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 also826 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