![Cardio-protective effects induced by Melissa officinalis L [78].](https://www.researchgate.net/publication/366144750/figure/fig5/AS:11431281106123040@1670594477347/Cardio-protective-effects-induced-by-Melissa-officinalis-L-78_Q320.jpg)
Access to this full-text is provided by IMR Press.
Content available from Frontiers in Bioscience-Scholar
This content is subject to copyright.
Front. Biosci. (Schol Ed) 2022; 14(4): 32
https://doi.org/10.31083/j.fbs1402016corr
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Correction
Correction: Wissam Zam et al. An Updated Review on The Properties
of Melissa officinalis L.: Not Exclusively Anti-anxiety. Frontiers in
Bioscience-Scholar. 2022; 14: 16
Wissam Zam1, Cristina Quispe2, Javad Sharifi-Rad3,*, María Dolores López4,
Mauricio Schoebitz5, Miquel Martorell6, Farukh Sharopov7,*, Patrick Valere Tsouh Fokou8,
Abhay Prakash Mishra9, Deepak Chandran10, Manoj Kumar11 , Jen-Tsung Chen12,*,
Raffaele Pezzani13,14,*
1Department of Analytical and Food Chemistry, Faculty of Pharmacy, Al-Andalus University for Medical Sciences, 35XQ+C2F Tartous, Syria
2Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, 1110939 Iquique, Chile
3Facultad de Medicina, Universidad del Azuay, 14-008 Cuenca, Ecuador
4Department of Plant Production, Faculty of Agronomy, Universidad de Concepción, Avenida Vicente Mendez, 595, 3812120 Chillán, Chile
5Departamento de Suelos y Recursos Naturales, Facultad de Agronomía, Universidad de Concepción, 4070386 Concepción, Chile
6Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, 4070386 Concepción, Chile
7Research Institution “Chinese-Tajik Innovation Center for Natural Products” of the National Academy of Sciences of Tajikistan, Ayni str. 299/2,
734063 Dushanbe, Tajikistan
8Faculty of Science, University of Bamenda, 39 Bamenda-Bambili, Cameroon
9Department of Pharmacology, University of Free State, 9300 Bloemfontein, South Africa
10Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University,
Coimbatore, 642109 Tamil Nadu, India
11Chemical and Biochemical Processing Division, ICAR – Central Institute for Research on Cotton Technology, 400019 Mumbai, India
12Department of Life Sciences, National University of Kaohsiung, 811 Kaohsiung, Taiwan
13Phytotherapy Lab (PhT-Lab), Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via Ospedale 105, 35128 Padova, Italy
14AIROB, Associazione Italiana per la Ricerca Oncologica di Base, 35046 Padova, Italy
*Correspondence: javad.sharifirad@gmail.com (Javad Sharifi-Rad); shfarukh@mail.ru (Farukh Sharopov); jentsung@nuk.edu.tw (Jen-Tsung Chen);
raffaele.pezzani@unipd.it (Raffaele Pezzani)
Academic Editor: Gustavo Caetano-Anollés
Submitted: 4 August 2022 Accepted: 24 November 2022 Published: 7 December 2022
The authors would like to make a correction to the ar-
ticle [1]. The authors clarify that the reference [2] in the
Fig. 5 caption is not cited in this review article in error. We
apologise to readers for any inconvenience caused and state
that the scientific conclusions are unaffected. This correc-
tion was approved by the Academic Editor. The references
in the article have also been updated.
References
[1] Zam W, Quispe C, Sharifi-Rad J, López MD, Schoebitz M,
Martorell M, et al. An Updated Review on the Properties of
Melissa officinalis L.: Not Exclusively Anti-anxiety. Frontiers
in Bioscience-Scholar. 2022; 14: 16.
[2] Draginic N, Jakovljevic V, Andjic M, Jeremic J, Srejovic I, et al.
Melissa officinalis L. as a Nutritional Strategy for Cardioprotec-
tion. Frontiers in Physiology. 2021; 12: 661778.
Front. Biosci. (Schol Ed) 2022; 14(2): 16
https://doi.org/10.31083/j.fbs1402016
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Publisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Review
An Updated Review on The Properties of Melissa officinalis L.: Not
Exclusively Anti-anxiety
Wissam Zam1, Cristina Quispe2, Javad Sharifi-Rad3,*, María Dolores López4,
Mauricio Schoebitz5, Miquel Martorell6, Farukh Sharopov7,*, Patrick Valere Tsouh Fokou8,
Abhay Prakash Mishra9, Deepak Chandran10, Manoj Kumar11 , Jen-Tsung Chen12,*,
Raffaele Pezzani13,14,*
1Department of Analytical and Food Chemistry, Faculty of Pharmacy, Al-Andalus University for Medical Sciences, 35XQ+C2F Tartous, Syria
2Facultad de Ciencias de la Salud, Universidad Arturo Prat, Avda. Arturo Prat 2120, 1110939 Iquique, Chile
3Facultad de Medicina, Universidad del Azuay, 14-008 Cuenca, Ecuador
4Department of Plant Production, Faculty of Agronomy, Universidad de Concepción, Avenida Vicente Mendez, 595, 3812120 Chillán, Chile
5Departamento de Suelos y Recursos Naturales, Facultad de Agronomía, Universidad de Concepción, 4070386 Concepción, Chile
6Department of Nutrition and Dietetics, Faculty of Pharmacy, and Centre for Healthy Living, University of Concepción, 4070386 Concepción, Chile
7Research Institution “Chinese-Tajik Innovation Center for Natural Products” of the National Academy of Sciences of Tajikistan, Ayni str. 299/2,
734063 Dushanbe, Tajikistan
8Faculty of Science, University of Bamenda, 39 Bamenda-Bambili, Cameroon
9Department of Pharmacology, University of Free State, 9300 Bloemfontein, South Africa
10Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University,
Coimbatore, 642109 Tamil Nadu, India
11Chemical and Biochemical Processing Division, ICAR – Central Institute for Research on Cotton Technology, 400019 Mumbai, India
12Department of Life Sciences, National University of Kaohsiung, 811 Kaohsiung, Taiwan
13Phytotherapy Lab (PhT-Lab), Endocrinology Unit, Department of Medicine (DIMED), University of Padova, via Ospedale 105, 35128 Padova, Italy
14AIROB, Associazione Italiana per la Ricerca Oncologica di Base, 35046 Padova, Italy
*Correspondence: javad.sharifirad@gmail.com (Javad Sharifi-Rad); jentsung@nuk.edu.tw (Jen-Tsung Chen); raffaele.pezzani@unipd.it (Raffaele
Pezzani); shfarukh@mail.ru (Farukh Sharopov)
Academic Editor: Gustavo Caetano-Anollés
Submitted: 2 February 2022 Revised: 30 March 2022 Accepted: 11 April 2022 Published: 7 June 2022
Abstract
Melissa officinalis L. is a plant of the Lamiaceae family known in numerous countries for its medicinal activities. This plant has been used
since ancient times to treat different disorders, including gastrointestinal, cardiovascular, neurological, psychological conditions. M. offic-
inalis contains several phytochemicals such as phenolic acids, flavonoids, terpenoids, and many others at the basis of its pharmacological
activities. Indeed, the plant can have antioxidant, anti-inflammatory, antispasmodic, antimicrobial, neuroprotective, nephroprotective,
antinociceptive effects. Given its consolidated use, M. officinalis has also been experimented with clinical settings, demonstrating inter-
esting properties against different human diseases, such as anxiety, sleeping difficulties, palpitation, hypertension, depression, dementia,
infantile colic, bruxism, metabolic problems, Alzheimer’s disease, and sexual disorders. As for any natural compound, drug, or plant
extract, also M. officinalis can have adverse effects, even though the reported events are very rare and the plant can be considered sub-
stantially safe. This review has been prepared with a specific research strategy, interrogating different databases with the keyword M.
officinalis. Moreover, this work analyzes the properties of this plant updating currently available literature, with a special emphasis on
human studies.
Keywords: Melissa officinalis L.; lemon balm; phytotherapy; phytochemicals; health properties; clinical trials
1. Introduction
In today’s world, the prevalence of anxiety disorders
has skyrocketed. Anxiolytics can be used to treat these
illnesses, although they can have some negative side ef-
fects despite their effectiveness. Because of the lack of
understanding about drug interactions and possible harm-
ful effects, traditional medicine poses a serious risk to pub-
lic health. Plants’ clinical efficacy must be evaluated in
research investigations. Melissa officinalis L., popularly
known as lemon balm, is utilized in traditional medicine
for its effects on CNS processes such as sedation and mem-
ory improvement and additionally possess various health
benefits if consumed in optimum concentration but unfor-
tunately, no comprehensive compilation has been done so
far [1]. The majority of beneficial effects of the Therefore,
it is important to present complete information of Melissa
officinalis L. are due to volatile oils, triterpenes, and phe-
nolic compounds.
An increasing body of evidence suggests that this plant
may have therapeutic potential in the management of dis-
orders such as diabetes and Alzheimer’s disease. It also
contains antioxidant, antibacterial, and anti-inflammatory
properties [2,3]. The low toxicity and lack of side effects
of this plant have been proven in several investigations uti-
lizing different experimental models [4]. But if the plant ex-
tracts are not used optimally, they may exert toxicity both in
cell and animal models. In the clinical trials, the effect of M.
officinalis extracts has been proved evaluated on a variety of
diseases, mainly related to neurological disorders, i.e., anx-
iety and sleeping difficulties, but also metabolic problems
and infantile colic and shown to have positive effects. The
present review was aimed to compile information on botany
and phytochemistry, traditional medicinal, and ethnophar-
macological uses of M. officinalis, and also various clinical
aspects and biomedical properties of this well-known plant
are discussed.
This review has been prepared through an interro-
gation of different databases, such as Chrocane library,
Embase-Elsevier, Google Scholar, Ovid, PubMed, Science
Direct, SciFinder, Scopus, Web of Science. Both articles,
papers, and books have been considered, while the search
strategy was based on the keyword Melissa officinalis, in
addition to its English translation or common names as
“common balm”, “honey balm”, “lemon balm”, “melissa
balm”, “sweet balm”.
2. Botany of Melissa officinalis
Melissa officinalis can be taxonomically classified as
follows: Kingdom: Plantae; Division: Tracheophyta; Sub-
division: Speramtophyta; Class: Magnoliopsida; Super-
order: Asteranae; Order: Lamiales; Family: Lamiaceae;
Genus: Melissa; Species: Melissa officinalis L. [5].
From a botanical point of view, Melissa officinalis L.
(Greek word “Melissa”—honeybee) is the only acceptable
name for the plant and possesses different accepted vari-
eties, i.e., M. officinalis var. altissima (Sm.) K.Koch, M. of-
ficinalis var. cordifolia (Pers.) K.Koch, M. officinalis var.
foliosa Briq., M. officinalis var. graveolens (Host) Nyman,
M. officinalis var. hirsuta K. Koch, M. officinalis var. ro-
mana (Mill.) Woodv. and M. officinalis var. villosa Benth
[6,7]. M. officinalis L. is also known as lemon balm, bee
balm, sweet balm, common balm, honey balm [5,6].
There is also an infraspecific taxon of the species M.
officinalis which are naturally expended in our wild flora:
M. officinalis ssp. altissima (Sm.) Arcang., M. officinalis
ssp. officinalis,M. officinalis subsp. inodora Bornm [8,9].
M. officinalis shows economic significance because there is
an increase in growth terrain and novel varieties exploration
[9].
A haploid base number of M. officinalis of x = 16 chro-
mosomes is likely, diploid genotypes with 2n = 2×= 32
chromosomes; tetraploid 2n = 4×= 64 chromosomes, and
triploid 2n = 3×= 48 chromosomes [9,10]. M. officinalis
is a perennial shrubby plant, with a height of 30–150 cm
with fluffy hairs surrounding all parts [8,11]. The stem is
erect, branched, usually glabrous, and quadrangular. The
leaves are in decussate pairs, petiolate, soft, ovate, 2–8 cm
long, 3 cm broad, the upper cuneate, the lower cordate at
base, crenate-toothed, subglabrous, sometimes with glan-
dular hairs or punctuate glands beneath. The leaf surface
is gross and deeply streaked, and the leaf edge is scalloped
or toothed [6,8]. Flowers are commonly white or pale pink
with small clusters of 4 to 12 blossoms in the summer. They
have a peculiar lemon-like flavor and fragrance [6,8]. The
subspecies of M. officinalis can be differentiated through
the shape of calyx and the density of different types of hairs.
The middle tooth of the three upper lip teeth of the fruiting
calyx is approximately three-sided for ssp. officinalis while
it is decent, shorten, or emarginated for ssp. altissima [9].
M. officinalis is a cross-pollinating species and has
complete flowers with petals. Two stamens and four-lobed
ovaries can give rise to 1–4 nutlets. The seeds are very
small about 1–1.5 mm long, with ovate dark brown or black
color. The weight of seeds is 0.5 to 0.7 g and they can be
considered fragile as a long storage period (5 years) can in-
duce a decrease in germination vigor [6,8]. The plant pos-
sesses a highly branched root system, which guarantees the
plant excellent adaptive capabilities; the upper parts of the
plant perish at the beginning of the winter, while in spring
new saplings re-emerge from the roots [7]. M. officinalis is
cultivated all over the world, with the Mediterranean basin
or Western Asia are considered as the area of origin [9].
There is a different opinion that suggests this plant is orig-
inated from a more wide area comprising South and Cen-
tral Europe, Northern Africa, the Caucasus, and Northern
Iran [11,12]. M. officinalis occurs naturally in sandy and
loamy fertile soils but sometimes can grow on moist waste-
land from sea level to the mountains [5,8,12]. The plant
prefers well-drained soils with a pH range from 5 to 7, it
can grow in full sun, but also partial shade. When the plant
grows in semi-shade, it produces bigger leaves compared
to the sunny situation. This means that M. officinalis can
promptly develop in a temperate environment (15 to 35 °C)
necessitating at least 500 to 600 mm precipitation during
all growing seasons. It suffers from drought, particularly in
the establishment year, however after the root system is de-
veloped, requires a reduced amount of water [8]. The plant
can be considered for easy cultivation and this reason can
be suggested for beginners. In addition, given its adaptive
capacities and strength, some gardeners consider it a weed
[5].
3. Biochemical Compounds of Melissa
officinalis
M. officinalis is widely used in food, medicine, and
cosmetics. Its application is particularly related to the pres-
ence of valuable phytochemicals such as pleasant volatile
compounds (e.g., Neral, geranial, citronellal), phenolic
acids (e.g., rosmarinic acid), flavonoids (e.g., luteolin) and
many others (Fig. 1). In 1998, Carnat and co-authors have
2
Fig. 1. Chemical structure of the main phytochemicals of M. officinalis L.
reported that M. officinalis leaves contained 0.32% essential
oil, 11.8% polyphenol compounds (hydroxycinnamic com-
pounds 11.3%, RA 4.1%, and total flavonoid compounds
0.5%) [13]. Later, Shakeri and co-workers described that
M. officinalis contained volatile compounds, triterpenoids,
phenolic acids, and flavonoids [6].
3.1 Volatile Oils
The volatile compounds of M. officinalis have been
intensively studied in many countries. The chemical com-
position of volatile oils of M. officinalis from different ori-
gins is represented in Table 1(Ref. [2,14–25]). Accord-
ing to the literature reports, the major components of the
M. officinalis essential oils are mono-, sesquiterpenes, and
aliphatic aldehydes, alcohols such as geranial, neral, and
citronellal, geranyl acetate, (E)-caryophyllene, caryophyl-
lene oxide, geraniol, pinene, sabinene, thymol, carvacrol
and muurolene, decadienal and trans-carveol [2,6,13–25].
The numerical cluster analysis has been carried out based
on 15 major essential oil components from thirty M. offic-
inalis samples published in the literature. Geranial/neral
(I); geraniol/caryophyllene oxide (II); citronellal (III); α-
pinene/caryophyllene oxide (IV) chemotypes have been re-
ported for the essential oil compositions of M. officinalis
[14].
3.2 Triterpenes
Several new triterpenes were discovered from M. of-
ficinalis. Mencherini and others have been isolated six new
ursane-type triterpenes from the leaves and leaves of M. of-
ficinalis [26]. Recently, three new ursene triterpene gly-
cosides (melissiosides A–C) with promising antimicrobial
actions have been isolated from the aerial parts of M. of-
ficinalis [27]. In 2015, Ji and co-authors isolated serrata-
genic acid, 2α,3β-dihydroxy-urs-12-en-28-oic acid, urso-
lic acid, oleanolic acid, 2α,3β,23,29-tetrahydroxyolean-12-
en-28-oic acid from M. officinalis leaves [28]. Ursolic and
oleanolic acids were also detected in the methanol extract
from dried aerial parts of lemon balm [29].
3.3 Phenolic Compounds
Hanganu and co-authors (2008) have reported that M.
officinalis leaves contain 0.64% flavonoids expressed in
rutoside and 8.962% phenyl-propane derivatives expressed
in caffeic acid [30]. Six polyphenolic compounds, i.e.,
caftaric acid, caffeic acid, p-cumaric acid, ferulic acid, lu-
teolin, and apigenin were identified from ethyl-ether, ethyl
acetate, and 1-buthanol extracts of M. officinalis leaves
[30]. Toth and co-authors have reported that an important
phenolic active compound of M. officinalis was RA [31].
In 2002, Patora and Klimek isolated for the first time a
new glycoside compound, 7-O-beta-D-glucopyranoside-
3’-O-beta-D-glucuronopyranoside from the leaves of M.
officinalis [32]. In 2015, Ji and co-authors isolated thirteen
compounds, including protocatechuyl aldehyde, vanillin,
luteolin, rosmarinic acid, luteolin-7-O-β-D-glucoside from
the M. officinalis leaves [28]. Luteolin, luteolin 7-O-beta-
D-glucopyranoside, apigenin 7-O-beta-D-glucopyranoside,
luteolin 7-O-beta-D-glucuronopyranoside, luteolin 3’-O-
beta-D-glucuronopyranoside and luteolin 7-O-beta-D-
glucopyranoside-3’-O-beta-D-glucuronopyranoside have
been isolated from the leaves of M. officinalis [32].
3.4 Others Compounds
β-Sitosterol and palmitic acid were isolated from the
leaves of M. officinalis [28]. Aqueous M. officinalis prepa-
rations were rich in total phenols (2.9–7.8 mg/mL) and the
examined macroelements, 4.4–11.6, 12.2–1152, and 200–
3
Table 1. Volatile compounds of M. officinalis.
Origin Plant’s part Composition References
Algeria leaves geranial (44.20%), neral (30.20%) and citronellal (6.30%) [15]
Bulgaria aerial parts citronellal (18.5%), geraniol (15.2%), citronellol (9.5%), geranyl acetate (7.2%) and geranial (5.9%) [16]
Egypt aerial parts geranial and neral (54.82%) [17]
Greece leaves β‐pinene (6.4–18.2%), sabinene (6.9–17.4%), (E)‐caryophyllene (7.2–15.3%), caryophyllene oxide
(12.6–24.4%)
[18]
Iran flowers trans-carveol (28.89%), citronellol (25.24%), δ-3-carene (5.26%), citronellal (4.9%), geraniol (2.2%),
1-octene-3-ol (2.03%) and spathulenol (2.06%)
[19]
Iran aerial parts geranyl acetate (27.9%), citral (24.2%), citronellal (8.4%), and citronellol (7.6%) [2]
Iran leaves before flowering stage: decadienal (29.38%), geraniol (25.3%), caryophyllene oxide (8.75%), geranyl acetate
(5.41%); in the flowering stage: decadienal (28.04%), geraniol (24.97%), caryophyllene oxide (7.55%),
caryophyllene E (4.65%); and after flowering stage: carvacrol (37.62%), methyl citronellate (32.34%), geranyl
acetate (5.82%), caryophyllene (5.50%)
[20]
Jordan leaves caryophyllene oxide (43.6%), muurolene (28.8%) [21]
Poland aerial parts camphene, citronellal, neral, methyl citronellate, geranial, α-copaene, β-caryophyllene, humulene,
caryophyllene oxide
[22]
Romania aerial parts citral (neral and geranial) (16.10%), citronellal (3.76%) and trans-caryophyllene (3.57%) [23]
Russia aerial parts citronellоl (36.71%), geraniol (27.20%) [24]
Tajikistan aerial parts geranial (43.2%), neral (31.5%), (E)-anethole (12.3%), (E)-caryophyllene (4.0%) and citronellal (2.8%) [14]
Turkey aerial parts citronellal (36.62–43.78%), citral (10.10–17.43%), thymol (0.40–11.94%), and β-caryophyllene (5.91–7.27%) [25]
Fig. 2. Various health properties of the Melissa officinalis.
740 µg/mL for Na, K, and Ca, respectively [33]. In sum-
mary, M. officinalis represents a promising source of phy-
tochemicals that can contribute to the beneficial properties
of the plant.
4. Health Properties of Melissa officinalis
The Melissa officinalis possess diverse biological and
health properties such as anxiolytic, antioxidant, antide-
pressant, anticancer, antinociceptive, anti-epileptic, anti-
angiogenesis, antimicrobial, anti-inflammatory, hypolipi-
demic, and hypoglycemic. Various health properties of the
Melissa officinalis are depicted in Fig. 2.
4.1 Antiviral Activity
COVID-19 has been defined as a pandemic on 11
March 2020 and entered the fifth position of the most
important and documented pandemics since the 1918 in-
fluenza outbreak [34]. Worldwide researchers and clini-
4
Fig. 3. Anti-viral activity of Melissa officinalis L.
cians hardly worked to find effective therapies and develop
vaccines to reduce and prevent infectivity. Plants’ bioactive
compounds represent a major field of research for the devel-
opment of safe and effective treatments potentially useful
to fight against COVID-19. Several studies showed that M.
officinalis possessed antiviral activity against a wide num-
ber of viruses (Fig. 3) [35]. Today’s research aims to rec-
ognize its antiviral bioactive compounds against the main
protease and spike protein of COVID-19. Docking exper-
iments conducted by Prasanth and his colleagues showed
that three phytoconstituents from M. officinalis, namely,
luteolin-7-glucoside-3′-glucuronide, melitric acid-A, and
quadranoside-III, possessed a greater binding affinity and
stability towards the primary protease and spike protein of
COVID-19 [36]. Similar results were previously published
by Elekofehinti et al. [37] who found that melitric acid A
and salvanolic acid A had higher affinity to the main pro-
tease of coronavirus COVID-19 than lopinavir and iver-
mectin using both AutodockVina and XP docking algo-
rithms.
Influenza viruses that belong to a virus family known
as Orthomyxoviridae are also a target of the active ingre-
dients of M. officinalis. The H9N2 subtype virus, a mem-
ber of the influenza family that has been classified as a low
pathogenic virus, had unfortunately developed viral resis-
tance to all the conventional drugs approved by the Food
and Drug Administration (FDA) [38,39]. Recent findings
showed that M. officinalis essential oil (monoterpenaldehy-
des citral a, citral b) could inhibit influenza virus replication
by different mechanisms of action such as masking the host
cellular surface protein, intracellular steps, and direct viru-
cidal effect by structural damage [40]. It was also demon-
strated that the combination of M. officinalis essential oil
with oseltamivir augmented the inhibitory effect of the an-
tiviral drug particularly at very low concentration (0.005
mg/mL) [40]. Similar results on the effect of the hydroal-
coholic extract of M. officinalis on the growth of influenza
virus subtype H1N1 in the MDCK cell culture were demon-
strated by Jalali et al. [41].
Antiviral activity of extracts from M. officinalis has
also been described for herpes simplex virus type 1 (HSV-
1) and type 2 (HSV-2) [42,43]. Astani et al. [44] evaluated
the antiviral activity of M. officinalis extract by choosing
active phenolic compounds against HSV-1 and investigat-
ing their mechanism of action. They found that both the
aqueous M. officinalis extract and the phenolic molecules
significantly decreased the infectivity of HSV-1 at the early
stage of virus replication. This action was mainly due to
the inhibition of herpes viral attachment caused by the pre-
dominant phenolic compound in M. officinalis extract RA
at a concentration of 9.75 µg/mL [44]. The plant extract
revealed superior virucidal activity if compared to single
compounds, probably imputable to multiple interactions of
phytochemicals [45]. The hydroalcoholic extract of M. of-
5
ficinalis rich with RA (4.1% w/w) decreased the cytopathic
effect of HSV-2 on Vero cells (ATCC CCL-81) at concen-
trations starting from 25 µg/mL with a maximum inhibit-
ing effect (60%) obtained at a concentration of 0.5 mg/mL
[21]. Allahverdiyev et al. [46] proved that the volatile oils
obtained from M. officinalis at concentrations above 100
µg/mL reduced the proliferation of HSV-2. They suggested
that this activity could be due to the citral and citronellal
that characterizes the plant’s volatile oil by inhibiting pro-
tein synthesis in virus cells [46].
Worldwide HIV in 2019 affected approximately 38
million people, mainly adults (36.2 million) and 1.8 mil-
lion children (<15 years old) [47]. Advances in HIV phar-
macotherapy produced the current antiretroviral therapy
(HAART), which significantly contributed to prolonging
survival and alleviating patients’ suffering [47]. Nonethe-
less, side effects and drug resistance are two key factors to
consider for the development of new antiviral to be poten-
tially added to the current regimen. Geuenich et al. [48]
proved that aqueous extracts from M. officinalis exhibited
high and concentration-dependent activity against HIV-1
virions due to the augmentation of the virion’s density be-
fore its surface engagement.
Enterovirus 71 (EV71) is one of the major pathogens
causing Hand, foot, and mouth disease (HFMD) in infants
and children aged under 5 [49]. A small proportion of
EV71-infected patients develop severe complications that
can lead to death which urge the progress toward novel
drugs affecting patients’ medical history [50]. It has been
reported that M. officinalis extract (due to its high RA con-
tent) could block plaque formation and viral protein synthe-
sis in EV71-infected cells, suggesting a cytopathic effect of
this methanolic extract [51].
4.2 Antibacterial Activity
Generally, aromatic plants are rich in essential oils
with significant antimicrobial properties. GC-MS analy-
sis revealed that the chemical composition of the essential
oils extracted from M. officinalis was citronellal (37.33%),
thymol (11.96%), citral (10.10%), and β-caryophyllene
(7.27%). According to the disk diffusion agar assay and
micro-dilution method, strong antimicrobial effects of the
oils against Salmonella typhimorium, Escherichia coli,
Listeria monocytogenes, and Staphylococcus aureus were
found [51]. Results also showed that S. aureus was the most
sensitive bacteria with the lowest MIC value (0.12 mg/mL)
[51].
E. coli ATCC 25922 and the multiresistant strain of
Shigella sonei IPH-MR exhibited high sensitivity to the es-
sential oil of M. officinalis [52]. The petroleum ether ex-
tract of M. officinalis demonstrated varying inhibitory po-
tencies against Gram-positive bacteria in particular Staphy-
lococcus aureus and Pseudomonas aeruginosa with MICs
ranging between 1.65 and 191.40 µg/mL, while no antibac-
terial effect was reported against Escherichia coli and Kleb-
siella pneumonia [53]. Similar results were recorded for the
hydro-alcoholic extract of M. officinalis which showed in-
teresting antibacterial activity against S. aureus and Staphy-
lococcus epidermidis, while gram-negative bacteria such as
E. coli were less involved [54].
Notably, essential oils revealed significant antifungal
activity, even if not in all cases. Prominent was the low
MIC and MFC of the essential oil of M. officinalis against
Trichophyton tonsurans if compared to the reference drug
bifonazole (antimycotic) [52]. Also, the crude petroleum
ether extract and its derived fractions demonstrated remark-
able antifungal activities against Candida albicans,Can-
dida krusei, and Candida glabrata with MICs of 0.30–
345.10 µg/mL [53].
4.3 Anti-inflammatory Effects
The anti-inflammatory activities of M. officinalis
leaves were widely examined. Results showed that its es-
sential oil possessed anti-inflammatory activities, support-
ing its traditional use in different diseases related to inflam-
mation and pain [55]. Recent works proved that the extract
of M. officinalis exerted anti-inflammatory and antinoci-
ceptive effects by interacting with muscarinic and nicotinic
receptors and the L-arginine-nitric oxide pathway which
were ascribable to RA, terpenoids, and flavonoids [56]. RA
and flavonoids are known to block different enzymes in-
volved in the inflammatory process, such as cyclooxyge-
nase, lipooxygenase, and monooxygenase [57].
Due to these anti-inflammatory properties, the ex-
tract of M. officinalis proved to have good effects in re-
lieving symptoms of atopic dermatitis [57]. The anti-
inflammatory property of M. officinalis is depicted in Fig. 4.
Ramanauskien et al. [58] investigated the effect of M. of-
ficinalis extract and its RA content on skin cells in normal
conditions and under oxidative stress. The work on human
keratinocyte cells showed that, in oxidative stress condi-
tions, RA decreased intracellular ROS by about 28%, while
enhancing cell viability by 10–24% (at a concentration of
0.25–0.5 mg/mL) and protecting cells from H2O2damage
[58].
Anti-inflammatory and antinociceptive effects of M.
officinalis were investigated with the histamine- and
carrageenan-induced paw edema tests in rats and mice. It
was found that pretreatment with the aqueous extract of
M. officinalis considerably lessened inflammagen-induced
paw edema in rats and diminished the nociceptive response
in mice [59].
Müzell and his colleagues assessed the anti-
inflammatory activity of an aqueous extract of M. officinalis
in hepatic and renal lesions caused by acetaminophen in
animal models [60]. Even if not hepatoprotective, the
extract demonstrated a nephroprotective activity against
acetaminophen lesions and exhibited an anti-inflammatory
effect on carrageenan-induced pleurisy [60].
6
Fig. 4. Anti-inflammatory property and neuroprotective effects of Melissa officinalis L.
M. officinalis was also found to be a good source of
chemopreventive agents. Its extracts demonstrated cytotox-
icity in breast cancer cells (MDAMB- 231) even at low con-
centrations (100 µg/mL), with also a pronounced impact on
cell migration and proliferation, while resulting in poorly
toxic for HaCat cells (500 and 1000 µg/mL). Differently,
stem extracts resulted highly cytotoxic (>100 µg/mL) [61].
4.4 Neuroprotective Properties
The number of people suffering from neurological dis-
orders such as neurodegenerative diseases as well as psy-
chiatric ones has lately increased worldwide [62]. M. offic-
inalis has traditionally been used for its impact on the ner-
vous system owing to elevated contents of phenolic com-
pounds and tocopherols [52]. Both crude ethanol extract of
M. officinalis and its fractions blocked acetylcholinesterase
in vitro and in vivo [63–65]. Similarly, methanol and aque-
ous extracts of M. officinalis possessed a significant protec-
tive effect on hydrogen peroxide-induced toxicity in PC12
cells mainly due to monoamine oxidase inhibition [66]. In
addition, the effects of an ethanol extract of M. officinalis
were tested in the hippocampus of pilocarpine treated rats,
as a potential model of epilepsy [67]. In particular, the
antioxidative and anti-inflammatory activity of the extract
orally administered at 250 mg/kg impacted positively on
Nrf2/HO-1 signaling pathway, Na+/K+-ATPase activity,
and GABA while glutamate and acetylcholine diminished
and reduced neuronal loss, adding a new potential benefi-
cial effect (anti-epileptic) of M. officinalis to its wide uses.
Hassanzadeh et al. [68] reported that aqueous ex-
tract of M. officinalis could support neuroprotective effects
against ecstasy-induced neurotoxicity in hippocampal pri-
mary culture. In addition, Yoo and his colleagues proved
that oral administration of M. officinalis could augment dif-
ferentiation and cell growth by lessening serum corticos-
terone while boosting GABA levels in the mouse dentate
gyrus [69].
The effect of M. officinalis on hypoxia-induced neu-
ronal death in a cortical neuronal culture system was tested
both in vitro and in transient hippocampal ischemia in vivo
models [70]. Cytotoxicity assays showed significant pro-
tection of M. officinalis against hypoxia in cultured neurons
by decreasing caspase3 activity and TUNEL-positive cells
significantly. M. officinalis oil was found to inhibit mal-
ondialdehyde levels and attenuate the decrease of the an-
tioxidant capacity in the hippocampus. Pro-inflammatory
cytokines TNF-α, IL-1β, and HIF-1αmRNA levels and
HIF-1αgene expression were highly decreased by the treat-
ment with the plant [70]. Rosmarinic acid, the predominant
compound of M. officinalis, demonstrated a cytotoxic ef-
fect on rat glioblastoma C6 cells by suppressing cell prolif-
eration and inducing cell death through necrosis [71]. Ex-
tracts prepared with 70% ethanol were the most active on
glioblastoma cells by initiating the generation of intracellu-
lar ROS and by inducing apoptosis and necrosis [71]. The
pathophysiology of spinal cord injury (SCI) has a typically
poor prognosis, that could lead to severe disabilities due
to motor, sensory, and autonomic nervous system damage
7
Fig. 5. Cardio-protective effects induced by Melissa officinalis L [78].
[72]. In a study conducted on adult male rats, Hosseini
et al. [73] showed that human umbilical cord blood stem
cells in combination with M. officinalis had neuroprotec-
tive effects in the SCI model. Researchers examined the be-
havioral mechanism of action of M. officinalis extracts on
scopolamine-induced memory impairment in rats [64,74].
Although some studies showed that M. officinalis extract
was completely inactive [74]; M. officinalis extract consid-
erably improved scopolamine-induced learning deficit by
enhancing the learning and memory of rats in other studies
[64,74]. Results proved that M. officinalis extract reduced
AChE mRNA level by 52% in the frontal cortex with a con-
comitant noteworthy blockade of BACE1 mRNA transcrip-
tion [75]. More recently, M. officinalis oil 1 µg/mL was
studied in isolated mouse ileum and atria tissues as a model
of anxiety-related disorders [76]. The work reported that
the oil could stop both spontaneous and induced ileum con-
tractions, however, it reduced only slightly AChE activity,
suggesting as other mechanisms (voltage-gated Ca2+ chan-
nels or muscarinic receptors) could be involved in M. offic-
inalis effects.
5. Human Clinical Trials
M. officinalis extracts have been proved in clinical tri-
als focused on a variety of diseases, mainly related to neuro-
logical disorders, i.e., anxiety and sleeping difficulties, but
also metabolic problems and infantile colic. M. officinalis
has been used as a cure for memory, cognition, anxiety, de-
pression, and heart palpitations for many centuries. Pre-
clinical animal studies on this plant confirmed its evocative
cardiovascular effects including anti arrhythmogenic, neg-
ative chronotropic and dromotropic, hypotensive, vasore-
laxant, and infarct size–reducing, by the use of different
extracts (aqueous, alcoholic, and hydroalcoholic), essential
oil, or isolated compounds. Nonetheless, only the effective-
ness of M. officinalis on heart palpitations has been verified
in humans. Antioxidant free radical–scavenging properties,
oxidative stress modulation, anti-inflammatory effects, ac-
tivation of M2 receptors and antagonism of β1 receptors
in the heart, blockage of voltage-dependent Ca2+ channels,
stimulation of endothelial nitric oxide synthesis, and pre-
vention of fibrotic disease are the biological and biomolec-
ular mechanisms suggested for the cardiovascular effects
of M. officinalis. Furthermore, the principal active element
of M. officinalis called rosmarinic acid has been demon-
strated to have significant cardiovascular effects [7]. More
recently, the same research group published a novel work
on myocarditis using a rat model, suggesting the protective
effects of this plant on cardiac function and related oxida-
tive stress [77]. The cardio-protective effects induced by
M. officinalis are depicted in Fig. 5(Ref. [78]).
For the neurological effects, some authors investi-
gated in the UK addressed the improvement of memory
and brain function in healthy people by applying a com-
bination of Salvia officinalis L., Rosmarinus officinalis L.,
and M. officinalis (SRM) [79]. The work showed that an
8
oral administration of M. officinalis combination at a dose
of 5 mL twice a day for 2 weeks was more effective com-
pared to placebo. Araj-Khodaei et al. [80] with a study on
neurological disorders used M. officinalis to treat 45 adult
outpatients who met the diagnosis (Diagnostic and Statis-
tical Manual of Mental Disorders) for major depression,
and were randomly assigned to 3 groups to daily receive
either 2 g of M. officinalis or 2 g of Lavandula angustifo-
lia Mill. or also fluoxetine (20 mg) and were assessed until
8 weeks [80]. Although the results were promising (use-
fulness of the extracts in moderate depression), the absence
of a placebo group was relevant for the conclusion of the
study, suggesting that more work is necessary to support
the use of these plants to treat depression.
Other authors, researched neurological disorders [81].
An M. officinalis extract enriched in RA was tested in a
randomized placebo-controlled double-blind 24-week trial
by evaluating the safety and tolerability (primary endpoint)
of RA (500 mg daily) and its clinical effects and disease-
related biomarker changes (secondary endpoints). The
group of patients (n = 23) was affected by mild dementia as
a result of Alzheimer’s disease (AD). The outcomes demon-
strated that no difference in vital signs or physical and neu-
rologic examination was perceived between the placebo and
M. officinalis groups. In addition, no severe adverse effects
were found while the cognitive function was not modified in
both groups. The authors concluded that M. officinalis ex-
tract (500 mg of RA taken daily) was safe and well-tolerated
for AD patients. Therefore, these data suggested that RA
can impact AD neuropsychiatric symptoms and can stop
the deterioration of AD patients’ conditions. Even though
these investigations have been recent, it should be noted
that several studies on the effect of M. officinalis to treat
neurological disorders were reported more than a decade
ago. Burns et al. [82] carried out a randomized, double-
blind, placebo-controlled trial to study the effect of M. of-
ficinalis oil against agitation in AD. However, aromather-
apy with M. officinalis oil was not effective. Also, years
before, Kennedy et al. [83] conducted a similar study. In
this case, the authors analyzed the effects of M. officinalis
on the modulation of mood and cognitive performance [83].
High doses of M. officinalis (1600 mg) could improve cog-
nitive performance. Other researchers conducted a similar
study focusing on the efficacy and safety of M. officinalis
extract in mild to moderate AD patients [84]. The use of 60
drops per day demonstrated an improvement in cognitive
function after 4 months of treatment.
Other researchers have reported that M. officinalis
could impact anxiety or sleep disorders. Indeed M. offic-
inalis leaves (Melissa capsule) were evaluated on anxiety
and sleep quality in patients undergoing coronary artery by-
pass surgery [85]. Eighty patients were administered three
times a day with an herbal drug (500 mg of M. officinalis
leaves) or a placebo (500 mg of wheat starch). Forty-nine
% of the patients reduced their anxiety levels at seven days
and 54% improved their sleep quality [85]. Other authors
showed that M. officinalis essential oil was effective in re-
ducing agitated behavior in the elderly affected or not by
dementia [86]. The study was conducted in a nursing home
recruiting 39 patients affected by dementia and 10 control
patients (no dementia). Treatment was given for two weeks
followed by a two-week washout period before starting sub-
sequent treatment. The results of the study suggested that
M. officinalis essential oil could effectively decrease anxi-
ety, however in patients without dementia.
Tavares-Silva and collaborators proved the usefulness
of M. officinalis and Phytolacca americana L. (syn. Phy-
tolacca decandra L.) alone or in combination, in children
affected by sleep bruxism [87]. Fifty-two children par-
ticipated in this trial, where M. officinalis reduced sleep
bruxism up to 30 days after treatment. Another research
group also discovered the combination of M. officinalis and
Nepeta menthoides Boiss. & Buhse in sleep disorder [88].
The trial evaluated 80 patients treated with the 1000 mg
dose of M. officinalis plus 400 mg of N. menthoides or a
placebo for four weeks. The study established that a com-
bined regimen possessed a substantial activity against in-
somnia.
In other studies carried out in Iran and UK through
randomized, double-blind, placebo-controlled trials, high
response to the use of M. officinalis to treat anxiety was
observed. In the study conducted by Alijaniha et al. [89]
M. officinalis extract was tested against heart palpitation.
Leaf extract of M. officinalis (500 mg two times per day up
to 14 days) considerably lessened the incidence of anxiety
and palpitation, while no side effect was reported. Simi-
larly, in the UK, two studies were carried out on the use of
M. officinalis for anxiety problems. In the first one, the ef-
fects of M. officinalis on laboratory-induced psychological
stress were examined using a 600 mg dose of herbal ex-
tract. This dose decreased the negative mood effects of the
defined intensity stressor simulation while augmenting the
self-ratings of calmness [90]. In the other work, the anx-
iolytic effect of the herbal combination was assessed dur-
ing laboratory-induced stress [91]. In this case doses of 80
mg of M. officinalis and 120 mg of Valeriana officinalis
L. improved the negative effects of the defined intensity
stressor simulation on ratings of anxiety. It is worth not-
ing that another study tested the effects of “cyracos” (stan-
dardized extract of M. officinalis) in anxiety disorders and
sleep disturbance [92]. Long-lasting administration of this
extract cyracos (600 mg per day up to 15 days) diminished
the stress-related effects, such as insomnia (42%), anxiety
(18%), and anxiety-associated symptoms (15%).
However, the use of M. officinalis has not only been
studied for neurological disorders or patients suffering from
anxiety and stress. Some other studies were redirected to
other problems. Darvish-Mofrad-Kashani and collabora-
tors studied the response of M. officinalis in behavior mod-
ifications [93]. In this work, the efficacy and safety of M.
9
officinalis in improving hypoactive sexual desire disorder in
89 women were evaluated. The treatment doses were 500
mg per day of aqueous extract of M. officinalis or placebo.
Results demonstrated that M. officinalis extract at 4 weeks
significantly increased desire, arousal, lubrication, orgasm,
satisfaction, and pain scores compared to placebo in hy-
poactive sexual desire disorder in women. Other investi-
gations were conducted on the use of M. officinalis by di-
abetic patients or for the treatment of metabolic disorders.
Nayebi et al. [94] described the potential effect of M. offic-
inalis in diabetic patients (type 2). The work analyzed 37
dyslipidemic diabetic patients treated or not with 500 mg
capsules per day for up to 3 months. M. officinalis could
significantly reduce only serum triglyceride level, while no
other metabolic alteration was noted if compared to the
control group. Another group of researchers also tested
the hydroalcoholic extract of M. officinalis in type 2 dia-
betic patients. The clinical trial was conducted with 62 pa-
tients treated with M. officinalis or placebo of 700 mg per
day twice for 12 weeks. M. officinalis caused a substan-
tial modulation in fasting blood sugar, glycated hemoglobin
(HbA1c), and systolic blood pressure [95]. On the same
line, M. officinalis were suggested to modify biomarkers
of oxidative stress, inflammation, and lipid profile in pa-
tients with stable chronic angina [96]. Indeed, 80 patients
participated in this clinical trial and were challenged with
a dose of 3 g per day for 8 weeks. M. officinalis capsules
significantly ameliorated the lipid profile, malondialdehyde
(MDA), highly sensitive c-reactive protein (hs-CRP) and
PNO1 in patients with stable chronic angina. More re-
cently, M. officinalis was studied in systolic and diastolic
blood pressures of 49 hypertensive patients, receiving 400
mg/d capsules of the extract for 4 weeks [97]. The plant
was able to significantly reduce blood pressure (systolic and
diastolic) up to the follow-up period of 10 weeks in this
double-blind, controlled, randomized crossover study. Fur-
thermore, a randomized, double-blind, placebo-controlled
trial with supplementation of M. officinalis evaluated bor-
derline hyperlipidemia patients [98]. Herbal capsules of M.
officinalis exhibited interesting results in hyper-lipidemic
patients, reducing low-density lipoprotein (LDL) and aspar-
tate transaminase (AST) in patients treated with 500 mg of
M. officinalis.
Finally, we must highlight the studies carried out with
this plant to treat infantile colic. Martinelli et al. [99]
demonstrated the effectiveness of Matricaria chamomilla
L., M. officinalis, and Lactobacillus acidophilus tyndallized
(HA122) in infantile colic. The children (n = 176) were
treated for up to 28 days. Crying time was significantly
shorter in the group that received M. chamomilla,M. offici-
nalis, and L. acidophilus tyndallized than the group that re-
ceived only Lactobacillus reuteri or simethicone. Similar to
the previous work, another study investigated the effective-
ness and side effects of M. officinalis associated or not with
Matricariae recutita and Foeniculum vulgare in infantile
colic during one-week treatment. Again crying time was
lessened in 85.4% of subjects compared to control (48.9%)
while no side effects were reported [100].
The use of M. officinalis for various diseases, from
neurological, metabolic disorders to infantile colic opens a
new insight into scientifically supported treatments.
6. Toxicity
As for numerous plants, also M. officinalis can exert
toxicity if not optimally used.
6.1 Cell-based Toxicity
An aqueous extract of M. officinalis exhibits showed
low toxicity on RC-37 cells a cultured line derived from
African green monkey kidneys, with a 50% cytotoxic con-
centration of 350 µg/mL and a maximum non-cytotoxic
concentration of 150 µg/mL [101] and inhibited the pro-
liferation of the NCI-H460 cells, with a growth inhibition
50% (GI50) concentration of 200 µg/mL [102]. M. offici-
nalis hydroethanolic extract showed a cell viability of 13%
at 1000 µg/mL after 72 h on Human Colon Cancer Cell
Line (HCT-116) [103] while its ethanolic inhibited the pro-
liferation of the NCI-H460 cells, with a GI50 concentra-
tion of 100.9 µg/mL [102]. M. officinalis decoctions and
hot extract showed an antiproliferative effect on human tu-
mor cell lines, with GI50 ranging from 51 to 258 µg/mL
for breast (MCF-7), non-small lung (NCI-H460), cervical
(HeLa), and hepatocellular carcinoma (HepG2) [104] and
at a concentration of 500–1000 µg/mL for human colon
cancer cell lines DLD-1 HCT116, SW620, HT-29, and in-
hibited HT-29 cells [105]. M. officinalis decoctions also
showed hepatotoxicity activity with GI50 greater than 400
µg/mL on fresh porcine liver cells, PLP2 [106]. M. offic-
inalis volatile oil was non-toxic to HEp-2 cells, a human
cervical carcinoma cell line at 100 µg/mL [46] but induced
a neurotoxicity effect on mixed cortical cell cultures from
16- to 18-day-old rat embryos (Sprague-Dawley strain) at
the same concentration via volt aggregated sodium channels
[106].
6.2 Animal-based Toxicity
M. officinalis leaves essential oil extract showed no
acute toxicity in rats treated with 2000 mg/kg [30]. The oral
administration of aerial parts essential oil of M. officinalis
presents the oral LD50 in BALB/c mice (2.57 g/kg). This
oil altered animal behavior and liver and kidney biochemi-
cal parameters at doses higher than 1 g/kg in BALB/c mice.
Besides, an increased rate of lipid peroxidation and a deple-
tion of antioxidant capacity of the liver and kidney suggest
moderate toxicity [107]. M. officinalis whole methanolic
and aqueous extracts were found to be safe or non-toxic to
rats up to 2000 (mg/kg b.wt.) with no mortality in swiss
albino mice [108]. This suggests that the organic extracts
of M. officinalis are less toxic through the oral route than
the essential oil extracts irrespective of the plant parts. In
10
addition, M. officinalis aqueous extract showed to cause
genotoxic and histopathologic damage to the liver, kidneys,
heart, and spleen if consumed by Oncorhynchus mykiss fish
at doses greater than 450 mg/kg [109], while ethanolic ex-
tract showed no antigenotoxic/antimutagenic properties in
Swiss albinos mice at 100–250 mg/kg [110]. However, the
European Commission, the Panel on Additives and Prod-
ucts or Substances used in Animal Feed could not conclude
on the safety of the use of a dried aqueous ethanol extract
of M. officinalis leaves as a sensory feed additive for all an-
imal species [111]. On the other hand, a randomized con-
trolled trial using a single dose of M. officinalis extract com-
prising 500 mg rosmarinic acid, showed to be harmless and
well tolerable in healthy humans [112]. This is confirmed
by randomized clinical trials where different treatment reg-
imens of M. officinalis extracts also showed no adverse ef-
fects in humans [84,94,95,113]. Overall, though M. offici-
nalis toxicity data are scarce and have been poorly investi-
gated despite the variety of practical applications in medical
science, available data point out its putative safety in human
beings.
7. Conclusions and Future Perspectives
M. officinalis is a medicinal plant with numerous
health properties and is a curative tool for fighting car-
diovascular, neurological, and psychological disorders.
Nonetheless, M. officinalis is commonly known and preva-
lently used for anti-anxiety and anti-depression properties,
particularly in the acute setting (among the general popula-
tion M. officinalis is used to calm and relax). As reported
in this work, this plant can be useful also in other human
conditions, such as palpitation, hypertension, dementia, in-
fantile colic, bruxism, metabolic problems, Alzheimer’s
disease, and sexual disorders. Even if the therapeutic ef-
fects of M. officinalis are well documented and studied,
its current use in clinical settings is scarce and anecdotic.
Thus this work wants to fill in this gap and suggest clini-
cians, general practitioners, physiotherapists, and interested
people expand the rational use of this recognized curative
plant. From a pharmacological point of view, M.offici-
nalis possesses a wide number of remarkable properties,
i.e., antiviral, anti-inflammatory, antibacterial, neuropro-
tective among the most common. In particular, antiviral ac-
tivity is of current interest, because COVID-19 pandemia is
still taking its toll and in the future, we will need new ther-
apeutic tools to fight this disease, even in the perspective
to co-exist with the SARS-CoV-2 virus. Moreover, given
its safety — it is generally well tolerated having no rele-
vant side effects, only occasionally headache, vomiting, ab-
dominal pain, nausea have been reported — M. officinalis
should be considered in general medicine to increase its use.
Medicinal plants should be considered a powerful means to
cure human conditions: this review sheds new light on the
potential of M. officinalis and encourages researchers to in-
crease the therapeutic possibilities of this medicinal plant.
Author Contributions
WZ, CQ, JSR, MDL, MS, MM, FS, PVTF, APM, DC,
MK, JTC, RP contributed to the manuscript. WZ, CQ, JSR,
MDL, MS, MM, FS, PVTF, APM, DC, MK, JTC, RP col-
lected resources and were responsible for data curation and
writing. Literature review analysis was performed by WZ,
CQ, JSR, MDL, MS, MM, FS, PVTF, APM, DC, MK, JTC,
RP. Reviewing and editing were carried out by JSR and RP.
All the authors read and approved the final manuscript.
Ethics Approval and Consent to Participate
Not applicable.
Acknowledgment
Not applicable.
Funding
This research received no external funding.
Conflict of Interest
The authors declare no conflict of interest. JTC is
serving as one of the Guest Editor of this journal. We de-
clare that JTC had no involvement in the peer review of this
article and has no access to information regarding its peer
review. Full responsibility for the editorial process for this
article was delegated to GCA.
References
[1] Świąder K, Startek K, Wijaya CH. The therapeutic properties of
Lemon balm (Melissa officinalis L.): Reviewing novel findings
and medical indications. Journal of Applied Botany and Food
Quality. 2019; 92: 327–335.
[2] Alizadeh Behbahani B, Shahidi F. Melissa officinalis essential
oil: Chemical compositions, antioxidant potential, total phenolic
content and antimicrobial activity. Nutrition and Food Sciences
Research. 2019; 6: 17–25.
[3] Ghazizadeh J, Hamedeyazdan S, Torbati M, Farajdokht F,
Fakhari A, Mahmoudi J, et al.Melissa officinalis L. hy-
dro‐alcoholic extract inhibits anxiety and depression through
prevention of central oxidative stress and apoptosis. Experimen-
tal Physiology. 2020; 105: 707–720.
[4] Eivani M, Khosronezhad N. Melissa officinalis: a memory en-
hancer remedy. Physiology and Pharmacology. 2020; 24: 159–
164.
[5] Miraj S, Rafieian K, Kiani S. Melissa officinalis L: A Review
Study With an Antioxidant Prospective. Journal of Evidence-
Based Complementary & Alternative Medicine. 2017; 22: 385–
394.
[6] Shakeri A, Sahebkar A, Javadi B. Melissa officinalis L.—A re-
view of its traditional uses, phytochemistry and pharmacology.
Journal of Ethnopharmacology. 2016; 188: 204–228.
[7] Draginic N, Jakovljevic V, Andjic M, Jeremic J, Srejovic I,
Rankovic M, et al.Melissa officinalis L. as a Nutritional Strat-
egy for Cardioprotection. Frontiers in Physiology. 2021; 12:
661778.
[8] Moradkhani H, Sargsyan E, Bibak H, Naseri B, Sadat-Hosseini
M, Fayazi-Barjin A, et al.Melissa officinalis L., a valuable
medicine plant: A review. Journal of Medicinal Plants Research.
2010; 4: 2753–2759.
11
[9] Kittler J, Schrader O, Kästner U, Marthe F. Chromosome num-
ber and ploidy level of balm (Melissa officinalis). Molecular Cy-
togenetics. 2015; 8: 61.
[10] Tutin TG, Heywood VH, Burges NA, Valentine DH. Flora Eu-
ropaea: Plantaginaceae to Compositae (and Rubiaceae). Cam-
bridge: Cambridge University Press. 1976.
[11] Pouyanfar E, Hadian J, Akbarzade M, Hatami M, Kanani MR,
Ghorbanpour M. Analysis of phytochemical and morphologi-
cal variability in different wild-and agro-ecotypic populations
of Melissa officinalis L. growing in northern habitats of Iran. In-
dustrial Crops and Products. 2018; 112: 262–273.
[12] Basar SN, Zaman R. An overview of badranjboya (Melissa of-
ficinalis). International Research Journal of Biological Sciences.
2013; 2: 107–109.
[13] Carnat AP, Carnat A, Fraisse D, Lamaison JL. The aromatic and
polyphenolic composition of lemon balm (Melissa officinalis L.
subsp. officinalis) tea. Pharmaceutica Acta Helvetiae. 1998; 72:
301–305.
[14] Sharopov FS, Wink M, Khalifaev DR, Zhang H, Dosoky NS,
Setzer WN. Composition and bioactivity of the essential oil of
Melissa officinalis L. growing wild in Tajikistan. International
Journal of Traditional and Natural Medicines. 2013; 2: 86–96.
[15] Abdellatif F, Boudjella H, Zitouni A, Hassani A. Chemical
composition and antimicrobial activity of the essential oil from
leaves of Algerian Melissa officinalis L. EXCLI Journal. 2014;
13: 772.
[16] Popova A, Dalemska Z, Mihaylova D, Hristova I, Alexieva I.
Melissa officinalis L.—GC profile and antioxidant activity. In-
ternational Journal of Pharmacognosy and Phytochemical Re-
search. 2016; 8: 634–638.
[17] Aziz EE, El-Ashry SM. Efficiency of slow release urea fertil-
izer on herb yield and essential oil production of lemon balm
(Melissa officinalis L.) plant. Journal of Agriculture and Envi-
ronmental Sciences. 2009; 5: 141–147.
[18] Basta A, Tzakou O, Couladis M. Composition of the leaves es-
sential oil of Melissa officinalis L from Greece. Flavour and Fra-
grance Journal. 2005; 20: 642–644.
[19] Adinee J, Piri K, Karami O. Essential oil component in flower
of lemon balm (Melissa officinalis L.). American Journal of Bio-
chemistry and Biotechnology. 2008; 4: 277–278.
[20] Saeb K, Gholamrezaee S. Variation of essential oil composition
of Melissa officinalis L. leaves during different stages of plant
growth. Asian Pacific Journal of Tropical Biomedicine. 2012; 2:
S547–S549.
[21] Barakat SA, Hudaib M, Burns DT. Composition of Volatile Oil
and Methanolic Extract of Jordanian Melissa Officinals L. and
Actions Againsthuman Cancer Cell Lines. Oriental Journal of
Chemistry. 2016; 32: 2355.
[22] Seidler-Łożykowska K, Zawirska-Wojtasiak R, Wojtowicz E,
Bocianowski J. Essential oil content and its composition in herb
of lemon balm (Melissa officinalis L.) breeding strains. Journal
of Essential Oil Research. 2017; 29: 351–356.
[23] Hăncianu M, Aprotosoaie AC, Gille E, Poiată A, Tuchiluş C,
Spac A, et al. Chemical composition and in vitro antimicrobial
activity of essential oil of Melissa officinalis L. from Romania.
Revista Medico-Chirurgicala a Societatii de Medici si Natural-
isti din Iasi. 2008; 112: 843–847.
[24] Efremov AA, Zykova ID, Gorbachev AE. Composition of the
essential oil from the lemon balm growing in the neighborhood
of Krasnoyarsk as indicated by gas chromatography–mass spec-
trometry data. Russian Journal of Bioorganic Chemistry. 2016;
42: 726–729.
[25] Cosge B, Arif I, Gurbuz B. GC/MS analysis of herbage essential
oil from lemon balms (Melissa officinalis L.) grown in Turkey.
Journal of Applied Biological Sciences. 2009; 3: 149–152.
[26] Mencherini T, Picerno P, Scesa C, Aquino R. Triterpene, antiox-
idant, and antimicrobial compounds from Melissa officinalis.
Journal of Natural Products. 2007; 70: 1889–1894.
[27] Abdel-Naime WA, Fahim JR, Abdelmohsen UR, Fouad MA, Al-
Footy KO, Abdel-Lateff AA, et al. New antimicrobial triterpene
glycosides from lemon balm (Melissa officinalis). South African
Journal of Botany. 2019; 125: 161–167.
[28] Akbar S. Melissa officinalis L.(Lamiaceae). Handbook of
200 Medicinal Plants. United States of America, New York:
Springer; 2020.
[29] Awad R, Muhammad A, Durst T, Trudeau VL, Arnason JT.
Bioassay-guided fractionation of lemon balm (Melissa offici-
nalis L.) using an in vitro measure of GABA transaminase ac-
tivity. Phytotherapy Research. 2009; 23: 1075–1081.
[30] Hanganu D, Vlase L, Filip L, Sand C, Mirel S, Indrei LL. The
study of some polyphenolic compounds from Melissa offici-
nalis L.(Lamiaceae). Revista medico-chirurgicala a Societatii de
Medici si Naturalisti din Iasi. 2008; 112: 525–529.
[31] Toth J, Mrlianova M, Tekelova D, Koremova M. Rosmarinic
acid an important phenolic active compound of Lemon Balm
(Melissa officinalis). Acta Facultatis Pharmaceuticae Universi-
tatis Comenianae. 2003; 50: 139–146.
[32] Patora J, Klimek B. Flavonoids from lemon balm (Melissa offic-
inalis L., Lamiaceae). Acta Poloniae Pharmaceutica. 2002; 59:
139–144.
[33] Papoti VT, Totomis N, Atmatzidou A, Zinoviadou K, An-
droulaki A, Petridis D, et al. Phytochemical content of Melissa
officinalis L. herbal preparations appropriate for consumption.
Processes. 2019; 7: 88.
[34] Liu YC, Kuo RL, Shih SR. COVID-19: The first documented
coronavirus pandemic in history. Biomedical Journal. 2020; 43:
328–333.
[35] Cohen RA, Kucera LS, Herrmann Jr EC. Antiviral Activity of
Melissa officinalis (Lemon Balm) Extract. Proceedings of the
Society for Experimental Biology and Medicine. 1964; 117:
431–434.
[36] Prasanth D, Murahari M, Chandramohan V, Bhavya G, Lak-
shmana Rao A, Panda SP, et al. In-silico strategies of some
selected phytoconstituents from Melissa officinalis as SARS
CoV-2 main protease and spike protein (COVID-19) inhibitors.
Molecular Simulation. 2021; 47: 457–470.
[37] Elekofehinti OO, Iwaloye O, Famusiwa CD, Akinseye O, Rocha
JBT. Identification of main protease of coronavirus SARS-CoV-
2 (Mpro) Inhibitors from Melissa officinalis. Current Drug Dis-
covery Technologies. 2021; 18: 38–52.
[38] Nili H, Mohammadi A, Habibi H, Firouzi S. Pathogenesis of
H9N2 virus in Chukar partridges. Avian Pathology. 2013; 42:
230–234.
[39] Ehrhardt C, Hrincius ER, Korte V, Mazur I, Droebner K, Poet-
ter A, et al. A polyphenol rich plant extract, CYSTUS052, ex-
erts anti influenza virus activity in cell culture without toxic side
effects or the tendency to induce viral resistance. Antiviral Re-
search. 2007; 76: 38–47.
[40] Pourghanbari G, Nili H, Moattari A, Mohammadi A, Iraji A.
Antiviral activity of the oseltamivir and Melissa officinalis L.
essential oil against avian influenza A virus (H9N2). Virusdis-
ease. 2016; 27: 170–178.
[41] Jalali P, Moattari A, Mohammadi A, Ghazanfari N, Pourghan-
bari G. Melissa officinalis efficacy against human influenza
virus (New H1N1) in comparison with oseltamivir. Asian Pa-
cific Journal of Tropical Disease. 2016; 6: 714–717.
[42] Nolkemper S, Reichling J, Stintzing FC, Carle R, Schnitzler P.
Antiviral effect of aqueous extracts from species of the Lami-
aceae family against Herpes simplex virus type 1 and type 2 in
vitro. Planta Medica. 2006; 72: 1378–1382.
[43] Vanden Berghe DA, Vhetinck AJ, Van Hoof L. Plant products as
potential antiviral agents. France: Bulletin de l’Institut Pasteur.
12
1986.
[44] Astani A, Reichling J, Schnitzler P. Melissa officinalis extract
inhibits attachment of herpes simplex virus in vitro. Chemother-
apy. 2012; 58: 70–77.
[45] Efferth T, Koch E. Complex interactions between phytochemi-
cals. The multi-target therapeutic concept of phytotherapy. Cur-
rent Drug Targets. 2011; 12: 122–132.
[46] Allahverdiyev A, Duran N, Ozguven M, Koltas S. Antiviral ac-
tivity of the volatile oils of Melissa officinalis L. against Herpes
simplex virus type-2. Phytomedicine. 2004; 11: 657–661.
[47] Clavel F, Hance AJ. HIV drug resistance. The New England
Journal of Medicine. 2004; 350: 1023–1035.
[48] Geuenich S, Goffinet C, Venzke S, Nolkemper S, Baumann I,
Plinkert P, et al. Aqueous extracts from peppermint, sage and
lemon balm leaves display potent anti-HIV-1 activity by increas-
ing the virion density. Retrovirology. 2008; 5: 27.
[49] Li P, Li T, Gu Q, Chen X, Li J, Chen X, et al. Children’s Care-
givers and Public Playgrounds: Potential Reservoirs of Infec-
tion of Hand-foot-and-mouth Disease. Scientific Reports. 2016;
6: 36375.
[50] Prager P, Nolan M, Andrews IP, Williams GD. Neurogenic pul-
monary edema in enterovirus 71 encephalitis is not uniformly
fatal but causes severe morbidity in survivors. Pediatric Critical
Care Medicine. 2003; 4: 377–381.
[51] Chen SG, Leu YL, Cheng ML, Ting SC, Liu CC, Wang SD, et
al. Anti-enterovirus 71 activities of Melissa officinalis extract
and its biologically active constituent rosmarinic acid. Scientific
Reports. 2017; 7: 12264.
[52] Mimica-Dukic N, Bozin B, Sokovic M, Simin N. Antimicrobial
and antioxidant activities of Melissa officinalis L.(Lamiaceae)
essential oil. Journal of Agricultural and Food Chemistry. 2004;
52: 2485–2489.
[53] Abdel-Naime WA, Fahim JR, Fouad MA, Kamel MS. Antibacte-
rial, antifungal, and GC–MS studies of Melissa officinalis. South
African Journal of Botany. 2019; 124: 228–234.
[54] Rabbani M, Etemadifar Z, Karamifard F, Borhani MS. Assess-
ment of the antimicrobial activity of Melissa officinalis and Law-
sonia inermis extracts against some bacterial pathogens. Com-
parative Clinical Pathology. 2016; 25: 59–65.
[55] Bounihi A, Hajjaj G, Alnamer R, Cherrah Y, Zellou A. In vivo
potential anti-inflammatory activity of Melissa officinalis L. es-
sential oil. Advances in Pharmacological Sciences. 2013; 2013:
101759.
[56] Miladi Gorgi H, Vafaee AA, RashidiPoor A, Taherian AA, Jar-
rahi M, Emami Abarghoee M, et al. The role of opioid receptors
on anxiolytic effects of the aqueous extract of Melissa officinalis
in mice. Razi Journal of Medical Sciences. 2005; 12: 145–153.
[57] Petersen M, Simmonds MSJ. Rosmarinic acid. Phytochemistry.
2003; 62: 121–125.
[58] Ramanauskienė K, Stelmakiene A, Majienė D. Assessment of
Lemon Balm (Melissa officinalis L.) Hydrogels: Quality and
Bioactivity in Skin Cells. Evidence-Based Complementary and
Alternative Medicine. 2015; 2015: 635975.
[59] Birdane YO, Buyukokuroglu ME, Birdane FM, Cemek M,
Yavuz H. Anti-inflammatory and antinociceptive effects of
Melissa officinalis L. in rodents. Revue de Medecine Veterinaire.
2007; 158: 75–81.
[60] Muezell DP, Lunardelli A, Leite CE, Fagundes RM, Saciura
VC, Reichel CL, et al. Nephroprotective and Anti-inflammatory
Effects of Aqueous Extract of Melissa officinalis L. on
Acetaminophen-induced and Pleurisy-induced Lesions in Rats.
Brazilian Archives of Biology and Technology. 2013; 56: 383–
392.
[61] Moacă EA, Farcaş C, Ghiţu A, Coricovac D, Popovici R,
Cărăba-Meiţă NL, et al. A Comparative Study of Melissa of-
ficinalis Leaves and Stems Ethanolic Extracts in terms of An-
tioxidant, Cytotoxic, and Antiproliferative Potential. Evidence-
based Complementary and Alternative Medicine. 2018; 2018:
7860456.
[62] Sanders S, Morano C. Alzheimer’s disease and related demen-
tias. Journal of gerontological social work. 2008; 50: 191–214.
[63] Pereira RP, Boligon AAi, Appel AS, Fachinetto R, Ceron
CS, Tanus-Santos JE, et al. Chemical composition, antioxidant
and anticholinesterase activity of Melissa officinalis. Industrial
Crops and Products. 2014; 53: 34–45.
[64] Soodi M, Naghdi N, Hajimehdipoor H, Choopani S, Sahraei
E. Memory-improving activity of Melissa officinalis extract in
naïve and scopolamine-treated rats. Research in Pharmaceutical
Sciences. 2014; 9: 107–114.
[65] Dastmalchi K, Ollilainen V, Lackman P, Boije af Gennäs G,
Dorman HJ, Järvinen PP, et al. Acetylcholinesterase inhibitory
guided fractionation of Melissa officinalis L. Bioorganic &
Medicinal Chemistry. 2009; 17: 867–871.
[66] López V, Martín S, Gómez-Serranillos MP, Carretero ME, Jäger
AK, Calvo MI. Neuroprotective and neurological properties of
Melissa officinalis. Neurochemical Research. 2009; 34: 1955–
1961.
[67] Abd Allah HN, Abdul-Hamid M, Mahmoud AM, Abdel-Reheim
ES. Melissa officinalis L. ameliorates oxidative stress and in-
flammation and upregulates Nrf2/HO-1 signaling in the hip-
pocampus of pilocarpine-induced rats. Environmental Science
and Pollution Research International. 2022; 29: 2214–2226.
[68] Hassanzadeh G, Pasbakhsh P, Akbari M, Shokri S, Ghahremani
M, Amin G, et al. Neuroprotective properties of Melissa offici-
nalis L. Extract against ecstasy-induced neurotoxicity. Cell Jour-
nal. 2011; 13: 25–30.
[69] Yoo DY, Choi JH, Kim W, Yoo KY, Lee CH, Yoon YS, et al.
Effects of Melissa officinalis L. (lemon balm) extract on neuro-
genesis associated with serum corticosterone and GABA in the
mouse dentate gyrus. Neurochemical Research. 2011; 36: 250–
257.
[70] Bayat M, Azami Tameh A, Hossein Ghahremani M, Akbari
M, Mehr SE, Khanavi M, et al. Neuroprotective properties of
Melissa officinalis after hypoxic-ischemic injury both in vitro
and in vivo. Daru. 2012; 20: 42.
[71] Ramanauskiene K, Raudonis R, Majiene D. Rosmarinic Acid
and Melissa officinalis Extracts Differently Affect Glioblastoma
Cells. Oxidative Medicine and Cellular Longevity. 2016; 2016:
1564257.
[72] Coutts M, Keirstead HS. Stem cells for the treatment of spinal
cord injury. Experimental Neurology. 2008; 209: 368–377.
[73] Hosseini SR, Kaka G, Joghataei MT, Hooshmandi M, Sadraie
SH, Yaghoobi K, et al. Assessment of Neuroprotective Prop-
erties of Melissa officinalis in Combination With Human Um-
bilical Cord Blood Stem Cells After Spinal Cord Injury. ASN
Neuro. 2016; 8: 1759091416674833.
[74] Orhan I, Aslan M. Appraisal of scopolamine-induced anti-
amnesic effect in mice and in vitro antiacetylcholinesterase
and antioxidant activities of some traditionally used Lamiaceae
plants. Journal of Ethnopharmacology. 2009; 122: 327–332.
[75] Ozarowski M, Mikolajczak PL, Piasecka A, Kachlicki P, Ku-
jawski R, Bogacz A, et al. Influence of the Melissa officinalis
Leaf Extract on Long-Term Memory in Scopolamine Animal
Model with Assessment of Mechanism of Action. Evidence-
Based Complementary and Alternative Medicine. 2016; 2016:
9729818.
[76] Stojanović NM, Mladenović MZ, Maslovarić A, Stojiljković NI,
Randjelović PJ, Radulović NS. Lemon balm (Melissa officinalis
L.) essential oil and citronellal modulate anxiety-related symp-
toms - In vitro and in vivo studies. Journal of Ethnopharmacol-
ogy. 2022; 284: 114788.
[77] Draginic ND, Jakovljevic VL, Jeremic JN, Srejovic IM, Andjic
13
MM, Rankovic MR, et al.Melissa officinalis L. Supplementa-
tion Provides Cardioprotection in a Rat Model of Experimen-
tal Autoimmune Myocarditis. Oxidative Medicine and Cellular
Longevity. 2022; 2022: 1344946.
[78] Draginic N, Jakovljevic V, Andjic M, Jeremic J, Srejovic I, et al.
Melissa officinalis L. as a Nutritional Strategy for Cardioprotec-
tion. Frontiers in Physiology. 2021; 12: 661778.
[79] Perry NSL, Menzies R, Hodgson F, Wedgewood P, Howes
MJR, Brooker HJ, et al. A randomised double-blind placebo-
controlled pilot trial of a combined extract of Sage,Rosemary
and Melissa, traditional herbal medicines, on the enhancement
of memory in normal healthy subjects, including influence of
age. Phytomedicine. 2017; 39: 42–48.
[80] Araj-Khodaei M, Noorbala AA, Yarani R, Emadi F, Emaratkar
E, Faghihzadeh S, et al. A double-blind, randomized pilot study
for comparison of Melissa officinalis L. and Lavandula angusti-
folia Mill. with Fluoxetine for the treatment of depression. BMC
Complementary Medicine and Therapies. 2020; 20: 207.
[81] Noguchi-Shinohara M, Ono K, Hamaguchi T, Nagai T,
Kobayashi S, Komatsu J, et al. Safety and efficacy of Melissa of-
ficinalis extract containing rosmarinic acid in the prevention of
Alzheimer’s disease progression. Scientific Reports. 2020; 10:
18627.
[82] Burns A, Perry E, Holmes C, Francis P, Morris J, Howes MJ,
et al. A double-blind placebo-controlled randomized trial of
Melissa officinalis oil and donepezil for the treatment of agita-
tion in Alzheimer’s disease. Dementia and Geriatric Cognitive
Disorders. 2011; 31: 158–164.
[83] Kennedy DO, Wake G, Savelev S, Tildesley NTJ, Perry EK,
Wesnes KA, et al. Modulation of Mood and Cognitive Per-
formance Following Acute Administration of Single Doses of
Melissa officinalis (Lemon Balm) with Human CNS Nico-
tinic and Muscarinic Receptor-Binding Properties. Neuropsy-
chopharmacology. 2003; 28: 1871–1881.
[84] Akhondzadeh S, Noroozian M, Mohammadi M, Ohadinia S,
Jamshidi AH, Khani M. Melissa officinalis extract in the treat-
ment of patients with mild to moderate Alzheimer’s disease: a
double blind, randomised, placebo controlled trial. Journal of
Neurology, Neurosurgery, and Psychiatry. 2003; 74: 863–866.
[85] Soltanpour A, Alijaniha F, Naseri M, Kazemnejad A, Heidari
MR. Effects of Melissa officinalis on anxiety and sleep quality in
patients undergoing coronary artery bypass surgery: A double-
blind randomized placebo controlled trial. European Journal of
Integrative Medicine. 2019; 28: 27–32.
[86] Watson K, Hatcher D, Good A. A randomised controlled trial of
Lavender (Lavandula Angustifolia) and Lemon Balm (Melissa
Officinalis) essential oils for the treatment of agitated behaviour
in older people with and without dementia. Complementary
Therapies in Medicine. 2019; 42: 366–373.
[87] Tavares-Silva C, Holandino C, Homsani F, Luiz RR, Prodes-
tino J, Farah A, et al. Homeopathic medicine of Melissa offici-
nalis combined or not with Phytolacca decandra in the treatment
of possible sleep bruxism in children: A crossover randomized
triple-blinded controlled clinical trial. Phytomedicine. 2019; 58:
152869.
[88] Ranjbar M, Salehi A, Rezaeizadeh H, Zarshenas MM,
Sadeghniiat-Haghighi K, Mirabzadeh M, et al. Efficacy of a
Combination of Melissa officinalis L. and Nepeta menthoides
Boiss. & Buhse on Insomnia: A Triple-Blind, Randomized
Placebo-Controlled Clinical Trial. The Journal of Alternative
and Complementary Medicine. 2018; 24: 1197–1203.
[89] Alijaniha F, Naseri M, Afsharypuor S, Fallahi F, Noorbala A,
Mosaddegh M, et al. Heart palpitation relief with Melissa of-
ficinalis leaf extract: double blind, randomized, placebo con-
trolled trial of efficacy and safety. Journal of Ethnopharmacol-
ogy. 2015; 164: 378–384.
[90] Kennedy DO, Little W, Scholey AB. Attenuation of laboratory-
induced stress in humans after acute administration of Melissa
officinalis (Lemon Balm). Psychosomatic Medicine. 2004; 66:
607–613.
[91] Kennedy DO, Little W, Scholey AB. Anxiolytic effects of a
combination of Melissa officinalis and Valerlana officinalis dur-
ing laboratory induced stress. Journal of Psychopharmacology.
2004; 18: A45–A45.
[92] Cases J, Ibarra A, Feuillère N, Roller M, Sukkar SG. Pilot trial of
Melissa officinalis L. leaf extract in the treatment of volunteers
suffering from mild-to-moderate anxiety disorders and sleep dis-
turbances. Mediterranean Journal of Nutrition and Metabolism.
2011; 4: 211–218.
[93] Darvish-Mofrad-Kashani Z, Emaratkar E, Hashem-Dabaghian
F, Emadi F, Raisi F, Aliasl J, et al. Effect of Melissa officinalis
(Lemon balm) on Sexual Dysfunction in Women: A Double-
blind, Randomized, Placebo-controlled Study. Iranian Journal of
Pharmaceutical Research. 2018; 17: 89–100.
[94] Nayebi N, Esteghamati A, Meysamie A, Khalili N, Kamalinejad
M, Emtiazy M, et al. The effects of a Melissa officinalis L. based
product on metabolic parameters in patients with type 2 diabetes
mellitus: A randomized double-blinded controlled clinical trial.
Journal of Complementary and Integrative Medicine. 2019; 16.
[95] Asadi A, Shidfar F, Safari M, Hosseini AF, Fallah Huseini H,
Heidari I, et al. Efficacy of Melissa officinalis L. (lemon balm)
extract on glycemic control and cardiovascular risk factors in
individuals with type 2 diabetes: A randomized, double-blind,
clinical trial. Phytotherapy Research. 2019; 33: 651–659.
[96] Javid AZ, Haybar H, Dehghan P, Haghighizadeh MH, Mo-
haghegh SM, Ravanbakhsh M, et al. The effects of Melissa offic-
inalis (lemon balm) in chronic stable angina on serum biomark-
ers of oxidative stress, inflammation and lipid profile. Asia Pa-
cific Journal of Clinical Nutrition. 2018; 27: 785–791.
[97] Shekarriz Z, Shorofi SA, Nabati M, Shabankhani B, Yousefi SS.
Effect of Melissa officinalis on systolic and diastolic blood pres-
sures in essential hypertension: A double-blind crossover clini-
cal trial. Phytotherapy Research. 2021; 35: 6883–6892.
[98] Jandaghi P, Noroozi M, Ardalani H, Alipour M. Lemon
balm: A promising herbal therapy for patients with borderline
hyperlipidemia-A randomized double-blind placebo-controlled
clinical trial. Complementary Therapies in Medicine. 2016; 26:
136–140.
[99] Martinelli M, Ummarino D, Giugliano FP, Sciorio E, Tortora
C, Bruzzese D, et al. Efficacy of a standardized extract of Ma-
tricariae chamomilla L., Melissa officinalis L. and tyndallized
Lactobacillus acidophilus (HA122) in infantile colic: An open
randomized controlled trial. Neurogastroenterology & Motility.
2017; 29.
[100] Savino F, Cresi F, Castagno E, Silvestro L, Oggero R. A ran-
domized double-blind placebo-controlled trial of a standardized
extract of Matricariae recutita, Foeniculum vulgare and Melissa
officinalis (ColiMil) in the treatment of breastfed colicky infants.
Phytotherapy Research. 2005; 19: 335–340.
[101] Astani A, Heidary Navid M, Schnitzler P. Attachment and
Penetration of Acyclovir-resistant Herpes Simplex Virus are In-
hibited by Melissa officinalis Extract. Phytotherapy Research.
2014; 28: 1547–1552.
[102] Magalhães DB, Castro I, Lopes-Rodrigues V, Pereira JM, Bar-
ros L, Ferreira ICFR, et al.Melissa officinalis L. ethanolic ex-
tract inhibits the growth of a lung cancer cell line by interfering
with the cell cycle and inducing apoptosis. Food & Function.
2018; 9: 3134–3142.
[103] Encalada MA, Hoyos KM, Rehecho S, Berasategi I, de Ciriano
MG-Í, Ansorena D, et al. Anti-proliferative effect of Melissa of-
ficinalis on human colon cancer cell line. Plant Foods for Human
Nutrition. 2011; 66: 328–334.
14
[104] Carocho M, Barros L, Calhelha RC, Ćirić A, Soković M,
Santos-Buelga C, et al. Melissa officinalis L. decoctions as func-
tional beverages: a bioactive approach and chemical characteri-
zation. Food and Function. 2015; 6: 2240–2248.
[105] Kuo TT, Chang HY, Chen TY, Liu BC, Chen HY, Hsiung YC,
et al.Melissa officinalis Extract Induces Apoptosis and Inhibits
Migration in Human Colorectal Cancer Cells. ACS Omega.
2020; 5: 31792–31800.
[106] Mahita M, Abuhamdah R, Howes M-J, Ennaceur A, Abuham-
dah S, Chazot P. Identification of a novel GABAA receptor
channel ligand derived from Melissa officinalis and Lavandula
angustifolia essential oils. European Journal of Medicinal Plants.
2014; 4: 810.
[107] Stojanović NM, Randjelović PJ, Mladenović MZ, Ilić IR,
Petrović V, Stojiljković N, et al. Toxic essential oils, part VI:
Acute oral toxicity of lemon balm (Melissa officinalis L.) essen-
tial oil in BALB/c mice. Food and Chemical Toxicology. 2019;
133: 110794.
[108] Bhat JU, Nizami Q, Aslam M, Asiaf A, Ahmad ST, Parray SA.
Antiepileptic activity of the whole plant extractof Melissa offic-
inalis in swiss albino mice. International Journal of Pharmaceu-
tical Sciences and Research. 2012; 3: 886.
[109] Jafarpour M, Amniat-Talab A, Nekuie-Fard A. Genotoxicity
and Histopathology Effects of Melissa officinalis Aqueous Ex-
tract on the Blood and Vital Tissues of Oncorhynchus mykiss
Fish. Iranian Journal of Toxicology. 2018; 12: 13–18.
[110] de Carvalho NC, Corrêa-Angeloni MJ, Leffa DD, Moreira J,
Nicolau V, de Aguiar Amaral P, et al. Evaluation of the geno-
toxic and antigenotoxic potential of Melissa officinalis in mice.
Genetics and Molecular Biology. 2011; 34: 290–297.
[111] Bampidis V, Azimonti G, Bastos ML, Christensen H, Kouba
M, Kos Durjava M, et al. Safety and efficacy of a dried aqueous
ethanol extract of Melissa officinalis L. leaves when used as a
sensory additive for all animal species. EFSA journal European
Food Safety Authority. 2020; 18: e06016.
[112] Noguchi-Shinohara M, Ono K, Hamaguchi T, Iwasa K, Nagai
T, Kobayashi S, et al. Pharmacokinetics, Safety and Tolerability
of Melissa officinalis Extract which Contained Rosmarinic Acid
in Healthy Individuals: A Randomized Controlled Trial. PLoS
ONE. 2015; 10: e0126422.
[113] Ulbricht C, Brendler T, Gruenwald J, Kligler B, Keifer D,
Abrams TR, et al. Lemon balm (Melissa officinalis L.): an
evidence-based systematic review by the Natural Standard Re-
search Collaboration. Journal of Herbal Pharmacotherapy. 2005;
5: 71–114.
15
Available via license: CC BY 4.0
Content may be subject to copyright.
