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34
Rosmarinus ocinalis L.
BurçinMersin andGülçinSaltancan
Abstract
Rosmarinus ofcinalis L. (Rosemary) is a
medicinal and aromatic herb belonging to the
Lamiaceae family. The geographical distribu-
tion of the plant covers especially the
Mediterranean Region and regions with a
Mediterranean climate. In addition, it has been
cultured in many countries around the world
so far. The aerial components of the plant, par-
ticularly the leaves, are rich in both volatile
and nonvolatile phytochemicals: terpenes, a-
vonoids, phenolic compounds, alcohols, and
esters. Phenolic compounds such as carnosol,
carnosic acid, and rosmarinic acid in its con-
tent have been associated with the plant’s anti-
cancer, anti-inammatory, antihyperglycemic,
antithrombotic, and antioxidant activities. The
antimicrobial and antioxidant bioactivities of
its essential oil have been utilized and accepted
as a safe conservator in the food industry.
While the bioactivity of the plant has been
proven by invivo and invitro experiments, the
results of clinical studies support the existence
of these bioactivities. The potential of rose-
mary to be transformed into herbal medicine
is considerable. In this chapter, we present an
overview of the distribution, ethnobotany, bio-
active and nutritional composition and avail-
able extraction techniques, scientic
evidences, clinical and toxicological studies,
available commercial formulations, and chal-
lenges and future recommendations as poten-
tial drug candidate of rosemary.
Keywords
Rosemary · Phenolic compounds ·
Rosmarinic acid · Biological activity ·
Toxicity
34.1 Introduction
Rosmarinus ofcinalis L., also known as rose-
mary, is a medicinal and aromatic plant belong-
ing to the Lamiaceae family. Nowadays, the plant
has a wide cultural area, but it grows specically
in the Mediterranean countries (Allegra etal.
2020; Andrade etal. 2018). The synonym of the
plant R. ofcinalis is reported as Salvia rosmari-
nus Schleid. and Rosmarinus angustifolius Mill.
(Borges etal. 2019; Heinrich etal. 2006).
According to the scientic classication, it is
known in the literature as a member of the
Magnoliopsida class, Asteridae subclass, and
B. Mersin (*)
Department of Pharmacognosy, Hamidiye Faculty of
Pharmacy, University of Health Sciences Turkey,
Istanbul, Turkey
G. S. can
Department of Pharmacognosy, Faculty of Pharmacy,
Ankara University, Ankara, Turkey
e-mail: gulcin.saltan@pharmacy.ankara.edu.tr
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
F. T. Güraaç Dereli et al. (eds.), Novel Drug Targets With Traditional Herbal Medicines,
https://doi.org/10.1007/978-3-031-07753-1_34
526
Lamiales order (Begum etal. 2013). R. ofcinalis
is subdivided due to morphological differences
such as the size of leaves, calyx, and corolla dif-
ferences, and it is scientically shown that there
are a multitude of varieties (Zaouali etal. 2010)
(Fig.34.1).
Among all Rosmarinus species, only R. ofci-
nalis has an importance in terms of covering all
these sectors in terms of medical, cosmetic, phar-
maceutical, and industrial aspects, especially
food industry (Zaouali etal. 2010; Hernández
etal. 2016).
Rosemary is used in the food industry in sev-
eral ways, one of which is as a avoring agent
(Hussain etal. 2010). Another way of usage is
with rosemary extracts’ anti-oxidation and
antimicrobial properties for food preservation. As
a preservative, rosemary extracts are reported to
have technological advantages and benets to
consumers (Nieto etal. 2018). Rosemary oil is
utilized in the food industry to preserve nearly all
meat products, including pork, beef, lamb, poul-
try, and sh products (Hernández etal. 2016).
Rosemary has been utilized in traditional
medicine for ages against various conditions
(Satyal etal. 2017). The branches of the plant
have been utilized as herbal tea in order to benet
from its abortive, stomachic, carminative, chola-
gogue, and antispasmodic effects (Soliman etal.
1994). Experimental studies have revealed that
the herb has antibacterial, antifungal, antidepres-
sant, antidiabetic, anticancer, antioxidant, anti-
inammatory, hepatoprotective, and
neuroprotective effects (Ribeiro-Santos etal.
2015; Hamidpour 2017; Olfat 2012; Kensara
etal. 2010).
Rosemary oil is not only used in therapeutic
areas, but also has a widespread use in the cos-
metic industry. Bath essences, cologne waters,
shampoo, and hair toners are also cosmetic prep-
arations in which rosemary essential oil is fre-
quently used (Éva Stefanovits-Bányai etal.
2003).
34.2 Distribution andStatus
ofSpecies
Rosemary is a medicinal and aromatic herb that
has been beneted by people for centuries. In
ancient Egypt, it is recorded that rosemary leaves
were used at funerals to help the Pharaohs nd
peace after death (Borges etal. 2019).
The plant has been used as a foliage plant in
various countries of the world since ancient
times. Although it is cultivated in many countries
of the world, its origin is Mediterranean region
(González-Minero etal. 2020).
Iberian Peninsula is a district where rosemary
is widely grown, but this distribution has been
reported to decrease towards the north and north-
west regions. With the recognition of Spain as the
region where the plant grows naturally, it has
been determined that it can grow naturally on
almost all kinds of land, especially in the sun-
shiny and arid regions of the forest areas in the
Fig. 34.1 Rosemary (Rosmarinus ofcinalis L.) plant.
(Source: Lešnik etal. 2021)
B. Mersin and G. S. can
527
Mediterranean region (Fig.34.2) (Salido etal.
2003).
In a study where the geographical coordinates
and sample numbers of the wild rosemary popu-
lations are grown in San Remo, Italy, and col-
lected and grown from the Tyrrhenian Sea
environment in 2013, Southern Tuscany, Island
of Capraia, Northern Corsica, and Central
Sardinia have been reported as the places where
the plant was collected (Li etal. 2016).
It has been recorded that there are four variet-
ies of R. ofcinalis in Tunisia: var. typicus Batt.,
var. laxiorus De Noé, var. troglodytorum Maire,
and var. lavandulaceum Batt (Yosr etal. 2013).
Considering the distribution of the taxon in
Turkey, it is reported to be located in the provinces
of Adana, Çanakkale, Hatay, and Mersin (Tübives
2021).
34.3 Comparison of
Traditional/Ethnomedicinal/
Local Uses
In Turkey, the owers, branches, and seeds of
rosemary are consumed as a herbal tea with infu-
sion and decoction methods. While its consump-
tion in the form of herbal tea is widely used for
ailments such as migraine, u, cold, and head-
ache, the oil of the plant is used for hair booster
(Polat and Satil 2012).
It has been analyzed that rosemary is mostly
utilized in the remedy of respiratory, circulatory,
and digestive tract diseases (Everest and Ozturk
2005). It is utilized for carminative and digestive
purposes among the people in the Espiye-Giresun
region (Polat etal. 2015). The use of decoction
prepared from the aerial parts of rosemary in the
Alasehir region for wound healing shows that
infusion and decoction methods are the most
common preparation methods for rosemary
(Ugulu 2011). It is shown that it is used in gastro-
intestinal diseases, atherosclerosis, rheumatism,
diabetes, and hypercholesterolemia (Sargin etal.
2013).
When the results of an ethnobotanical study
conducted in Bayramic-Çanakkale region were
evaluated, it was concluded that the people of the
region used the owers and leaves of the plant by
preparing tea by infusion and consuming before
breakfast against abdominal pain, cold, heart dis-
eases, and stomach ailments (Bulut and Tuzlac
2015). In a study conducted in Krkhan (Hatay)
between 2011 and 2013, some ethnobotanical
features of frequently consumed plants were
investigated by visiting herbalist in the area.
Fig. 34.2 Geographic dissociation of Rosmarinus ofcinalis. (Source: González-Minero etal. 2020)
34 Rosmarinus ocinalis L.
528
According to the results, it was found that the
rosemary leaves were used by the people of the
region to weaken and reduce cholesterol (Altay
etal. 2015).
According to an ethnobotanical survey con-
ducted between 2004 and 2006in Kapda
Peninsula, rosemary leaves act as a blood pres-
sure regulator (Uysal etal. 2010). According to
the results of an ethnobotanical study carried out
in a master’s thesis, it has been reported that all
parts of rosemary are used as mosquito repellents
in Izmit region (Kzlarslan 2012).
In North Africa, it is recorded that rosemary is
used to protect wounds from germs due to its
antiseptic properties (Dafni etal. 2019).
In Iran, decoctions prepared from rosemary
are used as cholagogue, diuretic, and antiseptic
against rheumatism and wounds (Naghibi etal.
2005).
In an ethnobotanical investigation on medici-
nal and aromatic plants in the Arribes del Duero
region of Spain, it was reported that the people of
the region prepared maceration from the branches
of the plant with ethanol and used it against vari-
cose veins (González etal. 2010).
34.4 Bioactive/Nutraceutical
andNutritional Composition
andAvailable Extraction
Techniques (Classication
andStructures ofFew
Representatives)
Rosemary has a lot of strong biological activities
such as anti-inammatory, antioxidant, antihy-
perglycemic, antibacterial, and antithrombotic.
When examined ethnobotanically, it has been
determined that especially its leaves are used to
cure many diseases. It is widely consumed as
food, especially in the Mediterranean diet
(Bourhia etal. 2019). Rosemary is available to be
used fresh, dry, or in the form of its essential oil
(Pintore etal. 2002).
Rosemary has a very high potential as a herbal
medicine due to its high content of nonvolatile
and volatile compounds. Many molecular groups
responsible for bioactivity have been discovered
in rosemary, including monoterpenes, di- and
tripenoids, esters, avonoids, sesquiterpenes,
ketone, alcohol, hydrocinnamic derivatives, and
other minor components (Ali etal. 2019).
When the structure of rosemary extracts pre-
pared by different extraction techniques is inves-
tigated, they are fundamentally divided into ve
representative classes. These are monoterpenes,
sesquiterpenes, diterpenes, waxes, and pentacy-
clic triterpenes (Bensebia etal. 2016).
34.4.1 Volatile Compounds
Secondary metabolites are special molecules
synthesized by almost all medicinal and aromatic
plants. Monoterpenes are compounds that are
formed by the combination of isoprene main
skeleton, constitute the fundamental substance of
essential oils, and have quite valuable biological
activities for plants and animals (Dehsheikh etal.
2020).
When the volatile compounds in rosemary
were examined, it was found that the most effec-
tive compounds in terms of both medical and
aroma were terpenoids (Boix etal. 2010).
Rosemary essential oil (95–98%) consists of
monoterpene and monoterpenic compounds, and
the rest consisted of sesquiterpene compounds
(Szumny etal. 2010).
In a study in which volatile compounds of
rosemary essential oil and hydrosols were
detected by gas chromatography (GC/MS), it was
found that two fractions contained 67 volatile
molecules (Tomi etal. 2016).
Comparison of different oils is as follows:
Rosemary (Spain): 1,8-cineole (12.1–14.4%),
camphor (17.2–34.7%), α-pinene (10.2–21.6),
α -terpineol (1.2–2.5%), borneol (3.2–7.7%),
camphene (5.2–8.6%), p-cymene, limonene,
myrcene, borneol, bornyl acetate, and
β-caryopliyllene. Rosemary (Tunisia, Beja):
1,8-cineole (33.08%), camphor (18.13%),
α-pinene (9.23%), α-terpinole (8.17%), borneol
(5.48%), camphene (5.07%), and p-cymene
(2.42%), limonene, bornyl acetate (Salido etal.
2003; Hcini etal. 2013).
B. Mersin and G. S. can
529
It has been recorded that 1,8-cineole is used
against respiratory tract infections such as colds,
inuenza, rhinitis, and sinusitis. Manifold experi-
mental studies have been published, including
animal experiments proving that eucalyptol has
anti-inammatory, analgesic, antimicrobial, anti-
oxidant, and spasmolytic activities (Seol and
Kim 2016).
Eucalyptol has been evaluated as an agent that
can be used against SARS-CoV-2 due to its
extremely low binding energy. However, the
number of invivo and invitro experiments that
will support these studies should be increased
and the level of contribution to drug discovery
should be investigated in further detail (Sharma
and Kaur 2020).
Rosemary essential oil can be acquired by dis-
tillation types from traditional essential oil
extraction methods. Analysis of the essential oil
obtained can be done by both GC and GC-MS
chromatography methods. In experimental stud-
ies, the compounds in the content of the essential
oil were detected by comparing the mass spec-
trometry and retention times of reference stan-
dards (Boutekedjiret etal. 2003).
34.4.2 Nonvolatile Compounds
Most of the bioactivities of the plant have been
associated with its phenolic compounds. While
the phenolic diterpenes carried by the plant are
listed as carnosol and carnosic acid, the major
compound as phenolic acid is rosmarinic acid.
Flavonoids such as genkwanin and cirsimaritin
are also important phenolic compounds that
increase the antioxidant activity of the plant
(Borras Linares etal. 2011).
In a study where the chromatographic analysis
of the ethanolic extract of rosemary was carried
out, it was revealed that it is a very rich plant in
terms of avonoids and phenolic substances. The
most common molecules in the leaves of the
plant as carnosic acid, rosmarinic acid, and car-
nosol have been associated with the plant’s anti-
inammatory, antioxidant, and antitumor effects
(Bai etal. 2010). Although Rosmarinic acid is
thought to be the most important antioxidant
molecule found in rosemary, there are numerous
scientic studies proving that these three mole-
cules are very important in terms of the plant’s
bioactivity (Bulduk and Gökce 2017).
Experimental studies revealed that Rosmarinic
acid also has antiangiogenic and antiproliferative
effects (Martins-Gomes etal. 2019).
It has been proven that rosemary extracts con-
tain six triterpenic molecules: micromeric acid,
benthamic acid, oleanolic acid, augustic acid,
betulinic acid, and ursolic acid (Martínez etal.
2012; Fernández-Ochoa etal. 2017.). There are
experimental studies that show that ursolic acid
obtained from Rosemary inhibits tumor initiation
(Liu 1995).
It has been proven that α, β-amyrin molecules
in pentacyclic triterpene structure have manifold
biological activities. Hepatoprotective, antimi-
crobial, and anti-inammatory activities are bio-
logical effects that have been dened until today
(Bensebia etal. 2016).
The analysis of the phenolic diterpene mole-
cules in the composition of rosemary, which pro-
vides antioxidant effects, was carried out in an
experimental study. According to the study, these
compounds were obtained by solvent, supercritical
uid extraction (SFE), and Soxhlet extraction by
reversed-phase HPLC method that was used for the
detection of the compounds (Bicchi etal. 2000).
Detailed information about the process of
obtaining and characterizing bioactive com-
pounds from the R. ofcinalis plant is schema-
tized in Fig.34.3 (Lešnik etal. 2021).
34.5 Scientic Evidences:
Pharmacological Activities
34.5.1 Antitumor Activity
Animal experiments and invivo studies on the
anticancer activity of rosemary have been
reported frequently. Anticancer activity was asso-
ciated with the antioxidant effect of rosemary,
and the main compounds rosmarinic acid, car-
nosic acid, ursolic acid, and carnosol, were also
blamed for anticancer activity (González-Vallinas
etal. 2015).
34 Rosmarinus ocinalis L.
530
R. officinalis collection
Extraction techniques
Microwave-assisted
extraction (MAE)
Supercritial fluid
extraction (SFE)
Pressurized liquid
extraction (PLE)
Nonvolatile extracts
Fractionation
Carnosic acid
and camosol
(moderate plarity)
Rosmarinic acid
(high polarity)
Analysis with
HPLC-MS
Ultrasound-assisted
extraction (UAE)
Steam distillation
(SD)
Hydrodistillation (HD)
Distillation techniques Microwave-assisted
hydrodistillation (MAH) Volatile essential oils
Fractionation
Light fraction
(a-pinene, myrcene)
Heavy fraction
(camphor, 1,8-cineol)
Analysis with
GS-MS
Solvent-free
microwave distillation
extraction (SFME)
Microwave hydrodifussion
and gravity (MHDG)
Fig. 34.3 Process of isolating the ingredients of R. ofcinalis plant. (Source: Lešnik etal. 2021)
The 7,12-dimethylbenz [a] anthracene
(DMBA) molecule has been found to be associ-
ated with breast tumors (Lai and Singh 2006).
Rosemary extract and carnosol intraperitoneally
(i.p.) were injected into female rats and inhibited
the DMBA-induced rat memory tumor forma-
tion. It was concluded that this injection dose of
rosemary and carnosol provided a notable reduc-
tion in the number of DMBA-mediated adenoca-
rinomas in each rat compared to the control
group. When the same experiments were repeated
with ursolic acid, no positive results were
obtained. According to this experimental study,
rosemary and carnosol were evaluated as having
high potential in terms of protective effect against
breast cancer (Singletary etal. 1996).
An invitro experiment was carried out with
rosemary extracts on colon cancer cells known as
CaCo-2 (Colorectal adenocarcinoma). It was
determined that CaCo-2 colon cancer cells were
exposed to rosemary extract at a dose of 30μg/
mL for 24h, which signicantly reduced colony
formation. Antitumor activity was associated
with the antioxidant capacity of the extract and
its mechanism was explained as the DNA chain
breaks induced by H2O2 and its reduction in oxi-
dative damage (Moore etal. 2016).
In distinctive survey on the antitumor effect of
rosemary, it has been discovered that components
isolated from diverse rosemary extracts show
anticancer activity in liver, bladder, cervix, breast,
pancreas, leukemia, ovarian, lung, colon, and
prostate tumors in invitro experiments (González-
Vallinas etal. 2015).
34.5.2 Anti-inammatory Activity
For the purpose of examining the anti-inamma-
tory effect of rosmarinic acid, inammation was
induced in two methods using rats. In the rst rat
modeling, locally carrageenan- induced paw
edema was created. In other modeling, a systemic
inammation was obtained in rats with models of
thermal injury and ischemia reperfusion in the
liver. In the rst rat modeling with local edema, it
was found that rosmarinic acid applied at 25mg/
kg effectively decreased paw edema at 6h, per-
forming a dose-response impact of over 60%. In
the second rat modeling, the same amount of ros-
B. Mersin and G. S. can
531
marinic acid was applied, and as a result, it was
dened that it could also decrease multi-organ
dysfunction markers by modulating NF-kB
(nuclear factor kB) and metalloproteinase-9
(Sánchez-Camargo and Herrero 2017).
The formation of nitrogen species and reac-
tive oxygen is stimulated by pro-inammatory
cytokines. Due to this pathway, it has been con-
cluded that the procurement of such reactive
species in macrophages is likely to be inhibited
when the formation of pro-inammatory cyto-
kines is decreased. Dimethylsulfoxide is pre-
ferred in experimental studies due to its ability
to mix with water and dissolve a wide variety of
polar and nonpolar small molecules. In addition
to protecting cells, tissues, and organs as an
advantage of use, it is also important to increase
the absorption of pharmaceutical agent. The
impact of rosemary extracts dissolved in DMSO
on pro-inammatory cytokine procurement by
peritoneal macrophages and J774 cells was
evaluated. It was concluded that rosemary
extracts have a more remarkable ability to
inhibit IL-1 and TNF-α in macrophages.
Inhibition of cytokines by rosemary extract has
been potentially evaluated as alternating
approaches in the healer of inammatory ail-
ments (Justo etal. 2015).
34.5.3 Antihyperglicemic Activity
α-Glucosidase enzyme breaks down oligosaccha-
rides and disaccharides found in brushy edge
cells in the small intestine into monosaccharides.
Acarbose is an oral antidiabetic agent that revers-
ibly binds to the α-glucosidase enzyme (Turan
and Kulakszolu 2015). A cell-free model
resulted in an invitro study where application of
rosemary extract (5.5mg/mL–55mg/mL) found
notable 60% reduction in α-glucosidase activity
(Naimi etal. 2017).
Carnosol is one of the fundamental compo-
nents of rosemary extract and has been analyzed
invitro to show remarkable α-glucosidase inhibi-
tory effect. In an invivo study, an oral sucrose
tolerance test (OSTT) was enforced in normal
mice to evaluate the hypoglycemic effect of car-
nosol. It was recorded that carnosol applied at a
dose of 10mg/kg caused a notable degree in the
postprandial blood glucose level (p<0.05)
30min after sucrose loading. The data were eval-
uated to prove that carnosol exhibits strong hypo-
glycemic effects in invivo, consistent with
invitro α-glucosidase inhibitory effect (Ma etal.
2020).
Skeletal muscle is one of the substantial target
tissues of insulin and plays a vital role in glucose
balance. Deteriorating effect of insulin on skele-
tal muscles emerges from increasing insulin
resistance and advanced stages of type 2 diabetes
mellitus (T2DM). As a result of activating the
AMP-activated kinase (AMPK), also known as
the energy sensor, it has been recorded that the
muscles increase glucose uptake. The use of
AMPK activators is considered an effective way
to combat insulin resistance. The effect of carno-
sol, a signicant ingredient in rosemary extract,
on L6 rat muscle cells was investigated in an
invitro experimental study. In the study, it was
recorded that use of carnosol enhanced glucose
uptake, similar to insulin and metformin, in L6
muscle cells, and this effect was associated with
an AMPK-dependent mechanism (Vlavcheski
and Tsiani 2018).
34.5.4 Antithrombotic Activity
In a study investigating the antithrombotic effects
of various plants both invivo and invitro, it was
concluded that rosemary is an important plant in
terms of antithrombotic activity. After the rose-
mary was crushed, centrifugation was applied
and the ltrate was separated. The effect of rose-
mary permeate on platelet-rich thrombus forma-
tion was evaluated by hemostatometry, a
share-induced invitro platelet function test. The
supernatants of plants display notable antithrom-
botic effect and were also evaluated using a laser-
induced invivo thrombosis test in mice.
Rosemary was also examined in this invivo
study, and as a result, it was found that thyme and
rosemary have signicant antithrombotic effects
because of their intrinsic inhibitory effect on
platelets (Yamamoto etal. 2005).
34 Rosmarinus ocinalis L.
532
In order to examine the impact of rosemary
and thyme herbs on experimental thrombosis,
thrombosis was induced on a group of male mice
with injury to their carotid arteries by He-Ne
laser. According to the experiment, the control
group mice were given a diet mixture of pure
nutrients rich in fat. On the other hand, the mice
in the experimental group were fed a diet con-
taining herbal ingredients by powdering both
rosemary and thyme plants, adding 0.5% and 5%
(w/w) concentration to the aforementioned pure
diet mixture. Hemorrhage time evaluation and
endothelium-dependent ow-mediated vasodila-
tion tests (FMV) were performed in groups of
mice with 12weeks of diet feeding. In conclu-
sion, it was revealed that long-term dietary intake
containing 5% or 0.5% rosemary or 5% thyme
remarkable suppressed the rate of thrombus for-
mation invivo, but the bleeding time did not pro-
long. The mechanism of the antithrombotic
activity has been described as pressing of platelet
reactivity and excitation of the vascular endothe-
lium (Naemura etal. 2008).
34.5.5 Antioxidant Activity
The carnosol molecule has been demonstrated to
have strong antioxidant impact in invitro cell
culture, cell-free and, invivo animal models in
various experimental studies conducted up to
date (O’Neill etal. 2020).
In a study in which essential oil was obtained
to determine the antioxidant impact of rosemary,
antioxidant impact was evaluated by DPPH
(1,1-diphenyl-2-picrylhydrazyl) radical method.
The amount of phenolic substance contained in
the essential oil of rosemary obtained with a yield
of 0.40mL/100g was determined and the nd-
ings were evaluated in accordance with the nor-
mal value ranges in the literature. It has been
proven that the powerful antioxidant impact in
rosemary leaves is due to the carnosol, rosma-
rinic acid, and carnosic acid contained in the
plant. Within the scope of the research, antioxi-
dant capacity values of essential oils were made
by DPPH radical scavenging activity analysis
and IC50 values were calculated and the results
were given in μg/mL extract. The IC50 value of
rosemary essential oil was found as 2.75μg
extract/mL. Rosemary essential oil has been con-
trived to include high amounts of total phenolic
substances and show antioxidant activity. Based
on this discovery, it has been reported that its
antioxidant effect is evaluated as a potential agent
for the food and pharmaceutical industry (Özbek
Yazc etal. 2020).
The nematode Caenorhabditis elegans, a free-
living nematode abundant in earth ecosystems,
can be used as an experimental model (Wu etal.
2012). In a study using C. elegans as a model, the
antioxidant and antiaging potential of carnosol
was investigated. Reactive oxygen species (ROS)
are formed as a by-product of cellular metabo-
lism. ROS formed in excessive amounts in the
cell cause many diseases from cancer to aging by
damaging lipids, proteins, and DNA.It was found
that C. elegans treated with various concentra-
tions of carnosol evinced a remarkable decline in
ROS levels compared to those of control C. ele-
gans. In particular, the amount of reactive oxygen
species in the group exposed to 180μM carno-
sole demonstrated a decrease of up to 76%, a
decrease compared to control group.
Consequently, carnosol has been reported to sig-
nicantly reduce ROS accumulation in C.Elegans
(Lin etal. 2019).
34.6 Clinical Studies
In a double-blind randomized restricted search
using university students, 68 students with age
ranges of 22.9±1.7 were randomly assigned to
receive placebo and 500mg rosemary two times
per day for one month. Students were divided
into two groups by block randomization, with 34
people receiving rosemary and 34 placebos. In
the study, dried aerial parts of rosemary were put
in capsules as 500mg and given to 34 twice a day
for a month. The other 34in the control group
were given starch in the capsule to create a pla-
cebo effect. According to the results, it was
revealed that rosemary can be used by college
students to strengthen prospective and retrospec-
tive memory, decrease dejectedness and anxiety,
B. Mersin and G. S. can
533
and enhance slumber quality (Nematolahi etal.
2018).
A clinical search was performed on the activ-
ity of rosemary extract on acetylcholinesterase
(AChE), total antioxidant capacity (TAC), effect
on lipid peroxidation, and protein carbonylation.
In a double-blind, randomized controlled study,
50 healthy participants aged 21–25years were
divided into two groups. While 25 people were
given 500mg of starch powder twice a day as a
placebo, 25 people were given 500mg of rose-
mary powder prepared from rosemary extract and
this administration was carried out for a month.
According to the results, it has been demon-
strated that rosemary has a preventive impulse on
both AChE impact and nonenzymatic antioxidant
defense system (Fatemeh etal. 2021).
An experiment was conducted in 22 healthy
volunteers to designate the impress of rosemary
tea on plasma anxiety and depression biomark-
ers. In the study, volunteers between the ages of
20 and 50 were given tea prepared by pouring
100mL boiled water over 5g of dried rosemary
per day for 10days. Before and 10days after the
experiment started, brain derived neurotrophic
factor (BDNF), tumor necrosis factor-alpha
(TNF-α), interferon-gamma (IFN-γ), interleu-
kine- 6 (IL-6), interleukine-4 (IL4), and cortisol
levels were evaluated with ELISA kits. According
to the ndings, in healthy volunteers participat-
ing in the trial, rosemary tea consumption was
found to have promising anxiolytic and/or antide-
pressant effects. This effect was associated with
the increase in BDNF level, which is considered
to be the most important marker in the depression
marker (Achour etal. 2021).
It was recorded that prehospital emergency
technicians had a signicant degree of occupa-
tional fatigue and also became depressed. A study
was conducted to investigate the impacts of rose-
mary essential oil on the symptoms of occupa-
tional fatigue and depression experienced by
prehospital emergency service technicians. The
rosemary oil used in the study was diluted with
odorless sweet almond oil to contain 25% pure
rosemary oil. Linen badges were prepared and
placed at a distance of 30cm from the uniforms
of the participants. Before each work shift, the
participants sprayed a mixture of 25% pure rose-
mary essential oil on their rosettes with a total
volume of 1cc in two breaths each morning. The
implementation continued for a month and the
participants shift three days a week. Although all
the procedures applied in the placebo group are
the same, unlike the control group, the sprayed
oil consists entirely of 100% sweet almond oil
without fragrance. On the day of the last applica-
tion, one hour after the application, DASS-42
(Depression subscale) and OFER-15 question-
naires were reapplied to the participants in both
groups. According to the evaluations, it has been
recorded that the mixture prepared with 25%
rosemary essential oil does not reduce occupa-
tional fatigue, but may have afrmative effects in
reducing depression in prehospital emergency
service technicians (Hatami etal. 2021).
There are no human studies that provide con-
vincing evidence of the activity of rosemary
extracts on the human inammation or immune
system mechanism. Only in a randomized clini-
cal study of 19 people, rosemary extract tablets
were given for 21days, and markers such as pro-
inammatory cytokine TNF-α, cellular adhesion
mediating proteins ICAM-1 and VCAM-1, and
high sensitivity C-reactive protein (hs-CRP) were
measured and recorded. According to the results,
no remarkable changes in biomarkers were
observed and no considerable link was estab-
lished between the consumption of rosemary
extract and inammation. More clinical research
on the subject should be done (Ahmed and
Babakir-Mina 2020).
34.7 Toxicological Studies
34.7.1 Dose andSafety Prole
Many studies have been carried out on the safety
of rosemary. The rosemary herb has been quali-
ed as “generally safe” or GRAS (CFR182.10;
182.20) by the FDA in America (Ghasemzadeh
Rahbardar etal. 2020).
EFSA could not determine acceptable daily
intake dose for rosemary due to insufcient toxi-
cological data (Belsito etal. 2013). Depending
34 Rosmarinus ocinalis L.
534
on the data supplied with the food industry, the
Panel was organized by the EFSA and the expo-
sure calculations of Rosemary extracts (E 392)
were redened. The highest mean was redescrip-
tioned, with the exposure estimate (non-brand-
related scenario) assessing 0.09mg/kg body
weight daily in kids (3–9years) and 0.20mg/kg
body weight daily in the highest 95th percentile
of exposure in children. The uncertainty factor
was also taken into account in the Panel; these
exposure estimates were interpreted and evalu-
ated as exaggerating the actual exposing from the
utilization of rosemary extracts (E 392) as food
additives according to Annex II (EFSA 2012).
34.7.2 Single Dose (Acute) Toxicity
In an acute oral safety study of rosemary extract,
Wistar rats were administered as a monadic per
os gavage at a dose of 2g/kg body weight. No
side effects or deaths were ascertained during the
two-week observation period, including changes
in behavior, food and water consumption, or
body weight. Hereby, rosemary extracts were
evaluated to have low acute toxicity, and oral
lethal doses (LD50) of more than 2g/kg body
weight were declared for both male and female
rats (Anadon etal. 2008).
In an experiment in which methanolic extracts
of rosemary leaves were injected intraperitone-
ally into mice, the mean lethal dose (LD50) was
limited to be 4.125g/kg (Ghasemzadeh Rahbardar
etal. 2020).
Rosemary extract did not cause death in rats
up to 1.2g/100g BW by intragastric administra-
tion; therefore, it was considered to have very
low lethality. The lethal dose 50 (LD50) of rose-
mary essential oil in intragastric administration
in rats was found to be 5.5kg BW (Ferreira
2010).
In addition, surveys have also been carried out
to show that the use of camphor in rosemary
causes serious side effects and deaths. Ingestion
of 1g of camphor in camphor oil to a 19-month-
old child resulted in death. Although adults sur-
vived the intake of up to 43g of camphor, the
conclusion was reached by the American
Academy of Pediatrics that intake of 2g usually
produces hazardous impacts. Intake of 0.7–1.0g
of camphor in children has proven to be lethal
(Ferreira 2010).
34.7.3 Repeated Dose Toxicity
A 21-day clinical study was conducted with
patients with seasonal allergic rhino conjunctivi-
tis, and rosmarinic acid was administered at a
dose of 50mg/day to 9 patients. A placebo at a
dose of 200mg/day was given to a control group
of 10 people. The symptoms of the patients were
followed up daily. As a result, no signicant
abnormality was detected in blood values and
side effects were not observed (Belsito etal.
2013).
Rosemary extracts prepared with acetone
were administered to a group of rats at dietary
concentrations of 0 (control), 2100, 3600 or
5000mg/kg, respectively, 14days before, during,
and after mating (during pregnancy and up to
Lactation Day 13 for females). In the study, gen-
eral toxicity (food consumption, clinical signs,
body weight) and reproductive/developmental
outcomes (estrous cycles, thyroid hormones, thy-
roid histopathology, anogenital distance, fertility
and mating performance, reproductive organ
weights) were examined. At the highest dose
administration (equivalent to the average daily
intakes of 149 or 189mg/kg bw/day carnosic
acid and carnosol), the result was determined as
the level with no adverse effects for general and
reproductive toxicity (Phipps etal. 2021a, b).
34.7.4 Mutagenicity
In a toxicological study, the mutagenic and geno-
toxic potency of rosemary essential oil in gnaw-
ers was investigated using comet, micronucleus,
and chromosome aberration tests. Three doses of
rosemary oil were administered by gavage to
experimental animals. These doses were admin-
istered as 0.3g, 1g, and 2g/kg. For the micro-
nucleus test (mutagenicity endpoint), peripheral
blood and liver jail cells were gathered along
B. Mersin and G. S. can
535
with bone marrow cells. As a result, it has been
concluded that rosemary essential oil causes
mutagenic and genotoxic activities when imple-
mented per os (Maistro etal. 2010).
The Ames test was performed for the extract
of rosemary prepared by supercritical carbon
dioxide method and it was proved to be non-
mutagenic as a result (Phipps etal. 2021a, b).
34.7.5 GRAS
It has been recorded (21CFR182.10) that R. of-
cinalis is predominantly considered safe (GRAS)
as a spice and other natural seasonings and a-
vorings (FDA 2021).
34.8 Available Commercial
Formulations/Products,
Uses, Administration
Methods
andPharmacokinetic
Studies
Since rosemary extract contains compounds
proven to have antioxidative effects, it has been
recognized as a food additive since 2008 by the
EFSA (Q-2003-140) (González-Minero etal.
2020).
Drying and grinding of rosemary leaves are
carried out to prepare trading accessible rose-
mary extracts. Extracts are obtained by using
various diluents such as methanol, hexane, ace-
tone, ethanol, and water or a solvent admixture as
solvent. It has been recorded that rosemary
extracts are commercially available in the form of
ne powder products or liquid forms after rar-
efaction/normalization with appropriate food
grade carriers that entrench dependable output
quality (Senanayake 2018).
The formulations of rosemary extract are mar-
keted in the European Union and the United
States as the solely trading accessible formula-
tions as an antioxidant. As the formulation, it is
commercialized in fat soluble form, as a dry pow-
der, and dispersed or dissolved in water forms
(Klannik etal. 2009).
In a research article, comparing the conven-
tional Rosemary extract (without carrier systems)
and the extract including the liposomal distribu-
tion system, its effect on skin permeability rate
invitro was investigated according to determined
parameters. As a result, it has been clearly exem-
plied that the rosemary extract mixture in the
liposomal carrier system at a volume ratio of 1:1
has an invitro release rate of approximately 30%,
respectively, compared to 100% in 40min com-
pared to the conventional formula (Aslan and
Kurt 2021).
An experiment has been conducted with com-
mercial rosemary essential oils to provide antimi-
crobial effect against vaginal infection in pregnant
women. According to the results, commercial
rosemary essential oils have been established to
be a promising treatment method for vaginal
infections. However, it has been concluded that
more toxicity and safety studies should be con-
ducted on the subject (Bogavac etal. 2017).
Rosemary’s extracts and essential oil have
been used in hundreds of cosmetic products.
Rosemary essential oils are used for massage and
aromatherapy. Rosemary has also been found to
be included in formulations such as eye cream,
shampoos, deodorant, aftershave lotion, rose-
mary water, anti-wrinkle cream, gels, and mois-
turizing face cream (González-Minero etal.
2020). It has been determined that rosemary
extracts have a stronger germicide impact on bac-
teria and molds. Due to its strong antimicrobial
activity, various extracts prepared from rosemary
leaves were allowed to be included in many cos-
metic preparations (Damianova etal. 2010).
Various surveys have proven that extracts of
rosemary have positive affect for hair growth,
especially leaf extracts. As a result, products
containing rosemary extracts for hair growth
have also found their way into the market as
commercially accessible forms. C57BL/6-coded
mice with testosterone-mediated alopecia were
cured locally with hydroalcoholic rosemary
extracts at a dose of 2mg per daytime. After the
16th day of cure, a signicant increase in hair
growth was observed in the experimental group
compared to that in the control group (de
Macedo etal. 2020).
34 Rosmarinus ocinalis L.
536
It has been reported that the pharmacological
potential of rosmarinic acid is important and
shows a low bioavailability. Some solid dosage
forms such as cyclodextrin complexes and lipid
nanotechnology-based delivery systems have
been proposed as solutions to increase the
bioavailability of rosmarinic acid and to facilitate
its application (Veras etal. 2019).
It has been reported that rosmarinic acid
extracts can be utilized intranasally, topically,
pulmonary, and by intravenous infusion routes.
Besides, oral administration has been evaluated
as the main route of taking rosmarinic acid into
the human body. Regarding the pathway of
metabolism, it is predicted to be metabolized by
the intestinal microora by splitting into phenolic
units in a simpler and easily absorbable way.
It has been determined that the rosmarinic
acid molecule also undergoes conjugation reac-
tions. The main route of elimination has been
recorded as renal excretion (Hitl etal. 2021).
Various studies have proven that essential oils
and their mono- and sesquiterpenoid components
probably interact with more than one type of
receptor, causing fast-acting neurotoxic effects in
insects. EcoTrolTM and TetraCURBTM are insecti-
cidal preparations produced by the United States,
consisting of active ingredients including rose-
mary essential oil (Isman 2019).
34.9 Gap Between
Ethnomedicinal
andScientic/Clinical
Evidences
It has been recorded that rosemary is a widely
used medicinal and aromatic herb against
migraine by various countries, especially in Iran.
Rosemary is widely used for analgesic, anti-
inammatory, and anti-neurodegenerative pur-
poses. This efciency of rosemary has been
particularly harnessed for rosmarinic acid, one of
the therapeutically rich components in it. To
investigate whether the use of rosemary in folk
medicine coincides with reality, a model of neu-
ropathic pain due to sciatic nerve chronic con-
striction injury (CCI) was created on rats, and the
potency anti-inammatory bears on rosemary
and rosmarinic acid were investigated. According
to the data, the conventional use of rosemary as
an efcient treat for pain allayment and inam-
matory ailments has been supported. The fact
that tea prepared from rosemary leaves, rosemary
extracts, and rosemary have an important poten-
tial use in the cure of different neurological disar-
rays such as neuropathic pain and inammation
should not be overlooked and this potential
should be evaluated (Jivad etal. 2016;
Ghasemzadeh Rahbardar etal. 2017).
Considering the current data, it has been deter-
mined that rosemary essential oil has important
effects to be considered in the remedy of acute
inamed circumstance, given its efcaciousness
and high safeness of use. In addition, more
chronic inammation models should be exam-
ined to explain and clarify the subject more
broadly. Clinical studies on the subject are insuf-
cient and their number should be increased.
When the studies are examined in general, the
accuracy of the ethno-pharmacological use of
rosemary essential oil against inammation-
related diseases is supported (Borges etal. 2019).
Numerous explorations have been handled
concerning the antimicrobial effect of rosemary.
It has been conrmed that Rosemary essential
oils with the best antimicrobial impact contain
the highest amounts of verbenone, camphor, and
borneol compounds (Santoyo etal. 2005).
Rosemary has been used in the folk medicine in
many regions of the world against inuenza,
colds, and inuenza from past to present and is
considered as an antiseptic herb. In this context,
the antimicrobial activity proven in experimental
studies with the ethnobotanical use of rosemary
is because its antimicrobial activity coincides.
Rosemary essential oil has the ability to pro-
long the shelf life of food stuffs and resume their
property during warehousing. Due to this feature,
it is seen in the markets that it is already used as
a biopreservative in the food sector (Raškovi
etal. 2014).
Another traditional utilization of rosemary is
its consumption due to its antidiabetic and anti-
hyperglycemic effects, as can be seen in the eth-
nobotanical studies section. In a study
B. Mersin and G. S. can
537
investigating the antidiabetic effect of rosemary,
it was observed that it improved hyperglycism in
rats as well as dyslipidemia in rats which devel-
oped alloxan-induced diabetes. According to the
result of the same study, it was recorded that
rosemary had a hepatoprotective effect (Kensera
etal 2010). In a inrmary survey handled to
probe the effect of rosemary on diabetic patients
and healthy people, signicant effects were
observed on the improvement of HbA1c and
Vitamin B12 levels in both diabetic patients and
healthy individuals (Shawabkeh and Jamal 2017).
These studies showed that the antihyperglycemic
and antidiabetic activities of rosemary are com-
patible with traditional use.
34.10 Challenges andFuture
Recommendations
asPotential Drug Candidate
The potential of carnosol and carnosic acid,
which are polyphenolic diterpene molecules of
rosemary, as protective agents against prostate
cancer has been evaluated in accordance with
epidemiologic investigations. Studies have been
executed to elucidate the mechanism of carnosic
acid and carnosol’s anticancer activity. Based on
the pathways elucidated, the potential use of
rosemary for a chemopreventive agent against
prostate malignant neoplastic disease is consid-
ered (Petiwala etal. 2013).
It has been proven in experimental applica-
tions that rosemary extracts show anticancer
effects against many types of cancer. Although
this activity was associated with the major com-
pounds in its content, it was reported that the
application of rosemary extract by itself created
synergism. Rosemary extracts were evaluated by
FDA and EFSA as being potent for human well-
ness and the application of the extract as a whole
was supported. Clinical studies should be focused
without ignoring the potency of using rosemary
extract as a tumor type-specic agent (González-
Vallinas etal. 2015).
In terms of a disease that may be arising from
assorted factors such as Alzheimer’s disease,
especially diterpenic molecules of rosemary have
been proposed as a viable solution against this
disease (Habtemariam 2016).
While medicinal and aromatic plants are
transformed into herbal medicine, various prob-
lems are encountered, which can be claimed as a
limiting factor in obtaining herbal medicine from
the rosemary plant.
There are many factors affecting the produc-
tion phase of herbal medicine such as quality,
processing and collection, standardization, pro-
cesses related to quality control, pharmacovigi-
lance, and regulations. The inadequate clinical
studies and the unreasonable use of herbal prod-
ucts with the perception of “harmless” are also
considered as one of the factors that restrict stud-
ies on drugs (Sen and Chakraborty 2017).
In summary, the promising effect of the scien-
tically proven bioactivity of rosemary has
shown to be a potential herbal medicine in the
future. However, further clinical studies are
needed.
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