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The Antidepressant Effects of Lavender (Lavandula angustifolia Mill.): A

Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials

Article  in  Complementary Therapies in Medicine · February 2021

DOI: 10.1016/j.ctim.2021.102679

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Journal Pre-proof

The Antidepressant Effects of Lavender (Lavandula angustifolia Mill.): A

Systematic Review and Meta-Analysis of Randomized Controlled Clinical
Trials

Toktam Sadat Firoozeei, Awat Feizi, Hossein Rezaeizadeh, Arman

Zargaran, Hamid Reza Roohafza, Mehrdad Karimi

PII: S0965-2299(21)00020-0
DOI: https://doi.org/10.1016/j.ctim.2021.102679
Reference: YCTIM 102679

To appear in: Complementary Therapies in Medicine

Received Date: 22 August 2020

Revised Date: 3 January 2021
Accepted Date: 1 February 2021

Please cite this article as: Firoozeei TS, Feizi A, Rezaeizadeh H, Zargaran A, Roohafza HR,
Karimi M, The Antidepressant Effects of Lavender (Lavandula angustifolia Mill.): A Systematic
Review and Meta-Analysis of Randomized Controlled Clinical Trials, Complementary
Therapies in Medicine (2021), doi: https://doi.org/10.1016/j.ctim.2021.102679

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The Antidepressant Effects of Lavender (Lavandula angustifolia Mill.): A Systematic Review

and Meta-Analysis of Randomized Controlled Clinical Trials

Toktam Sadat Firoozeeia, Awat Feizib, Hossein Rezaeizadeha, Arman Zargaranc, Hamid Reza

Roohafzad, Mehrdad Karimia

a
Department of Traditional Medicine, School of Persian medicine, Tehran University of Medical

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Sciences, Tehran 1668753961, Iran

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b
Department of Biostatistics and Epidemiology, School of Health, Isfahan University of Medical

Sciences, Isfahan 8174673461, Iran

c
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Department of Traditional Pharmacy, School of Persian Medicine, Tehran University of Medical
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Sciences, Tehran 1668753961, Iran
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d
Mental Health Department, Cardiac Rehabilitation Research Center, Cardiovascular Research

Institute, Isfahan University of Medical Sciences, Isfahan 8158388994, Iran

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Corresponding author: Mehrdad Karimi; MD, PhD

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Address: Department of Traditional Medicine, School of Persian Medicine, Tehran University of

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Medical Sciences, Sarparast St, Taleghani St, Tehran, Iran

Postal Code: 1668753961

Email: mehrdadkarimi@yahoo.com

Tel: +98-2188976528/ Fax: +98-2188976527

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Highlights

 . A systematic review and meta-analysis of the antidepressant effects of lavender was

carried out

 . Results conveyed the efficacy of lavender in decreasing depression scores compared to

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control groups

 . It seems that lavender can be an efficacious complementary treatment for depression

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Abstract
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Background and aims: Antidepressant drugs are accompanied with high rate of adverse effects.

Lavender is one of the most common herbal drugs mentioned in Traditional Persian literature with
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potential efficacy on mental disorders and less serious side effects. Thus, the aim of this study was

to determine the efficacy of lavender on depression severity by preforming a systematic review

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and meta-analysis.
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Methods: Databases including PubMed, Scopus, Cochrane library, Embase and Web of science

were searched for relevant articles till December 2020. Quality of studies were evaluated by Jadad

scale and the Cochrane collaboration tool. Depression as endpoint measure or as a subscale of any

valid assessment tool was subjected to quantitative data analyses. Both fixed and random effects

meta-analysis were conducted for data synthesis.

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Results: Out of 342 screened studies, 17 articles were included in the meta-analysis. Results

showed significant efficacy of lavender in decreasing depression scores compared to the control

group (pooled Standardized Mean Difference (SMD)= -0.66, 95% CI: -0.85 to -0.46; P<0.001,

I2=68.2%;). Subgroup analysis proved that the effect of lavender was marginally more pronounced

in participants with diagnosed depression (pooled SMD= -0.62, 95% CI: -1.26 to 0.01, P=0.055;

I2=88.1 %) while its effect was statistically significant in patients having other diseases with

concomitant depressive symptoms (pooled SMD= -0.65, 95% CI: -1.84 to -0.46, P<0.001;

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I2=52.1%), and the oral route (pooled SMD= -0.56, 95% CI: -1.07 to -0.05, P=0.032; I2=85.2%;)

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was the most effective route of administration.

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Conclusions: This systematic review and meta-analysis concluded that lavender has significant

antidepressant effects. However, due to some limitations, further large clinical trials are
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recommended with more homogeneous populations and rigorous designs.
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Keywords: Herbal medicine; Persian medicine; Lavandula angustifolia; Lavender; Depression

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1- Introduction

Depression is a severe, long standing, recurrent disorder (1), with a lifetime prevalence of 10 to 20

% (2), affecting the Iranian population between a wide range of 6 to 75% (3). Depression is

estimated to be the main cause of disease burden by the year 2030 (4). With a considerable socio-

economic burden due to reduced work capacity and increased healthcare utilization (5).

Second generation antidepressants such as selective serotonin reuptake inhibitors (SSRI’s) are the

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most common recommended form of treatment in depression (6). However, less than 50% of

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clinical trials reported that antidepressants are superior to placebos. Also, according to the second

largest survey conducted on antidepressant users, a high rate of emotional adverse effects such as

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emotional blunting, reduced positive thinking, emotional detachment and decreased libido was

reported (7). Thus, patients and clinicians are seeking other treatment possibilities.
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Due to the limitations of conventional antidepressant drugs, the use of complementary and
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alternative medicine (CAM) is common in mental health settings (8). In a survey carried out in the

United States on adults with self-reported depression, more than 50%, admitted of using CAM as
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a path to treatment in the past 12 months (9). Thus, by playing a distinct role in the treatment of

depression, herbal medicine has provided novel origins for efficient therapeutic phytochemical
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substances (10).

Lavender (Lavandula angustifolia Mill.), a species from the Lamiaceace family under the name
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Ostokhoddous in Persian medical literature (11), has been considered to possess anxiolytic,

antidepressant (12) neuroprotective (13) and anti-inflammatory (14) properties. Although there are

various randomized clinical trials (RCT) evaluating the antidepressant effects of lavender,

however, published reviews have only focused on its well-known anxiolytic abilities (15,16). On

4
the other hand, the results about the effects of lavender on depression are inconclusive. Thus, the

aim of this study was to assess the available literature, identify papers with strong evidentiary bases

and to determine the effects of lavender on depression through a systematic review and meta-

analysis.

2- Methods

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This study was conducted in accordance with Preferred Reporting Items for Systematic Reviews

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and Meta-Analyses (PRISMA) (17).

2-1-Eligibility criteria

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Studies included in this systematic review and meta-analysis were human randomized clinical

trials, evaluating the antidepressant effects of lavender (L. angustifolia) (Intervention), regardless
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of the participant’s disease or medical condition without any patient's sex or age restriction

(Patient). All routes of lavender administration, with any type of control group (placebo or active
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control: Control) were included. Depression as the main outcome measure or as a subscale of any

valid assessment tool was evaluated (Outcome) (Table 1). Articles written in English or Persian
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were included.

Uncontrolled studies, the usage of other species of lavender, combined methods of treatment with
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lavender, animal studies, case reports and literature reviews were excluded.

2-2-Search strategy

Online databases including PubMed, Scopus, Embase, Cochrane library and Web of science were

searched for potential eligible studies from January 2000 to December 2020. A combination of

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keywords by using the proper Boolean operators were searched for finding relevant articles. Search

strategy for the mentioned databases was as following:

PubMed/Medline: ((lavender [Title/Abstract] + OR Lavandula [Title/Abstract] + OR Lavandula

angustifolia [Title/Abstract] OR Lavandula officinalis [Title/Abstract] OR Silexan

[Title/Abstract])) AND ((depression [Title/Abstract] OR major depress* [Title/Abstract] OR

antidepressant [Title/Abstract]) OR MDD* [Title/Abstract] OR depressive [Title/Abstract] OR

dysthymia [Title/Abstract])).

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Web of Science: TS= (lavender OR lavandula OR "lavandula angustifolia" OR "lavandula

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officinalis" OR silexan) AND TS= (MDD OR depression OR antidepressant OR major depress*

OR dysthymia OR depressive) AND DOCUMENT TYPES: (Article)

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Scopus: TITLE-ABS-KEY (lavender OR lavandula OR "lavandula angustifolia" OR "lavandula
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officinalis" OR silexan AND MDD OR depression OR antidepressant OR major depress* OR

dysthymia OR depressive)
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Embase: (lavender:ab,ti OR lavandula:ab,ti OR silexan:ab,ti OR "lavandula angustifolia":ab,ti OR

"lavandula officinalis":ab,ti) AND (MDD:ab,ti OR depression:ab,ti OR antidepressant:ab,ti OR

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'major depress*':ab,ti OR dysthymia:ab,ti OR depressive:ab,ti) AND [randomized controlled trial]

AND [2000-2020]
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Cochrane library: lavender OR lavandula OR "lavandula angustifolia" OR "lavandula officinalis"

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OR silexan AND MDD OR depression OR antidepressant OR major depress* OR dysthymia OR

depressive in Title, Abstract, Keywords

In the preliminary search, after the removal of duplicate papers, retrieved articles were screened

by two separate authors (TF, AF) based on title and abstract. In each step, any disagreement was

discussed between the two authors or resolved by consulting a third author (MK). In the next stage,

6
articles were selected based on full text readings, where eligible studies were chosen based on the

initial inclusion criteria. Furthermore, references of the selected articles were hand-searched for

finding other relevant articles. The flow diagram of the search strategy is depicted in Figure 1.

2-3- Data extraction

The items extracted from the selected articles and summarized in Table 2 are as following, name

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of first author, name of country, language of article, sample size, patient population, description

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of the control and experimental groups, study duration, treatment frequency, drug dosage, drug

form, tools for measuring main outcome, main results, adverse events, route of administration,

study design, and depression status.

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2-4- Quality assessment:

The quality of articles was assessed by the Jadad scale and the Cochrane risk of bias assessment
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tool (18,19). In the jaded sale, scores ranged from 0 to 5, one point for each positive answer and

zero points for each negative answer was given to one of the following domains, study described
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as randomized, study described as double blind, randomization method appropriately described,

blinding method appropriately described, number and reasons of withdrawals and dropouts
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described. Scores ranging from 0 to 2 were indicative of low quality while scores 3 to 5 indicated
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high quality (18) (Table 3). For the Cochrane risk of bias, seven domains were evaluated, including

random sequence generation, allocation concealment, blinding of personnel and participants,

blinding of outcome assessment, incomplete data, other sources of bias and selective reporting.

For the first four domains, a positive answer was regarded as a low risk of bias, a negative answer

as a high risk of bias and an unclear answer meant there was an uncertain risk of bias. For the three

7
remaining domains, the answer yes was considered as high risk of bias while a negative answer as

low risk of bias (19).

2-5- Statistical analysis

Meta-analysis was conducted using STATA software version 11.2 (STATA, College Station, TX).

Net changes were calculated according the following approach: measure at end of treatment period

minus measure at its baseline. The standardized mean difference (SMD) was used to assess the

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effects of treatment on main outcome i.e. depression score. For those trials that did not report

standard error of mean (SEM) values, computation was done based on the available data using

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following standard formula: [standard error of the mean (SEM) = Standard deviation (SD)/ squared

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root of number of subjects] (20). SDs of the mean difference were calculated as: SD=square root

[(SD pre-treatment)2 + (SD post-treatment)2− (2 R ×SD pre-treatment ×SD post-treatment)],

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considering a correlation coefficient R = 0.7 (21).

Heterogeneity was evaluated by using Cochran Q test and I-squared statistics as well as visual
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inspection of forest plot (22). Values of lower than 50% and 50-75% and more than 75% for I2

were considered as low, medium and high levels of heterogeneity, respectively. Data were pooled
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and finally the effect size of lavender on depression score and corresponding 95% CIs was

calculated by random-effect model in cases of medium and high heterogeneity. Possible sources
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of heterogeneity were explored and adopted by sensitivity analysis, meta-regression, and subgroup

analyses if possible, according to mean age of participants, sample size, different routes of lavender
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administration (oral, aromatherapy, aroma-massage, dermal) and patient's depression status

(depressed versus nondepressed).

Subgroup analysis, Publication bias and sensitivity analysis

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In subgroup analysis, studies were categorized into two groups, a group of studies including

participants with diagnosed depression (depressed) and the second group included studies

comprised of patients having other diseases with concomitant depressive symptoms

(nondepressed). Participants with diagnosed depression were defined as patients who underwent a

specialized psychiatric interview and were diagnosed with depression based on a validated

diagnostic criterion, or were included in the study based on a defined baseline depression score (as

a predefined criterion for depression) via a validated tool.

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Patients having other diseases with concomitant depressive symptoms, were subjects whom a

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specific diagnosis of depression was not made as the inclusion criteria, but their main condition

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was indirectly associated with depression. We also did another subgroup meta-analysis based on

route of lavender administration (oral, aromatherapy, aroma-massage, dermal)

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In the current meta-analysis, publication bias was assessed by examining asymmetry in the Begg
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funnel plot and conducting weighted Egger linear regression and Begg and Mazumdar rank

correlation tests (23). The sources of publication bias were also evaluated using sensitivity analysis

based on the quality of included studies in which those studies with low quality based on both
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quality assessment tools i.e., Jadad and Cochrane risk of bias assessment tool were removed from

analyses and the results were obtained for the remaining studies.
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3- Results

3-1-Description of study selection

As shown in figure 1, a total of 342 articles were retrieved by applying the search strategy. After

conducting the removal of duplicates, 188 articles remained, of which 147 were excluded after

9
title and abstract screening. The 45 remaining articles were subjected to full text reading and

assessment of eligibility, and the references of reviewed articles were also searched, resulting in

an overall number of 19 articles. All 19 studies met the predefined inclusion criteria and were

included in the qualitive synthesis. Due to not having enough data, 2 studies (24, 25) were not

included in the quantitative synthesis, accordingly 17 studies (26,27,28,29,30,31,32,33,34,35,36,

37, 38,39,40,41,42) were enrolled for meta-analysis.

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3-2-Studies characteristics

3-2-1- Description of subjects in included studies

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Majority (73.7%) of studies were conducted in Iran (26,27,28,29,30,31,32,33,34,38,39,40,41,42),
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the remaining in Taiwan (35), UK (24), Germany (36) Turkey (37), Japan (25), and all were

published in English (24,25,26,27,30,31,33,34,35,36,37,38,39,41,42) or Persian (28,29,32,40).

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Also, 52.63% of studies were conducted only on females (25, 26, 31, 32, 33, 34, 35, 37, 39, 40).

Furthermore, studies were categorized into two groups including participants with diagnosed
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depression (depressed) (28,30,34,36,42) and patients having other diseases with concomitant

depressive symptoms (nondepressed) (24,25,26,27,29,31,32,35,37,38,39,40,41), which included

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patients with disorders such as cancer (24), diabetes (27), acute coronary syndrome(31),
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hemodialysis patients (29,38), women with PMS (37,25), postpartum (35,32,26) and pregnant

women (33) and menopausal women (39, 41). Characteristics of reviewed studies are summarized

in Table 2.

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3-2-2-Intervention

The majority of articles used lavender in the form of an essential oil, mostly via aromatherapy (25,

26,27,28,29,37,38,39,40,41), 2 trials via aroma-massage (24,31), 2 trials as a dermal cream

preparation (32,33) and in only one study, as an oral capsule containing lavender oil (36). Also,

four studies employed dried flowers of lavender, two in a form of herbal tea (30,35) and two in the

form of filled capsules (34,42). The most common method of lavender application in

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aromatherapy, was using a soaked cotton ball (28,38), fabric (27,29), tissue (40) or paper towel

(39) attached to the collar. Other methods included, rubbing lavender oil on hands and breathing

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it in (26), the usage of an aroma diffuser (25) steam inhalation (37) or breathing in the aroma from

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a glass container (41). Among all studies, only 2 studies used a single dose of lavender (25,31),

while the rest, administered lavender in a specific period of time.

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3-2-3-Control:

In the aromatherapy administration, 60% of studies used a placebo group as the control group such
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as water (25,39,40), liquid paraffin (28) sweet almond oil (27) and diluted milk (41). 40 percent

of studies used a no treatment option comprised of routine care or no intervention (26,29,37,38).

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In lavender application via aroma-massage, the control groups included placebo or no intervention

(24) and routine care alone (31). In studies which lavender was administered orally, two studies
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used a placebo group (34,36), two studies used a no treatment control group (30,35) and only one

study used an active treatment control group (fluoxetine) (42). In studies which lavender was

administered via dermal route (32,33) a placebo group was the most frequent control group.

3-2-4-Outcome evaluation tools

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As shown in Table 2, the most common instruments applied were Beck Depression Inventory

(BDI) (27,28,30,34), Depression, Anxiety, stress scales-21 (DASS-21) (26,28,32,33) and the

Hospital Anxiety and Depression Scale (HADS) (24,31,38,40). Also, the second most frequent

tool was the Edinburgh Postnatal Depression Scale (EPDS) (26,35). Other outcome evaluation

tools included the Green questionnaire (41), Hamilton Depression Rating Scale (HAM-D) (42),

Kupperman Menopausal Index (KMI) (39), Montgomery Asberg Depression Rating Scale

(MADRS) (36), Premenstrual Syndrome Scale (PMSS) (37) and the Profile of Mood States

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(POMS) (25).

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3-3-Efficay of Lavender in different routes of administration

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We conducted another subgroup analysis by routes of administration; accordingly, we reviewed

the efficacy of Lavender in terms of administration approaches.

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3-3-1-Oral
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Five articles evaluated the effects of orally consumed lavender on depression as the main outcome

measure (30,34,35,36,42). One study evaluated the effects of lavender in the form of Silexan (an
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immediate release capsule containing L. angustifolia essential oil) on patients with mixed anxiety

and depression (MADD). The results of the study conducted by Kasper et al, on patients with
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MADD showed statistically significant reduction in depression and anxiety scores after 4 weeks,

and managed to maintain positive effects at week 10 compared to the placebo group (36). Also, in
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an 8-week study carried out on patients with mild to moderate depression, there was a significant

reduction in depression scores in the group receiving oral lavender capsules comparable with the

group consuming fluoxetine (42). Also, in line with the aforementioned studies, Bazrafshan et al

(30) and Kamalifard et al (34) reported antidepressant effects compared to control groups.

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While Chen et al study, on postpartum woman with sleep disturbances, resulted in reduced

depression scores at week 2 post intervention with no significant sustained effects at week 4 of

follow up (35).

3-3-2-Aromatherapy

All studies in the aromatherapy group, showed positive antidepressant effects of inhaled lavender

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compared to the control group (25,26,27,29,38,37,39,40,41), except Jafari-Koulaee et.al.'s study

(28). A study conducted on patients with migraine, in which, despite a significant reduction was

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observed in depression scores in within group analysis, however there was no significant

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difference between the experimental (inhaled lavender) and placebo (inhaled liquid paraffin)

groups (28). Also, in 2 articles, long lasting effects of inhaled lavender was displayed (37,26). In
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which Uzunçakmak et al evaluated subscales of anxiety, depression and nervousness in students

with premenstrual syndrome (PMS), with positive effects lasting as long as two cycles after one
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cycle of treatment with lavender inhalation (37). Similarly, Kianpour et al reported long-acting

effects of inhaled lavender on anxiety and depression in postpartum woman, two months after the
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termination of a four-week intervention (26).

3-3-3-Aroma-massage
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Two studies employed the aroma-massage technique for lavender administration (24,31). Bahrami
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et al conducted a lavender oil foot massage on female elderly patients with acute coronary

syndrome (ACS), which resulted in positive antidepressant effects compared to routine care (31).

Whilst, Soden et al reported no significant differences between experimental and control groups

in hospice cancer patients after 4 weeks of 30 minutes weekly back massage (24).

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3-3-4-Dermal

In 2 studies, dermally applied lavender cream with or without a foot bath, in healthy pregnant (33)

or postpartum women (32) significantly reduced stress, anxiety and depression in comparison to

the control group.

3-4-Qaulity assessment:

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As demonstrated in Table 3, quality assessment of the reviewed studies was rated by Jadad scale

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and Cochrane collaboration tool.

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Based on the jaded rating scale, out of 15 studies, one study scored 1 (25), six studies had a Jadad

score of 2 (24,30,31,35,38,40), seven studies scored 3 (26,27,28,29,32,37,39), three studies scored

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4 (33,41,42) and two studies scored 5 (34,36). Also, all the studies reviewed, stated to be

randomized, but among all, only 13 studies provided an appropriate description of the
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randomization method (26,27,28,29,30,32,33,34,36,37,38,39,41). Whilst, two studies failed to do

so (31,42). Furthermore, 4 studies did not report the randomization method at all (24,25,35,40).
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Out of four studies (33,36,41,42) which stated to be double blind, three studies described the

blinding method appropriately (36,41,42). Also, more than half of the articles retrieved, reported
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the numbers and reasons of dropped out members or attrition appropriately

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(26,27,28,29,31,32,33,34,35,36,39,40,42).

Based on the Cochrane risk of bias tool, regarding selection bias, nine studies

(27,28,32,33,34,36,38,39,41) were classified as low risk in random sequence generation, and eight

studies (25,26,29,30,35,37,38,40) categorized as unclear in allocation concealment. In random

sequence generation, out of nine studies (27,29,30,32,33,34,36,37,41) which used the block

14
randomization method, three studies (29,30,37) failed to mention the process in which the blocks

were selected, thus classified as unclear. In the performance bias, due to the difficulty of blinding

lavenders distinct odor, with a probability of a broken blinding whilst attempting to blind the

participants and personnel, a total of ten studies (25,26,27,29,31,32,33,39,40,41) were classified

as high risk. Eight (25,26,29,30,35,37,38,40) out of nineteen studies did not report the allocation

concealment method.

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Regarding detection bias (blinding outcome assessment), ten (24,26,27,30,31,32,33,34,39,42) out

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of nineteen studies were classified as low risk of bias and nine studies

(25,26,28,29,35,37,38,40,41) as unclear. Regarding attrition bias, thirteen studies

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(24,28,29,30,31,32,33,34,36,37,39,40,42) were categorized as low risk of bias, two (27,35,) as

high risk of bias and four studies (25,26,38,41) did not report any information on this outcome, as
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a result they were classified as an unclear risk of bias. Based on selective outcome reporting, two
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studies were classified as high risk of bias, due to incomplete reporting of outcome data,

accordingly we did not include them in met-analysis (24, 41). Overall, out of nineteen studies, only

two studies (36, 34) were classified as low risk of bias in all domains, also, these two studies were
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the only papers which had scored 5 in the jaded rating scale. Furthermore, there were no high risk

of bias in the allocation concealment, blinding outcome assessment and other sources of bias
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categories.
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3-5-Meta-analysis and data synthesis

Before conducting the meta-analysis, two studies (24,41) were not included because of not having

enough data. Overall, 17 studies with 1486 participants (754 cases and 732 controls) were enrolled

in the quantitative synthesis, in which the results were in favor of lavender and it significantly

15
decreased depression scores in comparison to the control group (pooled SMD= -0.66, 95% CI: -

0.85 to -0.46; P<0.001, I2=68.2%; heterogeneity Chi-squared=50.29, P<0.001) (Fig 2). The

Funnel plot, Egger regression and Begg rank correlation tests were applied to evaluate publication

bias. None of the tests resulted in significant publication bias (Egger’s test, P=0.615 and Begg’s

test, P=0.484) (Fig 3).

Furthermore, age as a confounding variable, did not show a significant impact on study effect size

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based on the meta-regression test (Regression coefficient= -0.013, Std. Err=0.007, t=-1.86,

P=0.088). (Fig 4a)

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Also, the effect of sample size as a confounding variable was evaluated on the estimated pooled

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effect size and it did not show significant confounding effect (Regression coefficient= 0.0002, Std.

Err=0.002, t=0.12, P=0.904). (Fig 4b)

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In a subgroup analysis as shown in figure 5, studies were categorized into two groups, studies
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including participants with diagnosed depression and studies comprised of subjects having other

disease with concomitant depressive symptoms. The pooled SMD for studies on depressed subjects
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showed marginally significant effect (pooled SMD= -0.62, 95% CI: -1.26 to 0.01, P=0.055;

I2=88.1 %; heterogeneity chi-squared=25.23 P<0.001) (Fig 5a). However, after excluding Araj
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khodai’s study (the only study with an active control i.e., fluoxetine) from subgroup analysis we

reached a bigger and highly significant effect for lavender in this group (pooled SMD= -0.94, 95%
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CI: -1.52 to -0.37, P=0.001; I2=84.2 %; heterogeneity chi-squared=12.67 P= 0.002) (Fig 5b). The

subgroup analysis for subjects having other disease with concomitant depressive symptoms

showed significant effect for lavender compared to control (pooled SMD= -0.65, 95% CI: -0.84 to

-0.46, p<0.001; I2=52.1%; heterogeneity Chi-squared=25.05, p=0.015), resulting in a significant

effect for lavender (Fig 5).

16
We also conducted a subgroup meta-analysis based on different routes of lavender administration

(Fig 6). Significant effects were observed in all subgroups and based on the estimated effect sizes

it can be seen that the oral route was more effective (pooled SMD= -0.56, 95% CI: -1.07 to -0.05,

P=0.032; I2=85.2%; heterogeneity Chi-squared=27.10, P<0.001) than the other forms of

administration such as aromatherapy (pooled SMD= -0.69, 95% CI: -0.92 to -0.46, P<0.001;

I2=48.9%; heterogeneity Chi-squared=15.65, P=0.048), and the dermal route (pooled SMD= -0.49,

95% CI: -0.93 to -0.06, P=0.027 ; I2=53.7%; heterogeneity Chi-squared=2.16, P=0.142).

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Influence and sensitivity analysis

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Results of the influence analysis indicated that none of the studies influentially affects the

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estimated pooled SMD (Fig 7). Moreover, we conducted a sensitivity analysis by excluding

studies with low quality based on the Jadad score and Cochrane risk of bias assessment tool
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simultaneously (25,31,35,40), meta-analysis resulted in pooled SMD= -0.63, 95% CI: -0.87 to -
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0.39, P<0.001; I2=72%; heterogeneity Chi-squared=42.87, P<0.001); still indicating significant

decreasing effect for lavender on depression scores (Fig 8).

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3-6-Adverse effects

The documentation of adverse effects is important for decision making by physicians and patients
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who are willing to seek treatment (43). Considering this important factor, nearly half of the
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reviewed studies (27,30,32,33,34,35,36,42), had reported information regarding adverse effects.

Of these, 4 studies (30,32,33,35) stated zero manifestation of unwanted effects. Four studies

(27,34,36,42), reported the occurrence of side effects, in which, lavender was administered via the

oral route (34,36,42) except for one study which used the inhalation method (27). The reported

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side effects which are summarized in Table 2 included nausea (34,36), eructation (36), drowsiness

(42), headache (27,34,36), palpitation (34), diarrhea (36), nasopharyngitis (36) and coughing (27).

In the study conducted by Kamalifard et al, side effects including, nausea, headache and palpitation

were mild and transient with no further need to discontinue the treatment (34). However, Lari et

al, recommended stopping the intervention for participants manifesting adverse effects of

headache and coughing, which were resolved after drug discontinuation with no need for further

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intervention (27). Kasper et al, reported adverse effects with causal relationships such as headache,

diarrhea, nausea, nasopharyngitis and eructation. With eructation being the only difference

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between the two groups receiving Silexan vs placebo (36). Also, in the study by Araj Khodaei et

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al, one patient dropped out due to drowsiness, but other side effects such as increased appetite,

headache and dry mouth were less important and spontaneously resolved in the course of
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intervention (42).
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4-Discussion:
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The current systematic review and meta-analysis was conducted to determine the antidepressant

effects of Lavender in depressed patients or people affected by other disease with concomitant
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depressive symptoms. In the present meta-analysis, lavender significantly decreased depression

scores compared to the control group (pooled SMD= -0.66, 95% CI: -0.85 to -0.46, P<0.001),
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implying the effectiveness of lavender as a complementary treatment approach. Also, by

conducting a sensitivity analysis, and the exclusion of low-quality studies, the overall effect size

of the remaining studies was significant (pooled SMD= -0.63, 95% CI: -0.87 to -0.39, P<0.001).

Furthermore, through subgroup analysis, a marginally significant effect for lavender was observed

in the group with depressed subjects. But by excluding Araj khodai’s study (42) (the only study

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which used an active comparator as the control group i.e., fluoxetine) a pronounced significant

antidepressant effect for lavender was seen in participants with diagnosed depression.

In parallel with this finding, and considering lavenders' possible mechanism in the

pathophysiology of depression, including blockade of the glutamate NDMA receptors, inhibition

on serotonin transporter protein’s (44), reduced binding to the 5HT1A receptors (45), and voltage-

gated calcium channels (VGCCs) inhibition (46), it can be considered and suggested as an

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efficacious supplemental treatment for depression, not only in patients diagnosed with depression

but also in patients suffering from other diseases with concomitant depressive symptoms.

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In addition, our meta-analysis's results showed that the oral route administration was more

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effective (pooled SMD= -0.56, 95% CI: -1.07 to -0.05, P<0.001) than other routes. This

characteristic can be attributed to the most potent form of drug delivery (47), and the oral route
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consumption, is the most promising method of administration due to its beneficial characteristics
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such as patient compliance, controlled dosage and easy method of administration (48).

Also, nearly half of the reviewed studies, administered lavender using the inhalation method

(25,26,27,28,29,37,38,39,40,41). This may be ascribed to its effects via the olfactory pathway.
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Hence, obtaining an advantage of bypassing the blood brain barrier, permitting a speedy onset of

action, resulting in much fewer adverse effects and being more economically affordable (49).
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Aromatherapy with linalool, considered to be lavenders primary active component, has been
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reported to show alterations in gene expression associated with synaptic neurotransmission and

the upregulation of neurotransmitters including oxytocin and neuropeptide. Also, it has been

reported to promote neuroplasticity in the hypothalamus, with the reversal of dopamine,

acetylcholine and glutamate levels to normal states (50).

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Furthermore, results conducted on an animal study, concluded that lavender essential oil inhalation

promotes hippocampal neurogenesis and improved dendritic branching with the amelioration of

depressive like behavior (51). Ninety percent of studies administrating lavender via inhalation

method, in the present review, resulted in positive antidepressant effects. Also, all studies in this

group except for one (41) checked the intactness of the olfactory nerve before the commencement

of study to reduce potential risk of bias. Nevertheless, an important matter in all routs of lavender

administration, except for the oral rout, was the inability to properly blind the patients and

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assessors due to the pronounced odor of lavender. In a number of studies this biasing factor was

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stated clearly (25,26,27,29,31,32,33,39,40). But the remaining studies expressed only a brief

description of the unawareness of the subjects or/and assessors towards the given drugs without

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reporting the importance of the aroma factor and the difficulty of how to blind it (24,28,37,38,41).
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Other factors causing heterogenicity between the aromatherapy studies, were the various condition

of subjects, variability of the distance between the patient’s nose and aroma source, the frequency
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and duration of treatment and the type of facility used to deliver the aroma (47).

Also, an accountable factor in the aromatherapy- massage studies, was not using a control group
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consisting of massage with a carrier oil, hence resulting in bias where one would ask, whether the

positive effects were due to the lavender oil or the massage itself (31).
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Furthermore, individualized factors inducing low tolerance to treatment, such as fatigue in cancer
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patients (24) may have weakened true results.

Limitations:

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Potential limitations that should be considered regarding this meta-analysis are the heterogenous

populations under study, in which the majority of studies did not define a definite diagnosis of

depression for the included subjects. Thus, resulting in a variety of conditions as the inclusion

criterion. Studies with short durations, small sample sizes, varied doses of lavender and improper

blinding techniques are some other limitations that need to be considered.

5-Conclusions:

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The current meta-analysis concludes that lavender has significant antidepressant effects. However,

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due to aforementioned limitations such as diversity of population under study and small sample

sizes, further large clinical trials are recommended with more homogeneous populations and

rigorous designs.

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Conflicts of interest:
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The authors declare no conflicts of interest.

Funding:
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In a collaborative study between Tehran University of Medical Sciences and Isfahan University of
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Medical Sciences, the research has been supported in part by Isfahan University of Medical

Sciences. (Research Project NO:199280)

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Figure 1. Flow chart of study selection.

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Figure 2. Forest plot showing standardized mean difference (SMD) of change from baseline in

depression scores, comparing lavender with control group.

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Figure 3. Funnel plot to evaluate publication bias

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Fig 4a. Meta-regression results assessed the confounding effects of patients' age

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Fig 4b. Meta-regression results assessed the confounding effects of sample size

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Figure 5a. Subgroup analyses of standardized mean difference (SMD) of change from baseline in

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depression scores, comparing lavender with control group based on participants with diagnosed

depression (including Araj khodai’s study) and patients having other diseases with concomitant
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depressive symptoms.
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Figure 5b. Subgroup analyses of standardized mean difference (SMD) of change from baseline in

depression scores, comparing lavender with control group based on participants with diagnosed

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depression (with the exclusion of Araj khodai’s study) and patients having other diseases with

concomitant depressive symptoms.

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Figure 6. Subgroup analyses of standardized mean difference (SMD) of change from baseline in
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depression scores, comparing lavender with control group based on different routes of lavender

administration.
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Fig 7. Influence analysis's results for evaluating influential studies on the estimated effect size

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Fig 8. Sensitivity analysis results after excluding low quality studies on comparing lavender versus

control group.

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Table 1. PICOS criteria for eligibility of studies

PICOS criteria
Participant Regardless of the participant’s disease or medical
condition, without any sex or age restriction, who
were treated with L. angustifolia to evaluate its
antidepressant effects.
Intervention Treated with L. angustifolia, all routes of lavender
administration were accepted.
Comparator Any type of control group.

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Outcome Depression as the main outcome measure or as a
subscale of any valid assessment tool.
Study design Human randomized controlled clinical trials.

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Table 2. Articles assessing the effects of lavender on depression

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First author Condition Experimental Control treatment Main Main results Adverse effects Route of Study design Depression
(year) sample treatment (Form/Dosage/Duration) (Form/Dosage/Duration) outcome administration status
Country, size: measurement

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language s
Araj- MDD (mild to A1. Oral lavender capsules (powder of flower) B. Oral Fluoxetine 1. HAMD 1. A1=A2=B Drowsiness Oral Double- Depressed
Khodaei moderate) (1g) (every 12 hours) (8 weeks) capsules (10mg) (every 12 blind,
(2020), Iran (Base line hours) (8 weeks) (Significant reduction randomized

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English HAMD score of A2. Oral Lemon balm capsules (1gr) (every 12 in depression scores pilot study
8 -24) hours) (8 weeks) was observed in all
n=50 three groups with no
significant difference
between them)
Bazrafshan
(2020)Iran,
English
Elderly patients
(Baseline Beck
depression
score 14-28)
n=60
A. Lavender tea (2g teabag) (in 300 cc hot
water) (steeped 10-15 min) (twice daily)
(morning, night time) (for 2 weeks)
lP B. No placebo 1. BDI 1.A>B
(p < 0.001)

(Depression scores
were reduced
significantly in the
Had no side
effects in either
group
Oral Single
blinded,
Randomized
controlled
clinical trial
Depressed
na
lavender group
compared to the
control group)

Chen Postpartum A. lavender tea (2g dried flower) (in 300 cc hot B. Routine postpartum 1. EPDS 1.A>B (at 2 weeks No side effects Oral Randomized Non
(2015) women with water) (steeped 10-15 min) (one cup day) care follow up) reported controlled depressed
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Taiwan, sleep (night time) (for 2 weeks) (depression) clinical trial

English disturbance
n=80 1.A=B (at 4 weeks
follow up)
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(depression)

(Lavender
significantly reduced
depression scores
compared to the
control group at 2
weeks assessment
but failed to sustain
the anti-depressive

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 effects 2 weeks after
the discontinuation
of treatment.)

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Kamalifard Menopausal A1. Oral lavender capsules (powder of flower) B. Control group: Starch 1. BDI 1.(A1=A2) >B Lavender Oral Triple-blind, Depressed
(2017)Iran, depression (500mg) (twice/day) (8 weeks) capsules(500mg) (p<0.001) group: Nausea Randomized
English (Baseline Beck (twice/day) (8 weeks) (8.2%), controlled
depression A2. Oral Bitter orange capsules (500mg) (Lavender capsules headache clinical trial

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score 14-28) (twice/day) (8 weeks) reduced depression (4.1%),
n=156 compared to the palpitation
control group but had (4.4%)
no significant
difference compared Control group:

-p
to bitter orange.) Nausea
(10.4%),
headache
(6.3%),

re
palpitation
(2.1%)
Kasper Patients with A. Silexan capsule 80 mg/daily (70 days) B. Identical placebo 1. MADRS 1.A>B Silexan group: Oral Double blind, Depressed
(2016) MADD capsule/daily (70 days) (p<0.001) Eructation Randomized
Germany, n=318 (most common placebo-
English

lP (Silexan carried out a

statistically
significant reduction
in depression scores
after week 4 and
maintained results
related side
effect to drug
treatment with
a significant
difference
compared to
controlled,
parallel-
group clinical
trial
na
until week 10.) the placebo
group)
Bahrami Female ACS A. Aroma foot massage (lavender oil) + Routine B. Routine care 1. HADS 1. A>B Not reported Aroma- Randomized Non
(2017)Iran, patients care massage controlled depressed
English n=90 clinical trial
ur

Soden Cancer patients A1. (Aroma- massage group): massage with B1. no intervention. 1.HADS 1.A=B Not reported Aroma- Randomized Non
(2004) UK, n=42 lavender oil plus inert carrier oil (diluted to 1 massage controlled depressed
English %) (Whilst, a significant clinical trial
B2. (massage only group) within group
Jo

(received 30 min back massage weekly/four inert carrier oil only reduction in
weeks) (carrier oil=sweet almond oil) (received 30 min back depression scores
massage weekly/four was seen in the
weeks) (carrier oil=sweet massage group, the
almond oil) add on of lavender oil
did not prove to
enhance the
favorable effects of
massage.)

38
Effati- Pregnant A1. lavender cream with foot-bath (every B. placebo cream: 2g 1. DASS-21 1.(A2=A1) >B Had no serious Dermal Double-blind Non
Daryani women at 25 to night) (8 weeks) (every night) (8 weeks) side effects in placebo- depressed
(2015) Iran, 28 weeks (There were no either group controlled

of
English gestation n=141 A2. Only lavender cream notable statistical trial
(every night) ( 8 weeks) differences between
the interventional
groups.)

ro
Effati- Postpartum A1. Lavender cream with foot-bath (every B. Placebo cream: 2g 1. DASS-21 1. (A1=A2)>B Had no side Dermal Randomized Non
daryani women night) (6 weeks) (every night) (6 weeks) effects in either controlled depressed
(2017)Iran, n=141 (There were no group clinical trial
Persian A2. Only lavender cream notable statistical
(every night) (6 weeks) differences between

-p
the interventional
groups.)
Bagheri Hemodialysis A. Aromatherapy with lavender oil 5% (diluted B. Routine care 1.HADS 1.A>B (Depression Not reported Aromatherapy Randomized Non
Nesami patients in sweet almond oil 1:20) (3 drops, soaked subscale) clinical trial depressed

re
(2017) Iran, n=72 cotton ball, attached to collar) (for 10 min (p=0.005)
English during hemodialysis) (3 times a week) (for 4
weeks) (Lavender
aromatherapy
decreased

Jafari
(2019)Iran,
Patients
migraine
with
lP
A. Lavender oil Aromatherapy (3 drops, soaked
cotton ball, attached to collar) (for 15 min) (3
B. Inhalation of liquid
paraffin (3 drops, soaked
1. BDI
depression
significantly
compared to the
control group)
1. A=B
scores

Not reported Aromatherapy Single

blinded,
Non
depressed
na
Persian n=70 nights a week) (for 4 weeks) cotton ball, attached to (Although there were Randomized
neck) (for 15 min) (3 no significant controlled
nights a week for 4 differences between clinical trial
weeks) the 2 groups, mean
depression scores
were significantly
ur

reduced in both
groups)
Jokar Menopausal A. Aromatherapy with lavender oil 2% (2 drops B. Distilled water 1. KMI 1. A>B Not reported Aromatherapy Single-blind Non
(2018),Iran, women on paper towel, attached to collar) (20 min inhalation (2 drops, paper randomized depressed
Jo

English n=70 before sleep) (every night) (for 4 weeks) towel, attached to collar) placebo-
(20 min before sleep) controlled
(every night) (for 4 clinical trial
weeks)
Kianpour Postpartum A. Lavender oil inhalation (3 drops, rubbed on B. Received routine care 1. DASS-21 1.A>B Not reported Aromatherapy Randomized Non
(2016) Iran, woman (right hands) (every 8 hours) (4 weeks) 2. A>B clinical trial depressed
English after delivery) 2. EPDS (p<0.0001)
n=140
(depression was
significantly lower in

39
 the lavender group
up to week 12,
suggestive of a long

of
acting effect in
depression.)
Lari Patients with A. Lavender oil Aromatherapy (3 drops on B. Sweet Almond oil 1. BDI 1. A>B Lavender Aromatherapy Randomized, Non
(2020)Iran, diabetes and fabric) (inhaled 5 min before sleep) (2 periods inhalation (3 drops on (Lavender inhalation group: 2 placebo- depressed

ro
Enlglish insomnia of 4 weeks with a one-week interval) fabric) (inhaled 5 min caused significant patients with controlled
n=52 before sleep) (2 periods outcome in Headache, 3 cross-over
of 4 weeks with a one- depression scores patients with clinical trial
week interval) compared to placebo coughs
in both groups)

-p
Group1: (p<0.001)
Group2: (p<0.05)

re
Matsumoto Woman with A. Lavender oil inhalation (via diffuser) (for 10 B. Water inhalation (via 1. POMS 1. A>B Not reported Aromatherapy Randomized Non
(2013) PMS (mild to min) (within seven days of menstruation) diffuser) (for 10 min) (p=0.045) crossover depressed
Japan, moderate) (cross over design) (within seven days of (Lavender inhalation trial
English n=17 menstruation) significantly
decreased subscales

Nategh
(2020), Iran
Persian
ACS patients
admitted
CICU
to
A. Aromatherapy with lavender oil (2 drops onlP
tissue, attached to collar) (20 min each time)
(twice daily) (for 2 days)
B. Distilled water
inhalation (2 drops on
tissue, attached to collar)
1. HADS
of
dejection)

1. A>B
(p=0.01)
depression-

Not reported Aromatherapy Randomized

controlled
clinical trial
Non
depressed
na
n=110 (20 min each time) (twice (There was a
daily) (for 2 days) significant reduction
of depression scores
in the Lavender
inhalation group
compared to the
ur

placebo group)
Nikjou Menopausal A. Lavender oil Aromatherapy (inhaled from a B. Diluted milk inhalation 1. Green 1. A>B Not reported Aromatherapy Double blind, Non
(2017), Iran women glass container) (20 min each time) (twice a (inhaled from a glass questionnaire cross over depressed
English n=100 week) (for 2 weeks) (with a four-week interval) container) (20 min each (Depression has clinical trial
Jo

time) (twice a week) (for 2 significantly

weeks) (with a four-week decreased in the
interval) lavender group
compared to the
control group)
Tayebi Hemodialysis A. Lavender oil Aromatherapy (3 drops on B. Routine care 1. DASS-21 1. A>B Not reported Aromatherapy Randomized Non
(2015)Iran, patients fabric, attached to collar) (inhaled 1 hour (p=0.01) controlled depressed
Persian n=60 during hemodialysis) (3 times a week) (for 4 clinical trial
weeks)

40
Uzuncakma University A. Steam inhalation with lavender oil (3 drops B. No intervention 1.PMSS 1.A>B Not reported Aromatherapy Randomized Non
k students with in 200 cc boiling water) (5 days before the start (p<0.05) controlled depressed
(2018) PMS of menstruation, once a day) (for one cycle) clinical trial

of
Turkey, n=90 (there was no intervention in the next 2 cycles, (Compared to the
English only follow up) control group, the
intervention group
significantly reduced

ro
mean PMS scores
including subscales of
depressive affect and
thoughts.)

-p
re
Abbreviations:

ACS: Acute coronary syndrome; BDI: Beck Depression Inventory; CICU: Cardiac intensive care unit; DAS S-21: Depression, Anxiety, stress scales-21; EPDS: Edinburgh Postnatal Depression Scale; HADS:
Hospital Anxiety and Depression Scale; HAMD: Hamilton Depression Rating Scale; KMI: Kupperman Menopausal Index; MADD: Mixed anxiety and depression; MADRS: Montgomery Asberg Depression

lP
Rating Scale; MDD: Major depressive disorder; PMS: Premenstrual syndrome; PMSS: Premenstrual Syndrome Scale; POMS: Profile of Mood States
na
Table 3. Cochrane risk of bias assessment (a) and Jadad score (b)
ur

1st Author (year) Cochrane risk of bias Jadad scores (Total Reference number
score)
Jo

Araj Khodai (2020), H, L, L, L, L, L, L 1, 1,1, 0, 1 (4) 42

Bagheri Nesami (2017) L, U, U, U, U, U, L 1, 0, 0, 1, 0 (2) 38
Iran

Bahrami(2017)Iran U, L, H, L, L, L, L 1, 0, 1, 0, 0 (2) 31
Bazrafshan(2020)Iran U, U, U, L, L, L, L 1, 0, 0, 1, 0 (2) 30

41
 Chen(2015)Taiwan U, U, U, U, H, L, L 1, 0, 1, 0, 0 (2) 35
Effati-daryani (2017)Iran L, L, H, L, L, L, L 1, 0, 1, 1, 0 (3) 32

of
Effati-Daryani(2015)Iran L, L, H, L, L, L, L 1, 1, 1, 1, 0 (4) 33
Jafari(2019)Iran L, L, U, U, L, L, L 1, 0, 1, 1, 0 (3) 28
Jokar (2018) Iran L. L, H, L, L, L, L 1, 0, 1, 1, 0 (3) 30

ro
Kianpour(2016)Iran U, U, H, U, U, L, L 1, 0, 1, 1, 0 (3) 26
Kamalifard(2017)Iran L, L, L, L, L, L, L 1, 1, 1, 1, 1 (5) 34
Kasper(2016)Germany L, L, L, L, L, L, L 1, 1, 1, 1, 1 (5) 36

-p
Lari(2020)Iran L, L, H, L, H, L, L 1, 0, 1, 1, 0 (3) 27
Matsumoto(2013) Japan U, U, H, U, U, U, L 1, 0, 0, 0, 0 (1) 25
Nategh (2020) Iran U, U, H, U, L, L, L 1, 0, 1, 0, 0 (2) 40
Nikjou (2017), Iran L, L, H, U, U, H, L 1, 1, 0, 1, 1 (4) 41

re
Uzuncakmak(2018)Turkey U, U, U, U, L, L, L 1, 0, 1, 1, 0 (3) 37
Soden(2004)UK U, L, U, L, L, H, L 1, 0, 0, 0, 0 (1) 24
Tayebi(2015)Iran U, U, H, U, L, L, L 1, 0, 1, 1, 0 (3) 29

lP
a: High risk (H), unclear risk (U) or low risk (L) of bias in random sequence generation,
na
allocation concealment, blinding of participants, blinding of outcome assessors,
incomplete outcome data, selective outcome reporting, and other sources of
bias.
b: Yes (1) or No (0). The study is described as randomized, the study is double blind, the study has described the numbers and reasons of
ur

withdrawals and dropouts, the study has described an appropriate randomization method, the study has described an appropriate blinding
method.
Jo

42

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