Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210

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Pharmacological Research - Modern Chinese Medicine

journal homepage: www.elsevier.com/locate/prmcm

Essential oils: Chemical constituents, potential neuropharmacological

effects and aromatherapy - A review
Jiahao Liang a,1, Yuyu Zhang b,1, Penghao Chi a, Haonan Liu a, Zhaoxuan Jing a, Haojie Cao a,
Yongliang Du a, Yutong Zhao a, Xia Qin b, Wei Zhang b,∗, Dezhi Kong b,∗
a
School of Basic Medical Sciences, Hebei Medical University, Shijiazhuang, China
b
Department of Pharmacology of Chinese Materia Medica, School of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang, China

a r t i c l e i n f o a b s t r a c t

Keywords: Background: Essential oils (EOs) are a plant-derived volatile mixture. Due to their extensive biological activity,
Essential oils EOs have been utilized as ancient remedies to treat a variety of illnesses.
Chemical compositions Objectives: Our review aims to expand our understanding of EOs’ biological activity on the central nervous system
CNS
(CNS) and to highlight the importance of utilizing EOs in CNS disorders.
Therapeutic potentials
Method: A systematic literature search was conducted using PubMed, ScienceDirect, China National Knowledge
Aromatherapy
Infrastructure (CNKI), Springer Link, Wan-fang database, and Chinese Biomedicine Database (CBM). The search
was conducted to collect relevant journals and contents using the following terms: "essential oils", "aromatherapy",
"essential oils" and "CNS". Language of publications was unlimited.
Results: EOs are concentrated volatile aromatic liquids extracted from natural plants with different chemical
compositions, obtained by physical and chemical methods such as distillation and pressing. This paper explores
the effects of EOs products on CNS including promoting intelligence, improving sleep, promoting cognition and
memory, anti-anxiety and depression, sedation and anti-epilepsy. EOs exert their neuropharmacological effects
through blood circulation or the olfactory system. This paper summarizes clinical studies showing that aromather-
apy could improve sleep, relieve preoperative anxiety and postoperative PONV, relieve gynecological disease
pain, and play a role in hospice care.
Conclusion: The present findings suggest that EOs have neuropharmacological effects such as nootropic, sleep
improvement, anti-dementia, anti-anxiety and depression, analgesic effect, and antiepileptic, emphasizing the
importance of EOs in CNS disorders and indicating the potential clinical application.

1. Introduction
Essential oils (EOs) are concentrated volatile aromatic liquids de-
rived from natural plants and can be extracted from their flowers, leaves,
seeds, peels, branches, bark, wood, roots, underground stems, gums or
oily resin [1]. It is a collection of secondary metabolites that aid plants
in controlling their growth and interacting with other species or plants.
Each EO is a complex mixture made up primarily of alcohols, esters,
aldehydes, oxides, phenols, coumarins, ethers, ketones, acids, and other
ingredients [2]. EOs are frequently used in a variety of products for ap-
plications such as sterilization, virus killing, fungicidal, anti-parasitic,
insecticidal, pharmaceutical, and cosmetic. Especially in the cosmetic
industry, EOs are widely used for their aromatic scent, e. g. lavender oil,
rose oil and peppermint oil [3]. When using products containing EOs,
people have observed that these oils have specific effects on the central
nervous system (CNS), including promoting intelligence, affecting sleep,
promoting cognition and memory, anti-anxiety and anti-depression, se-
dation, etc. [4]. Although numerous studies have highlighted the ben-
eficial pharmacological effects of EOs and also discussed the possible
underlying mechanisms, more researches are still needed to pay more
attention the complexity and variety of EOs on CNS.
EOs can be used in a variety of ways, including inhalation through
the nose, oral administration, and oil massage, which can be collectively
referred to as aromatherapy. Aromatherapy in clinical settings has been
attempted by some researchers and nursing staff [5], and it appears to
be practicable as a complementary or alternative therapy due to the
affordability, ease of use, mild effects, rapid elimination, low toxicity,
and significant efficacy of EOs [6].

∗
Corresponding authors.
E-mail addresses: weizhang@hebmu.edu.cn (W. Zhang), kongdezhi@hebmu.edu.cn (D. Kong).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.prmcm.2022.100210
Received 1 November 2022; Received in revised form 21 December 2022; Accepted 23 December 2022
Available online 24 December 2022
2667-1425/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
J. Liang, Y. Zhang, P. Chi et al.
In this review, we focus on the composition of EOs, their roles and
mechanisms in the CNS, and their application in aromatherapy, which
would expand our understanding of EOs’ biological activity in the CNS
and highlight the importance of their utilization in neurologic disorders.
2. Ingredients of EOs
EOs are complex mixtures of volatile organic compounds, which
are usually composed of more than 500 chemicals. Some chemicals are
found in a variety of plant EOs, such as camphene and linalool. Some
substances are unique to some EOs, such as menthol and camphor. As a
well-known EO, lavender EO is mainly composed of linalool acetate,
linalool, perillyl alcohol, eucalyptus (eucalyptus) [7]. There are two
kinds of chamomile, both of which contain similar ingredients, includ-
ing sesquiterpene (myrrh alcohol, farnesene), sesquiterpene lactone (tea
matzolin, genistein), flavonoids (apigenin, luteolin) and volatile oil [8].
Peppermint contains menthol, menthone, menthol acetate as the main
ingredients. Secondary ingredients include 1,8-eucalyptol, propanone,
bitter substances, caffeic acid, flavonoids and tannins, as a part of plant
secondary metabolism, these compounds are synthesized and exist in
different parts of plants (flowers, leaves, roots, bark, fruits, seeds, resins,
etc.), and the chemical constituents of EOs obtained from different parts
of the plants are also different [9]. According to the chemical structure,
these EOs can be divided into phenols, terpenoids, aldehydes, ketones,
ethers, epoxides and other compounds [10]. The classification and rep-
resentative compounds are shown in Table 1. Most plant EOs can be
prepared by distillation (including steam distillation and step-by-step
distillation), pressing and other physical methods, and scientists can
also obtain the target essential oils by chemical synthesis, as detailed
in Table 1
3. Neuropharmacological effects of EOs
3.1. Nootropic effects
Modern pharmacological studies have proved that various aromatic
Chinese medicines such as rosemary have nootropic effects [34]. To
evaluate the effects of oral rosemary on memory performance, 68 col-
lege students were randomized to receive 500 mg either rosemary or
placebo twice daily for one month, and then their memory performance
was evaluated based on the Prospective and Retrospective Memory
Questionnaire at baseline and after one month [35]. Lower scores sug-
gest fewer memory problems. The results showed that the mean score
was significantly lower in the rosemary group, indicating that rosemary
significantly improved the memory performance of college students. Cao
[36] also tested the effect of rosemary EO on the learning and memory
ability of C57BL/6 mice with olfactory epithelial damage. The results
showed that rosemary EO could improve the learning ability of mice by
altering the expression of AChE and GluR1.
Hancianu et al. [37] assumed that lavender EO could improve learn-
ing and memory due to its antioxidant and anti-apoptotic activities, ten
rats were inhaled a total of 200 𝜇l of lavender essential oils over 60 min
(daily, for 7 days). The total content of reduced glutathione (GSH) and
malondialdehyde (MDA) were significantly decreased compared with
the control group and the positive control group. Increased MDA levels is
an important marker of lipid peroxidation in vivo, indicating that laven-
der essential oil has antioxidant properties. Additionally, the lavender
EO has anti-apoptosis activity, by inhibiting DNA fragmentation during
apoptosis. However, Moss et al. [38] didn’t believe that lavender EO
could improve learning and memory. He randomly divided 144 people
into 3 groups that received either one of the two EOs (lavender or rose-
mary) or no EO (control group). The result showed that both EOs signif-
icantly decreased the performance of working memory compared with
control group, while the rosemary group produced better performance
than the lavender group.
2
Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210
Besides lavender and rosemary EO, volatile oils from Acorus tatari-
nowii Schott and lemon could also improve learning and memory [39].
Zhou et al. [40] investigated the effect of Acorus on spatial learning
and memory ability in rats with learning memory impairment. They
found that the EOs-treated group exhibited a shorter escape latency and
a greater number of times crossing the platform according to the Mor-
ris water maze results. The reason may be that the expression levels
of glial fibrillary acidic protein (GFAP) and malondialdehyde (MDA)
were reduced, while superoxide dismutase (SOD) levels were increased
in the Acorus EO treated hippocampus. These findings imply that the
nootropic effects of Acorus is related to its antioxidant activities and
down-regulation of fibrillary acidic protein expression in hippocampal
astrocytes. Ogeturk et al. [41] discovered that rats inhaled lemon EO
spent less time looking for the target site than the controls, indicating
that lemon EO could increase memory and learning, and increasing the
attention level of rats. It can be found that the nootropic effects of essen-
tial oils are derived from the antioxidant and anti-apoptotic activities,
which are mostly reflected by superoxide dismutase, MDA, and other
molecules. Essential oils play a puzzling role by changing the expres-
sion level of these biomolecules.
3.2. Hypnotic or wake-promoting effect
Some studies have shown that certain EOs have sedative and hyp-
notic effects [42], including lavender, valerian and rose EOs. Buchbauer
et al. [43] investigated the sedative effects of lavender EO and its main
ingredients (linalool and linalyl acetate) on mice. The results demon-
strated that mice given lavender EOs showed a significant reduction
in spontaneous locomotor and sleep latency, and prolonged sleep time.
Even if the mice were overactive by caffeine, lavender EO could reduce
their activity to near normal levels.
However, some EOs or aromatic herbs are not hypnotic or even detri-
mental to sleep. Studies [44] have shown that styrax EO can significantly
prolong the sleep latency and shorten sleep duration in pentobarbital
sodium-treated mice. Zhang [45] found that styrax EO shortened the
time of righting reflex in mice after pentobarbital injection, suggest-
ing that styrax EO may have a wake-promoting effect. Cheaha et al.
[46] investigated the effect of the EO from vetiver (Vetiveria zizanioides)
inhalation on sleep and EEG patterns in rats. They found the rats inhal-
ing vetiver EO displayed a reduction in percentage time of slow-wave
sleep, as well as in total sleep time.
EOs exhibited a hypnotic or wake-promoting effect, which may de-
pend on the type of EOs. Komori et al. [47] studied the effects of in-
halation of multiple EOs on sleep in rats, and the results showed that
inhalation of valerian or rose EO significantly prolonged the time of
pentobarbital-induced sleep, while lemon EO shortened the sleep time.
EEG studies have showed that inhalation of rose EO had no significant
effect on sleep, but valerian EO significantly reduced sleep latency and
prolonged total sleep duration, while lemon EO increased sleep latency.
The content of 𝛾-amino acetic acid transaminases (GABA), which is ben-
eficial for sleep, was increased in valerian group, and decreased in the
lemon group in the brain.
3.3. Anti-dementia
Dementia is an intellectual disability syndrome characterized as im-
pairments in cognitive performance such as memory, judgment, atten-
tion span, and problem-solving capabilities. Alzheimer’s disease (AD)
is the most common type of dementia in the elderly. Numerous inves-
tigations have demonstrated that the causes of dementia are related
to amyloid beta-protein accumulation, tau protein hyperphosphoryla-
tion, acetylcholine reduction, oxidative stress, mitochondrial malfunc-
tion, unstable compensatory function, and mental disorder. However,
acetylcholine insufficiency, oxidative stress, inflammatory response and
amyloid-beta deposition play important roles in the occurrence of de-
mentia.
 J. Liang, Y. Zhang, P. Chi et al.
Table 1
Chemical composition of essential oils.

Chemical composition Another name Example Structural formula Preparation Industrial Pharmacological
method applications effects Refs.

Monoterpene alcohol
camphene camphor terpene Camphor, firoil, herbs, Prepared from Used in the synthesis of Neuropathic pain,
orange blossom, etc. isomerization of pinene spices, pesticides, Inhibition of [11]
with hydrated titanium camphor, etc. inflammation, Lowering
oxide as catalyst at 135 blood lipids
± 2°C

pinene pine terpene turpentine 𝛼-pinene and 𝛽-pinene Alpha-pinene is used as anxiolytic,
can be obtained by an antioxidant. The main anticonvulsant and [12]
fractional distillation of industrial use of neuroprotective
turpentine under 𝛽-pinene is thermal gastroprotective,
reduced pressure cracking to myrcene cytoprotective, action

Limonene Limonene Tangerine Oil, Lemon It is obtained by Raw materials for Anti-dementia,
Oil, Orange Oil, distillation from the preparing artificial anti-cancer, antioxidant, [12]
Camphor White Oil, corresponding essential orange blossom, sweet
Peppermint Oil, Neroli oils or as a by-product in flower, lemon, and
Oil the process of processing bergamot oil, and raw
3

camphor oil and materials for synthetic

synthesizing camphor. rubber
The obtained dipentene
can be purified by
distillation to obtain
limonene

Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210

Esters
Linalyl acetate Agaryl acetate Natural Bergamot, Linalool is added to a It is the main component Treatment of insomnia,
Lavender, Fragrance mixture of acetic of jasmine, ylang-ylang, analgesic and [13]
anhydride and sweet-scented antihypertensive
phosphoric acid for osmanthus, lilac and properties
esterification at low other floral fragrances
temperature

Methyl phthalate Methyl Salicylate Calfgrass Oil, Fractionation of It is often used as a toxicity
Wintergreen Oil, Birch wintergreen oil under flavoring agent for cavity [13]
Oil, Green Tea Seed vacuum, collecting the medicines and
Oil, Clove Oil, Oak middle part free of acid pharmaceutical
Tree Oil, Tuberose Oil and water preparations in
pharmaceutical
preparations.

(continued on next page)

 J. Liang, Y. Zhang, P. Chi et al.
Table 1 (continued)

Chemical composition Another name Example Structural formula Preparation Industrial Pharmacological
method applications effects Refs.

methyl benzoate methyl benzoate Molecular mechanism of For the preparation of kill insects
methyl benzoate fragrances and artificial [14]
biosynthesis in coronary essential oils
aneurysms

Monoterpene aldehyde
Citral Natural Citral Maple Cod Oil and Pine Citral can be separated Used as a flavoring agent Analgesic, Antibacterial,
Oil from essential oils, and to formulate Antioxidant, Anticancer, [15]
can also be obtained lemon-flavored products Antidiabetic and
from industrial geraniol such as lemon essence Antiinflammatory
by dehydrogenation of
industrial geraniol under
reduced pressure with a
copper catalyst.

Citronellal androgenic aldehyde Citronella Oil and Obtained by steam It is used to prepare Anticonvulsant,
Eucalyptus Eucalyptus distillation of citronella citrus and cherry flavors, antipyramidal and [16]
Oil oil and treatment with and also used to prepare wound healing,
sodium bisulfite low-grade soap flavors, antidiabetic
as raw materials for cardiomyopathy
other flavors. And it also
4

is used to synthesize
menthol.
Oxides

1,8-Cineole 1,8-Cineole Aromatic wolf leaf, Extracted from plant Manufacture of Inhibits nerve pain,
galangal, eucalyptus essential oils pharmaceutical products. anti-inflammatory and [17]
camphor, rosa white Flavor and spice antioxidant for the
camphor, cardamom blending treatment of respiratory

Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210

and cardiovascular
diseases

Phenol
Eugenol 2-Methoxy-4-allylphenol Clove Oil, Purple Natural eugenol is It can be used as a soap, Anesthetic,
Galangal Camphor mainly obtained from a fragrance for taking, neuroprotective, [18]
the volatile oil obtained and can also be made anti-inflammatory
by distillation of the into a unilateral essential potential and antioxidant
dried flower buds of oil of many flowers, properties
cloves and then through which can be used to
petroleum ether prepare
extraction, acidification, gypsophila-shaped
neutralization, spices, and can be used
rectification and other to prepare strong
steps. fragrance of dried fruits,
etc.
(continued on next page)
 J. Liang, Y. Zhang, P. Chi et al.
Table 1 (continued)

Chemical composition Another name Example Structural formula Preparation Industrial Pharmacological
method applications effects Refs.

Thymol 5-Methyl-2- Labiata thyme, thyme, It is prepared from It is one of the cigarette Antioxidant, antiseptic
isopropylphenol oregano, vanilla, m-cresol, fuming sulfuric additives. Used as a drug and antiproliferative [19]
umbelliferous parsley, acid and isopropanol and indicator, as a properties for anticancer
seeds through two-step preservative
reaction of sulfonation
and alkylation

Coumarin
coumarin Oxynaphthalene Black bean, fragrant Salicylaldehyde acetic Generally not for food, good anti-cancer
snake chrysanthemum, anhydride 73g treated smoking and external use substance [20]
wild vanilla, orchid anhydrous potassium are allowed
acetate, etc. were
prepared in distillation
apparatus
Ether
anethole Sheng Baining Essential oils such as Cool anise oil or anise oil Flavouring agents for Neuroprotective or
burley tobacco leaf, oil to separate out crystals, pastry, fennel essence antithrombotic. [21]
of fennel, oil of cumin, which can be obtained and licorice essence, for Anti-inflammatory,
and oil of star anise by distillation and beverages, etc. anticancer and
recrystallization with chemopreventive,
alcohol. antidiabetic,
immunomodulatory,
5

Methyl Eugenol Eugenol methyl ether Exist in extracts of Obtained by methylation For the preparation of reduce anxiety
natural plants such as of eugenol clove aroma [22]
asarum and cloves

Monoterpene alcohols
Linalool linalool, coriander Linalam oil, linalool It is obtained by Fragrances, deodorants, Sedative, anti-dementia,

Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210

alcohol, galolol, linalool oil, galago oil, fractional distillation of anti-caries, insecticides, antibacterial [23]
rosewood oil, lavender essential oil as raw
oil, bergamot oil, many material and synthesized
flower oils and in green by chemical method.
tea Synthesis of Linalool
from Turpentine

Menthol Menthol The main ingredient in Extraction of Menthol Used as a flavoring agent local analgesia
peppermint and from Peppermint by in toothpaste, perfume, [24]
peppermint essential Steam Distillation and beverages and candy,
oils Organic Solvent etc.
Extraction, Supercritical
Carbon Dioxide

(continued on next page)

 J. Liang, Y. Zhang, P. Chi et al.
Table 1 (continued)

Chemical composition Another name Example Structural formula Preparation Industrial Pharmacological
method applications effects Refs.

Citronellol vanillyl alcohol D-citronellol is mainly D- and racemic It is an indispensable raw Anti-dementia, in vitro
found in rue oil, citronellol are material for the antibiotic and antifungal, [25]
citronella oil and manufactured from the preparation of various etc.
lemon eucalyptus oil; citronellal moiety in rose flower fragrances,
L-citronellol is mainly essential oils and can be used in a
found in rose oil and variety of cosmetic
essential oils of fragrances
geranium plants

Sesquiterpene alcohols

patchouli alcohol Patchouli alcohol Patchouli Extracted from patchouli Patchouli Brain protection,
essential oil Oil—Determination of antibacterial, [26]
Patchouli Alcohol—Gas anti-inflammatory and
Chromatography other functions
6

nerol C10 H18 O Rutaceae plant sweet The geraniol is reacted Nerol is a valuable spice. Antibacterial
orange, bergamot, with hydriodic acid, and For the preparation of [27]
honeysuckle plant the excess hydriodic acid rose and orange blossom
honeysuckle is removed with alkali to and other floral
obtain nerol mixed with fragrances
geraniol, and then steam

Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210

distillation or vacuum
distillation is performed
to obtain the finished
nerol.

Sesquiterpenes
cerulean Variant allen Mostly found in Cerulean is a blue Extracted from Anti-allergic effect on
Asteraceae essential substance formed by Asteraceae essential oil skin [28]
oils distillation by distillation

(continued on next page)

 Table 1 (continued)

J. Liang, Y. Zhang, P. Chi et al.

Chemical composition Another name Example Structural formula Preparation Industrial Pharmacological
method applications effects Refs.

Ketones

Mentholone Mendonone Natural Mint, Menthone can be It is a spice for preparing Has analgesic effect with [9]
Miscanthus obtained by reduction of geranium oil, a raw peppermint
pulegone or piperonone material for edible
cooling flavors, and a
good spice for
toothpaste. Can be used
to make artemisinin

camphor 1,7,7-Trimethylbicyclo Camphor is extracted The extraction method is Mostly used in the It has certain toxicity,
[2.2.1]heptan-2-one from the trunk of the to cut the trunk into manufacture of but can be used as a [29]
camphor tree, and the small pieces and distill it mothballs traditional Chinese
older the camphor tree, with water. After the medicine
the higher the camphor oil is heated, it
proportion of camphor. rises with the water
vapor, and it can form
camphor after it comes
into contact with the
pre-placed pottery jar
and cools.
Acid
7

Lauric acid Dodecanoic acid Coconut Oil, Oil Palm One is obtained from
Seed Oil, Babassu Oil natural vegetable oils by
saponification or
decomposition under
high temperature and
high pressure; the other
is separated from
synthetic fatty acids
Cinamic acid is a raw suppress cancer
material for the [30]
production of soaps,
detergents, cosmetic
surfactants and chemical
fiber oils

Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210

cinnamic acid 𝛽-Phenylacrylic acid Cinnamon Bark, (1) Perkin synthesis
Benzoin method; (2) Benzoic
acid-acetone method; (3)
Benzylidene
dichloride-anhydrous
sodium acetate method
Flavors, Food Additives
Treatment of diseases of
the nervous system, [31]
cancer, bacterial
infections, diabetes and
other diseases

bay leaf C10 H16 O2 Exist in flue-cured is a plant extract used in cigarettes Inhibit melanin
tobacco leaves, burley [32]
tobacco leaves, oriental
tobacco leaves

isovaleric acid 3-Methylbutyric acid Naturally found in It is obtained by the
apples, cheese, bread, oxidation of isoamyl
valerian, lemongrass, alcohol or
melaleuca, spearmint, isovaleraldehyde.
lemon leaf. Refining method: used
for fractionation after
drying with water and
sodium sulfate
Commonly used in baked treat depression
goods, meat products. [33]
Used in the manufacture
of
medicines,spices,condiments,
etc.
J. Liang, Y. Zhang, P. Chi et al.
Many EOs present anti-dementia effects by reducing A𝛽 toxicity
and neurological dysfunction. Watson et al. found that lemon EO and
lavender EO could reduce physical non-aggressive behaviors in patients
with Alzheimer’s disease [48]. Other researchers indicated that Pinus
halepensis EO has neuroprotective effects as it could recover the mem-
ory misbehavior in y-maze tests caused by amyloid 𝛽 [49]. Bergamot oil
is another EO that could reduce A𝛽 deposition.
EOs improves AD symptoms by regulating cholinesterase activity.
Rosemary EO could inhibit acetylcholinesterase activity in rat brain
and thus improve the memory in model of AD rats. By GC-FID and
GC-MS, researchers found that 𝛽-ocimene, linalool, 𝛽-phenylnitroethane
and humulene were the main ingredients in Dennettia tripetala EO,
and these compounds maybe related to its anticholinesterase activ-
ity [50]. Eyup Bagci’s study showed that the inhalation of Anthriscus
nemorosa EO prevented dementia, anxiety, and depression caused by
scopolamine. Salvia multiflora EO also could reduce cognitive deficits
caused by scopolamine. According to the molecular docking experi-
ment, RS Boiangiu’s team found limonene in rose EO could diffuse into
the active sites (SER198, HIS438, LEU286, VAL 288, and PHE 329) of
acetylcholinesterase driven by van der Waals interactions. Thus, they
explained limonene’s anti-acetylcholinesterase activity at the molecular
level [51]. (S)-Limonene and (S)-Perillyl alcohol in lemon EO could im-
prove the dementia symptoms induced by scopolamine, because they
increased the level of catalase and superoxide dismutase, and decreased
the level of glutathione.
In addition, many EOs preserved cognitive and alleviated dementia-
like behaviors by their antioxidant effects via scavenging free radicals.
For example, bergamot EO is helpful for treating ADs, since it contains
polyphenols that have strong antioxidant activity and anti-inflammatory
activity [52,53]. Pistacia chinensis Frankincense EO prevented the de-
mentia induced by LPS by effectively scavenging free radicals and im-
proving the activity of SOD and CAT in the brain [54]. Lemongrass EO
could effectively improve the symptoms of AD caused by D-galactose
combined with AlCl3 , and the mechanism may be related to restoration
of glutathione peroxidase PX (GSH-PX) level, reduction of malondialde-
hyde (MDA), inhibition of TChE, increasement of ChAT and ACh content
in brain [55].
Some EOs have both antioxidant and cholinesterase inhibitory po-
tential for AD treatment. Muscimol, from thyme herb and muscadine,
has been considered as a free radical scavenger because of its good
iron-reducing ability, as well as an acetylcholinesterase inhibitor [54].
Lignum vitae EO could exert the antioxidant effects and regulate the
cholinergic activity in the hippocampus of rats [55]. According to Y
maze test and the new object recognition test, thyme EO ameliorated
dementia by scopolamine, and which partly attributed to its inhibiting
acetylcholinesterase (AChE) activity demonstrated by L Capatina and his
team [56]. Zataria multiflora Boiss EO exhibited the anti-dementia ef-
fect related to the antioxidant, anti-inflammatory and anticholinesterase
activities [57].
The garlic ethyl acetate fraction reduced oxidative stress in PC12
cells, and increased the 5-HT levels in rat brain, which may be the un-
derlying mechanisms that the rats treated with garlic homogenate were
less likely to develop dementia [58]. Curcumin exerts its anti-dementia
effects through multiple pathways. It inhibits the formation and pro-
motes the disaggregation of amyloid-𝛽 plaques and amyloid anterior
protein (APP), which is related with its phenol hydroxyl group and the
flexible part of the joint. It also attenuates the hyperphosphorylation of
Tau and enhances Tau clearance. Besides, it exerts anti-dementia effect
by lowering cholesterol, modifying microglial activity, inhibiting acetyl-
cholinesterase activity, exerting antioxidative effect, and mediating in-
sulin signaling pathways [59]. It should be mentioned that EOs exerts
anti-dementia effects through a synergistic effect of multiple compo-
nents. Rose EO could alleviate the symptoms of AD, however, the main
ingredients, 𝛽-citronellol and geraniol, are not as effective as the EO
itself [60].
8
Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210
3.4. Anti-anxiety effect
Excessive and uncontrollable worry that negatively impacts a per-
son’s physical and mental health is referred to as anxiety. Anxiety-
related disorders have become increasingly important medical and so-
cial issues. Currently, serotonergic nerve transmission, the D3 dopamine
receptor, as well as genetic factors are important causes of anxiety.
Previous studies have demonstrated that EOs have anxiolytic proper-
ties. The active constituents responsible for the anxiolytic effects have
also been identified, such as linalool in lavender, limonene in citrus,
caryophenol and 2-phenylethanol in rose, 𝛽-caryophyllene in propo-
lis, 4-eucalyptus in Salvia miltiorrhiza, apigenol in thyme, (E)-methyl
isobutyl phenol in Pimenta pseudocaryophyllus leaf, etc [61–70].
Zamanifar et al. [71] examined the effect of lavender EO on nurses’
anxiety levels. Nurses engaged in clinical work were randomly chosen
and divided into four groups: a control group, a group receiving mu-
sic therapy, a group receiving lavender aromatherapy, and a combined
treatment group. The levels of anxiety were measured using an anxi-
ety scale before and after the experiment. The results showed that the
anxiety levels in the lavender aromatherapy group were significantly
lower than those in the control group. The combination of aromather-
apy and music was also most effective in reducing anxiety. López et al.
[72], also demonstrated the anti-anxiety effect of lavender EO, and they
noted that the anxiolytic properties were related to the inhibition of the
serotonin transporters and N-methyl-D-aspartic acid (NMDA) receptors.
Geranium EO significantly reduced the maternal anxiety levels ac-
cording to a randomized clinical trial [73]. 20 women were randomly
split into two groups and treated with either a footbath infused with
EOs or a regular footbath. The group received footbaths infused with
Polyporus umbellate EO significantly reduced the experimenter’s anxi-
ety [74], demonstrating its potential ability for anxiety treatment.
The anxiety of mice was reversed after oral administration of propo-
lis EO in the elevated maze experiment [67], and female rats’ ex-
ploratory behavior in the elevated maze experiment was significantly
improved by propolis EO intraperitoneal administration [75]. Sabina
vulgaris EO could reduce male rats’ anti-anxiety levels by decreasing
the level of interleukin-6 and monocyte chemoattractant protein [76].
It was reported that sandalwood oil, reticulated Coptis chinensis EO,
Ducrosia EO and coriander oil also have anxiolytic effects [77–79].
3.5. Antidepressant effects
The most prevalent psychological ailment today is depression, which
is also the most significant kind of modern human mental illness due
to its long-term persistence [80]. Nowadays, front-line clinical antide-
pressants include selective serotonin reuptake inhibitors, traditional tri-
cyclic, tetracyclic antidepressants and monoamine oxidase inhibitors.
However, these antidepressants are not perfect. EOs have attracted
much attention as a complementary and alternative drug for the treat-
ment of depression because of its high efficacy and low side effects in
recent years. Shen Shen [81,82] examined the antidepressant effects of
rosemary and lemongrass EO based on the tail suspension test (TST).
The results revealed that the rosemary group and the lemongrass EO
group significantly reduced the immobility time compared to the control
group, indicating their significant antidepressant effect. The Edinburgh
Postpartum Depression Scale (EPDS) and Generalized Anxiety Disorder
Scale (GAD-7) were tested on postpartum patients treated with rose-
lavender EO treatment [83], and the depression mood of women was
improved with significant increasements in EPDS and GAD-7 scores at
both the midpoint (2 weeks) and endpoint (4 weeks). Li Hua [84] used
chronic unpredictability moderate-intensity stress (CUMS) and solitary
methods to study the effect of lavender EO on the depression behav-
ior in mice. Lavender could effectively alleviate depressive behavior in
mice due to the increased expression of 5-HT, c-fos, and c-jun in the
hippocampus, hypothalamus, and amygdala tissues. Zhang [85] used
J. Liang, Y. Zhang, P. Chi et al.
rosemary complex EOs to treat patients with post-stroke depression and
anxiety comorbidity (PSCAD), and the EO could significantly improve
the depression and anxiety symptoms of patients based on HAMD and
HAMA scores. Other EOs also have obvious antidepressant effects, such
as geranium and basil EO, sweet orange EO [86,87], etc.
3.6. Analgesic effects
Modern medicine’s concept of "pain" is a complex psychological and
physiological activity that is frequently caused by tissue damage. Pain
is a common feature of many diseases and is frequently used as a warn-
ing sign of disease. However, severe or chronic pain severely affects the
quality of life in patients. Reducing perceived pain intensity and inter-
vening in negative emotions are focused broadly by healthcare work-
ers. Lots of analgesic drugs are available in the clinic, but they have
some adverse effects more or less. Currently, the analgesic impact of
EOs raises concerns. The following is a summary of how EOs work as
analgesics.
The analgesic activity of lavender EO was studied by the researchers
using a formalin-induced pain model test. They found that lavender EO
had analgesic effects similar to those of indomethacin or tramadol by
targeting G-protein coupled receptors [88]. Similar reports can be found
for bergamot EO to alleviate formalin-induced or capsaicin-induced pain
[89–91].
Bornyl alcohol EO significantly reduced the pain induced by in-
traperitoneal injection of acetic acid, which was achieved by modulat-
ing TRPM8 ion channels to exert the analgesic effect [92–95]. Dose-
dependent antinociceptive effects of pod EO were demonstrated by
acetic acid-induced writhing test and hot plate test. Cis-basil and -
pinene have been discovered to be the main analgesic constituents of
pod EO [96]. Ophiopogon EO, especially the active component thymol,
attenuated acetic acid-induced pain behavior by blocking voltage-gated
sodium channels and inhibiting interferon-𝛾 (IFN-𝛾) production [97].
3.7. Antiepileptic effects
Epilepsy is a neurological disease that can lead to periodic sponta-
neous seizures as well as memory and learning disabilities. The causative
factors and detail mechanisms of epilepsy remain unclear. The patho-
geneses were related to the excessive activation of glutamate receptors,
imbalance between oxidation and antioxidant effects, oxidative stress,
function of GABA receptors, intracellular overload of calcium, mito-
chondrial failure, sodium pump activity, etc. [98,99]
Menthol, menthone, limonene, methyl acetate and other components
with antioxidant activity in peppermint EO have the prospect of treating
epilepsy [100]. It has been proved that the role of peppermint pepper
oil in epileptic models induced by PTZ and pilocarpine, prolonging the
duration of seizures and reducing the frequency and intensity of convul-
sions [101]. Other related mechanisms of them have also been explored,
e.g., limonene exerts the anti-epileptic effects through binding to GABA
receptor [102]; menthol mainly treats epilepsy via its enhancement of
tonic GABAergic inhibition [103]; linalool exerts antiepileptic effect by
blocking glutamate NMDA receptor [104].
By neutralizing specific ROS, EOs and their active components could
protect neurons, prevent neuronal death, and improve cognitive im-
pairment in epilepsy. Tambe et al. demonstrated that borneol delayed
catatonic seizures and progressive neuronal damage during application.
In the epileptic model, all groups treated with different doses of bor-
neol significantly reduced the level of oxidative stress triggered during
epileptogenesis. In addition, borneol also reduced the expression and ac-
tivation of inducible nitric oxide synthase and inhibited neuronal apop-
tosis, thus reducing the production of ROS in rat cortical neurons and
promoting neuroprotection [105].
EOs contain a large number of terpenoids, which play a role in regu-
lating sodium pump and thus they exert the anti-epilepsy. For example,
haw acid reduces the excitability of pyramid neurons by increasing the
9
Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210
amplitude of M current, thus producing antiepileptic activity. It sup-
presses sodium current mainly by affecting Nav1.2 and Nav1.7 sodium
channels [106].
Although these studies have shown that EOs has antiepileptic effects,
people with epilepsy should be careful when taking EOs, as many EOs
can also lead to epileptic symptoms. For example, camphor and euca-
lyptus EOs have been used in the past to trigger epilepsy in patients with
mental illness [107].
4. Aromatherapy
4.1. Sleep promotion
Aromatherapy has been widely used in CAM (Complementary and
Alternative Medicine) to improve sleep. A randomized clinical trial
of college students showed that rosemary EO improved sleep quality
and significantly reduced sleep latency in college students. The ex-
periment took rosemary in capsules (500 mg each twice a day for a
month) and at the end of the experiment, 21(61.76% of the total) of
the experimental group were considered to have better sleep quality,
while only 16 (47.06%) met the criteria based on the Pittsburgh Sleep
Quality Inventory (PSQI) before the treatment [35]. Similarly, laven-
der EO can be inhaled for sleep improvement. The experimental group
inhaled lavender for 20 minutes twice a week for a total of 24 times
over the course of 12 weeks. After 12 weeks of lavender aromather-
apy, the sleep quality of middle-aged women with insomnia was im-
proved [108]. 16 men and 15 women intermittently received lavender
EO stimulation between 23:10 and 23:40 (the first 2 minutes of each
10-minute interval). All participants feel more energized in the morn-
ing according to their higher percentages of slow-wave sleep (SWS). In
contrast to men, women experienced an increase in stage 2 sleep (light
sleep), and a decrease in REM (rapid-eye movement) sleep duration
[109]. Thus, lavender inhalation is a novel method of promoting deep
sleep and producing gender-related sleep effects in both young men and
women.
4.2. Improvement of preoperative anxiety
Aromatherapy significantly reduces preoperative anxiety in patients
awaiting low-risk surgery. The three most widely used aromatic reme-
dies are lavender EO, citrus EO, and rose EO. Inhalation, massage and
oral administration are typical methods of aromatherapy. Short-term
inhalation of EO aromatherapy appears to be more effective in clin-
ical application [110]. Lavender aromatherapy can reduce anxiety in
women undergoing breast surgery: two drops of 2% lavender oil ap-
plied to the inside of a plastic oxygen mask and inhaled by the subject
for 10 minutes was shown to help female patients feel happier [111].
Anxiety during dental surgery will have a significant physiological im-
pact, causing a number of undesirable physiological changes, including
trembling, pupil dilation, arrhythmia, vasovagal reaction, dyspnea and
even more pain due to a decreased excitability threshold, which will
prolong surgery time and produce poor postoperative recovery [112].
An interesting study was conducted: adding two drops of pure lavender
EO to 100ml of water in a humidifier and running the humidifier prior
to the pediatric patient’s arrival found a significant reduction in anxiety
in children during dental visits [113].
4.3. Mitigating PONV
Postoperative nausea and vomiting (PONV) are the most common
postoperative complication. Aromatherapy can reduce PONV in adult
surgical patients [114]. The researchers discovered that aromatherapy
using ginger oil or a combination (ginger, spearmint, mint, and car-
damom) could significantly reduce the severity of PONV in acute care
centers [115]. Patients who showed signs of PONV were given gauze
J. Liang, Y. Zhang, P. Chi et al.
Fig. 1. EOs are transmitted to the brain through olfactory, the respiratory system and the skin. (a) EOs affect the nervous system by transferring chemical signals
into electrical signals through the olfactory bulb. (b) Transmission pathway of EOs in the olfactory system. EOs cross the skin (c) and air-blood barrier (d) to enter
the blood circulation.
pads saturated with a randomly selected aromatherapy ingredient (gin-
ger EO, a blend of ginger, mint, and cardamom EO, or isopropyl alcohol),
and were instructed to inhale deeply three times. After 5 min, patients’
nausea was relieved. Besides, the use of peppermint or ginger EO vapor
may lessen the frequency and severity of PONV, as well as the require-
ment for antiemetics [116]. Ginger, spearmint or mint EO by massage
or inhalation could reduce PONV via their antispasmodic, painkilling,
and antispasmodic effects [117].
4.4. Alleviating gynecological diseases
As a complementary alternative therapy, aromatherapy significantly
relives primary dysmenorrhea. In a randomized, double-blind clinical
trial, EO of lavender (Lavandulaofficinalis), sage (Salviasclarea), and
maryulam (Origanummajorana) were mixed in a ratio of 2:1:1 and di-
luted in 3% unscented cream. 48 outpatients with primary dysmenor-
rhea diagnosed by gynecologists were randomly assigned to an EO group
or a synthetic fragrance group. In the EO group, the lower abdomen
was massaged with this ointment every day. The pain duration in the
EO group was shortened from 2.4 days to 1.8 days after aromatherapy
[118,119]. In another experiment, participants massaged the abdomen
in the region above the symphysis pubis with five drops of rose dama-
scene EO in a clockwise circular motion for 15 minutes in a quiet room
at a temperature of 24 to 26 °C. Final pain test revealed that the aro-
matherapy decreased the dysmenorrhea pain’s intensity [106,107]. For
mothers during pregnancy, childbirth and the postpartum period, aro-
matherapy could relieve stress, pain and discomfort to alleviate certain
physical, pathological and psychological disorders [120].
Moreover, aromatherapy could be effective in reducing menopausal
symptoms. The aromatherapist massaged the patient’s back, legs, chest,
neck and head for 20 min, then applied a hot compress on the patient
with lavender EO. The aromatherapy was performed 3-4 times a week.
As a result, 13 of the 15 menopausal patients achieved an improvement
in their sense of well-being [121,122].
10
Pharmacological Research - Modern Chinese Medicine 6 (2023) 100210
4.5. Hospice care
Elderly and terminally ill patients nearing the end of their lives have
a special need for humanistic care. Adding EOs to creams or lotions and
promoting their absorption through massage could help dying persons
feel relaxed, improve peripheral blood circulation, reduce chronic pain,
and, more importantly, feel touched and loved [123]. Hand massage
with EO mixtures (lavender EO and hydrocoagulant EO) for the elderly
significantly reduces the severity of chronic pain [124].
On the whole, aromatherapy is a wise choice for nursing care because
it has the potential to reduce drug use, exert the pharmacological effects
of EOs against anxiety and depression, and provide gentle care for the
elderly and terminally ill to ease their pain, depression, anxiety, and
stress.
5. The routes to exert neuropharmacological effects for EOs
Generally, EOs exert their potential neuropharmacological effects
mainly through the blood circulation (blood route) or the direct ol-
factory nerve conduction (nerve route) [125]. For the blood route, EO
molecules easily pass through the physiological barriers (mucosa, skin,
blood-brain barrier, etc.) because of the less polarity, and enter brain
tissue with blood circulation, then exert neuropharmacological effects
(Fig. 1). E. g., the inhaled EO components are transported through the
alveoli, enter the capillaries, and then transported to the nervous system
with the blood flow.
For the nerve route, EOs are inhaled in the nasal cavity, and pass
through the olfactory epithelium where they bind to dendritic receptors
of olfactory sensory neurons (OSN). The generated action potential sig-
nals are transmitted to the cervical glomerulus via olfactory nerves. The
same type of OSN project their axons into the corresponding glomerular
layer of the olfactory bulb where they synapse with dendrites of mitral
and tufted cells. Finally, the specific signals are transmitted to pyrami-
dal neurons in the olfactory cortex, where the signals further stimulate
J. Liang, Y. Zhang, P. Chi et al.
the corresponding regions of the brain, namely the olfactory area in the
anterior lobe of the brain, and finally to the "limbic system". The lim-
bic system, as the "emotional control center", consists of cortical and
subcortical structures including the amygdala, hypothalamus, and hip-
pocampus (Fig. 1). It can trigger emotional responses through the amyg-
dala, stimulate the autonomic nerve of the hypothalamus to affects the
function of various organs, and so on [126].
In addition, human olfactory receptors also exist in epidermal cells or
basal layer of the skin. When activated by EO molecules, they stimulate
cellular proliferation and induce the activation of intracellular cAMP-
dependent pathways and the phosphorylation of extracellular signal-
regulated kinases, which promote blood circulation and produce physi-
ological effects.
Funding
This work was supported by the National Science Foundation of
China (NSFC, 82174004 to D. Kong and 81872848 to W. Zhang), the Na-
tional Science Foundation of Hebei Province (H202206387 to D. Kong
and H202206211 to W. Zhang).
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
CRediT authorship contribution statement
Jiahao Liang: Data curation, Writing – original draft. Yuyu Zhang:
Writing – review & editing. Penghao Chi: Data curation, Writing –
original draft. Haonan Liu: Data curation, Writing – original draft.
Zhaoxuan Jing: Data curation, Writing – original draft. Haojie Cao:
Data curation, Writing – original draft. Yongliang Du: Data curation,
Writing – original draft. Yutong Zhao: Writing – review & editing. Xia
Qin: Data curation, Writing – original draft. Wei Zhang: Conceptualiza-
tion, Writing – review & editing. Dezhi Kong: Conceptualization, Writ-
ing – review & editing.
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