Javad Shariﬁ-Rad*, Cristina Quispe, Aknur Turgumbayeva, Zehra Mertdinç, Sena Tütüncü,
Elif Feyza Aydar, Beraat Özçelik, Stępień-Warda Anna, Staniak Mariola, Anna Koziróg,
Anna Otlewska, Hubert Antolak, Surjit Sen, Krishnendu Acharya, Natallia Lapava,
Simin Emamzadeh-Yazdi, Miquel Martorell, Manoj Kumar, Elena Maria Varoni, Marcello Iriti*
and Daniela Calina*
Santalum Genus: phytochemical constituents,
biological activities and health promoting-effects
Received April 2, 2022; accepted July 15, 2022;
published online September 7, 2022
Abstract: Santalum genus belongs to the family of Santa-
laceae, widespread in India, Australia, Hawaii, Sri Lanka,
and Indonesia, and valued as traditional medicine,
rituals and modern bioactivities. Sandalwood is reported
to possess a plethora of bioactive compounds such as
essential oil and its components (α-santalol and β-santalol),
phenolic compounds and fatty acids. These bioactives play
important role in contributing towards biological activities
and health-promoting effects in humans. Pre-clinical
and clinical studies have shown the role of sandalwood
*Corresponding authors: Javad Shariﬁ-Rad,Facultadde
Medicina, Universidad del Azuay, Cuenca, Ecuador,
E-mail: javad.shariﬁrad@gmail.com. https://orcid.org/0000-
0002-7301-8151 (J. Shariﬁ-Rad); Marcello Iriti,Departmentof
Biomedical, Surgical and Dental Sciences, Università degli Studi
di Milano, 20133 Milano, Italy; and National Interuniversity
Consortium of Materials Science and Technology (INSTM), 50121
Firenze, Italy, E-mail: email@example.com. https://orcid.org/
0000-0002-5063-1236 (M. Iriti); and Daniela Calina, Department
of Clinical Pharmacy, University of Medicine and Pharmacy of
Craiova, 200349 Craiova, Romania,
Cristina Quispe, Facultad de Ciencias de la Salud, Universidad Arturo
Prat, Avda. Arturo Prat 2120, 1110939, Iquique, Chile,
Aknur Turgumbayeva, Higher School of Medicine, Al-Farabi Kazakh
National University, Almaty, Kazakhstan; and School of Pharmacy, JSC
“S. D. Asfendiyarov Kazakh National Medical University”, Almaty,
Kazakhstan, E-mail: firstname.lastname@example.org
Zehra Mertdinç, Sena Tütüncü and Elif Feyza Aydar, Faculty of
Chemical and Metallurgical Engineering, Department of Food
Engineering, Istanbul Technical University, 34469 Maslak, Istanbul,
Turkey, E-mail: email@example.com (Z. Mertdinç),
firstname.lastname@example.org (S. Tütüncü), email@example.com (E.F. Aydar)
Beraat Özçelik, Faculty of Chemical and Metallurgical Engineering,
Department of Food Engineering, Istanbul Technical University, 34469
Maslak, Istanbul, Turkey; and BIOACTIVE Research & Innovation Food
Manufacturing Industry Trade LTD Co., Maslak, Istanbul 34469,
Turkey, E-mail: firstname.lastname@example.org
Stępień-Warda Anna and Staniak Mariola, Department of Forage Crop
Production, Institute of Soil Science and Plant Cultivation –State
Research Institute, Czartoryskich 8, 24-100 Puławy, Poland,
E-mail: email@example.com (S.-W. Anna),
firstname.lastname@example.org (S. Mariola)
Anna Koziróg, Anna Otlewska and Hubert Antolak, Faculty of
Biotechnology and Food Sciences, Lodz University of Technology,
Institute of Fermentation Technology and Microbiology, Wolczanska
171/173, 90 –924 Lodz, Poland, E-mail: email@example.com
(A. Koziróg), firstname.lastname@example.org (A. Otlewska),
email@example.com (H. Antolak)
Surjit Sen, Molecular and Applied Mycology and Plant Pathology
Laboratory, Department of Botany, University of Calcutta, 700019,
Kolkata, India; and Department of Botany, Fakir Chand College,
Diamond Harbour, West Bengal, 743331, India,
E-mail: firstname.lastname@example.org. https://orcid.org/0000-0002-4038-
Krishnendu Acharya, Department of Botany, Fakir Chand College,
Diamond Harbour, West Bengal, 743331, India,
Natallia Lapava, Medicine Standartization Department of Vitebsk
State Medical University, Vitebsk, Republic of Belarus,
Simin Emamzadeh-Yazdi, Department of Plant and Soil Sciences,
University of Pretoria, Gauteng 0002, Pretoria, South Africa,
Miquel Martorell, Department of Nutrition and Dietetics, Faculty of
Pharmacy, Centre for Healthy Living, University of Concepción,
4070386 Concepción, Chile; and Universidad de Concepción, Unidad
de Desarrollo Tecnológico, UDT, 4070386 Concepción, Chile,
Manoj Kumar, Chemical and Biochemical Processing Division, ICAR –
Central Institute for Research on Cotton Technology, 400019 Mumbai,
India, E-mail: email@example.com
Elena Maria Varoni, Department of Biomedical, Surgical and Dental
Sciences, Università degli Studi di Milano, 20133 Milano, Italy; and
National Interuniversity Consortium of Materials Science and
Technology (INSTM), 50121 Firenze, Italy,
Z. Naturforsch. 2022; aop
Open Access. © 2022 the author(s), published by De Gruyter. This work is licensed under the Creative Commons Attribution 4.0 International
extract as antioxidant, anti-inﬂammatory, antibacterial,
antifungal, antiviral, neuroleptic, antihyperglycemic, anti-
hyperlipidemic, and anticancer activities. Safety studies on
sandalwood essential oil (EO) and its extracts have proven
them as a safe ingredient to be utilized in health promotion.
Phytoconstituents, bioactivities and traditional uses estab-
lished sandalwood as one of the innovative materials for
application in the pharma, food, and biomedical industry.
Keywords: bioactivities; clinical studies; essential oil;
phytochemistry; safety; sandalwood.
The genus Santalum is a woody ﬂowering plant that
belongs to the family Santalaceae commonly known as
sandalwood. The members of the genus are generally trees
or shrubs. The plant is obligate hemiparasite attaching
itself by haustoria to establish contact with the host and
extracts xylem sap for nutrients and water . The family
Santalaceae comprises 29 genera with around 400 species
out of which 18 well-recognized species are under the
genus Santalum [1–7] (Table 1).
Sandalwood is generally popular for its fragrant
heartwood oil used by cosmetic industries for the pro-
duction of perfume [13, 18–21]. The high demand for
sandalwood oil and timber has resulted in drastic over-
harvesting; as a result, many taxa are now considered as
rare, threatened or listed as endangered . Moreover,
one species Santalum fernandezianum Phil. from the
Juan Fernandez Islands (South Paciﬁc Ocean), has been
reported extinct due to over-exploitation by human be-
ings . About 25 species belong to the genus Santalum,
they are evergreen trees or shrubs characterized by a
semi-parasitic lifestyle. They conduct photosynthesis;
however, they take in water and inorganic nutrients by
parasitizing on the roots of other plant species.
Plants of the genus Santalum are characterized by
the production of EOs with many biological properties due
to the high content of bioactive substances such as
lignans, glycosides, triterpenoids, and sesquiterpenoids
(α/β-santalol - the compound found in the largest
amount). These bioactive compounds include antioxidant,
anti-inﬂammatory, antibacterial, antifungal, antiviral, neuro-
leptic, antihyperglycemic, antihyperlipidemic, and anticancer
Santalum genus has been known to possess many
health beneﬁts proved based on traditional uses and
modern biological approaches through preclinical
studies. Traditionally, Santalum genus has been used as
an antipyretic, immune booster, antidiarrhea, and for
treating cold and cough. Modern uses have shown their
effect as antioxidant, anti-inﬂammatory, antibacterial,
Table :Section, recognized species, according to the International Union for Conservation of Nature (IUCN) category, common name and
geographical distribution of Santalum species.
Species and IUCN
Red List Category
Common name Geographical Occurrence Reference
S. album L. Indian sandalwood Australia, Belgium, Cambodia,
China, Germany, Great britain,
Holand, India, Indonesia, Japan,
Madagaskar, Malaysia, Norway,
Spain, Srilanka, Switzerland, and
the United States.
S. fernandezianum Phil. Freycinet sandalwood, or
Hawaiian islands (O‘ahu, Moloka‘i) [,]
S. haleakalae Hillebr. Haleakala sandalwood or
Hawaiian islands (Maui) [,]
S. pyrularium A. Gray Hawaiian sandalwood or
Hawaiian islands (Kaua‘i) [,,,
S. ellipticum Gaudich. Coastal sandalwood or
Hawaiian islands [,,]
S. paniculatum Hook. & Arn. Hawai‘i Hawaiian islands [,]
S. fernandezianum F.Phil. Chile sandalwood Juan fernandez islands 
Genus Eucarya T.Mitch. S. acuminatum (R.Br.) A.DC. Desert Quandong, native
2J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus
antifungal, antiviral, neuroleptic, antihyperglycemic,
antihyperlipidemic, and anticancer activities. One of the
most important parameters considered for the application
of plant extracts in the biomedical ﬁeld is its safety. The
safety aspects of EO components have been studied by
various researchers and it is concluded that extracts from
Santalum genus are fairly safe to be used as health-
promoting effects. The current review is the ﬁrst of its kind
that gives a snapshot of the Santalum genus concerning its
traditional uses, bioactive components, bioactivities (in
vitro,in vivo and clinical trials), and its safety aspects
while using it as a health-promoting agent in humans.
2 Review methodology
Available information on the genus Santalum, its biological
properties, and its potential mechanisms of action was
collected by searching the following databases: PubMed/
Medline, Web of Science and ScienceDirect. The following
MeSH terms were used: “Santalum/growth & development”,
“Santalum/chemistry”,“Plant Oils/isolation & puriﬁcation”,
effects”,“Cell Cycle Checkpoints/drug effects”,“Humans”,
“Mice”,“Plant Extracts/chemistry”,“Plant Extracts/thera-
peutic use”,“Plant Oils/therapeutic use”,“Antioxidants/
The study included research articles and reviews
published in extenso, written in English language in sci-
entific journals, book chapters and books with information
about Santalum genum and sandalwood. Editorials/letters
to publishers, case reports, conference abstracts, studies
that included homeopathic preparations were excluded.
The PlantList database was used to verify the taxonomy
and provide information on the classiﬁcation and distri-
bution of Santalum subspecies [24, 25].
Santalum is widely distributed to semi-arid areas from
Indonesia in the West to Juan Fernandez Islands (Chile) in
the East and from Hawaiian Archipelago in the North
to New Zealand in the South  (Figure 1). The major
production places of the plant are shown in Table 1.
The well-recognized species are broadly grouped into
four categories viz. Indian sandalwood (Santalum album
L.), Australian sandalwood (Santalum acuminatum (R. Br.)
A. DC.), Hawaiian sandalwood (Santalum ellipticum
Gaudich., Santalum freycinetianum F. Phil., Santalum
haleakalae Hillebr., Santalum paniculatum Hook. & Arn.,
and Santalum pyrularium A. Gray), and Paciﬁc Islands
sandalwood (S. fernandezianum Phil.).
A taxonomic grouping in Santalum is purely based on
morphological characters. It has been reported that Section
Santalum is described as reddish corollas that are longer
than wide and partly superior ovaries [12, 26, 27]. Based on
smaller ovaries, longer perianth tubes and absence of hairs
to the ﬁlament  separated the two Hawaiian members
(S. freycinetianum and S. haleakalae) from the section
Figure 1: Geographical distribution of Santalum genus.
J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus 3
Santalum into the endemic section Solenantha. The char-
acteristic features of the section Hawaiiensia are explained
as having white, brown, orange or green corollas that are as
wide as long and inferior ovaries [12, 26, 27].
Section Polynesica is similar in appearance to the
section Hawaiiensia but with partly superior ovaries . A
molecular phylogenetic study reveals that the sectional
classiﬁcation of Santalum needs revision . Skottsberg
[26, 29] suggested that sections Hawaiiensia and Polynesica
were closely related based on morphological characters
and section Polynesica was treated as a synonym of section
Hawaiiensia by . But molecular phylogenetic analysis
indicates that sections Hawaiiensia and Polynesica are not
close to one another rather related to other taxa of section
Santalum and should not be united taxonomically .
Revisionary studies based on molecular data considered
six species of Santalum in Hawaii, whereas previously
there were only four recognized species . Hawaiian
species are considered to be a result of two colonization
processes which comprises four species within red-
ﬂowered section Solenantha (i.e., S. freycinetianum,
S. haleakalae, and S. pyrularium); and two species within
white-ﬂowered section Hawaiiensia (i.e., S. ellipticum, and
S. paniculatum) .
General features of the genus Santalum are evergreen
trees or shrubs; leaves opposite rarely alternate, sometimes
in whorls, glabrous or sometimes glaucous, ovate, obovate
or lanceolate, coriaceous . Flowers cymose panicle,
axillary or in the terminal, tetra or pentamerous, her-
maphrodite; bracts small. Perianth-tube campanulate to
conical or ovoid, adnate to the base of the ovary; stamens
4-5, dorsiﬁxed, ﬁlament slender, short, anthers ovate;
4-lobed; style long, stigma 2-4 lobed; ovary inferior or
partly inferior; ovules 2-3. Flowers produce sweet to a week
or no fragrance. Fruit globose to sub-globose drupe,
annulate on the top by the deciduous perianth; seed sub-
globose; albumen copious. Morphological differences of
some important species are summarized in Table 2.
4 Traditional uses
The close-grained heartwood of Santalum is used for
ornamental and carving work. Santalum fruits are edible
and the seeds contain fatty oil which is suitable for the
manufacture of paint. Incense sticks are made of powdered
heartwood and are used in houses and temples. In addi-
tion, powered heartwood is ground into a paste and used as
a cosmetic . Santalum genus is mentioned in Indian
mythology, folklore, scripture, and the oldest literature (for
example, Vinaya Pitaka (400–300 BC) and Milinda Pahna
(200 BC)) and also in the epic Ramayana and Mahabharata.
The ancient Egyptians used Santalum plants oil for
embalming the dead and in the ritual burning to venerate
the gods. In certain communities among the Hindus it is
traditional to put a piece of sandalwood in the funeral pyre.
A beige-coloured paste obtained from sandalwood is put in
on the forehead and other body parts, especially by devo-
tees of God Krishna (Vaishnavites) and for ritual bathing of
Hindu gods . In Zoroastrian temples, Santalum burns in
sacred lights to soothe the problems of all mankind. It is
used by Jews, Buddhists, Hindus, as well as almost all
other belief systems for its huge variety in attributes .
5 Bioactive composition
5.1 Essential oil, terpenes, and derivatives
After 30 years of growth with a natural condition, oil is
collected from the heartwood of sandalwood. The yield of
the oil depends on the age of the tree; an old mature tree
gives an oil yield between 2.5–6%; the colour of the
heartwood, individual tree understudy, location within
the tree, and the environment of growth of the tree.
Sandalwood oil consists of main terpenoids: mono- and
sesquiterpenes and their oxygenated derivatives (mostly
the alcohols, ketones, and aldehydes) and also some fatty
acids, and phenylpropanoids chemical compounds [37–39]
The bark extract of S. album contains mainly santalol
(90%) [40, 41], exo-norbicycloekasantalal, β-santalic,
teresantalic, nortricycloekasantalic, bicycloekasantalic, di-
hydro-β-santalic acids, urs-12-en-3b-il-palmitate, β-sitos-
terol, (+)epi- β-santalol, (-) β-santalol, (-)trans-β-santalol,
α-santalol (52%), β-santalol (23%), epi-β-santalene, cis-
lanceol, cis-nuciferol, β-, epi-β-teresantalic acid, β-, epi-
β-norekasantalic acid, β-, epi-β-ekasantalic acid, α-santalic
acid, 11-keto-dihydro- α-santalic acid, bisabolenols A, B, C,
D and E, tricycloekasan-talol, α-andβ-santalenes, trans-
α-bergamotene, α-curcumone, nuciferol. The bark extract of
S. album includes l-allohydroxiproline, betulinic acid,
β-sitosterol, and fatty acids. The bark extract of S. album
contains betulinic acid (0.05%), β-sitosterol, glucose,
fructose, and sucrose [38, 40]. Although including a low
amount of trans-β-santalol, cis-lanceol hydrocarbons,
α-santalene, β-santalene, α-bergamotene, epi-β-santalene,
as α-curcumene, β-curcumene, γ-curcumene, β-bisabolene
and α-bisabolol; cis-α-santalol (53%), cis-β-santalol (23%),
α-trans-bergamotol, epi-cis-β-santalol sesquiterpene alco-
hols are the major components of the sandalwood oil
4J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus
5.1.1 Extraction of the Santalum Oil
EO is one of the important components of an important
component of sandalwood and its isolation from sandal-
wood depends on the methods of extraction. The EO of
the sandalwood is widely used in the fragrance industry
due to having a strong aroma and has various biological
activities such as: anticancer, antiviral, antidiarrheal,
cytotoxic activities, among others . The different
extraction methods can be applied to the Santalum during
oil extraction. Therefore, the composition and amount of
the fragrance and volatile compounds found in oil may
vary dependent on the extraction methods. The conven-
tional steam distillation and hydrodistillation methods
are performed under high temperatures (around 100 °C)
which can often result in loss of volatile compounds and
changes in the odour [48–50]. Maceration or Soxhlet type
solvent extraction are other techniques that have some
exposure to hazardous and ﬂammable liquid organic
solvents, and environmental issues . Therefore, the
useofsomesolvent-free“green methods”during the
extraction of EO has gained prominence in recent years.
Microwave-assisted extraction, subcritical CO
Table :Contrasting morphological characters of important Santalum species.
Category Species Size Leaves Flower Fruit Reference
S. album L. Small to the
Opposite, lanceolate to
ovate; acute to obtuse at
base, entire; apex acute to
acuminate; pale green to
Initially, straw yellow col-
oured and gradually turn
to deep purplish or brown
Green to purplish–
(R. Br.) A. DC.
A shrubby small
Opposite, more or less
lanceolate; pale green to
olive-green; acute apex
Small, creamy white or
turning to orange–
red to bright, glossy
red; persistent tepal
Shrub to small
Elliptic to orbicular, ovate,
or obovate; leathery to
succulent; glaucous; dull,
Greenish in bud but
tinged with brown, or-
ange, or salmon after
opening; produce a sweet
fragrance; ﬂower as long
Purple to black
drupes, with a
Hook. & Arn.
Shrub or tree Ovate, obovate or elliptic;
upper surfaces glossy and
lower surface dull;
yellowish orange to bluish
or olive green.
Greenish in bud but
tinged with brown, or-
ange, or salmon after
opening; produce a sweet
fragrance; ﬂowers as long
Purple to black with a
Shrub to tree Narrowly elliptic, oblong,
to narrowly ovate; acute to
rounded apex; bit glau-
Light pink turning deep
pink with maturity (rarely
with white interiors); pro-
duce a weak fragrance;
ﬂowers longer than wide
almost black with a
Small tree Ovate, obovate, or orbic-
ular; stiff to coriaceous
surfaces; olive green
Deep pink to red
throughout, or with white
to pink interiors; produce
a weak fragrance; ﬂowers
longer than wide
Black or purplish–
black with a distinc-
Small tree or
Opposite; elliptic, ovate,
to oblong; glaucous abax-
ially not much paler on
abaxial surface; acute to
obtuse apices; medium to
Cream to purple
throughout, greenish with
the purple interior, or
red with age
Red, elliptic, with
J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus 5
extraction and some other combined novel technologies,
such as microwave-assisted hydrodistillation method, are
preferred due to having higher selectivity and extraction
yield, need for less time for analysis and not posing
environmental and safety concerns [52, 53].
Kusuma and Mahfud  objected to looking into
the effects of the newly employed microwave air-
hydrodistillation method for extraction of EOs and
comparison with classical microwave hydrodistillation
method. Results of this research showed that additional
airﬂow to the microwave hydrodistillation can help obtain
the sandalwood oil in higher yield directly proportional
with air ﬂow rate. The compound composition of micro-
wave air-hydro distilled sandalwood oil is larger than
another method concerning identiﬁcation 43 compounds
whereas 37 compounds are recorded in microwave
hydrodistillation. Microwave air-hydrodistillation pro-
vides better aroma/fragrance quality than microwave
hydrodistillation extracts .
Nautiyal  mentioned that extraction yield and
quality affect the trade of sandalwood oil. It was also
highlighted that heartwood preparation and the extraction
method have an inﬂuence on α- and β-santalol levels in
the obtained oil. In the study, eight different extraction
methods which are SC–CO
, ethyl alcohol, benzene, diethyl
ether, toluene, steam distillation, hydrodistillation, and
alkaline-hydro distillation are examined. The highest yield
is obtained from SC–CO
extraction, 3.83 grams per liter
(g/L). In the analysis of extracted sandalwood oil for α- and
β-santalol levels were examined through gas chromatog-
raphy (GC). The most efﬁcient extraction methods are
, ethyl alcohol, and steam distillation; they include
nearly 84% total α- and β- santalol. Hydrodistillation is
the least efﬁcient in terms of having α:β- santalol ratio,
3:1, whereas SC–CO
, ethyl alcohol, and steam distillation
had 1.9:1. Furthermore, Nautiyal  stated that organo-
leptic characteristics are affected by the levels of α- and
β-santalol, besides other compounds. Pleasant sandal-
wood oil extracts are found via SC–CO
alkaline-hydro, and steam distillation. Furthermore,
Nautiyal  extracted sandalwood (S. album) oil via
at 200 bar and 28 °C under two conditions, and the
fractionation of the extract was analyzed continuously.
Extractions by steam distillation, hydro distillation,
Soxhlet extraction were conducted for comparison. The
results showed that SC–CO
extraction is much more
effective in terms of the physical properties of oil than
commercial sandalwood oil .
Over the last 25 years, about 65,000 chemical struc-
tures of the terpenoids and over 7,000 sesquiterpenes (C15)
have been reported in previous studies . The EO of the
S. album tree is composed of the mixture of sesquiterpenes
Figure 2: Illustrative scheme with the most important bioactive constituents of Santalum essential oil and their pharmacological properties.
6J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus
i.e., α-santalol, β-santalol, epi-β-santalol, α-trans-berga-
motol, α-bisabolol, lanceol, sesquisabinene hydrate, and
farnesol . According to the literature research, α-san-
talol and β-santalol (Figure 3) which are the main sesqui-
terpene alcohol compounds found in sandalwood oil are
known to indicate biological activities against the skin
and prostate cancer and malaria . In the same context,
GC analysis of S. album oil shows that Z-α-santalol and Z-
β-santalol are found with proportions 41–55% and 16–24%,
respectively according to the standard ; identiﬁed some
of the sesquiterpenes and monoterpenols, such as α-san-
talol, β-santalol, α-bergamotol, and cis-lanceol.
According to this chromatographic analysis, santalol
levels below these specifications can be related to extrac-
tion from undeveloped heartwood, adulteration with
synthetic or semi-synthetic substitutes, or substitution
with EOs from other species .
Mohankumar et al.  conducted a study on the
heartwood of S. album EO concerning antioxidant and
stress modulatory efﬁcacy. The traditional steam distilla-
tion method is preferred for S. album oil extraction and the
oil chemical proﬁle identiﬁed by the GC–MS technique.
Santalum album oil has at least 19 main components, ac-
counting for 96.81% of the total content. The main com-
pounds of S. album oil followed the order as α-santalol with
41.77% > β-santalol with 18.02% > (Z)-α-trans-bergamotol
(8.50%) > (Z)-lanceol (6.57%) > epi-β-santalol (5.78%), cis-
nuciferol (3.21%) > docosahexaenoic acid (2.54%) > β-trans-
santalol (2.24%) > β-costol (1.41%) > β-santalene (1.24%) >
(Z)-β-curcumen-12-ol (1.02%). Besides all components, the
pleasant odour of S. album oil was contributed by α- and
Subasinghe et al.  investigate the Indian sandal-
wood (S. album) EO content and composition in Sri Lanka.
Two naturally grown trees heartwoods are studied for
comparing the oil properties. The maceration method is
applied overnight with deionized water. One of the three
the oil yield was measured at 15 cm below ground and
found with the highest yield of EO whereas other trees
showed a yield varying from 1.46 to 3.35 % w/w.
Another study examines the phytochemical analysis
and antibacterial efficiency of extracts of S. album in
preclinical studies. In vitro extracts contain callus, somatic
embryo, and seedlings; non-oil-yielding young and oil-
yielding matured trees are included in vivo part. Combined
dichloromethane and methanol are used for the 18 h
maceration method. Seedlings have the highest amount of
sesquiterpenoids with 51.4 mg/g, and the old tree has the
least (8.07 mg/g). Monoterpenoids compound content
range changes between 3.1 and 4.5 mg/g, except young
tree leave extract that has the highest content with 9.5 mg/L
The volatile oil from S. album wood and of Boswellia
sacra Flueck, (syn. Boswellia carteri Birdw.) the resin ob-
tained by SC–CO
extraction and the effects of extraction
conditions on the composition is analyzed in the study of
. In general, oxygenated sesquiterpenes dominate the
composition of the oil with a 90% ratio and hydrocarbon
sesquiterpenes follow these compounds around 5%.
According to the results, the best operative conditions is
obtained working at 120 bar and 45 °C with the 0.658 g/mL
density of CO
in the extraction vessels for both matrices.
Another research was conducted on EO composition
from roots of S. album . Samples were kept in ethyl ether
at 48 h for extracting the oil from the root bark. Santalum
album root heartwood had 10.3% in fresh weight oil yield.
Fifty-three different chemical compounds are detected by
GC-MS; moreover, β-santalol and α- santalol were included
in the ethanolic extract at the highest level with 19.6 and
In the study of Jones et al. ; the yield of the oil from
22 S. album trees was evaluated with the use of core sam-
pling at two different heights (30 cm and 100 cm ground
level). The results showed that the total concentration of
sesquiterpene hydrocarbons is found in a slightly higher
proportion in samples. On the other hand, the ratio of
α-santalol and β-santalol is lower generally at 100 cm
above ground level.
In recent years, procurement of sandalwood resources
and their biologically active compounds such as EO or
terpenoids have been decreased due to the devastating of
the natural stocks and habitats. Therefore, some of the
strategies like the heterologous expression, plant cell cul-
tures and plant cell bioreactors have gained prominence to
promote the synthesis of sandalwood terpenoids [47, 64].
5.2 Fatty acids
The identification of fatty acid in the oil is generally
performed using gas chromatography/mass spectrometry
(GC-MS) [65–67]. Zhang et al.  examined the 60 com-
pounds from the pericarp-derived volatile oil of S. album
Figure 3: Structure of α-santalol and β-santalol.
J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus 7
with different extraction methods. Colourless EOs are ob-
tained in 2.6 and 5% yield by hydrolyzation and n-hexane
extraction and analyzed by GC and GC-MS. Fatty acids,
especially palmitic and oleic acids, dominated the total
extracted oil with 40–70% depending on the extraction
method. Santalum album berries proximate analysis, and
in vitro activities of these compounds have been done by Sri
Harsha et al. . Soxhlet method with hexane is used for
taking off the oil. The oil that contains a higher amount of
oleic acid (45.4%) and palmitic acid (32.5%) is measured
1.5 g/100 g fresh weight. Berries have a very low amount of
α-tocopherol when compared to other berry tocopherol
5.3 Phenolics and saponins
Santalum album berries phenolic content is found 310 mg
gallic acid equivalents (GAE)/100 g fresh weight in meth-
anolic extract of berries. Acidiﬁed methanolic extract of
S. album berries anthocyanin level is measured 0.21% in
fresh weight, and the anthocyanin is conﬁrmed as cyanidin
3-glucoside . Various extract of S. album has antioxi-
dant activity and a signiﬁcant role in ﬁghting against free
radicals. Kaur et al.  reported that the methanolic
extract of this strain indicates higher phenolic fractions
than other extracts. Besides, cyanidin-3-glucoside is one of
the anthocyanin pigments that show antioxidant proper-
ties and nutritional potential in S. album.
Like S. album callus, somatic embryo, and seedlings
(in vitro); non-oil-yielding young and oil-yielding matured
trees (in vivo) phenolic results, a similar result is shown in
saponin content, in vivo extracts with 31.6 and 43.6 mg/g
show higher saponin content than in vitro extract (9.4 and
17.1 mg/g) . Phytoconstituents and antioxidant activity
were analyzed in vitro grown callus cultures of S. album.
The yield of the extract for a dichloromethane–methanol
(1:1) solvent mixture was found as 4.3%. The results
uncover the abundance of phenolic extracts (18.2 µg).
Other major phytoconstituents are found in the extract as
terpenoids (16.4 µg/mg), saponins (9.4 µg/mg) and ﬂavan-
3-ols (7.0 µg/mg) .
Chintamani and Dikshit  investigated the antioxi-
dant potential and secondary metabolite of the fruit pulp
and the kernels of the S. album. As a result of the GC-MS
analysis, phenols that have been found in the free form are
detected in the acetonitrile extract of fruit kernel and sterol
derivatives such as cholest-4-en-3 one compound is
recorded mostly in the dichloromethane extract of fruit
pulp and. Besides, pyrazine amide and acetamide-2-cyano
were obtained as a major constituent of the kernel with the
extraction in the methanol and acetonitrile, respectively.
β-Sitosterol is found in the S. album combined hexane and
isopropanol solvent extract (85.35 mg/100 g oil) and
S. album supercritical CO₂extract (88.9 mg/100 g oil) at the
highest level. Stigmasterol and δ-5-avenasterol amounts
are quite higher than other types of chemical compounds
6 Pharmacological activities
6.1 Anticancer activity
Cancer is a population of cell cells with uncontrolled
growth and multiplication [74–77]. Natural bioactive
compounds help us with anti-inﬂammatory qualities to
ﬁght infections like bacterial, fungal and viral, but also
with antioxidant properties with cancer [78–81]. Cytotox-
icity is one of the biological activities that characterize
sandalwood oil. Mishra et al.  in their study showed that
new cyclic octapeptide cyclosaplin was cytotoxic against
MDA-MB-231 that are human breast cancer cells. Its anti-
cancer activity is based on inducing apoptosis in cells but
also on suppression of viability of the cells (Figure 4).
Different scientists from the world found that compounds
from sandalwood have anticancer activities in many types
of skin cancer and leukaemia cells [82–86]. Matsuo and
Mimaki  found new neolignan and known lignans
in sandalwood and this study, they showed that new
neolignan was cytotoxic towards HL-60 cells, which are
human promyelocytic leukaemia cells. In different work,
Matsuo et al.  showed that cis-β-santalol and -β-san-
taldiol were cytotoxic against HL-60 human promyelocytic
leukaemia cells by inducing apoptosis in them. According
to Santha and Dwivedi ; α-santalol from sandalwood oil
from Santalum album have anticancer properties, because
it can induce apoptosis, have an anti-angiogenic effect and
also antioxidant activity on various types of cancer cells.
6.2 Antibacterial, antifungal and antiviral
Antibacterial activities are another one that was found
among compounds of sandalwood oil due to the content
8J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus
of α/β-santalol and were active against Salmonella
typhimurium and Staphylococcus aureus which are bacteria
that cause well known and still threatening diseases
throughout the whole world [39, 61, 87]. Epi-β-santalene
was found to effective against S. typhimurium 
In seeds of Santalum album there is a compound
known as santalbic acid, which has antibacterial proper-
ties against gram-positive bacteria and antifungal effect
on many types of pathogenic fungi . Ochi et al. 
found that crude organic fractions and sesquiterpenoids
from sandalwood oil have antimicrobial activity against
Helicobacter pylori which caused peptic ulcers and also can
be the cause of gastric cancer. Vadnere et al.  purposed
to conduct phytochemical analysis and antimicrobial
screening of S. album seeds petroleum ether and ethanol
extracts. In vitro antimicrobial activity of both extracts was
analyzed using a disk diffusion method for Bacillus subtilis,
S. aureus, Pseudomonas aeruginosa, Escherichia coli and
C. albicans. The outcome of the investigations highlights
the potential high efﬁcacy of petroleum ether extract
related to santalbic acid, which can function as an anti-
microbial agent .
Different research showed that derivatives from
S. album possess signiﬁcant antifungal properties against
species as Microsporum canis,Trichophyton menta-
grophytes, and Trichophyton rubrum which is due to the
inhibitory effect on mitosis [39, 87, 92]. Powers et al. 
in their studies have shown that the most active, of the
60 EOs obtained from commercial sources against
Aspergillus niger, Candida albicans,andCryptococcus
neoformans, both in terms of antifungal and cytotoxic
activity, were the sandalwood species (S. album, S.
paniculatum), rich in santalols.
Gupta and Chaphalkar  found that aqueous root
extract of S. album has anti-inﬂammatory and antiviral
activities because it inhibits proliferation, production of
monocytes marker –CD14 and also inhibition of nitric
oxide in their study on immunopharmalogical activities of
it against hepatitis B virus surface antigen –HbsAg, and
New Castle disease virus. Antiviral properties were also
reported by other scientists in the study of Herpes simplex
viruses type 1 and 2 . The authors showed that antiviral
activity is dose-dependent and didn’t exist due to virucidal
activity but rather because of the effect on the replication.
Sandalwood oil has been also shown to be used against
warts, skin blemishes, and other viral-induced tumours on
the skin .
Antioxidants are a group of compounds that protect the
body from the chemical process called oxidation [97–99].
This process produces free radicals that attack cell
membranes, and for this reason natural antioxidants are
important for human health [100, 101]. Antioxidant efﬁcacy
is also a known property of sandalwood oil and methanolic
extracts from the heartwood of S. album  but Misra and
Dey  found it in vitro in callus extract of Sandalwood tree
and their study showed that it is comparable. Also, anti-
oxidative properties were found in anthocyanins pigment
6.4 Other pharmacological activities
Diabetes is a disease that is widespread along with all
the world and sandalwood oil is also found effective in
Figure 4: Illustrative scheme with the most representative pharmacological properties of Santalum genus and the correlation with bioactive
compounds. Symbols: ↑increase, ↓decrease.
J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus 9
managing the complications of this disease . Kulkarni
et al.  found that it has antihyperglycemic and anti-
hyperlipidemic activities in their studies with diabetic rats,
because of the antihyperlipidemic properties it can also
help with protecting the liver and also with cardiovascular
diseases. Sandalwood extract was reported to inhibit the
cardiac tissue damage via reduction of lipid peroxidation
damage on the doxorubicin induced cardiotoxicity rat
model and signiﬁcant protective effect against induced
myocardial infarction in albino rats in a dose-dependent
Sedative activities are known as properties of de-
rivatives from sandalwood [106–108]. Sandalwood oil is
reported to produce a relaxing effect on the nerves and is
used for headaches, insomnia and nervous tensions.
Studies carried out by  observed that inhalation of
sandalwood oil decreased the motility of mice to an extent
of 40–78%. Also showed in their studies that a mild
sedative effect occurred in female Swiss albino mice after
inhaling sandalwood oil.
Okugawa et al.  showed an antipsychotic effect in
vitro and in vivo on mice. In addition, α-santalol is a strong
inhibitor of both tyrosinase and cholinesterase in vivo, and
hence there is a great potential of the EO for use in the
treatment of Alzheimer’s disease .
The potential pharmacological property of S. album oil
in infective skin conditions have been examined during a
few clinical against a wide range of skin conditions. The
therapeutic potential of S. album oil in dermatology is
attributed to its antioxidant, anti-inﬂammatory and anti-
microbial properties. Furthermore, S. album oil inhibits the
hyper-proliferation of keratinocytes, which is problematic
in eczema and psoriasis . Dulal et al.  reported that
sandalwood oil restores and rejuvenates ageing and
wrinkled skin. Sandalwood oil has anti-inﬂammatory ac-
tivity as well as emollient used in skincare.
All these pharmacological activities show the value of
genus Santalum (Figure 4). Sandalwood or sandalwood oil
can be used in medicine, cosmetology, and aromatherapy.
These innovative materials can solve major issues or
diseases such as diabetes, cardiovascular problems, in-
fections of different types, cancer, and also help assist to
maintain healthy and beautiful skin and a calm mind.
7 Health-promoting effects:
Among all the Santalum species, the results of several
preclinical studies on S. album revealed the vast variety of
pharmaceutical properties of this valuable medicinal plant
[61, 91, 94, 112]. Although there are promising in vitro and in
vivo research results on S. album oil that shows the high
potential capacity of S. album oil to treat skin cancer, to
date there are limited human studies. Although the avail-
able information on sandalwood oil toxicity is limited, it is
considered safe due its long history of oral use without any
reported adverse effects.
Regarding skin safety, S. album oil has a good safety
proﬁle in terms of patch testing for contact dermatitis in
both irritation and allergy. According to Burdock and
Carabin ; undiluted S. album oil and 10% S. album oil
are non-irritant. In ﬁve dermatology reports, some allergic
reactions have been reported. Number of 12 out of 3,542
patients (0.34%) were sensitive to a 2% dilution of S. album
oil, and in three reports, 69 of 5,595 patients (1.2%)
exhibited sensitivity to a 10% dilution . In a subse-
quent multicenter European study, 3 fragrance markers
(FMs) (fragrance mix I, fragrance mix II, and Myroxylon
pereirae) have been tested on consecutive patients to
determine the frequency of positive patch-test reactions to
EOs tested in the baseline. The result revealed that 656 of
48,956 dermatitis patients (1.38%) revealed positive re-
actions to 10% S. album oil .
Skin inflammation and irritation, known as radio-
dermatitis, are common side effects in radiation therapy
for cancer patients . Radio dermatitis is associated
with oxidative stress and an increase in cytokines,
including interleukin (IL)-1β, IL-6, and IL-8 . In a study
conducted by ; the effectiveness of a turmeric and
sandalwood oil containing proprietary cream [Vicco®
turmeric cream (VTC); Vicco Laboratories, Parel, India] on
radiodermatitis in patients with head and neck cancer
undergoing radiotherapy have been assessed. In this
nine-week open-label clinical study, the degree of
radiodermatitis of 46 cancer patients experiencing radio-
therapy, signiﬁcantly inhibited (24 patients) compared to
baby oil (22 patients) applying Vicco®cream containing
16% turmeric extract and 0.5% S. album oil . In a
similar study, the same product (Vicco®) exhibited signif-
icantly delayed and moderated on 40 breast cancer pa-
tients (20 in each group) radiodermatitis in the sandalwood/
turmeric group compared to the control group .
Based on four clinical trial projects on photoallergy
testing, nine of 621 patients (1.45%) tested demonstrated
positive effect to S. album oil at 2% [119–122]. It should be
noted that photoallergy to EOs is very rare, and its clinical
application was generally not established.
The potential clinical anti-inflammatory action of
sandalwood oil was tested in a clinical trial performed in 50
patients with mild to moderate facial acne for 8 weeks. This
10 J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus
pilot study of a topical regimen treatment (foaming
cleanser, serum, spot treatment, and mask) containing
0.5% salicylic acid and up to 2% S. album oil was con-
ducted in teenage and adult subjects with mild to moderate
facial acne . For the eight-week treatment period,
treatment was well tolerated by nearly all patients (42 of 47
participants (89.4%). Patients experienced an improve-
ment when compared with baseline with notable re-
ductions in lesion counts in patients with more severe or
inﬂamed lesions, using the Global Aesthetic Improvement
Scale (GAIS). There is no report of limitation of use of this
regimen due to no adverse events .
According to the literature, it is assumed that S. album
oil might have therapeutic beneﬁts to psoriasis patients
due to its anti-inﬂammatory, antiproliferative properties
via inducing autophagy and cell death in proliferating
keratinocytes [124–126]. A Phase 2 clinical trial results in
patients with mild to moderate psoriasis illustrated that the
topically applied 10% S. album oil serum administered
twice a day for 28 days was well tolerated and alleviates
mild to moderate psoriasis symptoms .
In a pilot study, undiluted S. album oil to common
warts twice daily for 12 weeks has been applied to ten
candidates with the age range from six to adult. The results
showed that 10 of the 12 (80%) participants had complete
resolution of all treated warts over their hands, feet, legs, or
face, with the other two subjects experiencing moderate
improvement. There was no report of skin irritation,
redness, pain or other adverse symptoms .
8 Safety, adverse effects and
Due to the chemical composition of the sandalwood, its
EO is most popularly used in folk medicine, cosmetics,
pharmacy, as well as the food industry. The list of internal
and external health problems, in which the oils of Santa-
lum plants are used, contains inter alia general weakness,
headache and stomach ache, common colds, bronchitis,
skin diseases such as infectious sores, ulcers, acne, and
rashes, heart ailments, fever, infection of the urinary tract,
and inﬂammation of the mouth [129, 130].
Just as the positive effect of EOs depend on their
chemical composition, their safety and side effects
result from the main phytochemicals and as well as the
synergistic action of compounds that are present in lower
concentrations. The main components present in the san-
dalwood EOs, that should be taken into the consideration
regarding the safety are α-santalol, β-santalol, β-santalene,
Z-α-trans-bergamotol [43, 131].
In the food industry, natural flavouring substances
may be safely used in the products, meeting some criteria:
must be used in the appropriate forms, in the minimum
quantity required to produce their intended physical or
technical effect, and following all the principles of the good
manufacturing practice. Following this, the Food and Drug
Administration (FDA) recommendation, a wide range of
EO (clove, oregano, thyme, nutmeg, basil, mustard, and
cinnamon) and components (linalool, thymol, eugenol,
carvone, cinnamaldehyde, vanillin, carvacrol, citral) are
classified as generally recognized as safe (GRAS) and have
been accepted in the application in food products .
According to the FDA, S. album is an accepted natural
ﬂavouring substance and can be used in the food industry
in any kind of product, without restrictions.
Although some limitations with the dosage of the
S. album EOs are recommended. According to the data of
Flavor and Extract Manufacturers Association (FEMA)
published in the article of Burdock and Carabin  the
maximum doses of sandalwood oil in alcoholic beverages
should not exceed 0.77 ppm; in non-alcoholic beverages
1.96 ppm, hard candy 89.98 ppm, while in the case of baked
products the maximum level is 9.72 ppm. Even though it is
difﬁcult to determine how much sandalwood EO is
consumed with food by humans, National Academy of
Sciences (NAS) data are estimated to 0.0074 mg/day or
0.000123 mg/kg/day sandalwood oil for 60 kg individual.
On the other hand, FEMA reported that these values
are 0.0058 mg/day and 0.0001 mg/kg/day, while the mean
consumption of foods containing the usual amount- PADI
(Possible Average Daily Intake) - is estimated to 0.97 mg/
person/day or 0.016 mg/kg/day of sandalwood oil . In
general, the information on the safety and adverse effects
of the genus Santalum is extremely limited.
Even though the EOs are generally considered as safe,
toxicological studies showed that some of them may be
harmful to human health. Studies have been shown that
different chemicals of EOs (menthol, carvone, limonene,
citral, cinnamaldehyde, benzaldehyde, as well as methyl
anthranilate, geranyl acetate, furfural, and eugneol) taken
at high levels showed no carcinogenic effects .
Although low concentrations of EOs are usually devoid of
mutagenicity and carcinogenicity, some single compo-
nents or crude EOs may act as carcinogens. For example,
estrogen-dependent malignancy can be induced by Salvia
sclarea L. EOs, while estragole from Artemisia dracunculus
L. shows carcinogenic potential in rodents. Following,
psoralen (bergamia EOs) is photosensitive compound that
J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus 11
may induce DNA adduct formation and skin cancer, while
methyleugenol (Laurus nobilis L.) and D-limonene (citrus
EOs) is being known as carcinogenic in rodents .
The lethal dose (LD
) of the sandalwood EOs was
evaluated for rats (5.58 g/kg body weight) and rabbits
(>5 g/kg BW, body weight). The LD
was also estimated
for the major constituent of the EOs, α-santalol and the
values for rats were 3.8 g/kg BW, and for rabbits >5 g/kg
BW. 3 mL/kg of α-bisabolol showed a reduction in fetal
numbers in rats and rabbits, while 1 mL/kg showed no
teratogenic effects .
Interestingly, studies on the effects of the inhaled
sandalwood oil have shown that female Swiss exposed
to the oil for 1 h shown 40% decreased motility, and in
the blood of these animals, α- and β-santalols were present
[43, 135]. Some studies with animal models suggest that
sandalwood EO can irritate rabbit skin, but it seems that
this oil has no such effect on human skin . The results
of studies showed that sandalwood EO is characterized by
low sensitization potential. In the work of Paulsen and
Andersen  of 318 patients responded that 10% of
sandalwood EOs gave a positive effect.
At the same time, 2% concentration did not cause any
negative effects on any of the respondents . A total of
1.4% of all tested dentists and dental nurses responded to
sandalwood oil in the case of the paper published by Kiec-
swierczyńska and Krecisz . A total of 0.9% of patients
(total of 1606 patients) responded to 10% sandalwood oil,
at the same time 0.4% of patients responded to 2% con-
In the study with 641 patients with eczema, sandal-
wood oil had no response by any of the tested patients
, while in the case of 422 patients with suspected
contact allergy, 2.4% gave the positive response to
sandalwood, and 3.1% to cinnamic alcohol . Similar
percentage results were obtained in the studies on the
photoallergies’caused by sandalwood oil. 2.2% (3 of 138
patients) were positive to sandalwood oil reaction in the
study conducted by Fotiades et al.  while 2 of 1050
probable photodermatitis patients (0.19%) in the study of
Pigatto et al. .
In general sandalwood, EOs are recognized as
nontoxic in the matter of phototoxicity, but the suggested
maximum dose of the S. album EO is 2% . The results of
the study with 4266 Japanese people with cosmetic
dermatitis showed that 57 (1.34%) was positive to 2%
α-santalol. This suggests that the concentration of the
sandalwood EOs should be lower for people of Japanese
origin . In general, the use of sandalwood oil in
eczema, psoriasis, radiation dermatitis, and antifungal is
reported in the literature, and the EOs is well tolerated with
acceptable safety . What is more, the major constituent
of S. album EOs, α-santalol is being recognized as a
chemopreventive effect with nontoxic side effects against
normal cells .
9 Conclusions and future
The review highlighted the bioactive compounds present
in the sandalwood and bioactivities of its extract proven by
the in vivo,in vitro and clinical trials. The EO components
such as α-santalol and β-santalol are considered important
for evaluating the commercial value of the sandalwood.
These components are responsible for most of the biolog-
ical activities along with the soothing aroma of Santalum
species. Traditional uses of the EO from sandalwood
have been proven to be beneﬁcial in treating somatic
and other disorders such as common cold, fever, lung
infection, and many types of inﬂammations. Antioxidant,
anti-inﬂammatory, antibacterial, antifungal, antiviral,
neuroleptic, antihyperglycemic, antihyperlipidemic, and
anticancer activities of Santalum extracts have been
recently proved through clinical trials. Recent scientiﬁc
studies have not shown any adverse effect of consumption
of sandalwood EO in in vivo trials. Hence, extracts from
sandalwood are presently used in cosmetic products and
as a ﬂavouring agent in food items. More detailed studies
are needed to decipher the exact molecular mechanism of
the sandalwood extracts in improving human health.
These molecular studies will also assist in delineating the
more precise use of sandalwood extracts for human con-
sumption. Exhaustive clinical studies are also needed to
further promote the use of sandalwood ingredients in food
and pharma application. Pharmaceutical formulation of
the sandalwood extracts is another area that needs the
attention of the scientiﬁc community to further improve the
use of Santalum species in health promotion.
Acknowledgements: MM wants to thank ANID CENTROS
Author contributions: All authors made a signiﬁcant
contribution to the work reported, whether that is in the
conception, study design, execution, acquisition of data,
analysis, and interpretation, or in all these areas that is,
revising or critically reviewing the article; giving ﬁnal
approval of the version to be published; agreeing on the
journal to which the article has been submitted; and
conﬁrming to be accountable for all aspects of the work.
Research funding: None declared.
12 J. Sharifi-Rad et al.: Bioactive phytochemicals of Santalun genus
Competing interest: The author declares no conﬂict of
interest associated with this publication and there has been
no signiﬁcant ﬁnancial support for this work that could
have inﬂuenced its outcome.
Data availability: All supporting data for this manuscript
are included in the ﬁgures and available from the
corresponding authors on reasonable request.
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