Anxiolytic Effect of Essential Oils and Their Constituents: A Review

Review Cite This: J. Agric. Food Chem. XXXX, XXX, XXX−XXX

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Anxiolytic Effect of Essential Oils and Their Constituents: A Review Nan Zhang† and Lei Yao*,‡ School of Agriculture and Biology and ‡School of Design, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, People’s Republic of China

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†

ABSTRACT: Essential oils are usually used in aromatherapy to alleviate anxiety symptoms. In comparison to traditional drugs, essential oils have fewer side effects and more diversified application ways, including inhalation. This review provides a comprehensive overview of studies on anxiolytic effects of essential oils in preclinical and clinical trials. Most of the essential oils used in clinical studies have been proven to be anxiolytic in animal models. Inhalation and oral administration were two common methods for essential oil administration in preclinical and clinical trials. Massage was only used in the clinical trials, while intraperitoneal injection was only used in the preclinical trails. In addition to essential oils that are commonly used in aromatherapy, essential oils from many folk medicinal plants have also been reported to be anxiolytic. More than 20 compounds derived from essential oils have shown an anxiolytic effect in rodents, while two-thirds of them are alcohols and terpenes. Monoamine neurotransmitters, amino acid neurotransmitters, and the hypothalamic−pituitary−adrenal axis are thought to play important roles in the anxiolytic effects of essential oils. KEYWORDS: anxiolytic effect, essential oil, aromatherapy, effective compound, mechanism

1. INTRODUCTION Anxiety is an unpleasant emotion of inner nervousness and a normal response in the face of danger and stress. People did not treat anxiety disorders as a disease until the 20th century, when anxiety disorders were classified under mental illness.1 Anxiety disorder is defined as a general term for a wide range of mental disorders, including generalized anxiety disorder, panic disorder, specific phobia, social phobia, post-traumatic stress disorder, obsessive compulsive disorder, etc.2 Anxiety disorders are considered to be one of the leading causes of depression and drug abuse.3 A survey by Kessler et al.4 showed that the lifetime morbidity of anxiety disorders was 28.8%, with a median age of 11 years old. A survey from the World Health Organization found that the incidence of anxiety disorders in developed countries was higher than that in developing countries.5 There is a long history of relieving stress, tension, and anxiety using drugs. Alcohol was considered to be the earliest treatment.2 Before the 20th century, sedative and hypnotic drugs, including bromine and chloral hydrate, were mainly used to treat anxiety disorders. In the early and middle 20th century, barbiturates were used as mainstream drugs with strong addiction and side effects. They were not replaced by benzodiazepines (BDZs) until the 1950s.6 BDZs act on γaminobutyric acid (GABA) receptors, and their discovery was a major breakthrough in the treatment of anxiety disorders.7 However, excessive sedation, headache, and withdrawal symptoms were found in later clinical practice.8 A series of drugs based on 5-hydroxytryptamine (5-HT), neuropeptide, glutamate, and endocannabinoid systems were developed.6,9 These drugs included buspirone and serotonin reuptake inhibitor fluoxetine. From 1960 to 2012, more than 10 000 preclinical studies were held on nearly 1500 compounds.6 The number of these studies showed a clear upward trend since the 1980s. Huge investment did not bring satisfactory results. © XXXX American Chemical Society

Strong adverse reactions, dependence, and ineffective treatment still exist in many cases. In addition to the lack of new anti-anxiety drugs, how to receive proper treatments is also a major problem for mental health patients. The huge treatment gap has led to a global mental health crisis: in some countries, up to 90% of people with mental health problems cannot receive the basic treatment.10 In a survey during 2001−2005, only 8% of the people with mental illness in China sought help from professionals and only 5% of them had received treatments in psychiatry.11 On the basis of the above situations, promotion of complementary and alternative medicines (CAMs) is necessary. Aromatherapy, in which essential oils from natural plants are used, is one of the CAMs.12 Essential oils are mainly extracted from leaves, flowers, barks, rhizomes, seeds, and fruit peels of aromatic plants and composed of various volatile chemical components, including terpenoids, esters, ketones, alcohols, aldehydes, and ethers. In many areas and countries, such as India, Brazil, and Iran, folk medicine believes that essential oils have antibacterial, anti-inflammatory, analgesic, mood-adjusting, and insomnia-alleviating effects.13−15 In this review, we overviewed the clinical and preclinical studies on the anxiolytic effects of essential oils. We discussed the research methods in detail. All of the clinical studies in this review used randomized clinical trials, in which human subjects with or without clinical anxiety were treated with essential oils. We further summarized the major effective components and discussed the action pathway and mechanism. Special Issue: 2nd International Flavor Fragrance Shanghai Received: Revised: Accepted: Published: A

January 19, 2019 May 29, 2019 May 31, 2019 May 31, 2019 DOI: 10.1021/acs.jafc.9b00433 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

Review

Journal of Agricultural and Food Chemistry

2. CLINICAL TRIALS 2.1. Study Subject and Method. Since the mid-1980s, many researchers have begun to focus on the anxiolytic effects of plant essential oils in clinical practices. Table 1 lists the essential oils that have shown anti-anxiety or anti-stress effects in clinical trials. The subjects of these studies covered healthy volunteers,16−18 postmenopausal women, 19 primigravida women,20 patients with anxiety disorder,21 and patients who were in a palliative care center22 and intensive care unit (ICU)23 or would undergo colorectal surgery24 and dental care.25 Inhalation, oral, and skin application were three main administration ways of essential oils in the clinical trials. Inhalation administration was most commonly used in the acute experiments and was implemented in a variety of ways. Essential oils were usually infiltrated into filter papers/cotton balls and naturally volatilized to the testers. Warmers25,26 or ultrasonic ionizer diffusers27 were also used to diffuse the odors. In one study, essential oil was poured on absorbing patches that were connected inside the oxygen masks of patients.28 Skin application of essential oils was mainly administrated by massage, which might be the most widely used complementary therapy in nursing practice.29 It is important to set a control treatment to reduce the impact of other factors when performing the aromatherapy massage experiment. In one study, testers were asked to wear a breathing mask during the massage to prevent the effect induced by the olfactory pathway.17 In many studies, massages with no essential oil or carrier oil only were used as a control treatment to avoid the effect induced by massage itself.17,22,29 Oral administration has been less used in the clinical trials. Repeated administration lasting several weeks was preferred.19,21 Anxiety scales, especially Spielberger’s state-trait anxiety inventory (STAI), were used as anxiety measurements in most studies. Moreover, several physiological indicators, such as blood pressure (BP),26,30,31 heart rate (HR),26,30 and heart rate variability (HRV) parameters31,32 and salivary endocrinological stress markers cortisol16,32 and chromogranin A (CgA) levels,16 were detected after essential oil treatments in many studies. These physiological indicators contributed more evidence for the anxiolytic or anti-stress effects of essential oils. 2.2. Anxiolytic Effect of Essential Oils in Clinical Trials. Among all of the study objects, lavender essential oil was most widely studied. It could relieve anxiety23,24,33 symptoms through all three main application ways. In a study from Toda and Morimoto, inhalation of the lavender aroma after a 10 min complex mathematical operation significantly reduced the content of salivary CgA compared to the control treatment.16 Silexan is a capsule that contains a higher ester type of Lavandula angustifolia essential oil.34 It is a registered drug for anxiety treatment in Germany. Plenty of clinical trials have shown that Silexan could effectively alleviate anxiety symptoms in patients with generalized anxiety.34,35 Essential oils from Citrus plants were wildly used in clinical trials. Bitter orange (Citrus aurantium) oil was found to relieve anxiety after oral or inhalation administration.19,30 Inhalation of bergamot (Citrus bergamia) oil could regulate the BP, HR, and HRV parameters on healthy volunteers.32 Inhalation of orange (Citrus sinensis) oil reduced the anxiety level and improved mood in dental patients.36

Numerous studies reported that rose oil has physiological and psychological relaxation and anti-anxiety effects.37 Inhalation of rose oil could relieve anxiety in primigravida women20 and decrease salivary cortisol and testosterone levels in healthy participants.38 Igarashi et al.39 used a near-infrared time-resolved spectroscopic method to detect the prefrontal cortex (PFC) activity indicator oxyhemoglobin (oxy-Hb) concentration during the rose (Rosa damascena) odor inhalation. A significant decrease in the oxy-Hb concentration in the right PFC of the testers was observed, which indicated that olfactory stimulation by rose oil induced physiological and psychological relaxation. The anxiolytic effects of essential oils from genus Salvia also received the attention of scholars. Essential oils from several species, including Salvia lavandulaefolia18 and Salvia officinalis,40 were tested on healthy volunteers and post-cesarean women, respectively. Besides the essential oils above, many essential oils with practical application basis in aromatherapy, such as sandalwood (Santalum album) oil, 29 Roman chamomile (Chamaemelum nobile) oil,22 rosemary (Rosmarinus officinali) oil,41 lemon balm (Melissa officinalis) oil,42 and pelargonium oil,28 have been reported to exert an anxiolytic effect in clinical trials. Among all of the clinical trials, only a few studies showed the constituents of the essential oils. However, the chemical constituents might vary greatly as a result of the species, origin place, and extraction method. For instance, limonene content varied wildly (20 and 97.99%) in two studies of Citrus aurantium oil. The chemical components of Cananga odorata oil also varied a lot in different studies. The essential oil used in the study of Jung et al.26 mainly comprised of benzyl acetate (25.1%), p-cresyl ether (16.5%), and linalool (13.6%), while the essential oil used in another study mainly comprised of methyl benzoate (34.00%), 4-methylanisole (19.82%), and benzyl benzoate (18.97%).17 In a study of Satureja oil,43 essential oils from two species were used. Besides the differences in linalool content (21.1 and 12.8% respectively), essential oil from Satureja brevicalyx contained a much higher content of isomenthone (8.1%) and β-caryophyllene (6.5%), while essential oil from Satureja boliviana contained much more geranyl acetate (8.6%), germacrene D (7.8%), and carvacryl acetate (5.2%). The former species showed relatively more reduction of anxiety scores than the latter species. The author suggested that this result might be attributed to the chemical differences.

3. PRECLINICAL TRIALS 3.1. Study Subject and Method. The most frequently used animals in preclinical studies of anti-anxiety drugs are mice (Mus musculus) and rats (Rattus norvegicus).2 Rats are easy to operate. Many common anxiety models were first established in rats.2 However, with the continuous development of molecular biotechnology in the past 2 decades, mice are used more frequently.45 The evolution of human structures that regulate emotions in the limbic system, such as the hippocampus and amygdala, are conservative.46 Different animal anxiety models could correspondingly mimic some anxiety symptoms that occur in humans.2 The most popular type of animal model is the approach− avoidance test. In the process of exploring the novel environment, animals innately avoid to explore the bright, open, and potentially dangerous areas. When faced with threats, they would escape or defend. Such models include the B

DOI: 10.1021/acs.jafc.9b00433 J. Agric. Food Chem. XXXX, XXX, XXX−XXX

C

anxiety relief

decreasing blood pressure and a relaxing effect relaxation

acute modulation of mood and cognition reducing post-cesarean anxiety relaxation

anxiety relief anxiety relief

reducing test-taking stress reducing anxiety and improving life quality relieving clinical agitation

orange oil (Citrus sinensis)

ylang−ylang oil (Cananga odorata)

salvia oil (Salvia lavandulaefolia) salvia oil (Salvia officinalis)

rose oil pelargonium oil

rosemary oil (Rosmarinus officinali) Roman chamomile oil ( Chamaemelum nobile) lemon balm oil (Melissa officinalis)

rose oil (Rosa damascena)

anxiety relief

bergamot oil

anxiety relief

yes

yes

no

no no

no

skin application; essential oils were combined with a base lotion (200 mg/day, 4 weeks repeated)

inhalation; 3 drops of essential oils were infiltrated into a cotton ball (5 min) inhalation; inhaled air impregnated with odor (8.3 ppm, v/v, acute) inhalation and footbath (1%, 10 min) inhalation; poured 3 drops of essential oil on absorbing patches connected inside the oxygen masks of patients (acute) inhalation; inhaled a piece of cotton soak with 3 drops of essential oil (acute) skin application; massage (once a week, 3 weeks repeated)

no

no

inhalation; odors were diffused through a lamp (0.15 mL, 20 min) oral (25−50 μL, acute)

inhalation; essential oils were diffused by an ultrasonic diffuser (acute) inhalation; odors were diffused through an electrical dispenser (acute) skin application; massage and supplied pure air by breathing masks (20%, w/w, 5 min)

inhalation; essential oils were evaporated with water (0.1%, v/v, 15 min)

inhalation; odors were diffused through nebulization (5%, v/v, acute)

yes

yes

yes

no

yes

yes

anxiety relief

bergamot oil (Citrus bergamia)

yes

anxiety relief

bitter orange oil (Citrus aurantium)

skin application; massage (1%, 15−30 min)

inhalation; 150 μL of essential oils were infiltrated into filter paper (acute) oral (1000 mg/day, 8 weeks repeated)

no

anxiety relief

oral (1000 mg/day, 8 weeks repeated)

no

yes

anxiety relief

inhalation; odors were diffused through candle warmers

no

skin application; massage (5%, 10 min, twice before the surgery) inhalation; 5 drops of essential oil were diffused through a diffuser pad (5 min) oral (80 mg/day, 10 weeks repeated)

treatment of essential oil

no

no

subjective effects on mood anxiety relief

reducing anticipatory anxiety stress relief

no

anxiety relief

benefits

if the constituents of essential oil are shown

lavender oil

lavender oil (Lavandula hybrida) lavender oil (Lavandula angustifolia)

essential oil (Latin name of the plant resource)a

Table 1. Summary of Studies on the Anxiolytic Effect of Essential Oils in Clinical Trials

patients in palliative care center (N = 87) (78 women and 9 men) patients with clinically significant agitation in the context of severe dementia (N = 72)

graduate nursing students (N = 120)

primigravida women (N = 108) patients with acute myocardial infarction (N = 80) aged 18−60 years old (40 women and 40 men)

female university students (N = 20)

undergraduate volunteers (N = 24) aged 18−37 years old (16 women and 8 men) post-cesarean women (N = 120) aged 18−35 years old

healthy male volunteers (N = 29)

patients who were admitted to hospital for ambulatory surgery (N = 109) (65 women and 44 men) patients (N = 101) aged 18−77 years old (half women and half men) healthy volunteers (N = 40) aged 19−48 years old (24 women and 16 men)

healthy female students (N = 42) aged 20−23 years old

patients with anxiety disorder (N = 212) aged 18−65 years old (159 women and 53 men) postmenopausal women (N = 156) aged 45−60 years old patients admitted to ICU (N = 122) (53 women and 69 men) dental participants (N = 340) over 18 years (170 women and 170 men) healthy students (N = 30) aged 21−26 years old (23 men and 7 women) postmenopausal women (N = 156) aged 45−61 years old patients experiencing crack withdrawal (N = 51)

patients who would undergo colorectal surgery (N = 80) with an average age of 60.64 (36 women and 44 men) healthy adults (N = 96) (57 males and 39 females)

study subject

CMAI

STAI

TAS, BP, and radial pulse

PFC oxyhemoglobin (oxy-Hb) visual analogous scale STAI

Bond−Lader visual analogue scales STAI

BP and HR

visual analogue scales; BP

German version of STAI

STAI; electric conductance of the skin, BP, HR profile of mood state, STAI; salivary cortisol, HRV STAI

anxiety behavior scores; BP, HR STAI-6, modified dental anxiety scale cortisol and chromogranin A STAI

STAI

Bond−Lader visual analogue scales Hamilton anxiety scale

state anxiety inventory

main anxiety measurementb

42

22

41

20 28

39

40

18

26

17

36

27

32

30

19

16

25

23

19

21

44

24

reference

Journal of Agricultural and Food Chemistry Review


Review

Latin names of the essential oil plants that have been described in the paper were listed. bBR, blood pressure; HR, heart rate; STAI, Spielberger’s state-trait anxiety inventory; CMAI, Cohen-Mansfield agitation inventory; and HRV, heart rate variability.

elevated plus maze (EPM) test,47 open field (OF) test,48 light and dark box (LDB) test,49 social interaction (SI) test,50 holeboard test,51 marble-burying (MB) test,52 staircase test,53 etc. Conflict-based anxiety tests were another type of anxiety model used for the detection of anxiolytic agents in rodents. Conflict situations, in which a subject experiences two opposing impulses, are a common and clinically relevant feature of anxiety. Conflict-based models are the most GABAergic sensitive manipulation. Umezu et al. used the Geller−Seifter test and Vogel punished drinking test to evaluate the anticonflict effect of essential oils in several preclinical studies.54−56 Pharmacological agents could be used to generate anxiety before drug administration for a study of the drug effect on pre-existing anxiety. Zhang et al.57 used serotonin antagonist meta-chlorophenylpiperazine (mCPP) to induce anxiety in mice. Besides the models above, the maternal separation model,58 restraint stress model,59 and waterimmersion stress model60 were also used in several studies of essential oils. Unlike clinical research, skin administration was rarely used in the animal experiment. Oral, intraperitoneal injection, and inhalation were the three main ways for essential oil administration (Table 2). Similar to the clinical trials, several drops of essential oils were dripped into cotton balls or filter papers to volatilize naturally or diluted to 1−10% (v/v) water solution and diffused by vaporizers. Acute or chronic 7, 14, or 21 days repeated inhalation procedures were usually used. In the acute exposure experiments, diverse odor exposure times (5−120 min) were designed by different researchers. For the oral and intraperitoneal injection administration, the doses of essential oils were in the range of 1−2000 mg/kg in different studies. Many essential oils used in animal experiments were directly extracted by the researchers from plants with an accurate Latin name,51,61−67 and their compositions were analyzed by gas chromatography−mass spectrometry (GC−MS). In these studies, we could obtain more information about plant resources and chemical components than in clinical research studies. This might be due to the fact that many plant essential oils were first reported to have anxiolytic effects in these studies and still have not been widely used in aromatherapy. 3.2. Anxiolytic Effect of Essential Oils in Animal Models. Numerous essential oils from Lamiaceae, Rutaceae, and Apiaceae families have been proven to be anxiolytic in mice or rats. In the Labiatae family, Lavandula angustifolia oil was wildly studied. It showed an anxiolytic effect in different animal models after inhalation or intraperitoneal injection in both mice and rats.52,54,68−70 Oral administration of lavender oil capsule Silexan could reduce the anxiety behaviors of the female mice.71 Many species of Lavandula could be used for essential oil extraction. The choice of oil-derived species not only resulted in the quality of the essential oil but also contributed to the application in the aromatherapy. The study from Takahashi et al. suggested that the presence of both linalyl acetate and linalool was essential for the whole oil to work as an inhaled anti-anxiety agent.72 It is therefore not surprising that high-ester essential oil from L. angustifolia is used for Silexan production.34 Essential oils from three species of Ocimum plant were studied. Intraperitoneal injection of Ocimum gratissimum oil could reduce anxiety behaviors in the EPM test.64 Chronic inhalation of Ocimum sanctum and Ocimum basilicum oils could relieve the anxiety in β-amyloidtreated rats.73 There are several chemotypes of Thymus vulgaris

a

29 STAI patients (N = 750) no anxiety relief

skin application; massage (1%, 20 min, once per week for 4 weeks)

43 STAI healthy volunteers (N = 108) aged 25−45 years old (54 women and 54 men) inhalation; 0.1 mL of 2% essential oil was diffused by a diffuser (30 min/day, 12 days repeated in 2 weeks) yes anxiety relief

satureja oil (Satureja brevicalyx and Satureja boliviana) sandalwood oil (Santalum album)

essential oil (Latin name of the plant resource)a

Table 1. continued

benefits

if the constituents of essential oil are shown

treatment of essential oil

study subject

main anxiety measurementb

reference


D


Rutaceae

Lamiaceae

family

E

increased anxiety

D-limonene

anxiolytic effect

limonene (690.8 g/L), p-cymene (66.6 g/L), mycrene (14 g/L), and α-pinene (12.2 g/L) limonene (97.66%) and myrcene (1.11%) not shown

anxiolytic effect

anxiolytic effect

anxiolytic effect

sweet orange, Citrus. sinensis var. dulcis Casimiroa pringlei

(39.60%), linalyl acetate (31.09%), and linalool (9.55%)

limonene (26.70%), linalyl acetate (18.57%), and linalool (10.86%)

limonene (97.83%), myrcene (1.43%), and octanal (0.45%)

anxiolytic effect

anxiolytic effect

limonene (98.66%), β-pinene (0.41%), and β-myrcene (0.53%)

anxiolytic effect

yuzu, Citrus junos

bergamot, Citrus aurantium subsp. bergamia

bitter orange, Citrus aurantium

not shown

anxiolytic effect

lemon leaves, Citrus limon lemon

anxiolytic effect

limonene (52.77%), geranyl acetate (9.92%), trans-limonene oxide (7.13%), and neral (6.85%) not shown

anxiolytic effect

aciphyllene (66.415%), fenchyl alcohol (8.897%), α-pinene (8.188%), and caryophyllene oxide (4.648%) linalool (31.7%), β-myrcene (13.5%), terpinen-4-ol (10.5%), and γ-terpinene (9.1%)

linalool (31%), estragole (15.57%), 1,8-cineole (3.29%), and eugenol (2.64%)

thyme, Thymus vulgaris

anxiolytic effect on β-amyloid-treated rat

basil, Ocimum basilicum

anxiolytic effect

anxiolytic effect on β-amyloid-treated rat

Ocimum sanctum

methyl chavicol (42.8%), geranial (13.0%), neral (12.2%), and β-caryophyllene (7.9%) linalool (19%), estragole (7.59%), 1,8-cineole (3.90%), and eugenol (1.39%)

Stachys tibetica

anxiolytic effect

Ocimum gratissimum

linalyl acetate (26.32%), linalool (26.12%), caryophyllene (7.55%), and β-myrcene (5.33%) linalool (36.8%) and linalyl acetate (34.2%)

anxiolytic effect

inhaled; filter paper soaked in essential oil (3.4 and 6.7 mg/L of air, 90 min) inhaled; cotton soaked with 100−400 μL of essential oil (5 min) p.o. (795 and 100 mg/kg, acute)

inhaled; cotton soaked with essential oil (1−5%, w/w, 7 min) i.p. (250−500 μL/kg, acute)

p.o. (0.5−1 g/kg, acute or 15 days repeated)

p.o. (1−100 mg/kg acute or 14 days repeated)

inhaled; cotton soaked with 0.5 mL of essential oil (90 min) inhaled; 150 μL of essential oil was added to cages of animals (1 week)

p.o. (50−150 mg/kg, 30 days repeated)

inhaled; incense through an electronic vaporizer (200 μL of 1−3% oil, 60 min/day, 21 days repeated) inhaled; incense through an electronic vaporizer (200 μL of 1−3% oil, 60 min/day, 21 days repeated) p.o. (100−1600 mg/kg, acute and 7 days repeated) inhaled; filter paper soaked with essential oil (2−4 μL/L of air, 90 min)

i.p. (200 mg/kg, acute)

p.o. (1−30 mg kg−1 day−1, 3 days repeated)

not shown

anxiolytic effect

anxiolytic effect

inhaled; olfaction evaporation (0.1−2 mL, from 30 min to 2 h) inhaled; drug-embedded cotton wool ball (1.25−2.25%, w/w, 90 min) i.p. (200−1600 mg/kg, acute)

linalyl acetate (46%) and linalool (25%)

anxiolytic effect attenuated the serotonin syndrome anxiolytic effect

treatmentb inhaled; incense through an electronic vaporizer (24 h or 14 days) inhaled; 10−50 μL of essential oil was placed in a cotton wool ball (5 min)

major components of the essential oil linalyl acetate (43.98%), linalool (38.47%), lavandulyl acetate (4.81%), and β-myrcene (1.44%) linalyl acetate (53.5%) and linalool (46.5%)

anxiolytic effect

aim of the study

Silexan, Lavandula angustifolia

lavender, Lavandula angustifolia

essential oil name and Latin name of the plant resourcea

Table 2. Summary of Studies on the Anxiolytic Effect of Essential Oils in Animal Models

male Swiss mice male ICR mice male and female SD rat male Swiss mice male Swiss mice male Wistar rats male Wistar rats male ICR mice male Wistar rats male Wistar rats

male ICR mice

Wistar rats

male Wistar rats

male ICR mice female NMRI mice male Syrian mice male Wistar rats

male SD rats

male SD rats

Mongolian gerbil male Swiss mice

study objects

EPM, OF, hole-board test

EPM, LDB

EPM, OF, LDB

EPM, hole-board test OF, EPM

LDB, MB

LDB, rotarod test

81

EPM

87

78

77

124

76

82

79

85

75

80

51

73

73

64

71

54

70

69

123

52

reference

SI, hole-board test, EPM, LDB isolated and intraperitoneal injection stress model, EPM EPM, OF, rotarod test EPM, OF

EPM

EPM

EPM

Geller conflict test, Vogel conflict test EPM

EPM, OF

OF

serotonin syndrome; MB, EPM

EPM

anxiety evaluation models



F

Verbenaceae

Annonaceae

Apiaceae

Rosaceae

Gramineae

family

geranial (40.8%), neral (36.3%), and β-myrcene (13.2%) citral (71.29%), β-myrcene (16.5%), geraniol (1.28%), and 6-methyl-5-hepten-2-one (0.64%) 2-phenethyl alcohol (66.59%), citronellol (14.57%), geraniol (2.08%), and methyl eugenol (1.83%)

anxiolytic effect

anxiolytic effect

anti-stress effect

anxiolytic effect on scopolamine-treated mice anxiolytic effect

rose

Anthriscus nemorosa

anxiolytic effect

Kelussia odoratissima

anxiolytic effect

anxiolytic effect anxiolytic effect (chemotype 2 shows the best anxiolytic effect) anxiolytic effect in CORT-treated mice

ylang−ylang, Cananga odorata

Dennettia tripetala Lippia alba

Lippia sidoides

anxiolytic effect

Ducrosia anethifolia

Foeniculum vulgare

Ferulago angulata

coriander, Coriandrum sativum

anxiolytic effect on scopolamine-treated micee anxiolytic effect on β-amyloid-treated mice anxiolytic effect on scopolamine-treated mice anxiolytic effect

Pimpinella peregrina

anxiolytic effect

anxiolytic effect

Chinese angelica, Angelica sinensis

citronellol (28.15%), geraniol (16.46%), nerol (8.65%), and phenylethyl alcohol (4.84%) not shown

anxiolytic effect

rose, Rosa damascena rose, Rosa alba

inhaled; electronic vaporizer (200 μL of 1 and 3% oil, 21 days repeated, 15 min/day) inhaled; incense through an electronic vaporizer (200 μL of 1 and 3% oil, 60 min/day, 21 days repeated) inhaled; incense through an electronic vaporizer (200 μL of 1 and 3% oil, 15 min/day, 21 days repeated) p.o. (50−400 mg/kg, acute)

trans-pinocarveol (35.1%), pregeijerene (15.1%), α-cubebene (12.4%), and (+)-epi-bicyclosesquiphellandrene (7.5%) linalool (69.358%), γ-terpinene (7.729%), α-pinene (6.509%), and pinocarvone (4.388%)

not shown

not shown chemotype 1, citral (55.1%), β-myrcene (10.5%), and limonene (1.5%); chemotype 2, citral (63.0%) and limonene (23.2%); and chemotype 3, carvone (54.7%) and limonene (12.1%)

p.o. (2.5−400 mg/kg, acute)

n-decanal (70.1%), α-pinene (12.4%), dodecanal (5.4%), and trans-chrysanthenyl acetate (1.9%) benzyl benzoate (20.25%), linalool (11.00%), benzyl salicylate (9.53%), and benzyl alcohol (9.10%)

p.o. (100 and 200 mg/kg, 14 days repeated)

inhaled; a controllable heater was settled to heat the oil/water emulsion (10 mL of 1−10%, v/v oil, acute or 7 days repeated) i.p. (5−20 mg/kg, acute) i.p. (10−200 mg/kg, acute)

i.p. (50−200 mg/kg, acute)

ligustilide (85.9%)

not shown

α-pinene (24.10%), β-pinene (22.70%), β-phellandrene (20.50%), and α-phellandrene (12.1%)

p.o. (10−42 mg/kg, acute)

p.o. (7.5−60 mg/kg, acute)

inhaled; incense through an electronic vaporizer (600 μL/day, 1 or 14 days) inhaled; cotton soaked with essential oil (0.2 mL, 90 min) inhaled; cotton soaked with essential oil (2 mL of 1−5%, w/w oil, 7 min) inhaled (1 and 3%, 15 min)

p.o. (1−100 mg/kg, 30 min or 21 days repeated) subcutaneous injection (100−800 mg/kg, acute)

inhaled; cotton soaked with essential oil (1−5%, w/w, 7 min) p.o. (0.5 and 1 g/kg, acute)


treatmentb

not shown

not shown

caryophyllene (23.6%), D-cadinene (12.1%), caryophyllene oxide (12.3%), and trans-pinocarveol (9.8%)

not shown

anxiolytic effect

anxiolytic effect

β-caryophyllene (20.64%), γ-muurolene (17.7%), bicyclogermacrene (14.73%), and δ-cadinene (13.40%) khusimol (9.82%), α-vetivone (5.78%), and khusenic acid (5.43%)

major components of the essential oil

anxiolytic effect

aim of the study

rose, Rosa centifolia

Spiranthera odoratissima vetiver grass, Vetiveria zizanioides lemongrass, Cymbopogon citratus


Table 2. continued

male Swiss mice

mice male Swiss mice

male Swiss mice male NMRI mice male Swiss mice male ICR mice

male Wistar rats

male Wistar rats

male Wistar rats male Wistar rats

male Swiss mice

Mongolian gerbil male Wistar rats male Wistar rats male Wistar rats

male Swiss mice male Wistar rats male Swiss mice male Swiss mice male ICR mice

study objects

EPM

EPM EPM, OF, rotarod test

mCPP model, EPM, OF, LDB

EPM

EPM, OF, staircase test EPM

EPM

EPM

EPM

EPM, LDB, stress-induced hyperthermia test SI, hole-board test

EPM

chronic restraint stress model EPM

LDB, MB, rotarod test Geller conflict test and Vogel conflict test EPM, LDB

EPM, LDB

OF, rotarod test, hole-board test EPM


reference

113

114 111

57 and 84

89

94

90

91

65

93

88

126

92

125

95

83

56

61

62

102

86



G

anxiolytic effect

anxiolytic effect

anxiolytic effect

anxiolytic effect

rose geranium, Pelargonium roseum Abies sachalinensis

agarwood, Aquilaria sinensis

Celastrus paniculatus

myrtle, Myrtus communis

Geraniaceae

Thymelaeaceae

Celastraceae

Myrtaceae

anxiolytic effect

anxiolytic effect

Alpinia zerumbet

Zingiberaceae

Pinaceae

anxiolytic effect

SuHeXiang, Lipuidambar orientalis

Altingiaceae

anxiolytic effect

sandalwood, Santalum album

anxiolytic effect

anxiolytic effect

anxiolytic effect

anxiolytic effect

Santalaceae

Piperaceae

not shown

anxiolytic effect

not shown

p-cymene (18.5 g/L), 1,8-cineole (14.3 g/L), limonene (11.2 g/L), and α-pinene (10.7 g/L) citronellol (35.9%), geraniol (18.5%), linalool (5.7%), and δ-selinene (5.5%) α-pinene (146 g/L), camphene (142.4 g/L), bornyl acetate (80.4 g/L), and limonene (74.9 g/L) gualol (14.1%), 7-methyltridecane (11.2%), 2-cyclohexylanisole (6.2%), and 2,3,4,5-tetramethyltricyclo[3.2.1.02,7]oct-3-ene (5.716%) not shown

not shown

(Z)-α-santalol (51.1%) and (Z)-β-santalol (28.5%)

geranial (37.16%), neral (28.29%), D-limonene (22.90%), and β-myrcene (2.06%) linalool (41.8%), 3,5-dimethoxytoluene (10.9%), β-pinene (9.2%), and camphene (4.8%)

not shown

fragranyl acetate (44.7%), fragranol (29.9%), camphor (3.3%), and eugenol (0.6%) p-ocimene (23%), 1,8-cineole (20.8%), and carvone (19.13%)

(−)-α-cedrene (28.11%), (+)-cedrol (24.58%), (−)-thujopsene (17.71%), and (+)-β-cedrene (7.81%)

anxiolytic effect

anxiolytic effect

not shown

β-thujone (77.9%), α-thujone (10.5%), and sabinene (4.9%)

major components of the essential oil

anxiolytic effect

anxiolytic effect

aim of the study


p.o. (1 and 1.4 g/kg, 14 days repeated)

inhaled; filter paper soaked with essential oil (1.8−3.6 mg/L of air, 90 min) i.p. (15−60 mg/kg, 10 days repeated)

inhaled; cotton soaked with 2 mL of 10% essential oil (10 or 30 min once daily for a total of 12 days) inhaled; filter paper soaked with essential oil (3.5 mg/L of air, 5−150 min) i.p. (10−50 mg/kg, acute)

inhaled; filter paper soaked in essential oil (from 4.0 × 10−6 to 4.0 × 10−1 mg per cage, 60 min) inhaled; filter paper soaked with essential oil (4 μL/L of air, 90 min)



i.p. (0.5 and 1 mg/kg, acute)

inhaled; filter paper soaked with essential oil (50 μL, 30 min) p.o. (50−150 mg/kg, acute)

inhaled; vaporization (20 mL of 5%, v/v oil, 1 or 2 h/day, 21 days repeated) i.p. (100−1600 mg/kg, acute)

i.p. (acute)

treatmentb

Swiss mice

Wistar rats

male ICR mice male Swiss mice male ICR mice male ICR mice

male ICR mice

male ICR mice

male Fischer 344 rats male BALB/c mice male Wistar rats male Wistar rats male ICR mice male ddY mice

female SD rats pups of SD rats male ICR mice

study objects

restraint stress model, EPM, OF, LDB EPM, OF, thirsty conflict test staircase test, EPM, OF

EPM

EPM, OF

EPM

water-immersion stress model, EPM test OF test

OF, LDB

EPM, OF

EPM

EPM

restraint stress model, EPM OF, LDB

maternal separation (MS) model, EPM EPM, LDB

OF, EPM


53

119

63

67

96

116

120

60

66

105

122

117

118

59

101

58

127

reference

The essential oil name was listed if the Latin name of the plant was not shown in the references, and only the Latin name of the plant was listed if there is no common name of the essential oil. bi.p., intraperitoneal injection; p.o., oral gavage.

a

copaiba, Copaifera reticulata mountain pepper, Litsea cubeba Piper guineense

Fabaceae

Lauraceae

yarrows, Achillea umbellata Achillea wilhelmsii

Acantholippia deserticola Chamaecyparis obtusa eastern red cedarwood, Juniperus virginiana Thujopsis dolabrata

Compositae

Cupressaceae

family


Table 2. continued



Review

Journal of Agricultural and Food Chemistry oil.74 T. vulgaris oil with a high content of linalool could relieve the anxiety induced by isolated and intraperitoneal injection treatments in mice.75 Stachys tibetica oil is another essential oil extracted from the Lamiaceae plant family. It showed an anxiolytic effect in SI, hole-board, EPM, and LDB tests.51 In the Rutaceae family, essential oils of the genus Citrus are mainly extracted from the peels of fruits. Fruit oils from bergamot (Citrus aurantium subsp. bergamia),76 yuzu (Citrus junos),77 and sweet orange (Citrus sinensis var. dulcis)78 showed an anxiolytic effect after acute exposure to mice or rats. Both acute and chronic oral administrations of bitter orange (Citrus aurantium) oil relieved anxiety levels in several animal models.79 Lemon (Citrus limon) oil is known worldwide for its numerous applications. Komiya et al.80 reported its anxiolytic effect in an acute exposure study. However, in the study from Ceccarelli et al., chronic exposure to lemon odor significantly increased anxiety behaviors.81 In most of the current studies, essential oils with acute anxiolytic effects have also been reported to show anxiolytic effects in long-term administration studies.82−84 We suspect that differences in the chemical composition, exposure concentration, exposure method, and exposure duration of the essential oil might be considered to be the cause of conflicting results. Several leaf oils from the genus Citrus have also been studied. Chronic oral administration of essential oils from lemon leaves showed an anxiolytic effect in mice.85 Acute oral administration of essential oils from leaves of Spiranthera odoratissima86 and Casimiroa pringlei87 reduced anxiety levels in several anxiety models. In the Apiaceae family, essential oils with anxiolytic effects come from plants of different genera. Acute oral administration of Angelica sinensis oil88 and Ducrosia anethifolia oil89 could reduce anxiety levels in mice or rats. Chronic exposure to Foeniculum vulgare oil,90 Ferulago angulata oil,91 Coriandrum sativum oil,65 Anthriscus nemorosa oil,92 and Pimpinella peregrina oil93 and acute intraperitoneal injection of Kelussia odoratissima oil94 could significantly decrease anxiety behaviors in the EPM tests. Many plant essential oils that are commonly used in aromatherapy have been proven to have anxiolytic effects. Rose oil has a wide range of applications in aromatherapy. It has been believed to be an antidepressant for a long time. Rose oil in the market is usually extracted from Rosa plants, such as Rosa centifolia, Rosa damascena, and Rosa alba. Several studies have proven that inhalation of rose oil from these species could reduce anxiety levels in different anxiety models.56,83,95 Rose geranium (Pelargonium roseum) oil is usually used to replace rose oil by flavorist as a result of its rose-like odor and much lower price. Abouhosseini Tabari et al. reported that rose geranium oil presented an anxiolytic effect in mice after acute intraperitoneal injection.96 Ylang−ylang (Cananga odorata) essential oil is usually used for stress relief in aromatherapy practices. mCPP was a compound that induced anxiety in healthy people and people with panic anxiety disorder.97 Acute and chronic exposure to ylang−ylang odor could reverse the anxiety induced by mCPP.57 However, ylang−ylang essential oil did not show anxiolytic effects in conflict-based tests, such as the discrete shuttle-type conditioned avoidance task98 and Vogel and Geller conflict tests.55 The difference in results might arise from the model used in different studies. Moreover, we found that the chemical composition of the ylang−ylang essential oils used in previous studies, including two clinical trials,17,26

contained high ratios of esters. As we known, commercial grades strongly differ in chemical composition of ylang−ylang essential oils.99 Ylang−ylang essential oils with a high content of terpenes are also very common.100 Such differences in chemical compositions might also lead to differences in efficacy. Eastern red cedarwood (Juniperus virginiana) oil and vetiver grass (Vetiveria zizanioides) oil are used for sedation in aromatherapy. Eastern red cedarwood is native to eastern North America, while vetiver grass is widely cultivated in many tropical regions. Both of them showed an anxiolytic effect after acute intraperitoneal injection or inhalation.101,102 Lemongrass (Cymbopogon citratus) oil and mountain pepper (Litsea cubeba) oil are famous for their antibiosis effects.103,104 Citral was the major constituent of these two essential oils. Acute or chronic oral administration of the two essential oils showed an anxiolytic effect in mice.61,62,105 Myrtus communis is rich in essential oils and is used in Ethiopian traditional medicine.53 Its essential oil is known as myrtle oil. Acute oral intake of myrtle oil reduced anxiety behaviors in several anxiety models, including EPM, staircase, and OF tests, in mice.53 Indian sandalwood (Santalum album) is an evergreen tree that is native to Southern Asia.106 The essential oil is extracted from the heartwood by steam distillation. A 90 min inhalation of Indian sandalwood oil could reduce anxiety behaviors in water-immersion-stressed mice.60 There are another two kinds of sandalwood oil that are extracted from Australia sandalwood (Santalum spicatum) and New Caledonian sandalwood ( Santalum austrocaledonicum). The contents of the main effective component α-santalol varied greatly in these essential oils.107 This difference might lead to a difference in efficacy. Agarwood is a highly valuable forest product of Aquilaria species and wildly used for medical purposes.108 It has been traditionally used for tranquilizing in China, Southeast Asia, and the Middle East for centuries. Sesquiterpenes were the main components of agarwood essential oil.109 Chronic intraperitoneal injection of agarwood essential oil showed an anxiolytic effect in stressed mice.63 Many studies evaluated the anxiolytic effect of essential oil from plants used in folk medicine. Lippia alba is a very common herb in Brazil, and the tea from its leaves is used as a tranquilizer.110 Essential oils of three chemotypes [citral (55.1%), β-myrcene (10.5%), and limonene (1.5%) in chemotype 1; citral (63.0%) and limonene (23.2%) in chemotype 2; and carvone (54.7%) and limonene (12.1%) in chemotype 3] were tested in the study by Vale et al.111 All three chemotypes reduced anxiety behaviors in the EPM test, while chemotype 2 showed a better effect. Lippia sidoides is an odoriferous plant that grows wild in the northeastern region of Brazil and used as an anti-infective agent in traditional medicine.112 In a corticosterone (CORT)-induced depression model, oral intake of essential oil from L. sidoides produced an anxiolytic effect in the EPM test.113 Ducrosia anethifolia has been used in Iranian folk medicine as an analgesic and pain reliever.89 The essential oil was isolated by hydrodistillation from fresh aerial parts and contained high contents of n-decanal (70.1%) and α-pinene (12.4%). It increased the percentage of time and entries into open arms in the EPM tests. Dennettia tripetala is a medium-size tree, and its common habitat is the tropical rainforest of some West African countries.114 The essential oil could be extracted from the leaf, fruit, and seed by hydrodistillation. The essential oil from seeds H


Review

Journal of Agricultural and Food Chemistry Table 3. Constituents of Essential Oils with an Anxiolytic Effect compound

molecular formula

administration waya

benzyl alcohol 2-phenethyl alcohol 1-nitro-2-phenylethane linalool

C7H8O C8H10O C8H9NO2 C10H18O

inhalation i.p. i.p. i.p.; inhalation

linalool oxide (+)-limonene

C10H18O2 C10H16

inhalation i.p.

(+)-limonene epoxide

C10H16O

p.o.; i.p.

citronellol α-pinene

C10H20O C10H16

i.p. inhalation

isopulegol camphene (+)-borneol

C10H18O C10H16 C10H18O

safranal carvacrol R-(−)-carvone thymol (−)-myrtenol (E)-methyl isoeugenol carvacryl acetate α-asarone benzyl benzoate valerena-4,7(11)-diene β-caryophyllene

C10H14O C10H14O C10H14O C10H14O C10H16O C11H14O2 C12H16O2 C12H16O3 C14H12O2 C15H24 C15H24

i.p. i.p. i.p.; microinjection i.p. p.o. i.p. p.o. i.p. p.o. i.p. p.o.; i.p. inhalation i.p. p.o.

(+)-cedrol farnesol

C15 H26O C15H26O

i.p. i.p.

essential-oil-derived plantb

reference

Cananga odorata Rosa centifolia; Rosa alba Dennettia tripetala; Aniba canelilla Lavandula angustifolia; Ocimum sanctum; Ocimum basilicum; Thymus vulgaris; Coriandrum sativum; Cananga odorata; Piper guineense; Pelargonium roseum Lavandula angustifolia; Pelargonium roseum; Ocimum basilicum Thymus vulgaris; Citrus limon; Citrus aurantium; Citrus aurantium subsp. bergamia; Citrus junos; Citrus sinensis var. dulcis; Lippia alba; Litsea cubeba; Alpinia zerumbet Citrus limonc

84 56 114 50 and 129−131 139 137

Rosa centifolia; Rosa alba; Pelargonium roseum Stachys tibetica; Coriandrum sativum; Ferulago angulata; Ducrosia anethifolia; Abies sachalinensis; Alpinia zerumbet Eucalyptus citriodorac Piper guineense; Thymus vulgaris; Lavandula angustifolia; Abies sachalinensis Lavandula angustifolia; Thymus vulgaris Crocus sativus Origanum vulgare Lippia alba Thymus vulgaris; Lippia sidoides Myrtus communis Pimenta pseudocaryophyllusc Satureja boliviana Acorus tatarinowii; Acorus gramineus Cananga odorata Nardostachys chinensis;c Valeriana officinalisc Spiranthera odoratissima; Lavandula angustifolia; Anthriscus nemorosa; Thymus vulgaris; Ocimum basilicum Juniperus virginiana Rosa damascena

140 and 141 56 138 133 54 54 and 132 144 134 149 113 135 145 143 146−148 84 128 86 and 152 101 136

a i.p., intraperitoneal injection; p.o., oral gavage. bThe plants that we listed are those whose essential oils showed an anxiolytic effect, and their chemical compositions were reported. cThe anxiolytic effect of the essential oils of this plant was not reported.

luene (10.9%), and β-pinene (9.2%) were the main constituents of the essential oil. Inhalation of P. guineense oil could reduce anxiety behaviors in the LDB test.66 Acantholippia deserticola is a Verbenaceae plant that has been used in traditional medicine in Chile as an analgesic. α-Thujone and βthujone were the main components of its essential oil. Acute intraperitoneal injection of essential oil from the aerial parts could relieve anxiety in female rats. Celastrus paniculatus is a large woody, climbing shrub. Its essential oil was extracted from seeds with petroleum ether and exhibited significant anxiolytic activity in the EPM, OF, and thirsty conflict tests.119 SuHeXiang is extracted from the trunk resin of Lipuidambar orientalis. It is used in traditional Chinese medicine to treat seizures, sudden loss of consciousness, and stroke. Chronic exposure to the odor of SuHeXiang reduced anxiety behaviors in the OF test in mice.120 Copaiba is a stimulant oleoresin obtained from the trunk of several Copaifera species and used in folk medicine since ancient times.121 The different species of copaiba present different amounts of substances in the oil composition (most are sesquiterpenes and diterpenes). Oral administration of copaiba oil from Copaifera reticulata showed an anxiolytic effect in the EPM test.122

significantly increased the percentage of time and entries into the open arms in the EPM test after oral administration. Alpinia zerumbet is widely used in folk medicine in many regions in China and Japan. p-Cymene, 1,8-cineole, limonene, and α-pinene were the major components of its essential oil.115 Satou et al. reported that a time-dependent potentiation in the anxiolytic-like effect of A. zerumbet oil was observed when the inhalation time was altered from 0 to 120 min.116 An anxiolytic-like effect was observed to peak at 90 and 120 min of exposure and returned to normal with a 150 min exposure. Chamaecyparis obtusa, Thujopsis dolabrata, and Abies sachalinensis are large conifer trees. Essential oils from the three species contain a lot of terpenes. Studies from Japanese and Korean researchers found that inhalation of these essential oils could reduce anxiety behaviors in mice or rats.58,59,67 Achillea (Asteraceae) is a perennial herb that has around 100 species, and many species are used in folk medicine.117 Achillea umbellata is an endemic Greek plant. The major constituents of the essential oil are the rare monoterpene alcohol fragranol and fragranyl acetate.118 Achillea wilhelmsii is used as an anxiolytic plant in folk medicine. p-Ocimene (23%), 1,8cineole (20.8%), carvone (19.13%), and camphor (6.67%) were the major components of the essential oil.117 Oral or intraperitoneal administration of the two essential oils showed an anxiolytic effect in approach−avoidance tests.117,118 Piper guineense is native to Africa. The essential oil is extracted from the fruit. Linalool (41.8%), 3,5-dimethoxyto-

4. ANXIOLYTIC COMPOUNDS IN ESSENTIAL OILS To determine the effective compounds, researchers often selected the major compounds of the anxiolytic essential oils and tested them in the animal models. Alcohols and terpenes I


Review


oils of Stachys tibetica, Coriandrum sativum, Ferulago angulata, Ducrosia anethifolia, Abies sachalinensis, and Alpinia zerumbet. Significant anxiolytic activity of α-pinene exposure was observed and remained constant for a 5 day inhalation in the EPM test.138 In one study from Umezu et al., intraperitoneal injection of camphene exerted significant anticonflict effects in the Geller but not Vogel conflict test.54 Valerena-4,7(11)-diene (VLD) and β-caryophyllene are two sesquiterpenes that have been proven to be anxiolytic. Takemoto et al. isolated VLD from Nardostachys chinensis roots using preparative high-performance liquid chromatography (HPLC) and tested its anxiolytic effect in restraintstress-induced mice.128 The results indicated that inhalation of VLD suppressed stress-induced excitatory behaviors. In the study by Galdino et al., oral intake of β-caryophyllene produced an anxiolytic effect in the hole-board, EPM, and LDB tests.86 4.3. Oxide Compounds. Linalool oxide could be found in some herbal essential oils as a minority component. It could be formed from linalool by natural oxidation or produced by synthetic processes. Inhalation of linalool oxide produced an anxiolytic effect in EPM and LDB tests in mice. 139 (+)-Limonene epoxide is a mixture of cis and trans isomers and found in many plants, such as Citrus limon.85 The anxiolytic effect of (+)-limonene epoxide has been discussed in two studies by de Almeida et al. Oral or intraperitoneal injection of (+)-limonene epoxide reduced the anxiety behaviors of mice in MB and EPM tests.140,141 4.4. Nitrogen Compounds. Nitrogen compounds are rarely seen in essential oils. The odoriferous principle of leaf, bark, and trunk wood of Aniba canelilla is 1-nitro-2phenylethane.142 In the rainy season, the content of 1-nitro2-phenylethane reached approaching 90−95%. 1-Nitro-2phenylethane was also found in the fruit essential oil of Dennettia tripetala, and its content reached approaching 80%.114 Oyemitan et al. isolated 1-nitro-2-phenylethane from the crude pooled oil by chromatography and found that intraperitoneal injection of 1-nitro-2-phenylethane could reduce anxiety behaviors.114 4.5. Others. Esters are thought to be beneficial to mood adjustment of humans in aromatherapy. Carvacryl acetate and benzyl benzoate have been proven to be anxiolytic in mice.84,143 Safranal is the main component of Crocus sativus essential oil and is thought to be the main cause of the unique odor of saffron. This ingredient has shown many benefits, including an anxiolytic effect.144 (E)-Methyl isoeugenol is the characteristic fragrance of species Pimenta pseudocaryophyllus. Oral administration of (E)-methyl isoeugenol showed an anxiolytic effect in several behavioral tests in mice.145 α-Asarone is a major component of genus Acorus. Acorus tatarinowii is a well-known traditional Chinese medicine for treating central nervous system (CNS)-related disorders. The anxiolytic effect of α-asarone has been reported in several studies.146−148 Carvone was a major component of Lippia alba and displayed an anxiolytic effect in rats.149 It should be noted that α-asarone was reported to be genotoxic and hepatocarcinogenic in rodents and have mammalian toxicity and carcinogenicity.150,151 As a result of its toxicity, the dosage should be considered in the use of α-asarone. Some main components of anxiolytic essential oils, such as citral, myrcene, terpinen-4-ol,54 and citronellyl acetate,56 did not exert anxiolytic effects when administered to rodents. These results could be further confirmed using more

were the most studied compounds. Besides these compounds, some aldehydes, ketones, oxides, and nitrogen-containing compounds have been proven to have anxiolytic effects (Table 3). In these studies, most of the researchers used the standard substance, while a few researchers isolated target compounds directly from the essential oils by preparative chromatography.114,128 Oral, inhalation, intraperitoneal injection, and microinjection were the four main ways for compound administration (Table 3). In the inhalation experiments, essential oils were dripped into cotton balls or filter papers to volatilize naturally or diluted to 1−10% (v/v) water solution and diffused by vaporizers. In the oral and intraperitoneal injection experiments, the doses of essential oils were in the range of 1−1600 mg/kg in different studies. In the microinjection experiments, 1 mL of 0.1−5 nM essential oil was injected at 0.18 mL/min. 4.1. Alcohols. Numerous monoterpene alcohols [linalool, citronellol, isopulegol, (+)-borneol, carvacrol, thymol, and (−)-myrtenol], sesquiterpene alcohols [(+)-cedrol and farnesol], and aromatic alcohols (2-phenethyl alcohol) have been proven to be anxiolytic. Linalool is widely found in many plant essential oils, such as Lavandula angustifolia oil, Ocimum basilicum oil, Thymus vulgaris oil, and Coriandrum sativum oil. It was the most widely studied compound and has been proven to be anxiolytic after intraperitoneal injection or inhalation in mice.50,129−131 Borneol could be found in Lavandula angustifoli and Thymus vulgaris oils. Borneol at a high concentration produced a significant anticonflict effect in the Geller test.54 Moreover, microinjection of (+)-borneol into the dorsal but not ventral hippocampus could suppress anxiety behaviors in the OF, LDB, and EPM tests.132 Thymol is the major component of Lippia sidoides and Thymus vulgaris oils. Oral administration of thymol could reverse anxiety behaviors in CORT-treated mice.113 Citronellol and 2-phenethyl alcohol are two major compounds of rose oil. Both of them showed significant anxiolytic effects at moderate concentrations in the conflictbased tests. However, a relatively high concentration of the two compounds would induce anxiety behaviors.56 Interestingly, not all of the alcohols in rose oil showed an anxiolytic effect. Geraniol and eugenol, which were two important ingredients of rose oil, increased anxiety behaviors in the conflict-based tests.56 Carvacrol, isopulegol, and (−)-myrtenol are present in the essential oils of various plants. Carvacrol and (−)-myrtenol are the major components of oregano and thyme oils, respectively. The content of isopulegol is high in Eucalyptus citriodora oil.133 These three monoterpene alcohols have been proven to be anxiolytic after oral or intraperitoneal injection.133−135 Cedrol and farnesol are two sesquiterpene alcohols that could be found in essential oils from Juniperus virginiana and Rosa damascena, respectively. Intraperitoneal injection of cedrol and farnesol significantly decreased the anxiety behaviors in several approach−avoidance tests.101,136 4.2. Terpenes. Terpenes are wildly found in many essential oils. (+)-Limonene, α-pinene, and camphene were three monoterpenes that showed anxiolytic effects.54,137,138 Limonene commonly exists in the essential oils of Citrus plants. The relative content of limonene in the anxiolytic Citrus aurantium and Citrus sinensis essential oils was more than 97%.79,82 Intraperitoneal injection of (+)-limonene could reduce anxiety behaviors in mice.137 α-Pinene could be found in the essential J


Review


more studies using different administration ways to obtain a deeper understand of the action mechanism of these compounds. 5.2. Neurotransmitter System. Neurotransmitters and their metabolites in the limbic system are thought to be closely related to the regulation of anxiety. 5-HT, dopamine (DA), glutamic acid, and GABA were most widely studied. 5-HT is closely related to anxiety. In preclinical studies from 1960 to 2012, the proportion of drugs developed on the basis of the 5HT system exceeded 50%.6 DA plays an important role in fear response. When the aversive reaction occurs, the DA level of these brain regions increases significantly.156 GABAergic involvement in the pathophysiology and treatment of mood disorders is equally compelling and showing stress-related changes in GABAergic function.7,9 There is a balance between glutamate and GABA in the CNS, which involves pre- and postsynaptic feedback inhibition. BDZs, which are one of the most frequently prescribed anxiolytic drugs, exert a positive allosteric modulatory effect and increase inhibitory GABAergic neurotransmission.8 There is also a related regulatory relationship between these neurotransmitters. 5-HT could modulate PFC functions via the regulation of GABAA-receptor-mediated inhibitory synaptic transmission.157 It could also directly regulate the release of DA by acting on its receptor on DA neurons or acting on the ventral tegmental area and the substantia nigra pars compact GABAergic neurons and glutamatergic neurons.158 Many studies have shown that the effects of essential oils on the CNS are related to these neurotransmitters. Agonists or antagonists of neurotransmitter receptors, such as 5-HT receptor antagonist WAY-100635, 5-HT1A receptor antagonist NAN-190, and GABAA receptor antagonists picrotoxin and flumazenil, have been pretreated to rodents to investigate the mechanism of action underlying the anxiolytic effect.86,123 The contents of neurotransmitters in different brain areas were also detected using the HPLC method in several studies.70,84 The results of Komiya et al. showed that lemon essential oil affected DA and 5-HT systems. It enhanced the synthesis of 5HT in the PFC and enhanced the hippocampus and DAnergic activity in the PFC.80 The anxiolytic effect of lavender essential oil was closely related to the 5-HT system. WAY-100635 could block the anxiolytic effect of lavender essential oil, while the GABAA receptor antagonist did not affect the anxiolytic effect.123 Lavender essential oil also increased the level of 5-HT in the rat striatum and PFC.70 Moreover, Baldinger et al. established molecular and structural neuroimaging on humans. After 8 weeks of intake of Silexan, reduced binding potential at the 5-HT1A receptor in the hippocampus and anterior cingulate cortex has been observed using the radioligand [carbonyl-11C]WAY-100635.159 Costa et al. found that WAY-100635 blocked the anxiolytic effect of bitter orange fruit oil with no alterations in neurotransmitter levels in the cortex, striatum, pons, and hypothalamus.79 Pretreatment with WAY-100635 but not flumazenil was able to reverse the effects of rose geranium oil.96 The anxiolytic-like effects of manacá leaf oil were reduced by 5-HT1A receptor antagonist NAN-190 but not GABAA antagonist flumazenil.86 Zhang et al. reported that ylang−ylang essential oil could increase the content of 5-HT in the hippocampus and reduce the content of DA in the striatum of male mice.84 Components in essential oils could also affect 5-HT and DA systems in the brain. Limonene could affect DA levels in the rat brain.160 Benzyl benzoate reduced the content of DA in the

administration methods and different types of animal models. This is because some compounds, such as α-pinene, showed an anxiolytic effect after odor exposure in the EPM test but did not exert an anxiolytic effect after intraperitoneal injection in the conflict-based tests.54

5. ACTION MECHANISM 5.1. Delivery Way of Essential Oil. To understand the mechanism of action of essential oils, it is necessary to determine through which pathway the essential oils were acting. One special administration method of essential oil is the inhalation way. After exposure to the testers, the odor molecules combine with the olfactory receptors (ORs) that are located on the nasal olfactory epithelium and further transmit the signals from the olfactory tracts to the olfactory bulbs. Mitral/tufted cells in the olfactory bulb receive primary input from individual glomeruli and then transmit information from the bulb to higher brain areas.153 Most olfactory sensory neurons (OSNs) are narrowly tuned to detect a subset of odorants with related structures, with the vast majority of odorants activating a unique set of OSNs, usually two or more in combination.154 As a result of the olfactory pathways, a 5 min exposure of essential oils could work quickly and significantly.123 Moreover, in rats and humans, odor intensity grows systematically with the concentration and rapidly decreases with adaptation.155 This might be the reason that sometimes chronic inhalation of essential oils did not show a better effect than acute inhalation. Besides the olfactory signal pathway, essential oils can be absorbed into the human body through absorption by the lungs and nasal mucosa into the blood. Odor molecules could be detected in the blood or brain tissues after inhalation administration. In the study from Satou et al., α-pinene, camphene, and β-pinene, which were the major components of Abies sachalinensis oil, could be detected in both blood and brain tissues.116 In another study from Satou et al., the accumulation of α-pinene in the brain and liver showed no significant differences between the 1 and 3 days of exposure to α-pinene.138 However, the odor concentration in the air affected volatile compound accumulation in inhalation experiments. The amounts of limonene in the liver, kidney, and brain were higher in the 6.7 mg/L oil treatment group than in the 3.4 mg/L oil treatment group.77 Anosmia models were established to determine the active pathway of the essential oils in several studies. Several chemicals (zinc gluconate + zinc acetate,68 ZnSO4,128 and 3methylindole130) were used to irrigate the nasal cavity, so that the mice could not detect odors. It was interesting that anosmia did not interfere with the anxiolytic effect of lavender essential oil68 and VLD.128 However, linalool, which was a major component of lavender essential oil, did not display an anxiolytic effect in anosmia mice.130 These results indicated that the anxiolytic effect of linalool was only triggered by olfactory input, while the effects of lavender essential oil and VLD might be trigger by entering the blood circulation. In the studies that we listed in Table 2, 28 studies used inhalation for essential oil administration and 31 studies used other administration ways, such as oral gavage or intraperitoneal injection. A few essential oils, such as lavender, have been proven to be anxiolytic after oral, intraperitoneal injection, and inhalation administrations. In the studies of essential oil compounds that we listed in Table 3, only 5 of 25 compounds have been administrated by inhalation. It is necessary to do K


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norepinephrine, under anxiety or stress.168 Oral intake of Silexan non-selectively reduced calcium influx through several different types of VOCCs, such as the N-, P/Q-, and T-type VOCCs.71 Mitogen-activated protein kinase (MAPK) can be activated by 5-HT, acetylcholine, and β-adrenergic receptors and then activates the extracellular signal-regulated kinase (ERK).169 Acute stress could increase the phosphor-ERK expression in the PFC or hippocampus of rodents.170−172 cAMP-response element binding protein (CREB) is a downstream transcription factor of ERK and can further lead to the transcription of many immediate early gene expressions, such as c-fos.173 Studies have shown that CREB-mediated hippocampal structural plasticity may be required for 5-HT1 receptors to regulate anxiety-related behavior. CREB knockout mice exhibited anxiety behavior in anxiety-related behavioral tests, such as EPM, LDB, and OF.174 In an in vitro study, Caputo et al. found that linalool but not the lavender essential oil inhibited the phosphorylated ERK (pERK) and protein kinase A (PKA) expression in the SH-SY5Y cells.129 Zhang et al. found that ylang−ylang essential oil suppressed the ERK phosphorylation and affected its downstream phosphorylation of CREB and the c-Fos expression in the hippocampus.57 Inhalation of vetiver essential oil significantly increased c-Fos expression in the lateral division of the central amygdaloid nucleus in rats.102 These findings suggested that the MAPK pathway is involved in the anxiolytic effect of essential oils. Many studies have demonstrated that essential oils affected the electroencephalography (EEG) spectrum power in rats and humans. Rats receiving 250 μL/kg of BEO (i.p.) displayed behavioral arousal characterized by an increase in the energy power relative to alpha (8.25−13 Hz) and beta (13.25−21 Hz) rhythms in the hippocampus and relative to theta (4.25−8 Hz) and alpha frequency bands in the cortex.175 In a study from Medeiros et al., geraniol-treated (i.p.) animals exerted a depressant effect and demonstrated an increase in the percentage of delta (0.5−4 Hz) waves in the total spectrum power.176 This result is similar to the result reported by Rombola et al. that a low dose of bergamot oil (i.p.) induced a long period of immobility associated with an increase in the amplitude of delta waves in the cortex of rats.175 In another study from Masago et al., the alpha 1 (8−10 Hz) wave at parietal and posterior temporal regions of subjects who are “feeling comfortable” significantly decreased soon after the onset of inhalation of lavender oil.177 In the current study, researchers mainly measured the power changes of different bands of EEG to reflect changes in anxiety levels. It is noteworthy that studies from many researchers have indicated that reduction of left frontal brain activation might be associated with anxiety and depression symptoms. The study of Moscovitch et al. showed that resting frontal brain activity (alpha wave) of patients shifted from greater relative right to greater relative left from pre- to post-treatment of cognitive behavioral therapy in patients with social anxiety disorder.178 Functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) studies have shown that a decrease in cortical blood flow was accompanied by increasing alpha power.179 These findings suggested that a change of left frontal EEG activity, especially alpha wave, might be considered as one of the anxiety indicators to evaluate the anxiolytic effect of essential oils.

striatum of mice and increased the content of 5-HT in the hippocampus.84 Flumazenil was able to reverse the effects of carvacrol and (+)-limonene epoxide in the EPM test.134,140 Inhaled VLD could significantly reduce cerebral 5-HT and DA levels.128 Results of several studies indicated that the anxiolytic effects of essential oils and volatile compounds were related to amino acid neurotransmitters. Pultrini Ade et al.82 reported that picrotoxin could block the anxiolytic effect of lemongrass essential oil, while WAY-100635 did not work. The anxiolytic effect of carvacryl acetate was reversed by flumazenil but not WAY-100635 in the EPM and LDB tests.143 Linalool could affect the release and reuptake of glutamate in vitro.161 The study from Morrone et al. showed that bergamot essential oil (BEO) significantly elevated the extracellular concentration of aspartate, glycine, and taurine after intraperitoneal administration.162 BEO could also significantly increase the extracellular levels of GABA and glutamate through perfusing into the hippocampus in rats.162 At relatively high concentrations, [3H]D-aspartate release induced by BEO was almost entirely prevented by the glutamate transporter blocker in a Ca2+-independent manner. Moreover, the authors found that the monoterpene hydrocarbon-free fraction of the essential oil appeared to be inactive, while the bergapten-free fraction superimposed the releasing effect. They suggested that unidentified monoterpene hydrocarbons of BEO might be able to stimulate glutamate release by transporter reversal and/ or exocytosis, depending upon the dose administered. In a chronic inflammatory pain model, the anxiolytic effect of αasarone administration appeared to be related to the amino acid neurotransmitter system. It downregulated the GluR1containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and NR2A-containing N-methyl-D-aspartate receptors and upregulated the GABAA receptors in the basolateral amygdala,148 which was a site that plays an important role in regulating the emotional response.163 5.3. Other Mechanisms. The hypothalamic−pituitary− adrenal (HPA) axis is closely associated with the development of stress-related psychosomatic disorders. BEO could attenuate the CORT response to acute stress caused by exposure to the EPM.76 5-HT is thought to be one of the important neurotransmitters that affect the pituitary function controlled by the hypothalamus.164 Ylang−ylang essential oil reversed the CORT change caused by 5-HT2C receptor agonist mCPP in mice.84 Corticotrophin-releasing factor (CRF) and tyrosine hydroxylase are involved in stress-induced activation of the CNS.165,166 The number of CRF-immunoreactive neurons was significantly decreased after α-asarone treatment in the paraventricular nucleus region of the rats with dysregulation of the HPA axis. α-Asarone also blocked the tyrosine hydroxylase expression in the locus coeruleus.146 Besides the animal studies, many clinical trials have shown that inhalation of essential oils could reduce the salivary cortisol in humans.16,32 The importance of brain-derived neurotrophic factor (BDNF) gene polymorphism in anxiety and depression has received extensive attention in recent years. Stress could lead to a downregulation of BDNF mRNA expression in the hippocampal CA1 region.167 α-Asarone could increase mRNA expression of BDNF and its receptor TrkB in the hippocampus.146 Enhanced Ca2+ influx through N- and P/Q-type voltage operated calcium channels (VOCCs) might increase the release of neurotransmitters, such as glutamate and L


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6. DISCUSSION Most of the essential oils used in clinical studies have been proven to be anxiolytic in animal models. In clinical trials, researchers often chose essential oils used in aromatherapy, such as oils from lavender, bergamot, rosemary, rose, and clary sage. In preclinical studies, besides the above essential oils, essential oils derived from many herbal plants were used for research. Neurotransmitters and the HPA axis were proven to play important roles in the anxiolytic effects of essential oils in animal models. In the clinical trials, several studies also indicated that essential oils could affect the cortisol contents in saliva. In general, the clinical study of anxiolytic effects of essential oils might be more challenging as a result of the individual differences of participants. The combined use of biological indicators could help us obtain a better understanding of the action mechanism of essential oils. In some papers, especially those of clinical research, the Latin name of the plant for essential oil production and the chemical composition of the essential oil were not shown. A lack of such information has a certain impact on the reference value of these studies. In the usage of essential oils in aromatherapy, trained aromatherapists select essential oil products labeled with chemotype and plant Latin name. Different chemotypes of essential oil were used to solve different problems. Many different chemo-cultivars varying in their aroma have been selected or bred by crossing with other cultivars or closely related species.180 Infraspecific chemical variation is found in many essential oil plants, such as Lippia alba,111 Ocimum basilicum,180 Origanum vulgare,181 Thymus vulgaris,74 and Rosmarinus officinalis.182 Because the effects of the essential oil are dependent upon their chemical compositions, it is necessary to describe the Latin name of the essential oil source plant and the chemical components in the pharmacological study report. Inhalation and oral administration were two common methods for essential oil administration in preclinical and clinical trials. Massage was only used in the clinical trials, while intraperitoneal injection was only used in the preclinical trails. As far as we know, there were few studies reporting the anxiolytic effect of essential oils on animals through the skin application way. The skin application way was commonly used in aromatherapy for a long time and used in many clinical trials. It might involve both the transdermal and olfactory pathways. The action mechanism of this application way remains to be further studied. In the clinical trials, double- or triple-blind controlled methods are easier to carry out in studies of oral intake of essential oils for the reason that it is difficult for the tester to distinguish the capsules.33,35,159 Several researchers did tripleblind controlled studies.19,183 However, the inability to blind the application to the researcher might be a limitation of the design for massage or inhalation experiments. No odor treatment or carrier oil were usually used for control treatment. When performing the massage or inhalation of essential oils, the researcher is usually informed about the intervention received when the odors are released. Whether the subject knows essential oils might affect the implementation of the double-blind study. Testers with essential oil knowledge are more likely to obtain relevant information through smell. These factors need to be considered in the experimental design.

Another notable issue is the diffusing way of the essential oils in the inhalation experiments. In this review, we found that some researchers let the essential oils naturally volatilize at room temperature by putting a cotton ball or a filter paper soaked with essential oils. Other researchers used an electronic vaporizer or a warmer to diffuse the odor. These methods are similar to the ways that essential oils are used in aromatherapy. However, as we known, essential oils are composed of at least dozens of compounds with different boiling points and volatilization rates. The different odor diffusion methods and diffusion times made the constituents and concentration of odors in the inhalation environment quite different and usually differ from the GC−MS results of the essential oil. To better understand the mechanism of action components, qualitative and quantitative analyses of the odors in the inhalation box or test room are preferred. The anxiety disorder diagnosis rate of females is twice as many as males.4 There is a greater bias in favor of using male over female animals in anxiolytic drug discovery. In the clinical trials, both sexes were used as subjects. In some experiments, only females were considered as subjects. However, only a few studies used both sexes of rodents in preclinical trials. There is a significant influence of steroid hormones on anxiety behaviors.184 Sex hormones are often considered to be one of the main causes of differences in male and female behaviors. Studies have reported that high levels of estrogen could reduce anxiety behaviors in female rats.185,186 Compounds in essential oil, such as geraniol and nerol, exhibited certain estrogenic activity in yeast cells.187 Benzyl benzoate and benzyl salicylate could also exhibit certain estrogenic activity in MCF7 cells.188 Significant sexual differentiation was observed in the formation and function of anxiety circuits. The results of Oliveira-Pinto et al. showed that there were significant differences in the total number of cells and the proportion of neurons in the olfactory bulb of human males and females.189 It has also been reported that the combination of olfactory molecules and olfactory receptors results in a gender difference in the projection of the olfactory bulb to different brain regions.190 Several studies have shown that male and female rodents exerted different responses to the essential oils.81,83,84,191 On the basis of the above reasons, using both sexes of animals in research might help us obtain a more comprehensive vision of the action mechanism of essential oils.

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AUTHOR INFORMATION

Corresponding Author

*Telephone/Fax: 86-21-34206606. E-mail: [email protected]. ORCID

Nan Zhang: 0000-0002-3366-3754 Notes

The authors declare no competing financial interest.

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ABBREVIATIONS USED 5-HT, 5-hydroxytryptamine; BDNF, brain-derived neurotrophic factor; BDZ, benzodiazepine; BP, blood pressure; CAM, complementary and alternative medicine; CgA, chromogranin A; CMAI, Cohen-Mansfield agitation inventory; CNS, central nervous system; CORT, corticosterone; CREB, cAMP-response element binding protein; CRF, corticotrophinreleasing factor; DA, dopamine; EPM, elevated plus maze; ERK, extracellular signal-regulated kinase; GABA, γ-aminobutyric acid; GC−MS, gas chromatography−mass spectromM


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cognitive performance following administration of acute doses of Salvia lavandulaefolia essential oil to healthy young volunteers. Physiol. Behav. 2005, 83 (5), 699−709. (19) Farshbaf-Khalili, A.; Kamalifard, M.; Namadian, M. Comparison of the effect of lavender and bitter orange on anxiety in postmenopausal women: A triple-blind, randomized, controlled clinical trial. Complementary Ther. Clin. Pract. 2018, 31, 132−138. (20) Kheirkhah, M.; Vali Pour, N. S.; Neisani, L.; Haghani, H. Comparing the effects of aromatherapy with rose oils and warm foot bath on anxiety in the first stage of labor in nulliparous women. Iran Red Crescent Med. J. 2014, 16 (9), No. e14455. (21) Kasper, S.; Gastpar, M.; Muller, W. E.; Volz, H.-P.; Möller, H.J.; Dienel, A.; Schlafke, S. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of ‘subsyndromal’ anxiety disorder: A randomized, double-blind, placebo controlled trial. Int. Clin. Psychopharmacol. 2010, 25 (5), 277−287. (22) Wilkinson, S.; Aldridge, J.; Salmon, I.; Cain, E.; Wilson, B. An evaluation of aromatherapy massage in palliative care. Palliative Med. 1999, 13 (5), 409−417. (23) Dunn, C.; Sleep, J.; Collett, D. Sensing an improvement: An experimental study to evaluate the use of Dunn aromatherapy, massage and periods of rest in an intensive care unit. J. Adv. Nurs 1995, 21, 34−40. (24) Ayik, C.; Ozden, D. The effects of preoperative aromatherapy massage on anxiety and sleep quality of colorectal surgery patients: A randomized controlled study. Complementary Ther. Med. 2018, 36, 93−99. (25) Kritsidima, M.; Newton, T.; Asimakopoulou, K. The effects of lavender scent on dental patient anxiety levels: A cluster randomisedcontrolled trial. Community Dent. Oral Epidemiol. 2010, 38 (1), 83− 87. (26) Jung, D. J.; Cha, J. Y.; Kim, S. E.; Ko, I. G.; Jee, Y. S. Effects of Ylang−Ylang aroma on blood pressure and heart rate in healthy men. J. Exerc. Rehabil. 2013, 9 (2), 250−255. (27) Ni, C.-H.; Hou, W.-H.; Kao, C.-C.; Chang, M.-L.; Yu, L.-F.; Wu, C.-C.; Chen, C. The anxiolytic effect of aromatherapy on patients awaiting ambulatory surgery: A randomized controlled trial. EvidenceBased Complementary Alternat. Med. 2013, 2013, 927419. (28) Shirzadegan, R.; Gholami, M.; Hasanvand, S.; Birjandi, M.; Beiranvand, A. Effects of geranium aroma on anxiety among patients with acute myocardial infarction: A triple-blind randomized clinical trial. Complementary Ther. Clin. Pract. 2017, 29, 201−206. (29) Kyle, G. Evaluating the effectiveness of aromatherapy in reducing levels of anxiety in palliative care patients: Results of a pilot study. Complementary Ther. Clin. Pract. 2006, 12 (2), 148−155. (30) Chaves Neto, G.; Braga, J. E. F.; Alves, M. F.; de Morais Pordeus, L. C.; dos Santos, S. G.; Scotti, M. T.; Almeida, R. N.; Diniz, M. Anxiolytic Effect of Citrus aurantium L. in Crack Users. EvidenceBased Complementary Alternat. Med. 2017, 2017, 7217619. (31) Chang, K.-M.; Shen, C.-W. Aromatherapy benefits autonomic nervous system regulation for elementary school faculty in taiwan. Evidence-Based Complementary Alternat Med. 2011, 2011 (4), 946537. (32) Watanabe, E.; Kuchta, K.; Kimura, M.; Rauwald, H. W.; Kamei, T.; Imanishi, J. Effects of bergamot (Citrus bergamia (Risso) Wright & Arn.) essential oil aromatherapy on mood states, parasympathetic nervous system activity, and salivary cortisol levels in 41 healthy females. Forsch Komplementmed 2015, 22 (1), 43−49. (33) Kasper, S.; Gastpar, M.; Müller, W. E.; Volz, H. P.; Möller, H. J.; Dienel, A.; Schläfke, S. Silexan, an orally administered Lavandula oil preparation, is effective in the treatment of ‘subsyndromal’ anxiety disorder: A randomized, double-blind, placebo controlled trial. Int. Clin. Psychopharmacol. 2010, 25 (5), 277−287. (34) Kasper, S. An orally administered Lavandula oil preparation (Silexan) for anxiety disorder and related conditions: An evidence based review. Int. J. Psychiatry Clin. Pract. 2013, 17 (sup1), 15−22. (35) Woelk, H.; Schlafke, S. A multi-center, double-blind, randomised study of the lavender oil preparation Silexan in comparison to lorazepam for generalized anxiety disorder. Phytomedicine 2010, 17 (2), 94−99.

etry; HPA, hypothalamic−pituitary−adrenal; HPLC, highperformance liquid chromatography; HR, heart rate; HRV, heart rate variability; ICU, intensive care unit; LDB, light and dark box; i.p., intraperitoneal injection; MAPK, mitogenactivated protein kinase; MB, marble-burying; OF, open field; OR, olfactory receptor; OSN, olfactory sensory neuron; oxy-H, oxyhemoglobin; PFC, prefrontal cortex; p.o., oral gavage; SI, social interaction; STAI, Spielberger’s state-trait anxiety inventory; VLD, valerena-4,7(11)-diene

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Anxiolytic Effect of Essential Oils and Their Constituents: A Review

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