Anxiolytic properties of Melissa officinalis and associated mechanisms of action: A review of the literature

Abstract

The anxiety disorders prevalence has significantly increased in society. These disorders can be treated with anxiolytics which, despite great efficacy, may result in several adverse side effects. Several studies have reported that anxiolytic effects result from the indirect action on the GABAergic system and mechanisms related to the cholinergic system. Melissa officinalis has been widely utilized for its sedative action and its ability to reduce agitation. Several studies using this plant in different experimental models have demonstrated its low toxicity and lack of side effects. Therefore, this study presents a literature review of the active principles responsible for the anxiolytic effect of M. officinalis and the mechanisms involved in this effect.

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Vol. 9(3), pp. 53-59, 22 January, 2015
DOI: 10.5897/AJPP2014.4180
Article Number: DD55FEF50336
ISSN 1996-0816
Copyright © 2015
Author(s) retain the copyright of this article
http://www.academicjournals.org/AJPP
African Journal of Pharmacy and
Pharmacology
Full Length Research Paper
Anxiolytic properties of Melissa officinalis and
associated mechanisms of action: A review of the
literature
Bárbara Luisa Fermino1, Najeh Maissar Kahlil1, Juliana Sartori Bonini1*, Romaiana Picada
Pereira2, João Batista Teixeira da Rocha3 and Weber Claudio Francisco Nunes da Silva1
1Docente do Curso de Farmácia, Universidade Estadual do Centro-Oeste, UNICENTRO, Guarapuava, PR, Brasil
2Departamento de Química, Programa de Pós-Graduação em Química Aplicada, Universidade Estadual de Ponta
Grossa, PR, Brasil.
3Departamento de Química, Programa de Pós-Graduação em Bioquímica Toxicológica, Universidade Federal de Santa
Maria, RS, Brasil.
Received 16 September, 2014; Accepted 22 January, 2015
The anxiety disorders prevalence has significantly increased in society. These disorders can be treated
with anxiolytics which, despite great efficacy, may result in several adverse side effects. Several
studies have reported that anxiolytic effects result from the indirect action on the GABAergic system
and mechanisms related to the cholinergic system. Melissa officinalis has been widely utilized for its
sedative action and its ability to reduce agitation. Several studies using this plant in different
experimental models have demonstrated its low toxicity and lack of side effects. Therefore, this study
presents a literature review of the active principles responsible for the anxiolytic effect of M. officinalis
and the mechanisms involved in this effect.
Key words: Melissa officinalis, lemon balm, anxiolytic action.
INTRODUCTION
According to the World Health Organization (WHO),
approximately 80% of the world population uses
traditional medicine based on empirical knowledge for
primary health care (Taiwo, 2007). The use of plants in
traditional medicine in Brazil is popular because of the
natural diversity observed in the country and low costs
the deepening and expansion of studies on herbal
medicines have contributed to advances in this usage
(Carvalho, 2011) and discovery of new drugs. Melissa
officinalis was first described by Carolus Linnaeus in
1753 and initially cited in the French Pharmacopeain. It
belongs to the Lamiaceae family and is a perennial
lemon-scented herb in the mint family native to the
Mediterranean and Southern Europe popularly known as
lemon balm (Guginski, 2007). It was introduced to North
America and can be found currently in gardens and
*Corresponding author. E-mail: juliana.bonini@gmail.com. Tel:+55 42 99985198.
Author(s) agree that this article remain permanently open access under the terms of the Creative Commons Attribution
License 4.0 International License

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54 Afr. J. Pharm. Pharmacol.
roadside fields (Awad et al., 2009). This plant has been
widely used because of its several therapeutic actions
such as antioxidant (Dastmalchi, 2008; Pereira, 2009;
Ribeiro and Bernardo-gil, 2001; Kamdem et al., 2014),
anti-inflammatory, hepatoprotective (Birdane, 2007;
Bolkent et al., 2005; Encalada et al., 2011), antibacterial,
antifungal, antiviral, cholesterol-lowering (Bolkent et al.,
2005), antitumor (Saraydin et al., 2012), anti-spas and
antidepressant (L´opez et al., 2009).
The plant’s sedative properties (Cases, 2011),
including a reduction of stress, agitation, and anxiety
(Kennedy, 2006) have been widely explored. It is
believed that these properties could be related to the
citral, which is one of its most abundant secondary
metabolites (Lorenzi and Matos, 2002). Thus, as M.
officinalis becomes a promising alternative to the
treatment of anxiety, the understanding of factors that
alter the bio-synthesis of citral is critical for a safer use of
this herbal medicine.
The prevalence of anxiety disorders has significantly
increased in the current society, with 10 million people
currently suffering with this pathology (WHO, 2002) in
Brazil. Anxiety disorders are usually treated through the
use of drugs known as benzodiazepines.
Benzodiazepines and barbiturates are the most
commonly used despite their significant drawbacks such
as physical dependence, tolerance, depression, and
interference with memory mechanisms (Taiwo, 2007).
Therefore, the search for alternative therapies that are as
effective as those in use but with reduced adverse effects
is of utmost importance (Baldwin and Ajel, 2007;
Kennedy and Scholey, 2004; Millan, 2003; Sinclair and
Nutt, 2007; Taiwo, 2007).
Traditional medicines are important options to meet the
growing needs of health care; however, there is little
scientific evidence ensuring their effectiveness and
safety. This study reviewed the information published in
the literature about the properties of M. officinalis, with
the main focus on its anxiolytic roles and the major
mechanisms of action involved.
METHODOLOGY
This study conducted an integrative literature review using articles
that addressed the effects related to the anxiolytic properties of M.
officinalis between 1994 and 2014 and indexed in the Scopus,
Pubmed, Medline, and SciELO databases and SienceDirect. Eight
articles that were published in the last eighteen years and
addressed the anxiolytic activity of the plant in experimental models
and one in a clinical evaluation were compared in this study.
RESULT AND DISCUSSION
M. officinalis L., Lamiaceae, popularly known as melissa
or lemon balm is a perennial herbaceous species
originated in Asia, North Africa, and Southern Europe
where it is produced in large scale (Gurčik et al., 2005;
Sorensen, 2000). Melissa is reproduced through branch
cuttings or imported seeds and plants (Wanderer, 2004).
Melissa leaves have been used since ancient times
because of its action on the digestive system, mainly due
to its carminative and vermifuge properties in the
stomach, and as a tonic, antiseptic, and anti-inflammatory
(Bertolucci et al., 2008; Sorensen, 2000). Another
important use of its leaves and branches is as a
condiment (Bertolucci et al., 2008; Carvalho et al., 2005;
Couto, 2006).
Citral, citronellal, and geraniol are the main medicinal
and condiment constituents in M. officinalis. These
constituents are found in the essential oil obtained mainly
from leaves that can yield between 0.02 and 0.37% of the
majority of metabolites (MoradkhanI et al., 2010); the
leaves are also used in infusion to produce teas.
Hydroxycinnamic acids such as rosmarinic acid, and
polyphenols such as tannins and flavonoids, are other
constituents of M. officinalis reported to play important
pharmacological roles (MoradkhanI et al., 2010;
Sorensen, 2000).
In vitro studies showed that the essential oil from
ethanol extracts of M. officinalis leaves contain several
metabolites: tannin and rosmarinic derivatives, caffeic
acid, flavonoids, and triterpenoid acids. Lorenzi et al.
(2002) reported the following compounds as the major
components: citronellal (1), citral (2), followed by β-
caryophyllene (3), germancrene- D (4), ocimene (5), and
citronellol (6) (Lorenzi and Matos 2002) (Figure 1).
Conversely, Allahverdiyev et al. (2004) showed that the
most prevalent compounds are β–Cubebene, β–
Caryophyllene (the only common compound between the
studies), Sesquiterpene alcohol (C15H26O), α -Cadinol,
Geranial (citral a), and Neral (citral b) (Table 1).
The different results in these two previous studies could
come from the use of different extraction and
identification methods; Allahverdiyev et al. (2004) used
mass spectrophotometry ensuring greater reliability on
the results because of the high sensitivity of this method
compared to those using older identification methods.
However, compounds other than those cited in the
present article, such as rosmarinic acid (Boyadzhiev and
Dimitrova, 2007), have been found indicating that a wide
range of compounds in this plant could hinder the
identification of all compounds in its composition. This
could be the limiting factor for pharmacological
descriptions in other articles found in the literature.
According to Lorenzi and Matos (2002), the anxiolytic
action of M. officinalis results from the interaction of
limonene and citral with GABAA, one of the two ionic
channels activated by the ligand responsible for the
mediation of γ-aminobutyric acid (GABA), assuming a
similar benzodiazepine activity in the plant through
nicotinic and muscarinic receptors that are in direct

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Fermino et al. 55
Figure 1. Chemical structure of the major components of Melissa officinalis leaves: citronellal (1), citral
(2), β-caryophyllene (3), Germancreno-D (4), ocimene (5), and citronellol (6).
connection to the central nervous system (CNS). The
study of Wake et al. (2000) working with M. officinalis and
Valeriana officinallis to treat cholinergic receptors showed
that the extract from the plant’s leaves promoted
connections at different levels in the two subtypes of
these receptors; the level of connections was higher in
the nicotinic subtype because the concentration of this
receptor in the human occipital cortex is most expressive.
GABA is an inhibitory neurotransmitter of the central
nervous system that reduces nerve impulse transmission
between neurons through the hyperpolarization of
postsynaptic membranes and the reduction of neuro-
transmitter release into the synapse through presynaptic
G-protein coupled receptor inhibition of voltage-gated
Ca++ mechanisms (Weeks, 2009). The GABAergic
system is well known as a modulator of cognitive
function (Lewis et al., 2008; Menzies et al., 2007) and
emotional behavior (Ibarra et al., 2010; Radley et al.,
2009; Thoeringer et al., 2009). In this regard, Awad et al.
(2009) have reported that rosmarinic acid in plants works
by inhibiting the enzyme GABA transaminase (GABA-T),
thereby increasing the levels of the neurotransmitter
GABA and consequently, reducing anxiety. However, this
would only be possible in a moderate stress state,
because M. officinalis is not efficient when the stress
level is severe (Ibarra et al., 2010). The GABAA
receptors are ionic channels that mediate the effects of
GABA, producing an inhibitory action through the opening
of chloride channels preventing a neuronal action
potential. This is seen as the mechanism of action of
diazepam and is regarded as one of the possible
mechanisms of action of M. officinalis (Abuhamdah et al.,
2008; Akhondzadeh et al., 2003; Kennedy et al., 2002;
Wecker and Catalano, 2006).
Wake et al. (2000) reported anxiolytic effects of M.
officinalis on the CNS besides the proposed mechanism
of specific metabolites connections in the herb, such as
limonene and citral on the GABAA neurotransmitter.
These effects occur through cholinergic receptors, where
muscarinic receptors produce antagonistic effects
especially on the M1 receptor. This receptor is located in
the nerve ganglia and front-parietal cortex and acts by
mediating excitatory postsynaptic potential due to
stimulation of intracellular calcium entry (Gerber et al.,
2001; López et al., 2009). Wake et al. (2000) analyzed
Wistar rats in traditional behavioral models such as the Y-
maze, social interaction test, forced swimming, and
elevated cross maze and used tea from the leaves of M.
officinalis as the testing sample. These authors
demonstrated anxiolytic effects on the CNS through

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56 Afr. J. Pharm. Pharmacol.
Table 1. Percentage composition of identified compounds in M.
officinalis total oil (Allahverdiyev et al. 2004).
Compound %
β-Cubebene 15.41
β-Caryophyllene 14.24
Sesquiterpene alcohol (C15H26O) 7.39
α-Cadinol 7.18
Geranial (citral a) 6.62
Neral (citral b) 5.82
Cadinol isomer 3.96
trans-b-ocimene 3.96
β-Cadinene 3.62
Citronellal 2.92
β-Cedrene 2.53
α-Bisabolene 2.51
Nerolidol 2.36
Nonanal 2.34
α-Copaene 2.26
Calarene 2.12
γ-Elemene 1.7
Pinocamphone 1.34
Linalool 1.32
α-Cubebene 1.27
β-Elemene 0.89
1-Hepten-3-ol 0.5
6-Metyl- 5- heptene-2-one 0.42
Geraniol 0.38
cis-β-ocimene 0.37
Identified 93.43
Unidentified 6.57
the ingestion of high doses of plant extracts and teas,
which did not induce respiratory depression or depressive
attenuation at the level of the CNS frame. However,
Coimbra (1994) pointed out that the treatment with M.
officinalis essential oil in high doses can lead to
mutagenic and neurotoxic effects.
Kennedy et al. (2002) used several concentrations of
Melissa’s essential oils (0.6, 1.2, and 1.8 g/kg/day) in
humans to evaluate the anxiolytic action of M. officinalis,
which occurs in the CNS by modulation of mood and
cognitive processes. These authors reported that the
most effective anxiolytic action was observed with the
dose of 1.8 g/kg/day because it acted on the cholinergic
system by decreasing stress and agitation in patients,
thereby, confirming the proposed anxiolytic effect after
ingestion of the plant’s extract.
Wake et al. (2000) indicate that the main mechanism of
action of M. officinalis extracts is based on its interaction
with cholinergic receptors, the acetylcholine receptor
(ACh). It is pointed out that Melissa will act displacing the
molecule [3H] - (N)-nicotinic nicotinic, [3H] - (N)-
escopolaminica, and muscarinic receptors by increasing
ACh released after nerve stimulation in a mechanism that
may be involved in improving cognitive function and
reducing agitation. This hypothesis is not confirmed, and
details of such a mechanism are still unknown.
Nevertheless, in contrast to Kennedy et al. (2002),
Abascal and Yarnell (2004) reported in a randomized,
double-blind trial control study using placebo with 20
healthy volunteers, that M. officinalis promoted an
improvement in attention and stress reduction with a
reduced dose (300 mg/kg/day) and decreased alertness
and memory loss with an increased dose (900
mg/kg/day). However, the study failed to confirm
significant cholinergic action.
Akhondzadeh et al. (2003) administered M. officinalis
leaf extracts (600 mg/kg/day) to a group of Alzheimer's
disease patients at mild to moderate stages of the
disease. The study demonstrated that this treatment
during 16 weeks resulted in a significant cognitive

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improvement and reduction in the agitation experienced
by some patients with this disease. This study
demonstrates a possible effective treatment of
Alzheimer's disease with M. officinalis resulting from
modulatory actions on mood and cognitive performance,
and on acetylcholine receptors in the CNS, following
acute administration.
Nowadays, M. officinalis is not individually used as a
pharmacological treatment for any disease. It is widely
used in conjunction with another plant such as in
Sonhare® whose pharmacogens from Valeriana
officinalis L. and M. officinalis L. have therapeutic
indications in relieving sleep difficulties, tension,
restlessness, and irritability. The Sonhare® has a medi-
cation package and insert information sheet that do not
inform which part of the plant is used or illustrate self-
medication usage. Nevertheless, this is a controlled
medication that is an excellent option in the prophilaxis of
advanced stress (Moura, 2006).
There are few in-depth studies available reporting on
the action in other systems on this subject because they
failed to address pharmacological aspects. However,
some can be cited such as the digestive system (Simmen
et al., 2006; Schemann et al., 2006) in which the action
can be linked to gastrointestinal motility reduction
(Bolkent et al., 2005). Moreover, Sadraei et al. (2003)
reported anti-spasmodic effects in the ileum due to one of
its major components, indicating that M. Officinalis
represents a good choice of herbal treatment for spastic
episodes in the gastrointestinal system.
This plant can present a protective action in the hepatic
system because of the presence of phenolic compounds
(Simmen et al., 2006; Schemann et al., 2006). However,
a study conducted by Müzell (2006) pointed that M.
officinalis displayed hepatotoxic effects after toxicity was
induced in mice by Acetaminophen, resulting in inhibition
or modulation of the activity of cytochromes P450
conferred by flavonoids present in the plant, and enabling
these to increase or reduce the concentrations of various
therapeutic drugs in plasma (Hodek et al., 2002). In the
same study, Müzell (2006) covered the renal system,
seeking the possibility of its protection from the plant’s
activity; however, the results were unsatisfactory because
the drug toxicity was intensified in this case.
Anti-inflammatory activity is also promoted by phenolic
compounds present in the plant, such as flavonoids, that
have the ability to inhibit the activity of monooxygenases,
lipooxigenases, cyclooxygenases (Svobodová et al.,
2003), oxidoredutases, and hydrolases such as the
hyaluronate lyase that catalyzes the degradation of
hyaluronic acid; inhibitions can be competitive in some
cases or allosteric in others (Havsteen, 2002). The
rosmarinic acid is among the variety of compounds cited
or not by different authors, which has shown anti-
inflammatory activity and inhibitory activity to 5-
lipoxigense, 3R-hydroxysteroid dehydrogenase, and lipid
Fermino et al. 57
peroxidation as reported by Nakazawa et al. (1998). This
compound features astringent, antioxidant, and anti-
inflammatory activity by inhibiting lipooxigenases and
cyclooxygenases, antibacterial and antiviral activity, and
antimutagenic effect (Pereira et al., 2005; Petersen and
Simmonds, 2003).
In addition to the anti-inflammatory activity, the antiviral
activity to Herpex simplex can be cited, which was
reported for the first time by May and Willuhn (1978). In
this context, Schnitzler et al. (2008) observed reduced
viral replication activity when using M. officinalis oil in
vitro.
Conclusion
The use of traditional medicine presents a significant risk
to public health because of the lack of knowledge
regarding drug interactions and possible toxic effects.
Research studies assessing the clinical efficacy of plants
are necessary. Based on this literature review, it was
concluded that extracts of M. officinalis have effective
anxiolytic activity in reducing stress and physiological
disturbances due to its direct interaction with the CNS
and the cholinergic and GABAergic systems. Its
mechanism of action is still controversial. Some authors
suggest it is active on the GABAergic system and others
on the cholinergic system. Abascal and Yarnell (2004)
report no significant action on the cholinergic system
while Wake et al. (2000) indicate that the main
mechanism of action of M. officinalis is based on its
interaction with cholinergic receptors.
Conflict of interest
Authors declare that there are no conflicts of interest
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