《气味科学中的健康密码》课程教学资源（阅读材料）Is lavender an anxiolytic drug? A systematic review of randomised clinical trials

Phytomedicine 19(2012)825-835 Contents lists available at SciVerse ScienceDirect Phytomedicine Phytomedicine ELSEVIER journal homepage:www.elsevier.de/phymed Short communication Is lavender an anxiolytic drug?A systematic review of randomised clinical trials R.Perry*,R.Terry,L.K.Watson,E.Ernst Complementary Medicine,Peninsula Medical School.Veysey Building.Salmon Pool Lane,University of Exeter,Exeter EX2 4SG.United Kingdom ARTICLE INFO ABSTRACT Keywords: Background:Lavender(Lavandula angustifolia)is often recommended for stress/anxiety reliefand believed Lavender to possess anxiolytic effects. Anxiolytic drug Aim:To critically evaluate the efficacy/effectiveness of lavender for the reduction of stress/anxiety. Anxiety Methods:Seven electronic databases were searched to identify all relevant studies.All methods of laven- Stress RCT der administration were included.Data extraction and the assessment of the methodological quality of Systematic review all included trials were conducted by two independent reviewers. Results:Fifteen RCTs met the inclusion criteria.Two trials scored 4 points on the 5-point Jadad scale,the remaining 13 scored two or less.Results from seven trials appeared to favour lavender over controls for at least one relevant outcome. Conclusion:Methodological issues limit the extent to which any conclusions can be drawn regarding the efficacy/effectiveness of lavender.The best evidence suggests that oral lavender supplements may have some therapeutic effects.However,further independent replications are needed before firm conclusions can be drawn. 2012 Elsevier GmbH.All rights reserved. Introduction excessive intake)(Leung and Foster 1996),lavender intake seems to be reasonably safe. Lavender(Lavandula angustifolia)has a long history of medicinal This systematic review is aimed at critically evaluating the data use and is purported to possess anxiolytic,sedative and calming from randomised clinical trials(RCTs)of all types oflavender prepa- properties (Cavanagh and Wilkinson 2002).Most commonly it is rations(oral,olfactory,topical)for the treatment of anxiety. recommended for oral administration.More recently,lavender is also being employed in aromatherapy (Setzer 2009)although spe- Methods cific pharmacological effects of lavender aromatherapy are difficult to distinguish from any innate or learned preferences to this,or any The following electronic databases were searched from their other,odour(Bradley et al.2009). The chemical composition of lavender is complex and several of inception up to December 2010:Medline,EMBASE and PsychInfo (via OVID).AMED and CINAHL(via EBSCO).The Cochrane Library. its constituents (e.g.linalool and linalyl acetate)have been pro- and ISI Web of Knowledge.The search terms used included lavender, posed as being responsible for the perceived anxiolytic effects and anxiety or stress,and derivatives of these terms (see Appendix (Setzer 2009).In animal models,linalool has been found to inhibit GABA(A)binding reception in the CNS inducing a relaxed state A for electronic search strategy).Our own departmental files and the reference lists of all selected articles were searched for further (Brum et al.2001;Hossain et al.2004).Until recently,this activity relevant studies. had not been noted in human studies. Articles were included if they reported an RCT in which human Anxiety is a common disorder (14%of the EU population suf- subjects with or without clinical anxiety were treated with any type fer from one or more anxiety disorders each year (Wittchen et al. of lavender preparation(excluding those containing other ingredi- 2011))but can be severe and debilitating,often requiring med- ents(e.g.Corner et al.1995;Graham et al.2003:Nord and Belew ication.Lavender may provide a gentler treatment option than 2009))and which reported validated measures of anxiety or stress conventional anxiolytic drugs.Apart from rare allergic reactions as an endpoint (e.g.State Trait Anxiety Inventory;STAl,Hamilton (Coulson and Khan 1999)and gastrointestinal complaints (after Anxiety and Depression:HAD),standardised measures of anxiety (e.g.visual analogue scales were acceptable)or physiological mea- sures of stress (e.g.salivary levels of cortisol,heart rate,galvanic skin response).We excluded studies that were not randomised(e.g. Corresponding author.Tel.:+44 0 1392 726044. Willman et al.2009)along with studies comparing two different E-mail address:R.Perry@bath.ac.uk (R.Perry). forms of lavender treatments without a control condition,those 0944-7113/S-see front matter 2012 Elsevier GmbH.All rights reserved. doi:10.1016j-ohymed.2012.02.013

Phytomedicine 19 (2012) 825–835 Contents lists available at SciVerse ScienceDirect Phytomedicine journal h omepage: www.elsevier.de/phymed Short communication Is lavender an anxiolytic drug? A systematic review of randomised clinical trials R. Perry∗, R. Terry, L.K. Watson, E. Ernst Complementary Medicine, Peninsula Medical School, Veysey Building, Salmon Pool Lane, University of Exeter, Exeter EX2 4SG, United Kingdom a r t i c l e i n f o Keywords: Lavender Anxiolytic drug Anxiety Stress RCT Systematic review a b s t r a c t Background: Lavender (Lavandula angustifolia)is oftenrecommended for stress/anxiety relief and believed to possess anxiolytic effects. Aim: To critically evaluate the efficacy/effectiveness of lavender for the reduction of stress/anxiety. Methods: Seven electronic databases were searched to identify all relevant studies. All methods of laven￾der administration were included. Data extraction and the assessment of the methodological quality of all included trials were conducted by two independent reviewers. Results: Fifteen RCTs met the inclusion criteria. Two trials scored 4 points on the 5-point Jadad scale, the remaining 13 scored two or less. Results from seven trials appeared to favour lavender over controls for at least one relevant outcome. Conclusion: Methodological issues limit the extent to which any conclusions can be drawn regarding the efficacy/effectiveness of lavender. The best evidence suggests that oral lavender supplements may have some therapeutic effects. However, further independent replications are needed before firm conclusions can be drawn. © 2012 Elsevier GmbH. All rights reserved. Introduction Lavender (Lavandula angustifolia) has a long history of medicinal use and is purported to possess anxiolytic, sedative and calming properties (Cavanagh and Wilkinson 2002). Most commonly it is recommended for oral administration. More recently, lavender is also being employed in aromatherapy (Setzer 2009) although spe￾cific pharmacological effects of lavender aromatherapy are difficult to distinguish from any innate or learned preferences to this, or any other, odour (Bradley et al. 2009). The chemical composition of lavender is complex and several of its constituents (e.g. linalool and linalyl acetate) have been pro￾posed as being responsible for the perceived anxiolytic effects (Setzer 2009). In animal models, linalool has been found to inhibit GABA(A) binding reception in the CNS inducing a relaxed state (Brum et al. 2001; Hossain et al. 2004). Until recently, this activity had not been noted in human studies. Anxiety is a common disorder (14% of the EU population suf￾fer from one or more anxiety disorders each year (Wittchen et al. 2011)) but can be severe and debilitating, often requiring med￾ication. Lavender may provide a gentler treatment option than conventional anxiolytic drugs. Apart from rare allergic reactions (Coulson and Khan 1999) and gastrointestinal complaints (after ∗ Corresponding author. Tel.: +44 0 1392 726044. E-mail address: R.Perry@bath.ac.uk (R. Perry). excessive intake) (Leung and Foster 1996), lavender intake seems to be reasonably safe. This systematic review is aimed at critically evaluating the data fromrandomised clinicaltrials (RCTs) of alltypes oflavender prepa￾rations (oral, olfactory, topical) for the treatment of anxiety. Methods The following electronic databases were searched from their inception up to December 2010: Medline, EMBASE and PsychInfo (via OVID), AMED and CINAHL (via EBSCO), The Cochrane Library, andISIWeb ofKnowledge. The searchtermsusedincludedlavender, and anxiety or stress, and derivatives of these terms (see Appendix A for electronic search strategy). Our own departmental files and the reference lists of all selected articles were searched for further relevant studies. Articles were included if they reported an RCT in which human subjects with or without clinical anxiety were treated with any type of lavender preparation (excluding those containing other ingredi￾ents (e.g. Corner et al. 1995; Graham et al. 2003; Nord and Belew 2009)) and which reported validated measures of anxiety or stress as an endpoint (e.g. State Trait Anxiety Inventory; STAI, Hamilton Anxiety and Depression; HAD), standardised measures of anxiety (e.g. visual analogue scales were acceptable) or physiological mea￾sures of stress (e.g. salivary levels of cortisol, heart rate, galvanic skin response).We excluded studies that were not randomised (e.g. Willman et al. 2009) along with studies comparing two different forms of lavender treatments without a control condition, those 0944-7113/$ – see front matter © 2012 Elsevier GmbH. All rights reserved. doi:10.1016/j.phymed.2012.02.013

826 R.Perry et al.Phytomedicine 19(2012)825-835 comparing a combined lavender treatment against a no-treatment Muzzarelli et al.2006:Sgoutas-Emch et al.2001;Toda and control(e.g.Hoya et al.2008),uncontrolled trials and those in which Morimoto 2008)investigated the effect of lavender oil inhalation no clinical data were reported (e.g.Buckle 1993;Motomura et al Four trials(Braden et al.2009:Kritsidima et al.2010:Kutlu et al 1999).No language restrictions were imposed.Hard copies of all 2008;Motomura et al.2001)reported a significantly positive effect articles were obtained and read in full by two authors(RP,RT). for at least one anxiety outcome measure.Kritsidima et al.(2010) Data from the articles were independently extracted from all compared lavender oil aromatherapy with no oil (using a candle included studies by two reviewers(RP,RT)according to pre-defined burner)for patients waiting for a dental appointment.They found criteria (Tables 1 and 2).We only reported between-group analy- a significantly greater reduction in State Trait Anxiety Inventory ses from outcomes that conform to our inclusion criteria above (STAl)compared to the control group(p<0.001)but no significant To assess methodological quality,the Jadad scalel was used(Jadad between-groups difference in the Modified Dental Anxiety Scale et al.1996).To supplement the Jadad score,using Verhagen et al. (MDAS).Braden(Braden et al.2009)found a lavender aromather- (1998)and Boutron et al.(2005)as a guide,additional information apy group (lavender hybrid)had significantly less self-reported pertaining to risk of bias was extracted (Table 2).Discrepancies anxiety than either control group (p<0.01)for pre-operative anxi- were resolved through discussion between the authors.A meta- etv analysis was considered but deemed to be not appropriate because Both Motomura et al.(2001)Kutlu et al.(2008)induced stress- of the clinical and statistical heterogeneity of the primary studies. ful situations in healthy volunteers.Lavender odour was released in the experimental conditions but not the control conditions Results Motomura et al.(1999)found that anxiety levels were associated with reduced mental stress in the lavender condition although no The literature search identified 440 potentially relevant titles significant differences between conditions were found for physio- and abstracts.Fifteen RCTs involving 1565 participants met the logical measures.Kutlu et al.(2008)used an exam to induce anxiety inclusion criteria(Fig.1).Where possible,between-group analy- and found the lavender group had significantly lower anxiety scores ses of the main anxiety outcomes are presented in Table 1.The on the STAl than the control group (p<0.001)after the 60-min included studies were published between 1995 and 2010.origi- exam.Unfortunately as baseline anxiety scores would be likely to nated from six countries and were all written in English.Sample be very high prior to an exam,baseline anxiety scores were not sizes ranged from 16 to 340.The majority of trials used Lavandula taken,so it is impossible to establish change over time.Both trials angustifolia unless otherwise stated. suffer major methodological issues (Table 2) Eight trials(Bradley et al.2009:Howard and Hughes 2008;Kutlu Four inhalation trials (Howard and Hughes 2008;Muzzarelli et al.2008;Morris 2002:Motomura et al.2001:Sgoutas-Emch et al.2006;Sgoutas-Emch et al.2001:Toda and Morimoto 2008) et al.2001:Toda and Morimoto 2008:Xu et al.2008)used healthy did not demonstrate an effect.Muzzarelli et al.(2006)used patients volunteers with assumed normal levels of anxiety in which anx- waiting for an gastrointestinal endoscopy.Reductions in within- iety was induced for the purpose of the study.One trial (Soden group anxiety levels were reported in both the lavender(Provencal et al.2004)assessed the efficacy of lavender in cancer patients lavender)and grapeseed inhalation groups,however,no between- with high levels of anxiety and depression.Three studies (Braden group analyses were performed which limits its conclusiveness et al.2009;Kritsidima et al.2010;Muzzarelli et al.2006)looked at Longer inhalation time(more than 5 min)was suggested for future pre-procedural anxiety (e.g.,dental appointment,gastrointestinal trials. endoscopic procedure,pre-operation).One trial(Dunn et al.1995) The remaining trials(Howard and Hughes 2008;Sgoutas-Emch involved patients in an Intensive Care Unit (ICU)and two studies et al.2001:Toda and Morimoto 2008)of lavender inhalation focussed upon the value of lavender for individuals with gener- assessed efficacy in healthy volunteers.Stress was induced in a alised or sub-syndromal anxiety disorder(according to DSMIV or variety of ways e.g.arithmetic tasks(Sgoutas-Emch et al.2001; ICD-10)(Kasper et al.2010:Woelk and Schlafke 2010). Toda and Morimoto 2008)and an arousal task(Howard and Hughes The methodological quality of the included trials was variable 2008).In Toda's(Toda and Morimoto 2008)study it was found that but generally poor(Table 2):Jadad scores ranged from 0 to 4.with during the experimental period,neither group showed any signifi- just two trials(Kasper et al.2010;Woelk and Schlafke 2010)achiev- cant variation in levels of salivary cortisol (stress hormone).In the ing a score of 4 points.The majority of trials scored less than 2 lavender group.levels of chromogranin A(CgA is a novel stress Different methods of lavender administration were tested.Eight marker found in saliva (Nakane et al.1998,2002))that had been trials (Braden et al.2009:Howard and Hughes 2008:Kritsidima elevated at the end of the arithmetic task were statistically lower et al.2010:Kutlu et al.2008:Motomura et al.2001:Muzzarelli 10 min later whereas they were still elevated in the control group. et al.2006;Sgoutas-Emch et al.2001:Toda and Morimoto 2008) However,there was no significant difference between the groups at assessed the efficacy of lavender aromatherapy.Two trials(Dunn 5 and 10min implying that lavender may only help stress levels to et al.1995;Soden et al.2004)employed aromatherapy massage, drop quicker.There were no significant between group differences one used an oil-dripping technique(Xu et al.2008),one involved in subjective ratings of stress. bathing in lavender oil(Morris 2002)and three used oral capsules Sgoutas-Emch et al.(2001)compared four groups:two received (Bradley et al.2009:Kasper et al.2010:Woelk and Schlafke 2010). lavender aromatherapy and two groups did not receive aromather- The results of the 15 trials will be described in more detail in the apy.One group from each condition knew about their group following section,according to the method of administration. allocation,whilst the two other groups did not.The aim was to see if knowledge of treatment impacted on results.In fact,no sig- Inhalation of lavender nificant differences between the four groups were found on any measure.Interestingly,Group 3 had significantly higher levels of Eight trials (Braden et al.2009:Howard and Hughes 2008; anxiety prior to task than other three groups yet this group's anxiety Kritsidima et al.2010:Kutlu et al.2008:Motomura et al.2001: levels went down following the arousal task.In general,the authors felt a more stress-provoking task might be required in future trials. Howard and Hughes (2008)employed an experimental stress 1 Jadad score(1 for randomisation.1 for sequence generation and allocation con- task to compare lavender with tea tree oil odour(against a no odour cealment,1 for stating it is double blind and 1 for description of blinding and condition)in an attempt to compensate for previous experiments appropriateness and 1 for withdrawal stating number and reasons per group). that do not test lavender against another strong odour.They also

826 R. Perry et al. / Phytomedicine 19 (2012) 825–835 comparing a combined lavender treatment against a no-treatment control(e.g.Hoya et al. 2008),uncontrolledtrials andthose in which no clinical data were reported (e.g. Buckle 1993; Motomura et al. 1999). No language restrictions were imposed. Hard copies of all articles were obtained and read in full by two authors (RP, RT). Data from the articles were independently extracted from all included studies by two reviewers (RP, RT) according to pre-defined criteria (Tables 1 and 2). We only reported between-group analy￾ses from outcomes that conform to our inclusion criteria above. To assess methodological quality, the Jadad scale1 was used (Jadad et al. 1996). To supplement the Jadad score, using Verhagen et al. (1998) and Boutron et al. (2005) as a guide, additional information pertaining to risk of bias was extracted (Table 2). Discrepancies were resolved through discussion between the authors. A meta￾analysis was considered but deemed to be not appropriate because of the clinical and statistical heterogeneity of the primary studies. Results The literature search identified 440 potentially relevant titles and abstracts. Fifteen RCTs involving 1565 participants met the inclusion criteria (Fig. 1). Where possible, between-group analy￾ses of the main anxiety outcomes are presented in Table 1. The included studies were published between 1995 and 2010, origi￾nated from six countries and were all written in English. Sample sizes ranged from 16 to 340. The majority of trials used Lavandula angustifolia unless otherwise stated. Eighttrials (Bradley et al. 2009; Howard and Hughes 2008; Kutlu et al. 2008; Morris 2002; Motomura et al. 2001; Sgoutas-Emch et al. 2001; Toda and Morimoto 2008; Xu et al. 2008) used healthy volunteers with assumed normal levels of anxiety in which anx￾iety was induced for the purpose of the study. One trial (Soden et al. 2004) assessed the efficacy of lavender in cancer patients with high levels of anxiety and depression. Three studies (Braden et al. 2009; Kritsidima et al. 2010; Muzzarelli et al. 2006) looked at pre-procedural anxiety (e.g., dental appointment, gastrointestinal endoscopic procedure, pre-operation). One trial (Dunn et al. 1995) involved patients in an Intensive Care Unit (ICU) and two studies focussed upon the value of lavender for individuals with gener￾alised or sub-syndromal anxiety disorder (according to DSMIV or ICD-10) (Kasper et al. 2010; Woelk and Schlafke 2010). The methodological quality of the included trials was variable but generally poor (Table 2); Jadad scores ranged from 0 to 4, with justtwo trials (Kasper et al. 2010;Woelk and Schlafke 2010) achiev￾ing a score of 4 points. The majority of trials scored less than 2. Different methods of lavender administration were tested. Eight trials (Braden et al. 2009; Howard and Hughes 2008; Kritsidima et al. 2010; Kutlu et al. 2008; Motomura et al. 2001; Muzzarelli et al. 2006; Sgoutas-Emch et al. 2001; Toda and Morimoto 2008) assessed the efficacy of lavender aromatherapy. Two trials (Dunn et al. 1995; Soden et al. 2004) employed aromatherapy massage, one used an oil-dripping technique (Xu et al. 2008), one involved bathing in lavender oil (Morris 2002) and three used oral capsules (Bradley et al. 2009; Kasper et al. 2010; Woelk and Schlafke 2010). The results of the 15 trials will be described in more detail in the following section, according to the method of administration. Inhalation of lavender Eight trials (Braden et al. 2009; Howard and Hughes 2008; Kritsidima et al. 2010; Kutlu et al. 2008; Motomura et al. 2001; 1 Jadad score (1 for randomisation, 1 for sequence generation and allocation con￾cealment, 1 for stating it is double blind and 1 for description of blinding and appropriateness and 1 for withdrawal stating number and reasons per group). Muzzarelli et al. 2006; Sgoutas-Emch et al. 2001; Toda and Morimoto 2008) investigated the effect of lavender oil inhalation. Four trials (Braden et al. 2009; Kritsidima et al. 2010; Kutlu et al. 2008; Motomura et al. 2001) reported a significantly positive effect for at least one anxiety outcome measure. Kritsidima et al. (2010) compared lavender oil aromatherapy with no oil (using a candle burner) for patients waiting for a dental appointment. They found a significantly greater reduction in State Trait Anxiety Inventory (STAI) compared to the control group (p < 0.001) but no significant between-groups difference in the Modified Dental Anxiety Scale (MDAS). Braden (Braden et al. 2009) found a lavender aromather￾apy group (lavender hybrid) had significantly less self-reported anxiety than either control group (p < 0.01) for pre-operative anxi￾ety. Both Motomura et al. (2001) Kutlu et al. (2008) induced stress￾ful situations in healthy volunteers. Lavender odour was released in the experimental conditions but not the control conditions. Motomura et al. (1999) found that anxiety levels were associated with reduced mental stress in the lavender condition although no significant differences between conditions were found for physio￾logical measures. Kutlu et al.(2008) used an exam to induce anxiety and found the lavender grouphad significantly lower anxiety scores on the STAI than the control group (p < 0.001) after the 60-min exam. Unfortunately as baseline anxiety scores would be likely to be very high prior to an exam, baseline anxiety scores were not taken, so it is impossible to establish change over time. Both trials suffer major methodological issues (Table 2). Four inhalation trials (Howard and Hughes 2008; Muzzarelli et al. 2006; Sgoutas-Emch et al. 2001; Toda and Morimoto 2008) did not demonstrate an effect. Muzzarelli et al.(2006) used patients waiting for an gastrointestinal endoscopy. Reductions in within￾group anxiety levels were reported in both the lavender (Provencal lavender) and grapeseed inhalation groups, however, no between￾group analyses were performed which limits its conclusiveness. Longer inhalation time (more than 5 min) was suggested for future trials. The remaining trials (Howard and Hughes 2008; Sgoutas-Emch et al. 2001; Toda and Morimoto 2008) of lavender inhalation assessed efficacy in healthy volunteers. Stress was induced in a variety of ways e.g. arithmetic tasks (Sgoutas-Emch et al. 2001; Toda and Morimoto 2008) and an arousaltask (Howard and Hughes 2008). In Toda’s (Toda and Morimoto 2008) study it was found that during the experimental period, neither group showed any signifi- cant variation in levels of salivary cortisol (stress hormone). In the lavender group, levels of chromogranin A (CgA is a novel stress marker found in saliva (Nakane et al. 1998, 2002)) that had been elevated at the end of the arithmetic task were statistically lower 10 min later whereas they were still elevated in the control group. However,there was no significant difference between the groups at 5 and 10 min implying that lavender may only help stress levels to drop quicker. There were no significant between group differences in subjective ratings of stress. Sgoutas-Emch et al. (2001) compared four groups; two received lavender aromatherapy and two groups did not receive aromather￾apy. One group from each condition knew about their group allocation, whilst the two other groups did not. The aim was to see if knowledge of treatment impacted on results. In fact, no sig￾nificant differences between the four groups were found on any measure. Interestingly, Group 3 had significantly higher levels of anxietyprior to task thanother three groups yetthis group’s anxiety levels went down following the arousaltask. In general,the authors felt a more stress-provoking task might be required in future trials. Howard and Hughes (2008) employed an experimental stress task to compare lavender with tea tree oil odour (against a no odour condition) in an attempt to compensate for previous experiments that do not test lavender against another strong odour. They also

Table 1 RCTs of lavender. First author(year) Study design Condition(sample Experimental Control treatment Main anxiety Main results Author's conclusion Adverse events 【ref]country size randomised: treatment outcome (between-group analysed) measurements analysis) Kritsidima(2010) RCT,single-blind,2 Patients waiting for Odour of 5 drops of No odour in (1)State Trait (1)Experimental Although anxiety about No adverse events (Kritsidima, parallel groups. dental lavender oil in 10 waiting room using Anxiety Indicator group showed less future dental visits occurred in either Newton,and placebo-control appointment cc water using a water in a candle (STAl-6 item) STAI(p<0.001) seems to be unaffected, group Asimakopoulou. (340:340) candle burner. burner lavender scent reduces 2010)UK placed in waiting state anxiety in dental room (2)Modified Dental (2)No sig. Datlents Anxiety Scale difference in MDAS (MDAS) Muzzarelli(2006) RCT Single-blind 2 Patients Inhalation of 3 Inhalation of 3 STAI(state only) No between-group Although not Not reported groups (within undergoing a drops of 10% drops of 100% differences statistically be Force.Sebold groups) colonoscopy or lavender oil+90% grapeseed oil in a reported effective,patients 2006)U5A esophagogastroduo- grapeseed oil)in a 100 ml cup for reported the lavender denoscopy 100ml cup for 5min scent to be pleasant (118:118) 5min Braden(2009) RCT,single-blind,3 Pre-operative Group 1 Standard Group 2 Standard Pre-operative Experimental Lavedin was associated Not reported 8 (Braden, groups anxiety(150:150) care+lavender care without anxiety (100 mm group had sig.less with significantly Reichow,Halm aromatherapy (1 aromatherapy VAS) anxiety (p<0.01) lower anxiety on 2009)U5A inhalation of Group 3 Standard than the control operating room undiluted lavandin care+jojoba oil groups transfer,suggesting it then taped to gown aromatherapy is a simple,low-risk and topical (inhalation and and cost effective application-one topical application intervention drop on pulse as in Group 1) point) Motomura(2001) RCT Healthy volunteers Group 1 Inhalation Group 2 stressful (1)Cox McKay's Sig.difference in Lavender odourants Not reported (Motomura, (4242) of 3 ml lavender oil situation Stress/arousal stress/arousal were associated with Sakurai,and via diffuser for (soundproof room) adjective checklist scores between reduced mental stress Yotsuva 2001) 20 min during a for 20 min 1902012) (2)Blood pressure stress and Japan stressful situation Group 3 (3)Heart rate stress/lavender (soundproof room) non-stressful condition and situation between stress only and non-stress condition(p<0.01) No sig.differences between conditions for physiological measures Toda(2008)(Toda RCT Healthy volunteers Inhalation of Control (no odour) (1)Cortisol levels (1)No Lavender aroma has a Not reported and Morimoto (30:30) lavender for in saliva between-groups stress relief effect 2008)Jap3n 10min.Lavender (2)CgA levels in differences oil infiltrated onto saliva reported filter paper held (3)10-point VAS (2)In the lavender 10cm from nose group CgA was significantly lower 10min later but not in control gp. 3】No between-group differences reported 等

R. Perry et al. / Phytomedicine 19 (2012) 825–835 827 Table 1 RCTs of lavender. First author (year) [ref] country Study design Condition (sample size randomised: analysed) Experimental treatment Control treatment Main anxiety outcome measurements Main results (between-group analysis) Author’s conclusion Adverse events Kritsidima (2010) (Kritsidima, Newton, and Asimakopoulou, 2010) UK RCT, single-blind, 2 parallel groups, placebo-control Patients waiting for dental appointment (340:340) Odour of 5 drops of lavender oil in 10 cc water using a candle burner, placed in waiting room No odour in waiting room using water in a candle burner (1) State Trait Anxiety Indicator (STAI-6 item) (1) Experimental group showed less STAI (p < 0.001) Although anxiety about future dental visits seems to be unaffected, lavender scent reduces state anxiety in dental patients No adverse events occurred in either group (2) Modified Dental Anxiety Scale (MDAS) (2) No sig. difference in MDAS Muzzarelli (2006) (Muzzarelli, Force, Sebold 2006) USA RCT Single-blind 2 groups (within groups) Patients undergoing a colonoscopy or esophagogastroduo￾denoscopy (118:118) Inhalation of 3 drops of 10% lavender oil + 90% grapeseed oil) in a 100 ml cup for 5 min Inhalation of 3 drops of 100% grapeseed oil in a 100 ml cup for 5 min STAI (state only) No between-group differences reported Although not statistically be effective, patients reported the lavender scent to be pleasant Not reported Braden (2009) (Braden, Reichow, Halm 2009) USA RCT, single-blind, 3 groups Pre-operative anxiety (150:150a) Group 1 Standard care + lavender aromatherapy (1 inhalation of undiluted lavandin then taped to gown and topical application – one drop on pulse point) Group 2 Standard care without aromatherapy Group 3 Standard care + jojoba oil aromatherapy (inhalation and topical application – as in Group 1) Pre-operative anxiety (100 mm VAS) Experimental group had sig. less anxiety (p < 0.01) than the control groups Lavedin was associated with significantly lower anxiety on operating room transfer, suggesting it is a simple, low-risk and cost effective intervention Not reported Motomura (2001) (Motomura, Sakurai, and Yotsuya 2001) Japan RCT Healthy volunteers (42:42a) Group 1 Inhalation of 3 ml lavender oil via diffuser for 20 min during a stressful situation (soundproof room) Group 2 stressful situation (soundproof room) for 20 min Group 3 non-stressful situation (1) Cox & McKay’s Stress/arousal adjective checklist (2) Blood pressure (3) Heart rate Sig. difference in stress/arousal scores between stress and stress/lavender condition and between stress only and non-stress condition (p < 0.01) No sig. differences between conditions for physiological measures Lavender odourants were associated with reduced mental stress Not reported Toda (2008) (Toda and Morimoto 2008) Japan RCT Healthy volunteers (30:30a) Inhalation of lavender for 10 min. Lavender oil infiltrated onto filter paper held 10 cm from nose Control (no odour) (1) Cortisol levels in saliva (2) CgA levels in saliva (3) 10-point VAS (1) No between-groups differences reported (2) In the lavender group CgA was significantly lower 10 min later but not in control gp. (3) No between-group differences reported Lavender aroma has a stress relief effect Not reported

Table 1 (Continued) First author(year) Study design Condition(sample Experimental Control treatment Main anxiety Main results Author's conclusion Adverse events ref]country size randomised: treatment outcome (between-group analysed) measurements analysis) Kutu(2008) RCT Healthy volunteers Inhalation of Control (no odour) STAI(20-item) Lavender group Lavender aroma "Some"suffered (Kutlu,Yilmaz, (95:95) incenses of during 60 min showed sig.lower inhalation decreases discomfort due to and Cecen 2008) lavender(10 per examination STA1(p<0.001) exam anxiety odour and were Turkey classroom)during than control group excluded 60min (not accounting for examination baseline） Sgoutas-Emch RCT 4 groups Healthy volunteers Group 1 Inhalation Group 2 No (1)STAI(6-item) No sig.differences Although Not reported (2001) (80:62) of lavender via lavender (but told (2)Autonomic between groups on aromatherapy by itself (Sgoutas-Emch. humidifier(with there was) Perception any measure may not be the most Fox,Preston, prior knowledge) Group 4 No Questionnaire effective treatment in Brooks,and Group 3 Inhalation lavender (and not (APQ) reducing acute stress. Serber 2001)USA of lavender(no told anything) (3)Perceived Stress ones knowledge of the prior knowledge) scae5】 procedure may relate (4)Maths Anxiety to how one responds Scale (MAS) (5)Blood pressure (BP) Perry (6)Heart rate(HR) Howard(2008) RCT DB Healthy volunteers Group 1 Two Group 2 Two (1)STAl (20-item) No sig. Previous associations Not reported (Howard and (96:92) inhalations of 3 inhalations of 3 (2)Galvanic skin between-group of lavender aroma with Hughes 2008) drops lavender oil drops tea tree oil response(GSR) difference for assisted relaxation may Ireland in a screw top jar atter an arousal aroma on ether have been influenced after an arousal task.The jar measure by expectancy biases. task.The jar remained open and relevant remained open. Group 3 no odour expectancies are easily following an manipulable arousal task Dunn(1995) RCT,open,3 groups (1)Aromatherapy Massage may offer a 2012) Patients admitted Group 1 Group 2 Massage (1)Anxiety Not due to the (Dunn,Sleep,and to Intensive Care aromatherapy with carrier oil fo behaviour scores was associated useful therapy for therapy Collett 1995)UK Unit(122:66 massage with 30 min up to 3 (4-point scale)at with sig.g乎eater nurses to consider received all three lavender oil diluted sessions the end of an reductions of when planning the reatment sessions) to 1%for 30 min up Group 3 Bed rest aromatherapy perceived anxiety psychological are of to3 sessions session at time 1(Chi2, patients in ICU.The (2)Blood pressure P-0.05) addition of lavender (BP) (2)No significant essential oil appears to (3)Heart rate (HR) ditterence between enbance the eftects of (4)Number of groups on any massage. breaths per minute physiological measure Soden(2004) RCT DB Patients with Aromatherapy Massage with inert Anxiety and No sig. The addition of Not reported (Soden,Vincent, cancer(42:36) massage with carrier oil(sweet depression (HAD) between-groups lavender oil did not Craske,Lucas, lavender oil mixed almond)30 min 1x difference appear to increase the and Ashley 2004) with carrier oil week for 4 weeks beneficial effects of UK (sweet almond)to massage in patients a dilution of 1 with advanced cancer 30 min 1x week for however,patients with 4 weeks high levels of psychological distress responded best to these therapies

828 R. Perry et al. / Phytomedicine 19 (2012) 825–835 Table 1 (Continued) First author (year) [ref] country Study design Condition (sample size randomised: analysed) Experimental treatment Control treatment Main anxiety outcome measurements Main results (between-group analysis) Author’s conclusion Adverse events Kutlu (2008) (Kutlu, Yilmaz, and C¸ ec¸ en 2008) Turkey RCT Healthy volunteers (95:95) Inhalation of incenses of lavender (10 per classroom) during 60 min examination Control (no odour) during 60 min examination STAI (20-item) Lavender group showed sig. lower STAI (p < 0.001) than control group (not accounting for baseline) Lavender aroma inhalation decreases exam anxiety “Some” suffered discomfort due to odour and were excluded Sgoutas-Emch (2001) (Sgoutas-Emch, Fox, Preston, Brooks, and Serber 2001) USA RCT 4 groups Healthy volunteers (80:62) Group 1 Inhalation of lavender via humidifier (with prior knowledge) Group 3 Inhalation of lavender (no prior knowledge) Group 2 No lavender (but told there was) Group 4 No lavender (and not told anything) (1) STAI (6-item) (2) Autonomic Perception Questionnaire (APQ) (3) Perceived Stress Scale (PSS) (4) Maths Anxiety Scale (MAS) (5) Blood pressure (BP) (6) Heart rate (HR) No sig. differences between groups on any measure Although aromatherapy by itself may not be the most effective treatment in reducing acute stress, ones knowledge of the procedure may relate to how one responds Not reported Howard (2008) (Howard and Hughes 2008) Ireland RCT DB Healthy volunteers (96:92) Group 1 Two inhalations of 3 drops lavender oil in a screw top jar after an arousal task. The jar remained open. Group 2 Two inhalations of 3 drops tea tree oil after an arousal task. The jar remained open Group 3 no odour following an arousal task (1) STAI (20-item) (2) Galvanic skin response (GSR) No sig. between-group difference for aroma on either measure Previous associations of lavender aroma with assisted relaxation may have been influenced by expectancy biases, and relevant expectancies are easily manipulable Not reported Dunn (1995) (Dunn, Sleep, and Collett 1995) UK RCT, open, 3 groups Patients admitted to Intensive Care Unit (122:66 received all three treatment sessions) Group 1 aromatherapy massage with lavender oil diluted to 1%, for 30 min up to 3 sessions Group 2 Massage with carrier oil for 30 min up to 3 sessions Group 3 Bed rest (1) Anxiety behaviour scores (4-point scale) at the end of an aromatherapy session (2) Blood pressure (BP) (3) Heart rate (HR) (4) Number of breaths per minute (1) Aromatherapy was associated with sig. greater reductions of perceived anxiety at time 1 (Chi2, p = 0.05) (2) No significant difference between groups on any physiological measure Massage may offer a useful therapy for nurses to consider when planning the psychological are of patients in ICU. The addition of lavender essential oil appears to enhance the effects of massage. Not due to the therapy Soden (2004) (Soden, Vincent, Craske, Lucas, and Ashley 2004) UK RCT DB Patients with cancer (42:36) Aromatherapy massage with lavender oil mixed with carrier oil (sweet almond) to a dilution of 1%, 30 min 1× week for 4 weeks Massage with inert carrier oil (sweet almond) 30 min 1× week for 4 weeks Anxiety and depression (HAD) No sig. between-groups difference The addition of lavender oil did not appear to increase the beneficial effects of massage in patients with advanced cancer however, patients with high levels of psychological distress responded best to these therapies Not reported

Woelk(2010) RCT,DB.active Generalised 80 mg/day of an oral Lorazepam (1)Hamilton (1)HAMA Silexan is as effective 20 pps suffered (Woelk and control, anxiety disorder Lavender extract 0.5 mg/day)for 6 Anxiety Scale decreased by4 and well-tolerated as from 26 cases of Schlafke 2010) double-dummy (77:69) (Silexan)for 6 weeks weeks (HAMA) (lavender)versus lorazepam in adults AEs in the Silexan Germany (2)Penn State 46%(Lorazepam) with GAD group (mainly Worry Inventory (2)and (3)PSWS gastrointestinal (PSWS) and SAS decreased disorders)18 pps (3)Zung to a similar extent suffering from 19 Self-Rating Anxiety in both groups AEs in the Scale(SAS) lorezepam group (mainly fatigue/sedative effects) Kasper (2010) RCT DB pc Subsyndromal' 80 mg/day of an oral 1x day placebo Hamilton Anxiety HAMA decreased Lavender oil is both 30 pps(Silexan (Kasper.Gastpar. anxiety disorder lavender oil extract (0.08 mg of Scale(HAMA) by 59.3%with efficacious and safe for group)reported 55 Iler,Volz,ller. (221:212) (Silexan)for 10 weeks lavender so lavender oil versus the relief of AEs and 35pps and Dienel 2010) identical for smell) 35.4%with placebo (unspecified)anxiety (placebo group) Germany for 10 weeks (pc0.01) disorder reported 68 AEs. Four serious but not attributable 8 events occurred and all AEs that Perry resulted in withdrawal were not related to treatment Bradley(2009) RCT DB Healthy volunteers (1)Gelatine capsules Placebo gelatine (1)STAI-Y state Trend for200μl Lavender has anxiolytic Not reported (Bradley.Brown, (97:96) with sunflower oil and capsule with just anxiety scale lavender had more effects under Chu,and Lea lavender (100 ul)1x sunflower oil 1x (3)Heart rate(HR) of an eftect in low conditions of low 元ed 2009)UK (2)Gelatine capsules (4)Galvanic skin but not under high anxiety,but may not with sunflower oil and response(GSR) anxiety on both extend to conditions of avender200】】x physiological and high anxiety self-report measures (p<0.05) 1825 Xu(2008)(XL RCT single-blind 3 Healthy volunteers Ayurvedic oil-dripping (1)Ayurvedic (1)STAI at end of (1)No sig. The complicated Not reported Uebaba.Ogawa, groups(within (16:16) (sesame oil containing oil-dripping with procedure difference between pharmaco-physio- Tatsuse,Wang. groups) 0.3%lavender oil)1 sesame carrier oil (2)Heart rate(HR) lavender and psychologic action of Hisajima. session onlv 2]No ou-dnpping carner oil-dripping ayruvedic oil treatment Venkatraman but significant may provide a useful 2008)Japan difference between model for future both oil-dripping pharmaco-physio- conditions and the psychotherapy. control in STAI (2)HR-no significant differences found between groups Morris (2002) RCT single blind Healthy volunteers 10 min bath/day using 10 min bath/day UWIST Mood No between-group The results are Not reported (Morris 2002)UK (40:40) 3 pipettes of lavender using only Adjective Checklist differences encouraging and oil (20%)+grapeseed grapeseed oil reported on tense further work is needed oil (80%)added to bath (100元)for14days arousal scale of the water for 14 days UWIST DB:double blind:RCT:randomised controlled trial:pp:participants:pc:placebo-controlled:sig.:significant:AFs:adverse events. Assumed there were no drop-outs due to short trial duration (not directly reported) 臣

R. Perry et al. / Phytomedicine 19 (2012) 825–835 829 Woelk (2010) (Woelk and Schlafke 2010) Germany RCT, DB, active control, double-dummy Generalised anxiety disorder (77:69) 80 mg/day of an oral Lavender extract (Silexan) for 6 weeks Lorazepam 0.5 mg/day) for 6 weeks (1) Hamilton Anxiety Scale (HAMA) (2) Penn State Worry Inventory (PSWS) (3) Zung Self-Rating Anxiety Scale (SAS) (1) HAMA decreased by 45% (lavender) versus 46% (Lorazepam) (2) and (3) PSWS and SAS decreased to a similar extent in both groups Silexan is as effective and well-tolerated as lorazepam in adults with GAD 20 pps suffered from 26 cases of AEs in the Silexan group (mainly gastrointestinal disorders), 18 pps suffering from 19 AEs in the lorezepam group (mainly fatigue/sedative effects) Kasper (2010) (Kasper, Gastpar, ller, Volz, ller, and Dienel 2010) Germany RCT DB pc ‘Subsyndromal’ anxiety disorder (221:212) 80 mg/day of an oral lavender oil extract (Silexan) for 10 weeks 1× day placebo (0.08 mg of lavender so identical for smell) for 10 weeks Hamilton Anxiety Scale (HAMA) HAMA decreased by 59.3% with lavender oil versus 35.4% with placebo (p < 0.01) Lavender oil is both efficacious and safe for the relief of (unspecified) anxiety disorder 30 pps (Silexan group) reported 55 AEs and 35pps (placebo group) reported 68 AEs. Four serious but not attributable events occurred and all AEs that resulted in withdrawal were not related to treatment Bradley (2009) (Bradley, Brown, Chu, and Lea 2009) UK RCT DB Healthy volunteers (97:96) (1) Gelatine capsules with sunflower oil and lavender (100 l) 1× (2) Gelatine capsules with sunflower oil and Lavender (200 l) 1× Placebo gelatine capsule with just sunflower oil 1× (1) STAI-Y state anxiety scale (3) Heart rate (HR) (4) Galvanic skin response (GSR) Trend for 200 l lavender had more of an effect in low but not under high anxiety on both physiological and self-report measures (p < 0.05) Lavender has anxiolytic effects under conditions of low anxiety, but may not extend to conditions of high anxiety Not reported Xu (2008) (Xu, Uebaba, Ogawa, Tatsuse, Wang, Hisajima, Venkatraman 2008) Japan RCT single-blind 3 groups (within groups) Healthy volunteers (16:16a) Ayurvedic oil-dripping (sesame oil containing 0.3% lavender oil) 1 session only (1) Ayurvedic oil-dripping with sesame carrier oil (2) No oil-dripping (1) STAI at end of procedure (2) Heart rate (HR) (1) No sig. difference between lavender and carrier oil-dripping but significant difference between both oil-dripping conditions and the control in STAI (2) HR – no significant differences found between groups The complicated pharmaco-physio￾psychologic action of ayruvedic oil treatment may provide a useful model for future pharmaco-physio￾psychotherapy. Not reported Morris (2002) (Morris 2002) UK RCT single blind Healthy volunteers (40:40) 10 min bath/day using 3 pipettes of lavender oil (20%) + grapeseed oil (80%) added to bath water for 14 days 10 min bath/day using only grapeseed oil (100%) for 14 days UWIST Mood Adjective Checklist No between-group differences reported on tense arousal scale of the UWIST The results are encouraging and further work is needed Not reported DB: double blind; RCT: randomised controlled trial; pp: participants; pc: placebo-controlled; sig.: significant; AEs: adverse events. a Assumed there were no drop-outs due to short trial duration (not directly reported).