyranosyl‐β‐D‐glucopyranoside (Compound 63) isolated
from R. crenulata,
85
icariside D2 (Compound 64) isolated from R. crenulata,R. rosea, and R. sacra,
47,48,55,85
viridoside
(Compound 65) isolated from R. crenulata,R. rosea, and R. sachalinensis,
51,53,54,56
mongrhoside (Compound 66)
isolated from R. rosea,
51
and 4‐methylsalidroside‐6‐O‐β‐D‐arabinopyranoside (Compound 67) isolated from
R. quadrifida,
66
respectively. 2‐(4‐Hydroxyphenyl)ethyl 4‐methoxybenzoate (Compound 68) is an ester contains a
tyrosol group in the structure, which is isolated from R. sachalinensis.
56
Both 4‐[2‐[2‐(4‐methoxyphenyl)ethoxy]
ethyl]‐phenol (Compound 69) and aspergillol B (Compound 70) have two tyrosol groups, while Compound 70
contains a carbonyl group on the side chain of one tyrosol unit. Compound 69 is found in R. kirilowii, while
Compound 70 is found in R. rosea.
46,48
Another tyrosol derivative, 4‐ethoxy‐benzeneethanol‐1‐acetate (Compound
71), is isolated from R. kirilowii.
46
In addition, three other type of phenylethane derivatives without tyrosol group in
their structures have also been reported. Crenulatanoside C (Compound 72) is isolated from R. crenulata, which is
structurally more related to phenylethylglycosides.
103
Picein (Compound 74) shares a same mother nucleus of
FIGURE 4 Lignin derivatives and other phenylpropanoids present in Rhodiola species. a, R. crenulata;b,R. rosea;
c, R. sachalinensis;d, R. kirilowii;e,R. sacra;f,R. quadrifida;g,R. dumulosa
22
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TAO ET AL.

p‐hydroxyacetophenone with 2‐(β‐D‐glucopyranosyloxy)‐1‐(4‐hydroxyphenyl)ethanone (Compound 73), and has
been found in both R. crenulata and R. rosea.
74,85
Two other compounds contain a mother nucleus of
p‐hydroxyacetophenone in their structures are rodiolinozide (Compound 75) and domesticoside (Compound 76).
An additional phenolic hydroxyl group presents in both Compounds 75 and 76. The former one is isolated from
R. kirilowii, while the latter one is from R. crenulata.
54,97
The structures of phenylethane derivatives are shown in
Figure 2. It has been widely recognized that phenylethane derivatives have important chemical taxonomic
significance for Rhodiola plants, especially for tyrosol, salidroside and their derivatives. Multiple bioactivities of
FIGURE 5 Flavonoles and their glycosides present in Rhodiola species. a, R. crenulata;b,R. rosea;c,R.
sachalinensis;d,R. kirilowii;e,R. sacra;f, R. quadrifida;g,R. dumulosa
TAO ET AL.
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23

these compounds have been reported by many research, and thus they usually serve as key quality control
(QC) markers.
3.1.4 |Gallic acid derivatives
Gallic acid is an active polyphenol compound, which exhibits potent antioxidative and other bioactivities, and has
been regarded as a promising leading molecule for drug discovery. In Rhodiola plants, more than 16 gallic acid
derivatives have been found, with their structures shown in Figure 2. Gallic acid (Compound 77) is frequently
FIGURE 6 Flavones, flavanones, flavanonoles, flavanoles, as well as their glycosides and dimeric
proanthocyanidins present in Rhodiola species. a, R. crenulata;b,R. rosea;c,R. sachalinensis;d,R. kirilowii;e,R. sacra;
f, R. quadrifida;g,R. dumulosa
24
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TAO ET AL.

identified across Rhodiola species, such as R. crenulata,R. rosea,R. sachalinensis,R. sacra,R. kirilowii,R. quadrifida, and
R. quadrifida.
50,55,80,83,91,94,97,105
Nine gallic acid derivatives isolated from R. crenulata are as follows: 3‐O‐
methylgallic acid (Compound 78),
80
methyl gallate (Compound 79),
46,92,106
gallic acid ethyl ester (Compound
80),
94,99
4‐O‐β‐D‐glucopyranosyloxy‐3,5‐dimethoxybenzoic acid (Compound 82),
80
1,2,3,4,6‐penta‐O‐galloylglucose
(Compound 85),
50,81
2‐(4‐hydroxyphenyl)ethyl ester‐3,4,5‐trihydroxy‐benzoic acid (Compound 88),
106,108
6‐O‐
galloylsalidroside (Compound 89),
47,48,50,83
crenulatin (Compound 90),
83,109
and sachalinoside A (Compound
91).
50,53,54
From R. rosea, five gallic acid derivatives are isolated, namely Compound 79, 1,2,6‐tri‐O‐galloyl‐β‐D‐
glucoside (Compound 83),
48
1,2,3,6‐tetra‐O‐galloyl‐β‐D‐glucopyranose (Compound 84),
48,50
1,2,3,6‐tetra‐O‐galloyl‐
4‐O‐p‐hydroxybenzoyl‐β‐D‐glucopyranoside (Compound 86),
48
and Compound 89. Four gallic acid derivatives found
in R. sachalinensis are Compounds 84, 85, 89, and 91. Four gallic acid derivatives are identified in R. sacra, namely
gallic acid 4‐O‐β‐D‐glucopyranoside (Compound 81),
69,70
phenethyl gallate (Compound 87),
55
rhodiocyanoside B
(Compound 92),
55,72
and Compound 80. Only Compound 79 is isolated from R. kirilowii, while only Compound 92 is
from R. quadrifida. The mother nucleus of gallic acid contains three active phenolic hydroxyl groups and a carboxyl
group, making it not only an active donor but also a receptor for protons. Through dehydrated esterification, the
carboxyl group of gallic acid can react with compounds which contain multiple hydroxyl groups. As carbohydrate
consists of multiple hydroxyl groups, it would provide multiple binding sites for reaction with gallic acid. Taking
Compounds 83‐86 as examples, hydroxyl groups at the different sites of glucopyranose could react with galloyl
groups through esterification. Compound 90 also contains more than one galloyl group in the structure. In addition,
as Compound 92 is a nitrile compound, its potential toxicity should be taken into consideration. Though gallic acid
derivatives are widely distributed in the Plant Kingdom, they might be important material basis of Rhodiola plants
due to their bioactivities.
3.1.5 |Phenylpropanoid derivatives
Phenylpropanoids are a big class of Rhodiola compounds. According to their structural mother nucleus, they can be
divided into four subgroups as follows: cinnamaldehyde derivatives, coumarin derivatives, lignin derivatives, and
several other phenylpropanoids. To date, a total of 27 cinnamaldehyde derivatives, 7 coumarin derivatives,
29 lignin derivatives, and 5 other phenylpropanoid derivatives have been found in Rhodiola species.
Cinnamaldehyde derivatives
The mother nucleus of this type of compounds shares a common benzene ring with an allyl alcohol group on the
side chain. Based on the oxygen status of the terminal carbon on the side chain, these compounds can be divided
into cinnamyl alcohol‐type (Compounds 93‐106) and cinnamic acid‐type (Compounds 107‐119) derivatives
respectively (Figure 3). Cinnamyl alcohol (Compound 93)
92,100
and trans‐cinnamic alcohol (Compound 94),
56,64
along with three glycosides, rosavin (Compound 95), rosin (Compound 96), and rosarin (Compound 97) are found in
both R. rosea and R. sachalinensis. Rosavin and rosarin have also been isolated from R. crenulata and R. quadrifida,
while rosin is found in R. crenulata.
51,53,56,65,66,68,74
Two other cinnamyl alcohol glycosides, 3‐phenyl‐2‐propenyl 6‐
O‐β‐D‐xylopyranosyl‐β‐D‐glucopyranoside (Compound 98)
112
and (2E)‐3‐phenyl‐2‐propen‐1‐yl 6‐O‐β‐D‐xylopyrano-
syl‐β‐D‐glucopyranoside (Compound 99),
51
are found in R. rosea. Five cinnamyl alcohol derivatives containing
p‐hydroxyl group or methylated p‐hydroxyl group have been isolated from R. rosea, namely triandrin (Compound
100),
47,67
vimalin (Compound 101),
47,112
sachaliside 1 (Compound 103),
74
(2E)‐3‐(4‐methoxyphenyl)‐2‐propen‐1‐yl
β‐D‐glucopyranoside (Compound 104),
74
and (2E)‐3‐(4‐methoxyphenyl)‐2‐propen‐1‐yl 6‐O‐α‐L‐arabinopyranosyl‐β‐
D‐glucopyranoside (Compound 105).
113
Compounds 100 and 101 are also found in R. crenulata. For a R. crenulata
derived compound coniferoside (Compound 102),
47
not only glycyl substitution occurs at the p‐hydroxyl group
but also methylation happens at the m‐hydroxyl group. In R. rosea,acis‐cinnamyl alcohol glycoside,
3‐(4‐methoxyphenyl)‐2‐propenyl 6‐O‐α‐D‐arabinofuranosyl‐β‐D‐glucopyranoside (Compound 106), is found.
112
Both
p‐coumaric acid (Compound 107)
48,55,69,73
and its isomer trans‐p‐hydroxycinnamic acid (Compound 108)
50,56,70,91
TAO ET AL.
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25

appear in two Rhodiola species, R. rosea and R. sacra. The former one is also found in R. crenulata, while the latter one
is also derived from R. sachalinensis. The structures of their derivatives can be distinguished through different
substitutions at p‐hydroxyl or its meta‐position. Compared with Compounds 107 and 108, another pair of isomers,
caffeic acid (Compound 109)
48,53,69
and trans‐caffeic acid (Compound 110),
47,56
contain an additional m‐hydroxyl.
Caffeic acid has been found in R. crenulata,R. rosea, and R. sacra, while trans‐caffeic acid is isolated from R. crenulata
and R. sachalinensis. From R. crenulata, a caffeic acid derivative, ferulaic acid (Compound 111),
53
and a p‐coumaric
acid glycoside, p‐coumaric acid 4‐O‐β‐D‐glucopyranoside (Compound 112),
73
have been isolated. Structurally, the
carboxyl group of four caffeic acid derivatives (Compounds 113‐117) is esterified with their chemical names as
follows: Rhodiolate (Compound 113),
106
octacosyl ferulate (Compound 114),
86
chlorogenic acid (Compound 115),
66
and caffeic acid phenethyl ester (Compound 116).
115
Among them, Compounds 113 and 114 are found in
R. crenulata. The pyran cycloalkyl of Compound 115 contains three hydroxyl groups, and a carboxyl group on its
side chain, which appears in both R. rosea and R. quadrifida. Compound 116 is found in R. sacra, which results from
esterification of caffeic acid and phenylethyl alcohol structurally. In addition, rosmarinci acid (Compound 117)
116
is
atrans‐caffeic acid derivative from R. rosea, in whose structure the carboxyl group of trans‐caffeic acid is esterified
with the branched hydroxyl group of benzenepropanoic acid. There are two other caffeic acid derivatives found in
R. crenulata, namely 3‐[(2R,3R)‐2,3‐dihydro‐3‐(4‐hydroxy‐3‐methoxyphenyl)‐2‐(hydroxymethyl)‐1,4‐benzodioxin‐6‐
yl]‐2‐propenoic acid (Compound 118) and arteminorin D (Compound 119).
106
The two phenolic hydroxyl groups of
their caffeic acid unit are substituted by the branched carbons of dihydroconiferyl alcohol. Thus, three pyran rings
are formed in their structure. Compounds 118 and 119 are also a pair of isomers.
Coumarin derivatives
Only seven coumarin‐type phenylpropanoids have been found in Rhodiola species (Figure 3). Umbelliferone
(Compound 120)
94,117
is isolated from R. sacra and R. quadrifida. Mellein (Compound 121)
46
is found in R. kirilowii
with a different esterification‐type at B ring. The oxygen atom in B ring of mellein is folded with the benzene ring
(A ring) through a carbonyl carbon atom. Scopoletine (Compound 122)
117
and crenulatin (Compound 123)
82,86,93
are two umbelliferone derivatives, with different substitutions at 6‐or 7‐C. Compound 123 appears in both
R. crenulata and R. rosea, while compound 122 is only found in R. quadrifida. A coumarin dimer derivative ellagic acid
(Compound 124)
99
is also found in R. crenulata, which contains two 7,8‐dihydroxy‐hydrocoumarin subunits in its
structure. Adjacent to A ring, nodakenin (Compound 125)
56
contains a furananoxy ring. Glycosylation occurs at the
side chain of its furananoxy ring. Nodakenin is only found in R. sachalinensis. Besides, thunberginol C (Compound
126)
55
is a dihydroisocoumarin isolated from R. sacra. However, there remains a trans‐coumaric acid (Compound
127)
57
found in R. sacra, whose structure is incompletely defined yet.
Lignin derivatives
Lignin derivatives are quite common phytochemicals in plants. Though cinnamaldehyde derivatives are also lignin
compounds, this review discussed them in a separated section (see Section 3.1.5.1). The lignins of R. crenulata have
been systematically studied. A total of 25 lignins have been isolated from R. crenulata (Compounds 128‐133, 135‐
149,153‐155, and 157).
47,80,106
Among them, six are cedrusin derivatives (Compounds 128‐133), containing a
furananoxy ring, which is different from the pyrananoxy ring (C ring) of flavonoids. Two phenylpropane‐type lignin
glycosides, namely 3‐phenyl‐1‐propanol glucoside (Compound 134)
56
and dihydroconiferin (Compound 135),
47,73
have been isolated from R. sachalinensis and R. crenulata, respectively. Structurally, they share a same
phenylpropanol mother nucleus, with a saturated side chain different from cinnamyl alcohol. Compounds
136‐139 and 140‐143 are identified as optical isomers of two 8‐O‐4′neolignan glycosides. Compounds 144‐156
are isolated as aryl tetralin‐type lignans. Among them, isolariciresinol 9‐O‐β‐D‐glucopyranoside (Compound 150)is
from R. kirilowii
57
; a pair of isomers, (+)‐isolariciresinol‐3α‐O‐β‐D‐glucopyranoside (Compound 151) and (−)‐
isolariciresinol‐3α‐O‐β‐D‐glucopyranoside (Compound 152), are isolated from R. dumulosa
105
; and (−)‐cycloolivil‐9‐
O‐β‐D‐glucopyranoside (Compound 156) is from R. sacra.
55
Other aryl tetralin‐type lignans are found in R. crenulata.
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TAO ET AL.

As most photochemistry studies of lignin derivatives focus on R. crenulata, it is still difficult to identify lignins as the
characteristic components of R. crenulata. Chemically investigations on other Rhodiola species, followed by
comparisons, need to be done. The molecular structures of lignins are shown in Figure 4.
Others phenylpropanoid derivatives
There are four other phenylpropanoid derivatives found in Rhodiola species (Figure 4). Two phenylpropanoid
glycosides, namely 2‐methoxy‐4‐(2‐propen‐1‐yl)phenyl 6‐O‐D‐apio‐β‐D‐furanosyl‐β‐D‐glucopyranoside (Compound
158) and gein (Compound 159), are isolated from R. sachalinensis.
56
Syzygiresinol A (Compound 160),
106
and
(5aR,6S,11aR)‐1,5,5a,6,11,11a‐hexahydro‐6‐(4‐hydroxy‐3‐methoxyphenyl)‐9‐methoxy‐3,3‐dimethyl‐naphtho[2,3‐e]
[1,3]dioxepin‐8‐ol (Compound 161)
73
are found in R. crenulate.
3.1.6 |Flavonoids and their glycosides
A total of 85 flavonoids and their glycosides have been found in Rhodiola species, which is of great significance to
the phytochemical taxonomy. As multiple biological activities of flavonoids have been widely recognized, they are
important secondary metabolites in plants. In general, they are produced by shikimic acid pathway and polyketone
biosynthesis pathway in plants. The structure consists of two phenyl rings (A and B) and a heterocyclic ring (C),
which can be abbreviated as C6‐C3‐C6. According to their molecular structures, flavonoids found in Rhodiola
species can be divided into six subgroups: flavonoles, flavones, flavanones, flavanonoles, flavanoles, and
biflavonoids. Nevertheless, the structures of two flavonoid glycosides (Compounds 247 and 248) isolated from
R. rosea have not been completely defined yet.
124
Flavonoles and their glycosides
With a total number of 55, the majority of flavonoids identified from Rhodiola species are flavonoles and their
glycosides, which could be subdivided into kaempferol‐type, quercetin‐type, and other flavonoles. Their molecular
structures are shown in Figure 5. Flavonoles contain a common unsaturated carbon‐carbon double‐bond in C ring,
with a hydroxyl group at 3‐C position. Compared to kaempferol‐type, the hydrogen atom at 3′‐C position of
quercetin‐type flavonoles is substituted by a hydroxyl group.
Compounds 162‐201 are kaempferol‐type flavonoles. Among them, Compounds 162,
118
163,
47,99,119
164,
53
165
47,106
‐167,
53
168,
126
169,
118
171‐172,
118
173,
99,106,119
174,
83,106,119
176,
118
182‐183,
126
184,
106
186,
126
188,
99,106,119
189,
126
194,
53
195,
53,54
197,
126
198,
84
199,
68
and 201
68
have been found in R. crenulata; Compounds
163,164,
121
170,
48
171,
127
173,
93,107,121
174,
48,121,129
177,
114
178,
132
179,
51,132
181,
127
187,
124
189,
66,121
190‐
191,
132
193,
124
195,
114,135
and 196
114,135
have been found in R. rosea; Compounds 163,
50,56,87
168,
87
171‐172,
127
173,
104,120
174,
50,87,104
179,180,
56
185‐186,
50,133
189,
87,104
192,
56
194,
56
198,
120
and 200
87
are isolated from
R. sachalinensis; Compounds 163
55,94
and 174
55
are from R. sacra; Compounds 163
117
and 189
66
are isolated from
R. quadrifida; Compounds 163,
105,123
166,
123
167,
125
173,
123,128
174,
123,128,131
175,
125
188,
131
and 190
105
are
found in R. dumulosa. Five compounds, kaempferol (Compound 163), astragalin (Compound 171), kaempferol 7‐O‐α‐
L‐rhamnopyranoside (Compound 173), rhodionin (Compound 174), and rhodiosin (Compound 189) appear
frequently across Rhodiola species, making them potential chemical markers for Rhodiola plants. In addition to
these commonly occurred compounds, several kaempferol‐type flavonoles only appear in R. crenulata,R. rosea, and
R. sachalinensis, respectively. In particular, Compounds 162,165,169,176,182‐184,197,199, and 201 are only
found in R. crenulata, with Compounds 170,177‐178,181,187,191,193, and 196 in R. rosea, and Compounds 180,
185,192, and 200 in R. sachalinensis. Two kaempferol derivatives, namely kaempferide (Compound 167) and
kaempferide‐7‐O‐α‐L‐rhamnoside (Compound 175), have only been found in R. dumulosa. Due to the lack of
sufficient data, it’s still difficult to identify specific constituents within other Rhodiola species. Whether these
kaempferol derivatives, which only appear in R. crenulata,R. rosea, and R. sachalinensis based on available reports,
could be used as markers for distinguishing different species needs further investigations.
TAO ET AL.
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27

Compounds 202‐214 are quercetin‐type flavonoles. Quercetin (Compound 202) is a common flavonole
appeared in R. crenulata,R. rosea,R. sachalinensis,R. quadrifida, and R. dumulosa.
53,105,117,118,120,124
Two of its
glycosides rhodiolgin (Compound 208)
4,53,54,57,71,72,91
and rutin (Compound 211)
77,105,116,120,124
are frequently
found in Rhodiola species. Rhodiolgin is found in R. crenulata,R. rosea,R. kirilowii, and R. quadrifida. Rutin has been
isolated from R. crenulata,R. rosea,R. sachalinensis, and R. dumulosa. These flavonoles could be regarded as potential
chemical markers for Rhodiola plants. In addition, four quercetin derivatives, namely ayanin (Compound 205),
118
quercitrin (Compound 206),
53,54,118,124
isoquercitrin (Compound 207),
53,118
and isoquercitrin‐7‐O‐gentiobioside
(Compound 213),
53,54
are found in R. crenulata, while compound 206 appears in R. rosea. Meanwhile, two quercetin‐
type flavonoles gossypetin (Compound 203)
124
and corniculatusin (Compound 204),
107
along with two glycosides
gossypin (Compound 209) and spiraeoside (Compound 210),
124
are only found in R. rosea. These compounds could
be used as potential markers to distinguish R. crenulata and R. rosea with other species. Besides, rhodioflavonoside
(Compound 212) is a glycoside coshared between R. rosea and R. quadrifida,
4,71,72,91
while rhodiolgidin (Compound
214) is coexisted in R. crenulata and R. rosea.
53,54,114,135
There are three other flavonoles found in R. crenulata,
namely crenulatin A (Compound 215), crenulatin B (Compound 216),
99
and rhodiolin (Compound
217),
56,63,66,87,104,121,126,134
respectively. Of note, Compound 217 appears in R. rosea,R. sachalinensis, and
R. quadrifida.
Flavones and their glycosides
Compared to flavonoles, a hydroxyl group at 3‐C position of flavones is removed (Figure 6). Three luteolin‐type
flavones have been found in R. crenulata. They are luteolin (Compound 218),
56,97,106
3′,4′‐dimethoxyluteolin
(Compound 219),
118
and luteolin‐7‐O‐α‐L‐rhamnoside (Compound 222).
53
Luteolin is also found in R. sachalinensis
and R. kirilowii. Compounds 220‐221,223‐224 are four tricetin‐type flavones. Tricetin (Compound 220)
71,72,97
is a
common ingredient of R. kirilowii and R. quadrifida. Tricin (Compound 221) has been isolated from R. crenulata,R.
rosea,R. sachalinensis, and R. sacra.
55,56,63,118,136
Two other tricetin‐type glycosides named as tricin 5‐O‐glucoside
(Compound 223)
63,136
and tricin‐7‐O‐β‐D‐glucoside (Compound 224)
63,68,118,136
have been found in R. rosea.
Meanwhile, Compound 224 appears in R. crenulata. In addition, there is an apigenin‐type glycoside named
acetylrhodalgin (Compound 225)
107
isolated from R. rosea.
Flavanones and flavanonoles and their glycosides
Flavanones and flavanonoles share the same structural feature of a saturated C ring, and they can be distinguished
by whether there is a substitution of the hydroxyl group at 3‐C position or not (Figure 6). There are four flavanone
compounds isolated from Rhodiola plants, namely 5,7,3′,5′‐tetrahydroxy‐flavanone (Compound 226),
102
eriodictyol
(Compound 227),
53,54,56
(2S)‐5,7,3′,5′‐tetrahydroxy‐flavanone (Compound 228),
55,106
and naringenin (Compound
229),
55
respectively. Compounds 227 and 228 not only appear in R. crenulata but also in R. sachalinensis and R. sacra,
respectively. Up to date, Compound 226 has only been found in R. rosea, while Compound 229 is found in R. sacra.
From R. rosea and R. sacra, a flavanonole named dihydrokaempferol (Compound 230) has been isolated.
48,55
Flavanoles
The mother nucleus of flavanoles contains a saturated and common hydroxyl group at 3‐C position. A total of eight
flavanoles and their glycosides have been reported in Rhodiola plants (Figure 6). Compounds 231
53,54,137,138
and
232
139
are a pair of catechin racemates. The former one is found in R. crenulata, while the latter one is found in both
R. rosea and R. kirilowii. Epicatechin (Compound 233)
77,97,108,139
and (−)‐epigallocatechin (Compound 234)
50,97,139
are also isolated from R. rosea and R. kirilowii. Meanwhile, compound 233 and 234 appear in R. crenulata and R.
sachalinensis, respectively. In the molecular structure of epicatechin‐3‐O‐gallate (Compound 235),
48
the hydroxyl
group at 3‐C position is esterified with the carboxyl of gallic acid. Compound 235 and its isomer (Compound 237)
are isolated from R. rosea.
97,139
Another isomer, epicatechin gallate (Compound 236), is identified as a common
ingredient of R. crenulata and R. kirilowii.
108,138
Epigallocatechin 3‐gallate (Compound 238) have found in R.
28
|
TAO ET AL.

crenulata,R. rosea,R. sachalinensis,R. sacra, and R. kirilowii,
57,69,70,76,80,97,104,127
indicating its potential as a common
chemical marker for Rhodiola plants.
Dimeric proanthocyanidins
The dimeric proanthocyanidins found in Rhodiola species are mainly dimers of flavanonoles. Their molecular
structures are shown in Figure 6. Compounds 239,
54
240,
79,108
244,
53
and 246
68
only appear in R. crenulata.
Compound 241 is only found in R. kirilowii,
97
while compound 243
50
and 245
67
only appear in R. sachalinensis and
R. rosea, respectively. In addition, compound 242
69,70,97
is a common ingredient of R. sacra and R. kirilowii. With
multiple hydroxyl groups in their structures, these dimeric proanthocyanidins (Compounds 240‐243 and 245‐246)
might show stronger bioactivities than other monoflavonoids.
3.1.7 |Nitrile derivatives
Ten nitrile derivative glycosides (Compounds 249‐258) have been reported in Rhodiola plants. Among them,
rhodiocyanoside A (Compound 250) has appeared in six species, R. crenulata,R. rosea,R. sachalinensis,R. kirilowii,
R. sacra, and R. quadrifida. And heterodendrin (Compound 253) is a common ingredient in R. crenulata,R.
sachalinensis, and R. sacra. Meanwhile, lotaustralin (Compound 256) has been found in three species, R. rosea,R.
sachalinensis, and R. sacra.
50,53–56,59,65,67,69–73,76,77,80,96,140
As potential toxicities of nitrile derivatives do exist, their
frequent appearances among Rhodiola species should be highly valued. The QC of Rhodiola plants should consider
these compounds.
3.1.8 |Other constituents of rhodiola species
Several other compounds have been found in Rhodiola plants, including polyphenol, anthraquinone glycoside,
sesquiterpene, sterols, and glycoside, alkane derivatives, fatty acids, cycloalkanones, furanone derivatives, cyclo
glycosides, bicyclo[3.1.1] glycosides, saccharides, and pyrimidinone. A very simple polyphenol named as pyrogallol
(Compound 259) is found in R. crenulate.
82,83
Chrysophanol‐8‐O‐β‐D‐glucopyranoside (Compound 260)isan
anthraquinone glycoside found in R. dumulosa.
131
Two common sterols β‐sitosterol (Compound
261)
48,57,62,64,65,82,86,93–95,123
and daucosterol (Compound 263)
64,86,94,96,100,123,128,131
frequently appear across
Rhodiola species, such as R. crenulata,R. rosea,R. kirilowii,R. sacra, and R. dumulosa. Meanwhile, daucosterol is found
in R. sachalinensis. Stigmasterol (Compound 262) is an another sterol found in R. kirilowii.
46
From R. crenulata,an
alkane, an alkanol, and two fatty acids were isolated, namely nonadecane (Compound 264), n‐hexacosanol
(Compound 265), octadecanoic acid (Compound 267), and hexacosanoic acid (Compound 268), respectively.
47,86
Rosiridol (Compound 267) is an alkene isolated from R. rosea.
51,62,64,93
Besides, suberic acid (Compound 269)isa
fatty acid isolated from R. sacra.
69,70
Compounds 270‐273 are compounds containing a furan ring in their
structures. Compounds 271‐273 have been found in R. sachalinensis,
50,53
while compound 270 only appears in
R. rosea,
61
and compound 273 is found in R. crenulata. Sacranoside D (Compound 274)
55
and crenulatanoside B
(Compound 275)
103
are two pyrancyclo glycosides found in R. sachalinensis and R. crenulata, respectively. In
addition, three bicyclo[3.1.1] glycosides (Compounds 276,
70
277,
55
and 280
53,59,69
) have been isolated from
R. sacra. Four bicyclo[3.1.1] glycosides (Compounds 278‐281) have appeared in R. sachalinensis.
56
Meanwhile,
sacranoside A (Compound 280) and sachaloside II (Compound 281)
53,54
are found in R. crenulata. Besides, thiouracil
(Compound 282) is a pyrimidinone isolated from R. rosea.
64
3.2
|
Quality control
According to the above data, the number of compounds found in different Rhodiola species are 160 in R. crenulata,
109 in R. rosea,78inR. sachalinensis,52inR. sacra,41inR. kirilowii,18inR. quadrifida, and 18 in R. dumulosa,
TAO ET AL.
|
29

respectively. The chemical compositions of seven species are shown in Figure 7. The phytochemical studies have
been mainly focused on R. crenulata,R. rosea, and R. sachalinensis, while R. quadrifida and R. dumulosa are less
investigated. The largest chemical class of Rhodiola species is flavonoid. Among 55 flavonoids found in Rhodiola
plants, there are 40 kaempferol‐type and 13 quercetin‐type flavonoles. As kaempferol‐and quercetin‐type
flavonoles are frequently appeared in plants, whether they have great chemical taxonomic significance for Rhodiola
species or not needs to be treated carefully. By comparison of R. crenulata with other species, it can be concluded
that 29 lignins are found in R. crenulata, while only seven lignins are in others, indicating that lignins might be
characteristic ingredients of R. crenulata to be distinguished from others. Other types of compounds are generally
not outstanding in number. With a deeper investigation, six compounds have appeared in all the species, that is,
tyrosol, salidroside, gallic acid, rhodiocyanoside A, kaempferol, and daucosterol. Four compounds, including
epigallocatechin 3‐gallate, quercetin, rhodionin, and β‐sitosterol, are frequently appeared among Rhodiola species.
In addition, 11 compounds, including rosavin, rhodiolin, rhodiosin, rhodiolgin, rhodioloside E, kenposide A, rutin,
rhodiooctanoside, kaempferol 7‐O‐α‐L‐rhamnopyranoside, tricin, and lotaustralin, appear in at least four species.
These characteristic compounds could be potential chemical markers for QC process.
QC of various Rhodiola extracts is displayed in Table 2. Actually, many commonly used QC methods have chosen
tyrosol and salidroside as chemical markers,
189,190
including some methods documented in Pharmacopoeia. From
the results, there are great variations in the contents of tyrosol and salidroside in various Rhodiola extracts.
Importantly, quantification of one or two makers can hardly represent the complex chemical compositions of plants.
Recently, several novel methods based on high performance liquid chromatography‐diode array detector (HPLC‐
DAD) or liquid chromatography‐mass spectrometry (LC‐MS) have been developed for simultaneous determination
of multiple ingredients. In these studies, 5 to 10 marker compounds are usually selected for QC.
112,113,126,191–193
Apart from tyrosol and salidroside, other frequently used chemical markers include rosarin, rosavin, rosin, rosiridin,
sachaliside 1, gallic acid, and ethyl gallate, kaempferol and some glycosides, and so forth. As polyphenols such as
gallic acid and its derivatives and flavonoids are important material basis for Rhodiola plants, total phenolics assay is
frequently used for QC.
Based on current knowledge of QC of Rhodiola, the major challenges include the following: (i) QC markers
should be pharmacologically relevant. Potentially toxic compounds should be considered as well. For example, the
cyanogenic nitrile derivatives can be highly toxic, and thus are advocated to be subjected to QC process. Most
FIGURE 7 Distribution of isolated chemical constituents of Rhodiola species [Color figure can be viewed at
wileyonlinelibrary.com]
30
|
TAO ET AL.

TABLE 2 Bioactivities of Rhodiola species extracts
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
Antioxidant activity
1 Water extract b PBS; 3:1 liquid material
ratio (vol/wt); 25°C
Antioxidative activities RBC; human
16
Con.: 1, 2.5, 3 mg/mL; PC:
N/A
2 Water extract b Water; 3:1 liquid
material ratio (vol/wt)
Glycosylated phenolic
compounds 1% dw
Antioxidative activities NCTC 2544 cells; human
141
Con.: 40 μg/mL; PC: N/A
3 b Antioxidative activities 143B, IMR‐90, IMR‐32 cells;
human
18
Con.: 0.001, 0.1, 1 μg/mL;
PC: N/A
4 b Root UPLC, total rosavins
5% dw
Antioxidative activities C2C12 myotubes; mouse
142
Con.: 1, 10, 25, 50, 100 μg/
mL; PC: N/A
Anticancer activity
5 10% ethanol
extract
powder
a Root 10% ethanol Total phenolic content
12.5% dw;
salidroside 1% dw
Anticancer MDA‐MB‐231,76Ntert,
HMECs; human V14 cells;
mouse
BALB/c mice; female
42
Con.: 0.5, 20 mg/kg/d;
Con.: 25, 50, 75, 100 μg/mL; PC: N/A
PC: N/A
6 a Root Anticancer U87 GBM cells; human
143
Con.: 200 μg/mL;
PC: N/A
7 a Root HPLC, tyrosol
0.005%‐0.021% dw,
salidroside 0.214%‐
0.216% dw, gallic
acid 0.196%‐
0.258% dw
Anticancer MCF‐7 cells; human 129/C57Blk6 c mice;
female
144
Con.: 100 μg/mL; Con.: 20 mg/kg/d;
PC: 10 nM 17 β‐estradiol PC: N/A
8 a Root Antitumorigenic and
antimetastatic
activities
B16‐F10 cells; mouse C57BL/6 mice; female
145
Con.: 200 μg/mL; Con.: 100 mg/kg/d in
drinking water;
PC: N/A PC: N/A
9 96% ethanol
extract
b 96% ethanol; 6:1 liquid
material ratio (vol/
wt); 25°C; 12 h
HPLC, rosavin and
cinnamyl alcohol
0.13% dw
Anticancer HL‐60 cells; human
43
Con.: 45, 90, 180, 225,
450 μg/mL;
PC: N/A
(Continues)
TAO ET AL.
|
31

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
10 SHR‐5 and
salidroside
b Root Standardized
extraction
HPLC, salidroside
1.7% dw, total
rosavins 4.5% dw
Anticancer RT4, T24, UMUC3, 5637,
J82 cells; human
44
IC
50
s: 264, 71, 100, 151,
165 μg/mL, resp.;
PC: N/A
11 50% ethanol
extract and
salidroside
f Rhizome 50% ethanol Anticancer Balb/c mice
146
Con.: 40, 200, 400 mg/
kg/d;
PC: N/A
Antidiabetic activity
12 12% ethanol
extract
a 12% ethanol; 10:1
liquid material ratio
(vol/wt); 40°C; 2 h
Total phenolics assay
13.2% dw; HPLC,
gallic acid 0.617%
dw, coumaric acid
0.033% dw, tyrosol
0.207% dw
α‐Glucosidase
inhibitory activity;
antioxidant activity;
ACE inhibitory
α‐Amylase and α‐glucosidase
inhibition assay
23
IC
50
: 173.4 and 60.2 μg total
phenolic/mL, resp.
13 Water extract a Water; 10:1 liquid
material ratio (vol/
wt); 1.5 h
Total phenolics assay
12.19% dw; HPLC,
gallic acid 1.072%
dw, coumaric acid
0.059% dw, tyrosol
0.147% dw
α‐Glucosidase
inhibitory activity;
antioxidant activity;
ACE inhibitory
activity
α‐Amylase and α‐glucosidase
inhibition assay
23
IC
50
: 98.1 and 60.3 μg total
phenolic/mL, resp.
14 12% ethanol
extract
b 12% ethanol; 10:1
liquid material ratio
(vol/wt); 40°C; 2 h
Total phenolics assay
11.17% dw; HPLC,
gallic acid 0.166%
dw, coumaric acid
0.01% dw, tyrosol
0.278% dw
α‐Glucosidase
inhibitory activity;
antioxidant activity;
ACE inhibitory
activity
α‐Glucosidase inhibition
assay
23
IC
50
: 44.7 μg total
phenolic/mL
15 Water extract b Water; 10:1 liquid
material ratio
(vol/wt); 1.5 h
Total phenolics assay
7.64% dw; HPLC,
gallic acid 0.264%
dw, coumaric acid
0.014% dw, tyrosol
0.219% dw
α‐Glucosidase
inhibitory activity;
antioxidant activity;
ACE inhibitory
activity
α‐Amylase and α‐glucosidase
inhibition assay
23
IC
50
: 120.9 and 52.3 μg total
phenolic/mL, resp.
(Continues)
32
|
TAO ET AL.

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
16 RCE (95%
ethanol)
a Root 95% ethanol; 10‐fold
extraction first;
fivefold reflux second
HPLC, salidroside
3.5% dw
Antihyperglycemic
insult in diabetes
mellitus
HUVECs; human
147
Con.: 1.5, 3, 15, 30 μg/mL;
PC: N/A
17 RCE (95%
ethanol)
a Root 95% ethanol; 10‐fold
extraction first;
fivefold reflux second
HPLC, salidroside
3.5% dw
Anti‐type II diabetes HepG2 cells; human SD rats; male
148
Con.: 1.5, 3, 15, 30 μg/mL; Con.: 50 mg/kg/d
(PO, 3 d);
PC: N/A PC: N/A
18 RCE (95%
ethanol)
a Root 95% ethanol; 10‐fold
extraction first;
fivefold reflux second
HPLC, salidroside
3.5% dw
Antiobesity and anti‐
type II diabetes
activities
HepG2 cells; human SD rats; male
149
Con.: 1.5, 3, 15, 30 μg/mL; Con.: 50 mg/kg/d
(po, 3 d);
PC: N/A PC: N/A
19 RCR (50%
ethanol)
a Root 50% ethanol; 7:1 liquid
material ratio (vol/
wt); 50°C; 5 h; three
times
HPLC, salidroside
2.5% dw
Anti‐insulin resistance SD rats; male
150
Con.: 10 and 50 mg/kg/d
(PO, 5 wk);
PC: N/A
20 RCR
(methanol)
a Root Methanol; 3 h reflux;
three times
HPLC, salidroside
1.1063% dw, tyrosol
0.3183% dw, trans‐
caffeic acid 0.036%
dw, kenposide A
0.0195% dw
Ameliorating metabolic
derangements
ZDF rats; male
25
Con.: 100 and 500 mg/kg/
d (PO, 4 wk);
PC: N/A
ddY mice; male
Con.: 100, 250, 500 mg/
kg (PO);
PC: N/A
SD rats; male
Con.: 100, 250,
500 mg/kg (PO);
PC: N/A
21 70% ethanol
extract
b Root 70% ethanol Antihyperalgesic
activity
Wistar rats; male
151
22 85% ethanol
extract
b Root and
rhizome
85% ethanol; 1:1.3
liquid material ratio
(vol/wt); 73°C‐75°C;
2 h; three times.
Antihyperglycemia and
antidiabetic
complications
C57BL/Ks db/db
mice; male
26
Con.: 200 mg/kg/d
(PO, 12 wk);
PC: N/A
(Continues)
TAO ET AL.
|
33

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
23 95% ethanol
extract
b 95% ethanol; 20:3
liquid material ratio
(vol/wt); 55°C; 7 h;
three times
Antidiabete Wistar rats; male
24
Con.: 75 mg/kg/d
(PO, 16 d);
PC: N/A
24 Water extract b Water; 20:3 liquid
material ratio (vol/
wt); 55°C; 7 h; three
times
HPLC, salidroside
0.84% dw; tyrosol
0.19% dw
Antihyperglycemia Wistar rats; male
152
Con.: 35, 50, 75 mg/kg/d
(IP, 3 d);
PC: N/A
Antialtitude sickness activity
25 RCE (95%
ethanol)
a root 95% ethanol; 10‐fold
extraction first;
fivefold reflux second
HPLC, salidroside
3.5% dw
Antialtitude illness SD rats; male
153
Con.: 50 and 100 mg/kg/d
(PO, 3 d);
PC: N/A
26 RCE (95%
ethanol)
a root 95% ethanol; 10‐fold
extraction first;
fivefold reflux second
HPLC, salidroside
3.5% dw
Antihypoxia A549 cells; human
36
Con.: 1.5, 3, 15, 30 μg/mL;
PC: 10 µM NAC
27 RCE (95%
ethanol)
a root 95% ethanol; 40:1
liquid material ratio
(vol/wt)
HPLC, salidroside
3.5% dw
Antihypoxic pulmonary
edema
SD rats; male
35
Con.: 50 and 100 mg/kg/d
(PO, 3 d);
PC: 100 mg/kg/d
acetazolamide (PO, 3 d)
28 Water extract a Root and
rhizome
Water; 100°C; 2 h;
twice
HPLC, salidroside
1.234% dw
Antihypoxia HEK293T, HepG2 cells;
human
37
Con.: 0‐1 mg/mL;
PC: N/A
29 a Antihypoxic cardiac
dispersed apoptosis
C57BL/6J mice
154
Con.: 90 and 270 mg/kg/d
(PO, 4 wk);
PC: N/A
Antistress and antidepressant activities
30 70% ethanol
extract
b 70% ethanol; 2 h; twice HPLC, salidroside
4% dw
Antidepressive activity SD rats; male
30
Con.: 1.5, 3, 6 g/kg/d
(PO, 3 wk);
PC: 2.2 g/kg/d fluoxetine
(PO, 3 wk)
(Continues)
34
|
TAO ET AL.

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
31 90% ethanol
extract
b Root 90% ethanol; 10:1
liquid material ratio
(vol/wt); twice
HPLC, salidroside
0.1105%‐0.1149%
dw root; tyrosol
0.1322%‐0.1402%
dw root; rosarin
0.0524%‐0.0546%
dw root; rosavin
0.1265%‐0.1353%
dw root; rosin
0.0287%‐0.0329%
dw root
Anxiolytic activity SD rats; male
155
Con.: 8, 25, 75 mg/kg/d
(PO, 3 d);
PC: 2 mg/kg/d diazepam
(PO, 3 d)
32 RHO (60%
ethanol)
b Rhizome 60% ethanol HPLC rosavin 3% dw,
salidroside 1% dw
Antidepressant activity CD1 mice; male
156
Con.: 10, 15, 20 mg/
kg (IG);
PC: N/A
33 RHO (60%
ethanol)
b Rhizome 60% ethanol HPLC rosavin 3% dw,
salidroside 1% dw
Antistress Wistar rats; male
31
Con.: 10, 15, 20 mg/
kg (IG);
PC: N/A
34 SHR‐5 b Root Standardized
extraction
HPLC salidroside 1.7%
dw, total rosavins
4.5% dw
Antistress Chinchilla rabbits; male
32
Con.: 1 mg/kg/d (PO, 7 d);
PC: N/A
35 ADAPT‐232 b Root A fixed combination of
three genuine (native)
extracts of
Eleutherococcus
senticosus,Schisandra
chinensis, and Rhodiola
rosea
RP‐HPLC salidroside
0.33% dw, rosavin
0.37% dw
Antistress BALB/c mice; female
33
Con.: 30, 90, 180 mg/kg/d
in drinking water
(PO, 7 d);
PC: N/A
36 ADAPT‐232 b Root A fixed combination of
three genuine (native)
extracts of E.
senticocus,S. chinensis,
and R.rosea
RP‐HPLC, salidroside
0.33% dw, rosavin
0.37% dw
Antistress T98G cells; human
157
Con.: 0.005, 0.05, 0.5,
5μg/mL;
PC: N/A
(Continues)
TAO ET AL.
|
35

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
37 ADAPT‐232 b A fixed combination of
three genuine (native)
extracts of E.
senticocus,S. chinensis,
and R. rosea
RP‐HPLC, salidroside
0.33% dw, rosavin
0.37% dw
Antistress T98G cells; human
158
Con.: 3 and 300 μg/mL;
PC: N/A
38 SHR‐5 b Root Standardized
extraction
HPLC, salidroside
1.7% dw, total
rosavins 4.5% dw
Beneficial effects on
emotional behavior
T98G cells; human
159
Con.: 40 μg/mL;
PC: N/A
39 b Root HPLC, rhodioloside
2.7% dw, rosavin
6.0% dw, tyrosol
l0.8% dw
Antidepressant activity Wistar rats; male
34
Con.: 10, 20, 50 mg/kg/d
(PO, 3 d)
PC: 30 mg/kg
amitriptyline and
imipramine
hydrochloride
40 b Root Dissolved in 2%
ethanol and
administered by
gavage 1 h before
access to HPF at
doses of 10 or
20 mg/kg
3% rosavin, 3.12%
salidroside dw
Antidepressive activity SD rats; female
160
Con.: 10 and 20 mg/kg/d
(PO, 24 d);
PC: N/A
Neuroprotective effect
41 RCE (70%
ethanol)
a Root 70% ethanol; 2 h; twice HPLC, salidroside
4% dw
Neuroprotective effect SD rats; male
27
Con.: 1.5, 3, 6 g/kg/d
(PO, 3 wk);
PC: N/A
42 80% ethanol
extract and
salidroside
b 80% ethanol; counter
current extraction;
10:1 drug–extract
ratio
HPLC, salidroside 3%
dw, phenolic
compounds 40% dw
Neuroprotective effect HCN 1‐A cells; human
28
Con.: 0.1‐100 mg/mL;
PC: N/A
43 Capsule
extract
b Neuroprotective effect Wistar rats; male
161
Con.: 250 mg/kg/d
(PO, 3 wk);
PC: N/A
(Continues)
36
|
TAO ET AL.

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
44 Methanol
extract
b Root Methanol; 25°C Anti‐inflammatory and
neuroprotective
effects
BV2 cells; mouse ICR mice; male
162
Con.: 500 mg/kg (PO);
Con.: 1, 10, 50 μg/mL; PC: N/A
PC: N/A
45 b Neuroprotective effect SD rats; male
29
Con.: 1.5, 3.0, 6.0 g/kg/d
(PO, 3 wk);
PC: N/A
Immunomodulatory effect
46 50% ethanol
extract
b Root and
rhizome
50% ethanol; 10:1
liquid material ratio
(vol/wt)
HPLC, gallic acid 0.3%
dw, rosarin 0.17%
dw, rosavin 0.27%
dw, rosin 0.14% dw,
salidroside 0.73%
dw, tyrosol 0.12%
dw, chlorogenic acid
0.11% dw, tannins
8.37% dw
Immunomodulatory
effect
Balb/c mice; female
163
Con.: 0.04 and
0.2 mg (PO);
PC: N/A
47 70% ethanol
extract
b Root 70% ethanol; 10:1
liquid material ratio
(vol/wt); 2 h; twice
Immunomodulatory
effect
BALB/c mice; male
164
Con.: 50 mg/kg (i. p.);
PC: N/A
48 RRSS (water) b Water; 5:1 liquid
material ratio (vol/
wt); 100°C; 1 h
HPLC, salidroside
4.39% wt/vol, rosarin
5.15% wt/vol,
rosavin 4.12% wt/vol
Immunomodulatory
effect
Balb/c mice; female
165
Con.: 50, 100 or 200 mg/
kg/d (PO, 4 wk);
PC: 5 mg/kg/d caffeic acid
phenethyl ester
(PO, 4 wk)
49 Water and
50% ethanol
extract
d Root and
rhizome
Water or 50% ethanol;
twice
Immunity enhancing RBA, PKA test and
proliferative response of
lymphocytes to ConA
or LPS
Balb/c, Balb/c x
DBA2 mice
19
Con.: 50, 100, 200,
400 µg/d (PO, 7 d);
PC: N/ACon.: 1, 5, 10 µg/mL
PC: N/A
(Continues)
TAO ET AL.
|
37

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
50 50% ethanol
extract
f Root and
rhizome
50% ethanol; 10:1
liquid material ratio
(vol/wt)
HPLC, gallic acid
1.37% dw,
salidroside 2.39%
dw, tyrosol 2.04%
dw, chlorogenic acid
0.3% dw, tannins
16.21% dw
Immunomodulatory
effect
Balb/c mice; female
163
Con.: 0.04 and
0.2 mg (PO);
PC: N/A
51 Water and
50% ethanol
extract
f Root and
rhizome
Water or 50% ethanol;
twice
Immunity enhancing RBA, PKA test and
proliferative response of
lymphocytes to ConA
or LPS
Balb/c, Balb/c x
DBA2 mice
20
Con.: 50, 100, 200,
400 µg/d (PO, 7 d);
PC: N/ACon.: 1, 5, 10 µg/mL
PC: N/A
Anti‐inflammatory and analgesic activities
52 Water extract a Root Water; 10:1 liquid
material ratio (vol/
wt); 25°C; overnight
first; 3 h boil second;
twice
HPLC, salidroside
1.503% dw (Tibet)
and 0.641% dw
(Sichuan)
Antimicrobial and anti‐
inflammatory
activities
Drosophila melanogaster
166
Con.: 2.5% (wt/vol);
PC: N/A
53 20% ethanol
extract
b Root 20% ethanol Analgesic and anti‐
inflammatory
activities
Wistar rats; male
167
Con.: 50 and 100 mg/
kg (PO);
PC: N/A
54 40% ethanol
extract
b Root 40% ethanol; 10:1
liquid material ratio
(vol/wt); 25°C; 12 h
Anti‐inflammatory
activity
Wistar rats; male
21
Formaldehyde‐induced
arthritis
Con.: 50 mg/kg/d (IP, 7 d);
PC: 50 μg/kg
dexamethazone
Carrageenan‐induced paw
edema
Con.: 250 mg/kg (IP);
PC: 1 mg/kg
dexamethazone
Nystatin‐induced edema
Con.: 50, 150, 250 mg/
kg (IP);
(Continues)
38
|
TAO ET AL.

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
PC: N/A
55 70% ethanol
extract
b Root 70% ethanol HPLC, rosavin 2.7%
dw; salidroside
2.5% dw
Antinociceptive
activity
ICR mice; female
168
Con.: 10‐177 mg/kg (PO);
PC: N/A
56 Water extract c Root Water; 100°C; 7 h Anti‐inflammatory
activity
RAW 264.7 cells; mouse
22
Con.: 1, 10, 100, 1000 μg/mL;
PC: N/A
Antifatigue and physical function enhancing effects
57 40% ethanol
extract
a Root and
rhizome
40% ethanol; 12 h HPLC, rosavines 0,
salidroside 2.05% dw
Improving physical
working capacity
SD rats
38
Con.: 50 mg/kg/d
(PO, 6 d);
PC: N/A
58 40% ethanol
extract
b Root and
rhizome
40% ethanol; 12 h HPLC, rosavines
3.02% dw,
salidroside 0.89% dw
Improving physical
working capacity
SD rats
38
Con.: 50 mg/kg/d
(PO, 6 d);
PC: N/A
59 Powder b Rhizome HPLC, salidroside
1.9% dw, total
rosavins 2.5% dw
Life extension,
antistress, and
improving physical
working capacity
D. melanogaster
169
Con.: 2.5, 5, 10, 30 mg/mL;
PC: N/A
60 SHR‐5 b Root Standardized
extraction
HPLC, salidroside
1.7% dw, total
rosavins 4.5% dw
Life extension,
antistress, and
improving physical
working capacity
D. melanogaster
39
Con.: 5, 25, 125 mg/mL;
PC: N/A
61 SHR‐5 b Root Standardized
extraction
HPLC, salidroside
1.7% dw, total
rosavins 4.5% dw
Life extension,
antistress, and
improving physical
working capacity
D. melanogaster
170
Con.: 25 mg/mL;
PC: N/A
62 Water extract
(liquid)
b Water; 20:1 liquid
material ratio (vol/
wt); 100°C; 30 min
HPLC, salidroside
1.72%‐1.82% dw
Life extension Saccharomyces cerevisiae
YPH250; yeast
40
Con.: 20 μl/mL;
PC: N/A
(Continues)
TAO ET AL.
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39

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
63 b HPLC, salidroside
1.18%‐1.52% dw,
rosin 0.284%‐0.44%
dw, rosarin 0.272%‐
0.48% dw, rosavin
0.826%‐1.16% dw
Antifatigue Wistar rats; male
41
Con.: 5, 25, 125 mg/kg/d
(IG, 2 or 4 wk);
PC: N/A
Other effects
64 12% ethanol
extract
a 12% ethanol; 10:1
liquid material ratio
(vol/wt); 40°C; 2 h
Total phenolics assay
13.2% dw; HPLC,
gallic acid 0.617%
dw, coumaric acid
0.033% dw, tyrosol
0.207% dw
Antiadipogenesis
activity
3T3‐L1 preadipocytes;
mouse
171
Con.: 0.01, 0.1, 1.0 mg/mL;
PC: N/A
65 RHO (60%
ethanol)
b Rhizome 60% ethanol HPLC, rosavin 3% dw,
salidroside 1% dw
Reducing rewarding
properties and
preventing relapse to
nicotine
SD rats; male
172
Con.: 5, 10, 20, 40 mg/kg/
d (PO, 2 wk);
PC: N/A
66 RHO (60%
ethanol)
b Root 60% ethanol HPLC, rosavin 3% dw,
salidroside 1% dw
Reducing rewarding
properties and
preventing relapse to
nicotine
CD1 mice; male
173
Con.: 10, 15, 20 mg/kg/d
(IG, 5 d);
PC: 0.2 mg/kg/d SDS
(IG, 5 d)
67 RHO (60%
ethanol)
b Rhizome 60% ethanol HPLC, rosavin 3% dw,
salidroside 1% dw
Therapeutic potential
for treatment of
opioid addiction
CD1 mice; male
174
Con.: 10, 15, 20 mg/kg/d
(IG, 6 d);
PC: 5 mg/kg naloxone (IP)
68 RHO (60%
ethanol)
b Rhizome 60% ethanol HPLC, rosavin 3% dw,
salidroside 1% dw,
tyrosol 0.8% dw
Therapeutic potential
for treatment of
opioid addiction
CD1 mice; male
175
Con.: 10, 15, 20 mg/kg/d
(IG, 12 d);
PC: N/A
69 RHO (60%
ethanol)
b Root 60% ethanol HPLC, rosavin 3% dw,
salidroside 1% dw,
tyrosol 0.8% dw
Therapeutic potential
for treatment of
opioid addiction
OF1 mice; male
176
Con.: 15, 20, 25 mg/
kg (IG);
PC: N/A
70 b Root Nuclear magnetic Improving learning and Wistar rats; male
177
(Continues)
40
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TAO ET AL.

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
resonance,
salidroside 2.18% dw
memory Con.: 50, 100 mg/kg/d
(PO, 12 d);
PC: N/A
71 c Protective effects of
liver function
SD rats; male
178
Con.: 0.5 g/kg/d
(PO, 15 wk);
PC: N/A
72 Water extract c Root Water; 100°C; 5 h Protective effects of
liver function
SD rats; male
179
Con.: 50, 100, 200 mg/kg/
d (PO, 4 wk);
PC: N/A
73 20% ethanol
extract
b Root 20% ethanol; 30:1
liquid material ratio
(vol/wt); 25°C; 24 h
first; 1 h sonication
second
HPLC, salidroside
0.68%‐0.726% dw;
tyrosol 1.587%‐
1.631% dw
Tyrosinase and
melanogenesis
inhibitory activity
B16‐F0 cells; mouse
180
Con.: 50, 100, 200 μg/mL;
PC: 200 μg/mL arbutin
74 20% ethanol
extract
hydrolysate
b Root 80°C; 30 min acid
hydrolysis first; ethyl
acetate; twice second
HPLC, salidroside
0.025%‐0.031% dw;
tyrosol 1.398%‐
1.452% dw
Tyrosinase and
melanogenesis
inhibitory activity
B16‐F0 cells; mouse
180
Con.: 5, 10, 50 μg/mL;
PC: 50 μg/mL arbutin
75 c Hypopigmenting
activity
B16‐F10 cells; mouse
181
Con.: 50 and 100 µg/mL;
PC: N/A
76 95% ethanol
extract
b Root and
rhizome
95% ethanol; 10:1
liquid material ratio
(vol/wt); 2 h reflux;
three time
Antifibrotic lung injury SD rats; male
182
Con.: 125, 250, 500 mg/
kg/d (PO, 4 wk);
PC: 3.34 mg/kg/d
prednisone acetate (PO,
weeks)
77 Water extract b Water; 20:3 liquid
material ratio (vol/wt);
55°C; 7 h; three times
HPLC, salidroside
0.84% dw; tyrosol
0.19% dw
Hypotensive effect SHR rats; male
183
Wistar‐Kyoto rats; male
Con.: 5, 50, 75 mg/
kg (PO);
PC: N/A
78 Water‐soluble e Methanol; 20:3 liquid Hypotensive, positive SD rats; male
45
(Continues)
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41

TABLE 2 (Continued)
No. Extracts Species Part Condition Quality control Activity In vitro model In vivo model References
fraction
(WtF)
material ratio
(vol/wt); 55°C; 7 h;
three times first;
suspended in
distilled water and
fractionated by
liquid–liquid
partition with n‐
hexane,
dichloromethane,
ethyl acetate, and n‐
butanol second
inotropic and
chronotropic effects
Con.: 10, 25, 35, 50,
75 mg/kg (IP);
PC: N/A
79 n‐butanol‐
soluble
fraction (BtF)
e Hypotensive effect SD rats; male
45
Con.: 10, 25, 35, 50,
75 mg/kg (IP);
PC: N/A
80 b prophylaxis of the
ischemic cerebral
circulation disorders
184
81 SHR‐5 b Root Standardized
extraction
HPLC, salidroside
1.7% dw, total
rosavins 4.5% dw
Alleviating renal
damage
Wistar rats; male
185
Con.: 20 mg/kg/d (IG, 1
or 2 wk);
PC: N/A
82 SHR‐5 b Root Standardized
extraction
HPLC, salidroside
1.7% dw, total
rosavins 4.5% dw
Antitorsion induced
testicular injury
Wistar rats; male
186
Con.: 75 mg/kg (IP)
83 Water extract c Root Water; 10:1 liquid
material ratio (vol/
wt); 100°C; 3 h
Inhibiting ethanol
absorption
SD rats; male
187
Con.: 0.375, 0.75, 1.5,
3 g/kg (IG);
PC: N/A
84 Water extract e Water; 5:1 liquid
material ratio (vol/
wt); 100°C; 1 h; three
times
Prolyl endopeptidase
inhibitory effect
Prolyl endopeptidase
inhibitory assay
188
IC
50
: 0.77 µg/mL
Abbreviations: a, R. crenulata; ACE, angiotensin I‐converting enzyme; b, R. rosea;c,R. sachalinensis; Con., concentration; d, R. kirilowii; e, R. sacra; f, R. quadrifida; IG, intragastric;
IP, intraperitoneal; LPS, lipopolysaccharide; N/A, not applicable; NMR, nuclear magnetic resonance; PC, positive control; PO, per os; RP‐HPLC, reversed‐phase high performance
liquid chromatography; SHR, spontaneous hypertension; UPLC, ultra‐high‐performance liquid chromatography.
42
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studies have largely ignored this issue, and, importantly, the pharmacological and toxicological data are usually
unavailable for most compounds, which will be further discussed. (ii) Comparison of chemical compositions of
different Rhodiola is still lacking. LC‐MS represents as one of the most powerful techniques, which enables rapid
and sensitive qualitative and quantitative analysis of herbal extracts. It might be helpful to apply LC‐MS for
investigating and comparing the chemical profile of Rhodiola species.
4
|
PHARMACOLOGICAL ACTIVITIES
4.1
|
Bioactivities of rhodiola extracts
Multiple bioactivities of Rhodiola extracts, such as antioxidative, anti‐inflammatory, immunomodulatory,
antidiabetic, antihypertensive, antialtitude sickness, antifatigue, and anticancer activities, have been reported in
many in vitro, in vivo models, as well as clinical investigations. However, preparation methods of these extracts are
usually quite different from each other considering extraction solvents and conditions (temperature and time, etc).
Another concern is that different extraction process would give out different contents of ingredients. As the
contents of active ingredients closely relate to bioactivities, QC of these extracts is essential for comparison.
Notably, since the in vitro studies of plant extracts have not taken into consideration of systemic absorption or
metabolism of constituents, the results from an in vitro study might be biased. In the present review, the
bioactivities of different Rhodiola extracts are summarized in Table 2 based on Rhodiola species, plant parts, extract
condition, QC, bioactivity, and cell or animal model used in the study.
4.1.1 |Antioxidant activity
Natural antioxidants, such as tyrosol, salidroside, gallic acid, and multiple flavonoids have laid the material basis for
antioxidant activity of Rhodiola plants. The antioxidative activities of two water extracts (Extract 1and 2)
16,17,141
and two other extracts of R. rosea (Extract 3‐4)
18,142
have been investigated using different cell lines such as human
red blood cells, erythrocytes, NCTC 2544 cells, 143B, IMR‐90, IMR‐32 cells, and mouse C2C12 myotubes.
Interestingly, the major antioxidant defense level (antioxidant response element and heme‐oxygenase‐1
expression) in 143B, IMR‐90, and IMR‐32 cells were not affected by R. rosea extract. Its protective effects against
oxidative stress might be through a pro‐oxidant hormetic mechanism. In C2C12 myotubes, it has been found that
the antioxidant activity of R. rosea extract was through the modulation of the molecular chaperone HSP70. There is
no other research directly looking into the mechanisms of the antioxidative activities of Rhodiola plants.
4.1.2 |Anticancer activity
A 10% ethanol extract of R. crenulata (Extract 5), with 12.5% phenolic components and 1% salidroside, has been
investigated for its potential anticancer activity.
42
It can induce caspase‐mediated death of breast cancer cells, and
inhibit cell motility and invasion, but not in normal breast epithelial cells. In BALB/c mice bearing tumor xenografts,
it can increase mice survival time. In MCF‐7 human breast cancer cells, a R. crenulata extract (Extract 7) could
induce an early estrogenic response (ER) and reduce proliferation and tumor sphere formation.
144
However, in
129/C57Blk6 c mice, it couldn’t change ER expression or activity in murine mammary glands, indicating that there
might not be sufficient bioactive compounds to reach the target tissues.
144
The anticancer activity of another R.
crenulata extract (Extract 6) has been investigated on U87 GBM cells, which involves the inhibition of Wnt‐β‐
catenin signaling.
143
In addition, Extract 8could induce cell death and antiproliferation effect in B16‐F10 mouse
melanoma cells, and inhibit metastatic melanoma in a mouse model.
145
A 96% ethanol extract of R. rosea (Extract 9)
could induce apoptosis and necrosis in HL‐60 cells by cell cycle arrest in G1 phase.
43
SHR‐5 (a standardized extract
by Swedish Herbal Institute; Extract 10), along with its active ingredient salidroside, exhibits antiproliferation
TAO ET AL.
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activity in human bladder cancer cells (RT4, T24, UMUC3, 5637, and J82 cells) with different IC
50
s (264, 71, 100,
151, and 165 μg/mL, respectively) by inhibiting mechanistic target of rapamycin (mTOR) pathway and inducing
autophagy. However, no significant inhibition on the growth of TEU‐2 cells is seen in the research. Considering the
different p53 status and TSC1/2 expression of TEU‐2 cells from other cells, the antibladder cancer effects of SHR‐5
might relate to p53 and TSC1/2.
44
In addition, 50% ethanol extract of R. quadrifida (Extract 11) and salidroside
show anticancer potential in vivo through decreasing neovascular reaction.
45
Based on the results, the anticancer
effect of Rhodiola extract needs further investigations, in particular in animal models.
4.1.3 |Antidiabetic activity
An in vitro screening research of α‐amylase, α‐glucosidase, and angiotensin I‐converting enzyme (ACE) inhibitory
activities was carried out using 12% ethanol and water extracts of R. crenulata and R. rosea (Extract 12,13,14, and
15), respectively.
23
With highest content of tyrosol (0.278% dw), Extract 14 showed the strongest α‐glucosidase
and ACE inhibitory activity, indicating a dose‐effect relationship between tyrosol content and its inhibition of α‐
glucosidase and ACE. On the other hand, with the highest contents of gallic acid (1.072% dw) and coumaric acid
(0.059% dw), Extract 13 showed the strongest inhibition of α‐amylase. With the highest content of total phenolics
(132.0 mg/g, dw), Extract 12 showed the strongest antioxidant activity in 2,2‐diphenyl‐1‐picryl‐hydrazyl‐hydrate
(DPPH) assay. Taken together, it can be anticipated that different compounds should be responsible for different
bioactivities. Moreover, this is very preliminary evidence for its antidiabetic potential. Treatment with high glucose
to human umbilical vein endothelial cells could simulate endothelial injury, which mimics hyperglycemic insult in
diabetes mellitus. This injury could be attenuated by the treatment with RCE (95% ethanol extract, Extract 16) via
influencing the AMP‐activated protein kinase (AMPK) pathway.
147
Treatment with RCE by the same extraction
process (Extract 17) could suppress glucose production in HepG2 cells, which was further confirmed by animal
experiments. Gluconeogenic gene expression was suppressed along with the activation of AMPK signaling
pathway.
148
Another study demonstrated the antiobesity and anti‐type II diabetes potential of RCE (Extract 18)by
regulating hepatic glycogen and lipid metabolism in high glucose‐induced HepG2 cells and activating AMPK
signaling pathway.
149
A different RCE (50% ethanol extract; Extract 19), with lower salidroside content (2.5% dw)
than 95% ethanol extracts (3.5% dw), exhibited anti‐insulin resistance activity in fructose‐fed rats by modulating
CD36 redistribution.
150
In streptozotocin (STZ)‐induced diabetic rats, R. rosea 70% ethanol extract (Extract 21)
could reduce formalin‐induced hyperalgesia,
151
indicating its potential to treat diabetic hyperalgesia. In STZ‐
diabetic rats with heart failure, a 95% ethanol extract of R. rosea (Extract 23) showed its ability to increase cardiac
output, which was associated with an increase of peroxisome proliferator‐activated receptor‐δ.
24
Meanwhile, a
water extract of R. rosea (Extract 24) showed antihyperglycemia activity in STZ‐type I diabetic rats via an increase
of β‐endorphin secretion in the adrenal gland.
152
In animal models of the metabolic syndrome and type II diabetes,
treatment with the powder of a R. crenulata methanol extract (Extract 20) resulted in the ameliorated
derangements of glucose and lipid metabolism.
25
In a type II diabetic model of C57BL/Ks db/db mice, an 85%
ethanol extract of R. rosea (Extract 22) exhibited antihyperglycemia and diabetic complication effects.
26
Overall,
growing evidence based on animal models have suggested an antidiabetic role of Rhodiola extracts.
4.1.4 |Antialtitude sickness activity
Rhodiola plants, especially for R. crenulata, have long been used to relieve altitude reaction in high‐altitude areas as
folk medicine. Pharmacological studies have provided some laboratory evidence, and unfolded some mechanisms
behind it. In several studies, Sprague‐Dawley (SD) rats were exposed to a simulated altitude of 8000 m in a
hypobaric hypoxia chamber for 9 h to achieve altitude reaction model. One R. crenulata 95% ethanol extract known
as RCE (Extract 25) could alleviate this altitude‐like reaction by modulation of endothelial nitric oxide synthase and
Arg‐1 pathways.
153
Meanwhile, the high‐altitude pulmonary edema complication of hypoxic rats was attenuated by
44
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a different RCE (Extract 27) along with the reversal of hypoxia‐induced oxidative stress.
35
In related research on
hypoxic A549 cells, the treatment of RCE of Extract 26 could increase the hypoxia‐induced reduction of Na,
K‐ATPase expression through inhibition of reactive oxygen species (ROS)‐AMPK‐PKC? pathway.
36
A possible
molecular mechanism for a water extract of R. crenulata (Extract 28) was the induction of erythropoietin expression,
as well as the accumulation of HIF‐1αvia blocking the degradation pathway.
37
Moreover, R. crenulata extract
(Extract 29) showed antihypoxic cardiac dispersed apoptosis activities, which might be related to Fas‐and
mitochondrial‐dependent antiapoptotic pathways and vascular endothelial growth factor‐related prosurvival
pathways.
154
4.1.5 |Antistress and antidepressant activities
The Rhodiola plants are known to be abundant in adaptogens, which could prevent or reduce stress‐induced
impairments and disorders. It should be mentioned that two R. rosea‐derived adaptogen products, namely SHR‐5
and ADAPT‐232, were developed by Swedish Herbal Institute. SHR‐5 is a standardized extract of R. rosea
containing 1.7% salidroside and 4.5% total rosavins, while ADAPT‐232 is a fixed combination of three genuine
(native) extracts including SHR‐5. As both SHR‐5 and ADAPT‐232 have subjected for clinical trials, which were
reviewed somewhere else,
7
their antistress and antidepression activities are well‐recognized. The animal studies
and their mechanisms will be discussed in this review. Unlike R. rosea, no significant research has revealed the
adaptogen‐like effects of R. crenulata.
In depressive rats, a 70% ethanol extract of R. rosea (Extract 30) showed antidepression activities by improving
5‐hydroxytryptamine (5‐HT) level and inducing neural stem cell (NSC) proliferation at hippocampus. At a low
dosage (1.5 g/kg), Extract 30 has already shown its ability to reverse injured neurons at hippocampus.
30
In another
research, a 90% ethanol extract of R. rosea (Extract 31) could exhibit anxiolytic effect independent of GABAA‐
benzodiazepine site of the GABAA receptor in a dose‐dependent manner (per os [PO], 8, 25, and 75 mg/kg).
155
With a single intragastric administration (10, 15, and 20 mg/kg), a commercial 60% ethanol extract of R. rosea (RHO;
Extract 32) has shown its antidepressant‐like effect in mice. Interestingly, in the predictive forced‐swimming test,
the immobility time of tested mice could be reduced the most at the dose of 10 mg/kg. In the light‐dark test, only at
this dose could mouse anxiety behavior be alleviated. Nevertheless, in the swimming to exhaustion test and open‐
field test, a higher dose of 15 mg/kg was needed for anxiolytic effects, indicating a dose‐response issue should be
seriously considered. However, in similar research, RHO showed no analgesic effect among all three tested
dosages.
156
In another research conducted by the same group, RHO (Extract 33) could reverse corticotropin‐
releasing factor (CRF) injection (0.2 μg/rat) induced anorectic effects at 15 and 20 mg/kg, while the similar appetite‐
promoting effect was not observed in lipopolysaccharide (LPS; intraperitoneal [IP], 100 μg/kg) and FLU (IP, 8 mg/kg)
induced models at the same dosage. Taken together, it can be concluded that RHO could selectively reduce stress‐
and CRF‐induced anorexia in rats.
31
In stressed rabbits, treatment with 1 mg/kg/d (po, 7 d) of SHR‐5 (Extract 34)
could relieve stress‐induced anxiety by inhibition of p‐SAPK/p‐JNK.
32
The molecular mechanisms underlying the
antistress activity of ADAPT‐232 have been demonstrated by several research. In a swimming to exhaustion mice
model, ADAPT‐232 (Extract 35‐37) exerted a stress‐protective effect in a dose‐dependent manner (30, 90, and
180 mg/kg/d, 7 d) by modulation of expression of molecular chaperones.
33
Neuropeptide Y and Hsp72 expression
and transcriptional metabolic regulation were found to be involved in T98G neuroglial cells with dose‐dependent
increase (0.005, 0.05, 0.5, and 5 μg/mL).
157
To investigate its effects on the transcriptional level of metabolic
regulation, gene expression profiling of T98G cells was performed after treatment with ADAPT‐232 (3 and 300 μg/
mL). It has been suggested that targets of ADAPT‐232 include G‐protein‐coupled receptor pathways (ie, cAMP,
PLC, and PI3K), ERαreceptor, CEPT, Hsp70, neuroserpin, and 5‐HT3 receptor, which provides molecular
mechanisms of its beneficial effects.
33,157,158
Meanwhile, gene expression profiling of T98G cells treated with SHR‐
5 (Extract 38,40μg/mL) has been performed, which showed part of results in consistent with ADAPT‐232.
159
Actually, in a previous research, a rough R. rosea extracts (Extract 39) has already exhibited considerable
TAO ET AL.
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45

antidepressant activity in rats in a dose‐dependent manner (10, 20, and 50 mg/kg/d), which even performed better
than the positive control of imipramine.
34
Stress will induce binge eating (BE). In a rat BE model, a R. rosea extract
(Extract 40) could alleviate bingeing‐related eating disorder dose‐dependently (10 and 20 mg/kg/d), while 20 mg/kg
almost abolished BE.
160
4.1.6 |Neuroprotective effect
It has been acknowledged that the neuroprotective effects of Rhodiola plants contribute greatly to their antistress
and antidepression activities. In a STZ‐induced neural injury rat model, a 70% ethanol extract of R. crenulata (RCE;
Extract 41) could improve STZ‐induced impaired neurogenesis through protecting NSCs, and scavenging
intracellular ROS in the hippocampus, while the optimal effect was achieved at the medium dosage (3 g/kg/d).
27
An 80% ethanol extract of R. rosea (Extract 42, 0.1‐100 mg/mL) could protect human cortical neurons (HCN 1‐A
cells) against glutamate and hydrogen peroxide‐induced cell death by decreasing the accumulation of intracellular
calcium. Salidroside was thought to be the main active ingredient contributing to their activities.
28
Extract 41
contained 4% salidroside of its dry weight, while extract 42 contained 3%. In a study of commercial R. rosea capsule
extract (Extract 43), 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced oxidative stress and neurotoxicity in
Wistar rats were attenuated by R. rosea treatment (250 mg/kg/d).
161
Another in vivo investigation on STZ‐induced
rat model revealed that R. rosea extract (Extract 45) treatment could protect rats against cognitive deficits,
neuronal injury, and oxidative stress with the best outcome at the dosage of 3.0 g/kg, while its antioxidative effects
in the hippocampus were involved.
29
In LPS‐induced BV2 cells, a crude methanol extract of R. rosea (Extract 44)
could decrease the expression of iNOS and proinflammatory cytokines dose‐dependently (1, 10, and 50 µg/mL). The
neuroprotective effect was also confirmed in ICR mice with brain injection of LPS and L‐glutamate‐treated primary
cortical neurons.
162
4.1.7 |Immunomodulatory effect
As resources of adaptogens, Rhodiola plants have been recognized as immunity enhancers, more precisely to be
immunomodulator. In one study, both 50% ethanol extract of R. rosea (Extract 46)andR. quadrifida (Extract 50)
presented stimulating activity on the proliferation of mouse splenic lymphocytes responding to another T‐cell
mitogen‐phaseolus vulgaris hemagglutinin.
163
In septic rats, a 70% ethanol extract of R. rosea (Extract 47, i. p., 50mg/
kg) could suppresses thymus T‐lymphocyte apoptosis, increase Th1 cytokines by downregulating TIPE2.
164
AR. rosea
standardized solution (Extract 48), along with its major constituent salidroside, have shown their abilities to increase
secretion of both Th1‐(interleukin‐2[IL‐2] and interferon γ[IFN‐γ]) and Th2‐(IL‐4andIL‐10) pattern cytokines in
OVA‐primed mice time‐and dose‐dependently, while no acute or subacute toxicities were observed.
165
In addition,
water (RKW) and 50% ethanol (RKA) extracts of R. kirilowii (RK, Extract 49) were reported to stimulate granulocyte
activity and lymphocyte response to mitogens in vitro with the best outcome at medium dosage of 5 µg/mL. Besides,
they could enhance the ability of lymphocytes to induce local cutaneous graft‐versus‐host reaction in F1 hybrids. The
optimal active dosage for RKW was 0.1mg per mouse, while for RKA was 0.2 mg per mouse, indicating the necessity
to compare the chemical composition of each extract.
19
The same group also demonstrated the immunity enhancing
effect of R. quadrifida extracts (Extract 51).
20
However, it is hard to compare the immunomodulatory effects between
R. kirilowii and R. quadrifida, as they have independent experimental groups.
4.1.8 |Anti‐inflammatory and analgesic activities
The anti‐inflammatory activities of many Rhodiola extracts have been reported. In a Drosophila melanogaster model,
the gut immunity was induced by bacteria and SDS treatment. Both the water extracts of two different originated
R. crenulata extracts (Extract 52) could increase the survival rates of adult flies and expression of antimicrobial
46
|
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peptide genes. However, the Tibet R. crenulata extract exhibited stronger activity than the Sichuan one. By
comparison of their salidroside content, Tibet extract gave out 1.503%, while Sichuan gave out 0.641%.
166
The
difference in salidroside content might partially explain their differences in pharmacological action. In general, this
study has indicated their potential for the treatment of inflammatory intestine diseases. Using classic hot‐plate test,
Randall–Selitto test and the formalin test, the analgesic activity of a R. rosea 20% ethanol extract (Extract 53) was
examined. R. rosea could increase the latency reaction in hot‐plate test at both dosage (50 and 100 mg/kg). In
analgesy‐meter test, 50 mg/kg R. rosea could increase pressure reaction time‐dependently, while at the dosage of
100 mg/kg the pressure reaction was increased in 1h but decreased at 2 and 3 h continuously, indicating the dose‐
response depends on time of treatment greatly. In the formalin test, only 100 mg/kg R. rosea could decrease the
paw licking time in early reaction. In plethysmometer test, R. rosea exhibited significant anti‐inflammatory activity
at both dosage but time‐dependently.
167
Another pharmacological research using 40% ethanol extract of R. rosea
(Extract 54) revealed its anti‐inflammatory activities against acute and subacute inflammation at the dosage of
250 mg/kg. Meanwhile, it also exhibited an inhibitory effect on nystatin‐induced edema under a dose‐dependent
manner (50, 150, and 250 mg/kg), which might be associated with its inhibitory activities over cyclooxygenase‐1
(COX‐1), COX‐2, and phospholipase A2.
21
In combination with B‐vitamins, a R. rosea 70% ethanol extract (Extract
55) presented an antinociceptive effect in a synergistic manner through targeting nitric oxide/cGMP/K(+) channel
pathway dose‐dependently (10‐177 mg/kg).
168
In earlier research of R. sachalinensis water extract (Extract 56), the
Extract 56 was found to increase NO synthesis in IFN‐γ‐primed RAW 264.7 cells,
22
providing a possible mechanism.
It should be mentioned that the neuroprotective effect of Rhodiola extracts could be presented in a way of
alleviating nerve inflammation.
4.1.9 |Antifatigue and physical function enhancing effects
Rhodiola plants are good choices for supplementary alternative medicine. Several clinical trials revealed that
additional supplement with R. rosea could improve athlete performance. An in vivo study has carried out to compare
the effect of 40% ethanol extract of R. crenulata (Extract 57) and R. rosea (Extract 58).
38
Treatment with extract 58
resulted in longer exhaustive swimming time than Extract 57 and control, with activation of adenosine triphosphate
(ATP) synthesis in mitochondria and stimulation of reparative energy processes after intense exercise. As detected
by HPLC, Extract 57 contained 2.05% salidroside, while Extract 58 contained 3.02% rosavines and 0.89%
salidroside. The distinct pharmacological actions of the two extracts might be attributed to the different ingredient
contents. In a D. melanogaster based research, R. rosea powder (Extract 59) could increase lifespan at the dosage of
5.0 and 10.0 mg/mL, and also delay the age‐related decline of physical activities, while at 30.0 mg/mL a decrease in
lifespan was observed.
169
SHR‐5 (Extract 60‐61) has been reported to increase lifespan and improve physical
activity’sD. melanogaster.
39,170
A decrease in endogenous superoxide levels could be one of the possible
mechanisms. Another explanation was the involvement of dietary restriction‐related pathways. Under H
2
O
2
‐
induced oxidative stress, survival of S. cerevisiae cells could be decreased by supplementation of R. rosea water
extract (Extract 62,20μl/mL), while the viability and reproduction success of yeast cells were increased.
40
However, no activation of major antioxidant enzymes (catalase) was involved. The chronic R. rosea supplementation
(Extract 63) could improve exhaustive swimming‐induced fatigue by the increasing glycogen content, SREBP‐1,
FAS, Hsp70, Bcl‐2/Bax ratio and oxygen content in a rat model. Meanwhile, swimming‐enhanced serum BUN, GOT,
and GPT levels could be reduced by R. rosea in a dose‐dependent manner (5, 25, and 125 mg/kg/d).
41
4.1.10 |Other effects of rhodiola species extracts
A study carried out on 3T3‐L1 preadipocytes has demonstrated the antiadipogenesis activity of 12% ethanol R.
crenulata extract (Extract 64) in a dose‐dependent manner (0.01, 0.1, and 1.0 mg/mL), while this effect was related
TAO ET AL.
|
47

to the inhibition of proline dehydrogenase, glucose‐6‐phosphate dehydrogenase, lipid accumulation, and ROS
production
171
Two independent studies have shown the abilities of 60% ethanol extract of R. rosea (RHO; Extract 65‐66)to
reduce rewarding property and prevent relapse to nicotine.
172,173
RHO could increase 5‐HT content, along with
serotonin receptor 1A, which might be the key molecular mechanism. Meanwhile, RHO (Extract 67‐69) also
exhibited therapeutic potential for treatment of opioid addiction in several in vivo studies, with unknown molecular
mechanisms.
174–176
A recent study has shown the beneficial effect of a commercial R. rosea extract (Extract 70) could improve
learning ability and memory of scopolamine‐induced memory impairment in rats in a dose‐dependent manner (50
and 100 mg/kg/d).
177
In earlier studies, compound R. sachalinensis (Extract 71)
178
and a water extract (Extract 72)
179
showed their
protective effects of liver function in the CCl
4
‐induced liver injury rat model. The potential mechanism of Extract
71 could be its abilities to decrease the production of transforming growth factor β1 (TGF‐β1), collagen, expression
of messenger RNAs of TGF‐β1, a1(I) and Na
+
/Ca
2+
exchanger, and inhibit the activation of hepatic stellate cells
(HSCs). The activation of HSCs could also be inhibited by Extract 72, while the liver hydroxyproline
malondialdehyde, and serum enzyme activities were reduced.
A 20% ethanol extract (Extract 73)ofR. rosea and its hydrolysate (Extract 74) presented the inhibitory
effect on melanogenesis in B16‐F0 cells, while the hydrolysate (50 μg/mL arbutin) exhibited even stronger
effect than prototypical extract (200 μg/mL arbutin).
180
Interestingly, the contents of both salidroside and
tyrosol have been decreased by acid hydrolysis, especially salidroside, which indicates that these two
compounds might not be the main active substances. However, as the ratio of tyrosol to salidroside in
hydrolysate (51.0) is higher than in prototypical extract (2.3). This difference might also explain the enhanced
activity from acid hydrolysis. The R. rosea extract and its hydrolysate could reduce expression of MC1R,
MITF, and TRP‐1, phosphorylation of CREB, and activation of AKT and GSK3β. In another research, the
hypopigmentation effect of R. sachalinensis extract was also tested in B16‐F0 cells, along with four
components: catechin, chlorogenic acid, p‐coumaric acid, and tyrosol. However, only p‐coumaric acid could
inhibit melanin synthesis.
181
As the contents of these four compounds were unknown in this study, it is hard
to draw conclusion about which compound should be responsible for its activity.
The lung‐protective effect of R. rosea has been investigated on BLM‐induced pulmonary fibrosis (PF) rat model.
The 95% ethanol extract of R. rosea (Extract 76) could alleviate fibrotic lung injury in PF rats dose‐dependently
(125, 250, and 500 mg/kg/d).
182
HYP was reduced by R. rosea, along with increase of GSH and T‐SOD. Meanwhile,
the bronchoalveolar lavage fluid levels of TNF‐α, TGF‐β1, and IL‐6 were decreased. The expression levels of
mitochondrial membrane potential 9 (MMP‐9) and αsmooth muscle actin were decreased, in line with the trend of
TGF‐β1 and MMP‐1 in the lung tissues.
In spontaneous hypertension (SHR) rats, a water extract (Extract 77)ofR. rosea exhibited considerable
hypotensive effect in a dose‐dependent manner (5, 50, and 75 mg/kg).
183
Systolic blood pressure (SBP) of
SHR rats could be decreased by R. rosea. However, an even stronger decrease of SBP was presented in normal
group (Wistar‐Kyoto [WKY] rats). Interestingly, the increase of β‐endorphin was higher in SHRs than in
WKYs. Taken together, the underlying mechanism might be the induction of β‐endorphin secretion. In
addition, the water‐soluble fraction (WtF; Extract 78)ofR. sacra has exhibited dose‐dependent (10, 25, 35,
50, and 75 mg/kg) hypotensive effect, which might be mediated by the withdrawal of sympathetic vasomotor
tone and interaction with the circulatory angiotensin system. Whereas, the same hypotensive effect of n‐
butanol‐soluble fraction (BtF; Extract 79) only achieved at the highest dosage of 75 mg/kg.
45
There is a
necessity to gain a better understanding of the detailed chemical composition of WtF and BtF, which might
explain their different performance of bioactivities.
In a unilateral ureter obstruction induced kidney damage rat model, 20 mg/kg/d standardized R. rosea extract
(SHR‐5, Extract 81) could reduce serum levels of MDA and GPx, and the apoptotic cell number in kidney tissues,
48
|
TAO ET AL.

demonstrating its renoprotection effect.
185
A further study also demonstrated the preventive effects on testicular
injury of SHR‐5 (Extract 82, 75 mg/kg) in a torsion‐induced rat model.
186
A water extract (Extract 83)ofR. sachalinensis exhibited its inhibitory effect against ethanol absorption in
adose‐dependent manner (0.375‐3 g/kg) in rats.
187
R. sachalinensis could reduce serum triglyceride levels
increased by ethanol. However, two ethanol metabolism related enzymes, ADH, and ALDH, were not
affected.
In a screening test, the water extract of R. sacra (Extract 84) has shown its potent inhibitory activity against
prolyl endopeptidase among all herbal crude extracts (IC
50
= 0.77 µg/mL), indicating its beneficial potential of
learning and memory abilities.
188
4.2
|
Bioactivities of chemical constituents from rhodiola species
4.2.1 |Antioxidant activity
Nineteen ingredients of R. kirilowii (Compounds 34, 37‐39, 46, 51, 55‐56, 77, 81, 108‐109, 238, 242, 249‐250, 253,
269, and 276) have been examined for their free radical scavenging activities against superoxide anion radical
(·O
2−
) and hydroxyl radical (·OH). Their relative activities were compared.
70
At 50 mg/mL, caffeic acid, gallic acid,
epigallocatechin 3‐O‐gallate, and 3‐O‐galloylepigallocatechin‐(4β→8)‐epigallocatechin 3‐O‐gallate exhibited stron-
ger ·O
2−
inhibition than other compounds, while epigallocatechin 3‐O‐gallate displayed the strongest ·OH
inhibition. As this study was a single concentration test, more rigorous comparisons should be carried out using
different concentrations. Meanwhile, 16 phenolic ingredients of R. crenulata (Compounds 63, 73, 77, 79, 88, 163,
165, 173‐174, 184, 188‐189, 217‐218, 228, and 238) have been screening their antioxidant activity using DPPH
assay.
85,87,104,106
Among them, 11 ingredients (Compounds 79, 88, 163, 165, 173‐174, 184, 188‐189, 218, and 228)
showed their considerable scavenging activity against ABTS· free radical,
106
while other two compounds, rhodionin
and rhodiosin could also scavenging ·O
2−
.
87
In addition, the antioxidant activities of salidroside and tyrosol were
also demonstrated.
79,85
4.2.2 |Immunomodulatory effect
Histamine release is a key factor in the body’s inflammatory reaction to infection or allergy. Using an in vitro model
of rat exudate cells induced by antigen‐antibody reaction to release histamine, two compounds (rhodiocyanoside A
and B)
71,72
from R. quadrifida, and eight ingredients (Compounds 18, 28, 34, 56, 252, 253, 256, and 280)
59
of R.
kirilowii have shown their inhibitory activity in a dose‐dependent manner (10
‐5
‐10
‐4
M). Similar with positive control
of disodium cromoglycate, rhodiocyanoside A, lotaustralin, and rhodiooctanoside showed the potential inhibitory
activity. The anti‐inflammatory activity of caffeic acid phenethyl ester (CAPE, IP, 1 mg/kg) from R. sacra has been
investigated by LPS‐induced mouse model. The plasma TNF‐αand IL‐1βinduced by LPS were significantly
attenuated, while the activation of nuclear factor κB was inhibited. CAPE could also downregulate MMP‐9
activity.
115
The drawback of the study is the lack of quantification of CAPE in R. sacra. Whether the purity would
have influence on activity remains unknown. In another research, compared with the positive control of NG‐
monomethyl‐L‐arginine (L‐NMMA) (IC
50
= 8.57 ± 2.76 μM), kaempferol could moderately inhibit NO production
induced by LPS in RAW 264.7 cells (IC
50
= 21.34 ± 2.52 μM).
87
On the other hand, seven phenolic compounds
(Compounds 113, 118‐119, 128, 144, 184, and 189) from R. crenulata exhibited IFN‐γproduction inducing
activity.
106
As NO production by activated macrophages is dependent on IFN‐γ, it indicates that Rhodiola plants
might play a two‐way role in inflammatory immunoregulation. Th1‐(IL‐2 and IFN‐γ) and Th2‐(IL‐4 and IL‐10) pattern
cytokines could be increased by salidroside treatment in ovalbumin‐primed mouse model but not in a dose‐
dependent manner.
165
Rosavin and rosarin could improve cell viability of Jurkat T cells, while enhance the
apoptosis of mouse T cells. Rosavin could inhibit TRAIL upregulation, while rosarin showed an opposite effect by
inhibiting ERK phosphorylation.
194
TAO ET AL.
|
49

4.2.3 |Neuroprotective effect
In STZ‐treated NSCs, salidroside treatment could downregulate ROS levels and inhibit NSC death.
27
In another
research, salidroside showed protective effects against Ab25‐35‐induced oxidative stress in neurons, which
involves induction of antioxidant enzymes, thioredoxin, heme‐oxygenase‐1, and peroxiredoxin‐I, the down-
regulation of proapoptotic protein Bax and the upregulation of antiapoptotic protein Bcl‐XL. Furthermore,
salidroside could also restore the loss of MMP.
195
The L‐glutamate‐induced neurotoxicity of neuronal BV2 cells
could be suppressed by rosin but not by rosarin. Meanwhile, the level of phosphorylated MAPK, pJNK, and pp38,
which increased by L‐glutamate, were decreased by rosin and salidroside.
162
4.2.4 |Hepatoprotective effect
Both salidroside and kaempferol showed preliminary hepatoprotective activity against tacrine‐induced cytotoxicity
in HepG2 cells.
100
In addition, trans‐caffeic acid, rhodiosin, sachalosides III, and sachalosides IV showed protective
effect against D‐galactosamine‐induced cytotoxicity in primary cultured mouse hepatocytes.
56
4.2.5 |Others effect of constituents from rhodiola species
Crenulatanoside B and C have displayed cytotoxicities on A549, Bel7420, BGC‐823, HCT‐8, and A2780 cell
lines.
103
Salidroside could inhibit the growth of bladder cancer cell lines with a minimal effect on nonmalignant
bladder epithelial cells TEU‐2, which is associated with inhibition of the mTOR pathway and translation initiation
and induction of autophagy.
44
Salidroside and tyrosol could significantly prevent the hypoxia‐mediated endocytosis
of Na,K‐ATPase by inhibiting the ROS‐AMPK‐PKC? pathway in A549 cells.
36
In addition, the antiviral effects of
salidroside against coxsackievirus B3 was also reported.
196
Four other compounds (rhodisin, epicatechin‐3‐O‐
gallate, 3,3′‐digalloylprocyanidin B2, epigallocatechin 3‐gallate) were found to be anti‐hepatitis C virus agents.
97
Epicatechin‐(4β,8)‐epicatechin gallate and 4′‐hydroxyacetophenone showed inhibitory activity against xanthine
oxidase, indicating their antigout potential.
79
Using a cell‐based fluorescence assay, epicatechin gallate and
epigallocatechin 3‐gallate were identified as inhibitors of the cystic fibrosis transmembrane conductance regulator,
indicating their antidiarrheal potential.
138
Five compounds (Compounds 88, 233, 236, 238, and 240) have been
identified as potential α‐glucosidase inhibitors with IC
50
of 29.85 ± 2.20, 0.31 ± 0.01, 4.77 ± 0.22, 96.8, and
0.71 ± 0.01 μM, respectively.
80,108
Thirteen compounds (Compounds 21, 39, 50‐51, 77, 81, 84‐85, 174, 189, 238,
and 242‐243) were examined for their prolyl endopeptidase inhibitory activity, among which compound 84 showed
the strongest activity (IC
50
= 0.025 μM).
50,69
5
|
SAFETY ISSUE
Rhodiola is traditionally used as a nontoxic drug, which has been supported by results from both animal and human
studies. Clinical studies of various Rhodiola extracts have demonstrated that Rhodiola is well tolerated with no or
few side effects observed on healthy subjects or patients with life‐stress symptom, ischemic heart disease, or
neurological disorder.
197–199
Only a few reports have indicated that repeated doses of Rhodiola caused mild
dizziness and gastrointestinal discomfort.
200
However, whether these side effects are Rhodiola‐or patients‐related
remains to be further explored. Based on known toxicological data on animal studies, Rhodiola, including R. rosea,R.
heterodonta,R. imbricate,R. fastigiata,R. sacra, and R. kirilowii , are generally evidenced to be safe, particularly with
no acute and chronic toxicity under the experimental conditions at their therapeutic windows or far beyond.
201–205
In addition, studies indicated that salidroside, as one of main active components of Rhodiola, does not lead to
maternal or embryonic toxicity at a dose of 0.5, 0.25, and 0.125 g/kg in rats,
206
and is not genotoxic at doses up to
1.5 g/kg in mice.
207
50
|
TAO ET AL.

However, two critical issues should be highlighted regarding the safe use of Rhodiola. The first one is that
combinational use of Rhodiola with conventional drugs leads to herb‐drug interactions that may increase the risk of
side effects/toxicity. A case report on a 68‐year‐old female patient with recurrent moderate depression developed
serotonergic syndrome after taking R. rosea together with paroxetine, indicating a potential pharmacokinetic and
dynamic interactions.
208
Concurrent use of R. rosea significantly altered pharmacokinetic properties of losartan in
rabbits.
209
It is demonstrated that Rhodiola extracts and some of the constituents such as rhodiosin and rhodionin
are potential inhibitors of cytochrome P450 enzymes and P‐gp transporter.
210–212
Second, due to the presence of
cyanogenic compounds such as rhodiocyanosides and lotaustralin in Rhodiola, it should be paid attention to the
chronic use of Rhodiola. It is acknowledged that many nitriles which readily release cyanide ions are highly toxic.
Although rhodiocyanosides and lotaustralin have been reported to possess antiallergic and histamine release
inhibitory effect,
213,214
their potential toxicities are seldomly investigated.
6
|
CLINICAL TRIALS
Clinical trials of Rhodiola using randomized controlled methodology have been carried out since 1960s.
215
Till now,
a total of over 30 related reports could be found in PubMed database. In addition, a large number of publications
(of varying methodological rigor) on clinical efficacy of Rhodiola are documented in locally published journals in
Russia, China, India, and so forth. The most studied Rhodiola species include R. crenulate,R. rosea,R. kirilowii, and R.
sacra. Majority of studies have focused on the efficacy of Rhodiola on fatigue, depression, mountain sickness, and
cardiovascular disease. The results are summarized in Table 3.
A systematic review of these studies reveals that Rhodiola preparations exhibit ergogenic, antifatigue and
antidepressant properties, indicated by an enhancement of both physical and mental performance. Although
contradictory results exist in different studies,
242,243
most studies show that both R. rosea and R. crenulate are able
to enhance physical performance in healthy subjects, indicating an ergogenic effect.
219,230
Several commercially
available R. rosea preparations, such as ADAPT‐232, SHR‐5, and WS 1375, are highly evidenced to benefit burnout
patients or subjects with work‐or stress‐related fatigue after repeated doses or a single dose.
220,226,229
It is
demonstrated that R. rosea reduced symptoms of fatigue mainly through increasing mental performance
particularly via improving attention.
223,224
The antidepressant effect of R. rosea has been investigated on mild to
moderate depressive patients in several trials.
221,225
A randomized controlled study indicated that R. crenulate
extract improved mild or moderate depression after repeated administration.
200
Overall, since most of these
studies have mostly focused on the two Rhodiola species, R. rosea and R. crenulate, clinical trials on other species are
advocated. Besides, more highly confident evidence on ergogenic and antidepressant effects of Rhodiola should be
added.
Although Rhodiola is traditionally used to alleviate symptom of mountain sickness, most clinical trials have
failed.
217,233
For instance, Chiu et al
217
enrolled 102 Chinese volunteers and carried out a randomized, double‐
blind, placebo‐controlled crossover study using R. crenulate capsule. The results showed that R. crenulate is not
effective in reducing the incidence or severity of acute mountain sickness compared with placebo. However, some
studies, mostly using low‐quality methodology, have obtained positive results supporting the use of R. crenulate in
mountain sickness.
244
Therefore, whether Rhodiola has a preventive or therapeutic effect on mountain sickness
warrants further investigation.
A few trials demonstrate that Rhodiola preparations help to alleviate symptom of chronic obstructive pulmonary
disease,
218
and in combination with conventional drugs improve quality of life of patients with acute nonspecific
pneumonia.
231
Moreover, a R. kirilowii extract, Dazhu Hongjingtian injection, is used together with chemotherapy to
treat patients with non–small‐cell lung cancer, resulting in better efficacy and enhanced immunity.
235
In addition, R.
kirilowii and R. sacra have been widely used in China for treatment of cardiovascular diseases (eg, angina pectoris
and cardiovascular neurosis).
236–238
However, most of these studies which usually lack of details of blinding and
TAO ET AL.
|
51

TABLE 3 Clinical trials of Rhodiola species and the active constituents
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
Rhodiola crenulata
Rhodiola‐ginkgo capsule,
RGC (Integrated
Chinese Medicine
Holdings Ltd, Hong
Kong; each capsule
containing 270 mg
herbal extracts with
23.8 mg/g salidrosides,
12.55 mg/g flavonoids
per capsule)
70 Healthy male
Chinese volunteers
aged 18‐22
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
RGC/placebo group
(35/35 cases): four
capsules per day for
7wk
Endurance exercise,
serum levels of
testosterone, and
cortisol
RGC improves the
endurance performance by
increasing oxygen
consumption and
protecting against fatigue
Ib
216
Four in placebo and five in
RGC group experienced
transient sleepiness in
initial phase of treatment
R. crenulate capsule, RCC
(Kaiser Pharmaceutical
& Biotanico, Tainan;
2.38% salidroside and
0.44% p‐tyrosol per
capsule)
102 Chinese
volunteers aged 23‐
55 who reside
principally at an
elevation of 250 m
or lower
Randomized, double‐
blind, placebo‐
controlled crossover
study
RCC and placebo
groups receiving
either 800 mg RCC
or placebo capsule
daily for 7 d before
ascent and 2 d
during
mountaineering,
before crossing over
to the alternate
treatment after a 3‐
mo wash‐out period
Lake Louise scoring,
pulse
oximetry (SpO
2
)
RCC is not effective in
reducing the incidence or
severity of acute mountain
sickness as compared with
placebo
Ib
217
No adverse effect
R. crenulate capsule, RCC
(Chuang Song Zong
Pharmaceutical Co, Ltd,
Taiwan; 250 mg RC
extract per capsule with
1.99 mg salidroside)
57 Taiwan patients
with moderate to
severe COPD aged
40‐80
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
RCC/placebo group
(38/19 cases): one
capsule twice per
day for 12 wk
Anthropometric
measurements,
OCD, Mmrc, BODE,
quality of life,
pulmonary function,
exercise capacity,
maximum
cardiopulmonary
exercise
RCC does not improve the
six‐minute walk test
distance but does improve
tidal breathing and
ventilation efficiency in
patients with COPD during
incremental maximum
exercise
Ib
218
Side effects in 55.3% of the
RC group, and in 57.9% of
the placebo group
(Continues)
52
|
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TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
R. crenulate capsule, RCC
(Tibet GaoYuanan
Biotechnology Co, Ltd;
0.3 g RC extract per
capsule)
220 Mild or
moderate major
depressive disorder
Chinese patients
with deficiency of
both heart and
spleen syndrome
Randomized, double‐
blind, placebo‐
controlled, three‐
parallel‐group study
Low‐/high‐dose RCC
group (73/74 cases):
two/four capsules
every day for 8 wk
HAMD and BDI
scores
RCC improves mild or
moderate depression
Ib
200
Placebo group (73
cases): equivalent
placebo capsule for
8wk
No side effects in placebo
group, while three cases in
low‐dose RCC group and
three cases in high‐dose
group showing minor
dizziness or gastrointestinal
discomfort
R. crenulate plus
Cordyceps sinensis,RC
(each capsule containing
1000 mg extract)
18 Male Taiwan
long‐distance track
and field athletes
aged 19.66 ± 0.18
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
RC/placebo group (9/
9 cases): one
capsule, twice daily
for 2 wk
Autonomic nervous
system activity,
circulatory
hormonal, and
hematological
profiles
Significantly improved
maintenance of
parasympathetic activity
and accelerated
physiological adaptations
after treatment.
Ib
219
Rhodiola rosea
Standarised R. rosea
extract SHR‐5 tablet
(Swedish Herbal
Institute; 144 mg
extract per tablet with
4 mg rhodioloside)
60 Swedish subjects
of both sexes aged
20‐55 with fatigue
syndrome
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
SHR‐5/placebo group
(30/30 cases): two
tablets twice daily
for 28 d
Symptoms of fatigue,
attention,
depression, quality
of life, salivary
cortisol
Significantly improved
symptoms of fatigue,
attention, and salivary
cortisol compared with
placebo
Ib
220
No adverse effect
Standarised R. rosea
extract SHR‐5 tablet
(Swedish Herbal
Institute; 170 mg
extract per tablet)
89 Armenian subjects
aged 18‐70 with
mild or moderate
depression
Randomized, double‐
blind, placebo‐
controlled, three‐
parallel‐group study
Low‐/high‐dose SHR‐
5 group (31/29
cases): two/four
tablets daily for
6wk
HAMD and BDI
scores
Statistically significant
improvement of overall
depression, together with
insomnia, emotional
instability and somatization,
but not self‐esteem, in the
treatment group (SHR‐5)
Ib
221
Placebo group (29
cases): two placebo
tablets daily for
6wk
(Continues)
TAO ET AL.
|
53

TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
Standarised R. rosea
extract SHR‐5 tablet
(Swedish Herbal
Institute; 50 mg extract
per tablet)
40 Male Indian
students aged 17‐19
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
SHR‐5/placebo group
(20/20 cases): one
tablet twice daily for
20 .
Psycho‐motoric
function, mental
work capacity,
mental fatigue,
general well‐being
Significant improvement in
physical fitness, mental
fatigue and neuromotoric
tests in the treatment
group
Ib
222
No adverse effect
Standarised R. rosea
extract SHR‐5 capsule
(Swedish Herbal
Institute; 185 mg
extract per tablet)
161 Male Russian
cadets aged 19‐21
with work‐related
fatigue
Randomized, double‐
blind, placebo‐
controlled, four‐
parallel‐group study
Low‐/high‐dose SHR‐
5 group (41/20
cases): two/three
SHR‐5 capsules
Capacity for mental
work, physiological
parameters
Significantly better mental
and physiological
parameters (antifatigue
effect) in SHR‐5 groups
Ib
223
Placebo group (40
cases): two placebo
capsules
One subject in placebo group
complained of
hypersalivation lasting
40 min after intake
Control group (20
cases): untreated
Standarised R. rosea
extract SHR‐5 capsule
(Swedish Herbal
Institute; 170 mg
extract per tablet with
4.5 mg salidroside)
56 Armenian healthy
physicians of both
sex aged 24‐35 with
work‐related fatigue
Randomized, double‐
blind, placebo‐
controlled,
crossover study
Low‐/high‐dose SHR‐
5 group (31/20
cases): two SHR‐5
tablets daily (340/
680 mg/day) for
42 d
Mental fatigue,
perceptive, and
cognitive functions
such as associative
thinking, short‐term
memory, calculation
and ability of
concentration, and
speed of audio‐
visual perception
Significant improvement in
perceptive and cognitive
cerebral function in the
treatment group during the
first two weeks period
Ib
224
Placebo group (40
cases): two placebo
tablets daily for 42 d
No adverse effect
Standarised R. rosea
extract SHR‐5 capsule
(Swedish Herbal
Institute; 340 mg
extract per tablet with
rosavin 3.07%/
rhodioloside 1.95%)
57 American patients
with mild to
moderate major
depressive disorder
aged 18‐70
Randomized, double‐
blind, placebo‐
controlled study
SHR‐5/sertraline
(50 mg/tablet)/
placebo group: 12‐
wk dose‐escalating
schedule from one
capsule daily to 4
capsules daily
according to
HAMD score, CGI/C,
BDI scores
SHR‐5 produces less
antidepressant effect
versus sertraline but with
significantly fewer adverse
events
Ib
225
(Continues)
54
|
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TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
patients’condition
Ethanolic (60% wt/wt)
extract from R. rosea
roots, WS 1375, Rosalin
(Dr Willmar Schwabe
GmbH & Co, KG,
Germany; 200 mg
extract per tablets)
118 Austrian subjects
of both sex aged 30‐
60 suffering from
burnout symptoms
Exploratory, open‐
label, multicenter,
single‐arm study
400 mg/day for
12 wk
Overall satisfaction
with sexual life,
severity of the
disorder, mood. and
well‐being, the
negative impact of
the burnout
symptoms on the
patient’s work,
social life and family,
speed of executive
function
Significant improvement
over time after treatment
III
226
Low incidence of adverse
events with 0.015 events per
observation day
Ethanolic (60% w/w)
extract from R. rosea
roots, WS 1375, Rosalin
(Dr Willmar Schwabe
GmbH & Co, KG,
Germany; 200 mg
extract per tablets)
101 Subjects of both
sex with life‐stress
symptoms
Multicenter,
nonrandomized,
open‐label, single‐
arm study
One tablet twice
daily for 4 wk
Stress symptoms,
disability, functional
impairment
Significant improvements
after 3 d of treatment,
continuing improvements
after 1 and 4 wk
III
227
No serious adverse events
Extract of R. rosea roots
(128 mg extract/capsule
with 0.28% total
rosavins)
48 Canadian nursing
students aged 18‐55
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
R. rosea group (24
cases): two tablets
at the start of the
subjects’wakeful
period and up to one
additional capsule
within the following
4 h on a daily basis
over a 42‐d period
Fatigue symptoms,
health‐related
quality of life,
individually selected
outcomes
Significant increases in
fatigue in the R. rosea group
Ib
228
No differences of total
number of adverse events
between two groups
Placebo group (24
cases): identical to R.
rosea group for 42 d
(Continues)
TAO ET AL.
|
55

TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
ADAPT‐232 tablets, a
standardized fixed
combination of R. rosea
27.6%, S. chinensis
(Turcz.) Baill. 51%, and
E. senticosus Maxim
24.4% (Swedish Herbal
Institute; each tablet
containing 270 mg
extract with 0.32%
rhodioloside, 0.5%
rosavin, 0.05% tyrosol,
0.37% schizandrin,
0.24% g‐schizandrin,
and 0.15%
eleutherosides B and E)
40 Healthy women
aged 20‐68
performing stressful
cognitive tasks
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
ADAPT‐232/placebo
group (20/20 cases):
one tablet
Mental performance
(attention, speed,
and accuracy),
arterial blood
pressure and
heart rate
Significant improvement in
attention and increase in
speed and accuracy during
stressful cognitive tasks in
comparison to placebo
Ib
229
A few minor adverse events,
such as sleepiness and cold
extremities, were observed
in both groups
ADAPT‐232 capsule
(Swedish Herbal
Institute; each capsule
containing 0.5 mg of
salidroside, 1.0 mg pf
schizandrin, and
0.35 mg of
Eleutherosides B and E)
160 Healthy
Caucasian athletes
aged 18‐35
Randomized, double‐
blinded, placebo‐
controlled study
ADAPT‐232/placebo
group (92/68 cases):
two capsules twice
daily for 28 d
Fatigue, blood
testosterone/
cortisol ratio, blood
lactate
Significantly enhanced
tolerance to physical and
emotional stress as well as
the recovery of athletes
during and after high‐
intensity exercise and
competitions
Ib
230
The total numbers of
adverse events did not
differ between groups
(Continues)
56
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TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
ADAPT‐232 liquid,
Chisan (Swedish Herbal
Institute; each capsule
containing 0.068 mg/mL
salidroside, 0.141 mg/
mL rosavin, 0.177 mg/
mL shisandrin,
0.105 mg/mL
shisandrin, and 0.011
and 0.027 mg/mL
eleutherosides B and E)
60 Armenian patients
of both sex aged 18‐
65 with acute
nonspecific
pneumonia
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
In addition to a
standard
antipneumonia
treatment,
Mental performance,
quality of life
As an adjuvant, significant
improvement in quality of
life and mental
performance in treatment
group
Ib
231
ADAPT‐232/placebo
group (30/30 cases):
120 mL twice daily
for 10‐15 d
R. rosea extract, Rhodax
(Bodyonics Ltd; each
tablet containing
170 mg extract with
30 mg of each of the
compounds, rosavin,
rosarin, salidrosides,
rosin, rhodalgin,
acetylrhodalgin,
rosaridin and rosaridol)
10 American patients
of both sex with
generalized anxiety
disorder aged 18‐64
Nonrandomized,
open‐label, single‐
arm study
Two tablets twice
daily for 10 wk
HARS score Significantly decreases in
mean HARS scores
III
232
Mild to moderate adverse
event: dizziness (N=2;
20%) and dry mouth
(N= 4; 40%)
R. rosea extract
(American
Phytotherapy Research
Laboratory; each
capsule containing
447 mg extract)
15 Healthy American
subjects of both sex
aged 20‐33
Ramdomized, double‐
blind, placebo‐
controlled,
crossover study
R. rosea/placebo: four
capsule per day for
7d.
Blood oxygen level,
pulse oximeter
oxyhemoglobin
saturation, serum
levels of oxidative
stress markers
Lack of significant effect on
hypoxemia and oxidative
stress
Ib
233
(Continues)
TAO ET AL.
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57

TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
Rhodiola kirilowii
Dazhu Hongjingtian
injection (R. kirilowii
water extract;
Tonghuayusheng
Pharmaceutical Co,
China)
104 Chinese patients
with acute severe
carbon monoxide
poisoning
Open‐label,
ramdomized, two‐
parallel‐group study
Control group: MMSE, LVEF, serum
NO/NOS/iNOS/H‐
FABP/Myo
Significantly increased
MMSE and LVEF scores and
decreased serum NO/NOS/
iNOS/H‐FABP/Myo levels
compared to control group
III
234
basic treatment
(dexamethasone,
mannitol, citicoline,
ganglioside, and
edaravone) Significantly reduced
adverse events in
combination group
Combination group:
basic treatment plus
10 mL Dazhu
Hongjingtian
injection once daily
for 14 d
Dazhu Hongjingtian
injection (R. kirilowii
water extract;
Tonghuayusheng
Pharmaceutical Co,
China)
98 Chinese patients
of both sex with
advanced NSCLC
Ramdomized, two‐
parallel‐group study
Chemotherapy
group:
KPS, CD4
+
/CD8
+
Significantly higher total
effective rate, KPS score
and CD4
+
/CD8
+
ratio in
combination group
III
235
4‐cycle oxaliplatin
plus pemetrexed
Combination group: No difference in adverse
event incidence between
groups
10 mL Dazhu
Hongjingtian
injection once daily
for 10 d in each
cycle of
chemotherapy
Dazhu Hongjingtian
injection (R. kirilowii
water extract;
Tonghuayusheng
Pharmaceutical Co,
China)
176 Chinese patients
with angina pectoris
Eight ramdomized,
controlled studies
10 mL once daily, for
10‐14 d
Disease symptom,
ECG change
Angina remission: OR, 4.81;
95% CI, (2.86, 8.08); Z, 5.92;
ECG improvement: OR, 2.8;
95% CI, (1.83, 4.3); Z, 4.71
III
236
No serious adverse events
(Continues)
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TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
Rhodiola sacra
Nuodikang capsule (Tibet
Rhodiola
Pharmaceutical Holding
Co, China; each capsule
containing 280 mg R.
sacra extract)
46 Chinese patients
of both sex with
coronary heart
disease
Open‐label,
ramdomized, two‐
parallel‐group study
Nuodikang group (30
cases): two capsules,
three times a day for
4wk
ECG change, platelet
agglutinate rate
Significant reduction in
platelet agglutinate rate
and improvement in chest
pain and ST‐T abnormal
after Nuodikang treatment,
showing a better efficacy
compared with
Fufangdanshen group
III
237
Fufangdanshen tablet
group (16 cases): four
tablets, three times a
day for 4 wk
No adverse effect observed
Nuodikang capsule (Tibet
Rhodiola
Pharmaceutical Holding
Co, China; each capsule
containing 280 mg
extract)
120 Chinese patients
of both sex with
coronary disease
with stable angina
pectoris
Randomized, single‐
blind, two‐parallel‐
group study
Nuodikang group (60
cases): two capsules,
three times a day for
4wk
ECG change, blood
pressure, blood
viscosity,
hemorheology
Significantly improved
disease symptom and
alleviated ECG abnormal
after Nuodikang treatment,
showing a better efficacy
compared with isosorbide
dinitrate group
III
238
Isosorbide dinitrate
group (60 cases):
10 mg, three times a
day for 4 wk. No adverse effect observed
Nuodikang capsule (Tibet
Rhodiola
Pharmaceutical Holding
Co, China; each capsule
containing 280 mg
extract)
108 Chinese patients
of both sex with
chronic fatigue
syndrome aged
30‐50
Randomized, open‐
label, two‐parallel‐
group study
Nuodikang group (55
cases): two capsules,
three times a day for
4wk
Fatigue symptom,
serum CD4
+
/CD8
+
/
IgA/IgG/IgM
Significant improvement in
fatigue symptom after
Nuodikang treatment,
showing a better efficacy
compared with Guipi Pill
group
III
239
Guipi pill group (53
cases): 8 g, three
times a day for 4 wk
(Continues)
TAO ET AL.
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59

TABLE 3 (Continued)
Drugs Subjects Study design Intervention Primary endpoint Outcome
Quality of
evidence
a
References
Nuodikang capsule (Tibet
Rhodiola
Pharmaceutical Holding
Co, China; each capsule
containing 280 mg
extract)
72 Chinese patients
of both sex with
cardiovascular
neurosis aged 22‐56
Randomized, open‐
label, two‐parallel‐
group study
Nuodikang plus
metoprolol group
(36 cases): two
Nuodikang capsules,
three times a day,
and 25 mg
metoprolol, twice
daily, for 4 wk
Disease symptom,
HAMD score.
Significant improvement of
symptom and HAMD scores
in both groups, with a
better efficacy in the
combination group
III
240
One case of mild dizziness in
combination group
Metoprolol group (36
cases): 25 mg, twice a
day for 4 wk
Salidroside
Salidroside (National
Institute for the Control
of Pharmaceutical and
Biological Products,
China)
60 Female Chinese
patients with
untreated breast
cancer aged 54 ± 12
Randomized, double‐
blind, placebo‐
controlled, two‐
parallel‐group study
Salidroside/placebo
group (30/30 cases):
600 mg/d at 1 wk
before epirubicin‐
based
chemotherapy and
continued during
the entire period of
chemotherapy
Strain rate, LVEF,
serum levels of
oxidative stress
markers
Normalized strain rate peak
and significantly reduced
ROS after salidroside
treatment
Ib
241
No adverse event
Abbreviations: BDI, Beck Depression Inventory; BODE, BMI, airflow obstruction, dyspnea and exercise capacity; CGI/C, Clinical Global Impression Change; CI, confidence interval;
COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; HAMD, Hamilton depression scale; HARS, Hamilton anxiety rating scale; H‐FABP, heart‐type fatty acid‐binding
protein; IgA, immunoglobulin A; iNOS, inducible nitric oxide synthase; KPS, Karnofsky performance status; LVEF, left ventricular ejection fraction; mMRC, modified medical research
council dyspnea; MMSE, mini‐mental state examination; NSCLC, non–small‐cell lung cancer; OCD, oxygen cost diagram; OR, odds ratio.
a
According to World Health Organisation, Food and Drug Administration, and European Medicines Agency: Ia, meta‐analyses of randomized and controlled studies; Ib, evidence from at
least one randomized study with control; IIa, evidence from at least one well‐performed study with control group; IIb, evidence from at least one well‐performed quasi‐experimental
study; III, evidence from well‐performed nonexperimental descriptive studies as well as comparative studies, correlation studies and case‐studies; and IV, evidence from expert
committee reports or appraisals and/or clinical experiences by prominent authorities.
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randomization are of low quality. In this regard, clinical trials of R. kirilowii and R. sacra using more rigorous
methodological design are further needed. Notably, as one of the main active constituents of Rhodiola, salidroside
has been investigated in clinical trials. Zhang et al
241
demonstrated that repeated doses of salidroside significantly
reduced serum levels of oxidative stress markers and normalized strain rate peak in breast cancer patients
receiving epirubicin‐based chemotherapy. The results suggest that salidroside has the potential to be used as an
adjuvant drug in chemotherapy.
Current knowledge of clinical trials of Rhodiola demonstrate that, apart from traditional indications, Rhodiola
has a wide range of new applications. However, there are several major limitations regarding previous studies: (i)
most reports did not describe details on the QC of Rhodiola extract, while some used only one or two QC
markers. Inconsistent in quality of varied Rhodiola extracts makes it difficult for comparison or assessment of
results. (ii) Only one dosage has been used in most studies. Inappropriate selection of doses may lead to false
negative results. (iii) Although promising data are shown in some reports, they have not applied the randomized
controlled experimental design. Overall, more trials on Rhodiola using rigorous study design are highly advocated
in future.
7
|
CONCLUSION AND PERSPECTIVES
In this review, we provide integrated research progresses of Rhodiola species, especially from the aspects of
phytochemistry, pharmacology, toxicology, and clinical studies. For a better understanding of both traditional and
modern use of Rhodiola, scientific gaps in current knowledge are highlighted. In particular, there are several critical
issues that need to be aware of in future studies.
Generally, clinical trials have supported most of the traditional uses of Rhodiola species. Firm evidence are
mainly coming from studies on R. rosea and R. crenulata. The R. rosea has long been used as botanical adaptogens in
European countries, and many R. rosea related health products or dietary supplements are already in the market.
Two classical products are SHR‐5 and ADAPT‐232, which were developed by Swedish Herbal Institute. Products of
R. rosea are popularly used as antistress and antidepressant agents in Europe. Interestingly, while the geographical
distributions of R. rosea and R. crenulata are quite different from each other, their folk applications are different as
well. R. crenulata has long been used in Tibetan medicine and documented in Chinese Pharmacopoeia as an official
species. Different from R. rosea, it is used to improve physical working capacity, antihypoxia, antialtitude sickness,
and antifatigue. Although a clinical study of R. crenulata has failed to display the antialtitude sickness effect, it has
demonstrated that both R. rosea and R. crenulata are effective against stress‐and physical‐related fatigue and
depression, and in improving physical working capacity. Therefore, despite the difference in traditional use, R. rosea
and R. crenulata may be mutually replaced. This is also supported by the fact that they share similar chemical
compositions when taking 46 commonly appeared chemical constituents into account, and exhibit similar
bioactivities, such as antioxidative, anti‐inflammatory, antidiabetic, and neuroprotective effects. Based on the
above analysis, future clinical studies may focus on, (i) comparison of efficacy of R. rosea and R. crenulata to see
whether or not they can be mutually replaced; (ii) antialtitude sickness effect of Rhodiola using rigor methodology.
Clinical studies have provided emerging evidence that Rhodiola have novel indications for using in the treatment
of cancer, chronic obstructive pulmonary disease, acute nonspecific pneumonia, and cardiovascular diseases. Most
of these studies have focused on two other Rhodiola species, R. kirilowii and R. sacra, which are mostly of low quality.
Therefore, more studies using high‐quality methodology should be conducted.
Although many phytochemical studies have been carried out on Rhodiola plants, most of them have focused on
R. rosea and R. crenulata. Besides, the direct comparison of chemical compositions of different Rhodiola species is
seldomly investigated. The development of high‐throughput simple methods such as LC‐MS is thus highly
advocated for qualitative and quantitative analysis and comparison of chemical profile of Rhodiola and for
identification of unique markers to distinguish different species.
TAO ET AL.
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61

Pharmacological evaluation of Rhodiola extracts and components has been carried out in both animal and in
vitro models. However, the underlying molecular mechanisms for actions of Rhodiola remain largely unclear.
Moreover, it is challenging that a link is to be established between chemical constituents and activities, as synergy
may exist among multiple components. To ensure reproducibility, QC of Rhodiola extracts should also be paid
attention to. One thing needs to note is that when testing extracts in cell models, the obtained results may lead to
false conclusions as systemic process is not considered in these models.
Although Rhodiola is generally safe, two critical points need to be considered, the first one is herb‐drug
interaction, while the other one is the potentially toxic nitrile compounds. Since Rhodiola and its constituents are
identified as modulators of some drug metabolizing enzymes and transporters, it is of great risk that they cause
pharmacokinetic or pharmacodynamic interactions with concomitantly used drugs, especially for the drugs with
narrow therapeutic windows. Moreover, the nitrile compounds may pose a safety risk when Rhodiola is given under
a long‐term use.
ACKNOWLEDGMENTS
This study was supported by grants from the Research Fund of the University of Macau (MYRG2016‐00143‐ICMS‐
QRCM) and Macau Science and Technology Development Fund (071/2017/A2).
ORCID
Yitao Wang http://orcid.org/0000-0001-8068-1392
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AUTHOR’SBIOGRAPHIES
Hongxun TAO obtained his bachelor degree from Chengdu University of Traditional Chinese Medicine (2011), and
master degree from Shanghai University of Traditional Chinese Medicine (2014). After then, he became a Ph.D
candidate in University of Macau. Ever since, the quality control and bioactivities of Rhodiola species have been Mr.
Tao's main research focus.
Xu WU obtained his Ph.D. at The Chinese University of Hong Kong in 2016. He now works as an assistant
professor at School of Pharmacy, Southwest Medical University since 2017. The research interests of Dr. Wu
include PK/PD evaluation of anticancer natural products as well as herb-drug interactions.
Jiliang CAO received his master and bachelor degrees from Chengdu University of Traditional Chinese Medicine in
2010 and 2013, respectively and further earned his doctoral degree from University of Macau in 2017. He is now a
postdoctoral research fellow in University of Macau, Macau, China. His research mainly focuses on the quality
control of Chinese medicine and the discovery of bioactive components based on LC-MS technique.
Yu PENG obtained her bachelor degree of Biochemical Pharmaceutical Technology of joint training in Nanjing
University and China Pharmaceutical University (2010), and Master degree from Shanghai University of TCM
(2014). Since then, she became a Ph.D candidate of Institute of Chinese Medical Sciences in University of Macau.
Anqi WANG obtained his Ph.D degree in State Key Laboratory of Quality Research in Chinese Medicine, Institute
of Chinese Medical Sciences, University of Macau (2017). Presently he is serving as a postdoctoral research fellow
in State Key Laboratory of Quality Research in Chinese Medicine of University of Macau. His research interest
includes screening of bioactive constituents from Chinese herbal pairs for prevention and treatment of
inflammatory bowel diseases and potential mechanisms study, research and development of novel delivery
systems for bioactive constituents from Chinese herbal pairs.
Jin PEI received her Ph.D degree from Chengdu University of Traditional Chinese Medicine. She is now a professor
in pharmacognosy at College of Pharmacy, Chengdu University of Traditional Chinese medicine. Her research
primarily focuses on the evaluation of germplasm resources of medicinal plants and the formation mechanism and
regulation of the quality of medicinal herbs.
Jianbo XIAO obtained his PhD in nutritional science from Okayama Prefectural University, Japan (2009). He
worked as Humboldtian at University of Wuerzbug, Germany (2013‐2015), prior to join University of Macau in
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2015. Dr. Xiao has published over 100 papers on international journals, and been selected as 2016 and 2017
Clarivate Analytics Highly Cited Researcher (HCR) in agricultural science. Dr. Xiao is currently the associate editor
of Phytochemical Analysis (Wiley) and Journal of Berry Research (IOS), the editorial boards of several international
journals including Critical Reviews in Food Science and Nutrition, Food Chemistry, Food and Chemical Toxicology,
Phytomedicine, Industrial Crops and Products. He was a chairman of 2015 International Symposium on
Phytochemicals in Medicine and Food (1‐ISPMF2015) organized by PSE and its second edition (2‐ISPMF 2017),
third edition (3‐ISPMF 2018).
Shengpeng WANG received his bachelor degree from Chengdu University of Traditional Chinese Medicine in 2010
and obtained his doctoral degree from University of Macau in 2016. He is currently an assistant professor of
Institute of Chinese Medical Sciences in University of Macau. Dr. Wang primarily focuses on drug discovery from
Chinese medicine for prevention and treatment of cancer and inflammatory bowel disease, as well as development
of novel delivery systems and health products of Chinese medicine.
Yitao WANG is the founding Director of the Institute of Chinese Medical Sciences and Chair Professor at
University of Macau as well as the Director of the State Key Laboratory of Quality Research in Chinese Medicine.
He is also the Chief Scientist of Chinese Academy of Chinese Medical Sciences and the Director of International
Research Centre of Medicinal Administration at Peking University. He is known internationally for his pioneering
contributions to the modernization of Chinese medicine, with an emphasis on systematic evaluation and quality
control of Chinese medicine. He has a long‐standing interest in efficacy, safety, stability and controllability
evaluation of Chinese medicine.
How to cite this article: Tao H, Wu X, Cao J, et al. Rhodiola species: A comprehensive review of traditional
use, phytochemistry, pharmacology, toxicity, and clinical study. Med Res Rev. 2019;1‐72.
https://doi.org/10.1002/med.21564
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