Abstract Background: Pyrosis and regurgitation are the cardinal symptoms of gastroesophageal reflux disease. Several herbs have been used for treating gastrointestinal disorders worldwide. This systematic review was conducted to investigate the effects of medicinal herbs on gastroesophageal reflux disease and adverse events. Methods: MEDLINE (via PubMed; The United States National Library of Medicine, USA), Scopus, ScienceDirect, Cochrane Central Register of Controlled Trials, Web of Science, Magiran, and Scientific Information Database were systematically searched for human studies, without a time frame, using medical subject heading terms such as “gastroesophageal reflux disease”, “reflux”, “esophagitis” and “herbs”. Manual searches completed the electronic searches. Results: Thirteen randomized controlled trials were identified, including 1,164 participants from 1,509 publications. In comparing herbal medicine to placebo, there were no significant differences in terms of heartburn (P = 0.23 and 0.48), epigastric or abdominal pain (P = 0.35), reflux syndrome (P = 0.12), and effective rate (P = 0.60), but there was a significant difference in terms of acid regurgitation (P = 0.01). In comparing herbal medicine to drugs, there was a significant difference in terms of effective rate (P = 0.001), and there was one trial that reported a significant difference in terms of epigastric pain (P = 0.00001). Also, in comparing herbal medicine to drugs, there were no significant differences in terms of acid regurgitation (P = 0.39). Conclusion: This meta-analysis showed that herbal medicines are effective in treating gastroesophageal reflux disease. Further standardized researches with a large-scale, multicenter, and rigorous design are needed.

1. REVIEW
doi: 10.12032/TMR20200929200
TMR | November 2020 | vol. 5 | no. 6 | 464 Submit a manuscript: https://www.tmrjournals.com/tmr
Persian Medicine
Effects of herbal medicine in gastroesophageal reflux disease
symptoms: a systematic review and meta-analysis
Fariba Sadeghi1
, Seyed Mohammad Bagher Fazljou1
, Bita Sepehri2
, Laleh Khodaie3*
, Hassan Monirifar4
, Mojgan
Mirghafourvand5
1
Department of Iranian Traditional Medicine, School of Traditional Medicine, Tabriz University of Medical Sciences, Tabriz,
Iran; 2
Liver and Gastrointestinal Diseases Research center, Tabriz University of Medical Sciences, Tabriz, Iran; 3
Department
of Traditional Pharmacy, Faculty of Traditional Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; 4
Horticulture
and Crops Research Department, East Azarbaijan Agricultural and Natural Resources Research and Education Center,
Tabriz, Iran; 5
Social Determinants of Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
*Corresponding to: Laleh Khodaie, Department of Traditional Pharmacy, Faculty of Traditional Medicine, Tabriz University
of Medical Sciences, Univesity Main Sreet, Tabriz, Iran.
Highlights
This systematic review provides a comprehensive estimate of the application of herbal medicine in the
management of gastroesophageal reflux disease symptoms. The results showed that herbal medicines have a
positive efficacy in the treatment and relief of gastroesophageal reflux disease symptoms.
Traditionality
The first recorded prescription of Pistacia lentiscus and Coriander Triphala for treating gastrointestinal
disorders in Persian medicine was in Liber Medicinalis Almansoris. It was compiled by Abu Bakr
Muhammad ibn Zakariyya al-Razi (865–925 C.E.), known to the Latin world as Rhazes, an Iranian scientist.
Then, Abu Rayhan al-Biruni (973–1048 C.E.), another Iranian scientist, in his Book on the Pharmacopoeia
of Medicine and his contemporary Abu Ali Sina (980–1032 C.E.), famed as Avi-cenna in Europe, in his
Canon of Medicine described the use of single and combined forms of Pistacia lentiscus and Coriander
Triphala for treating various disorders such as gastralgia, reflux, and dyspepsia. Jorjani (1042–1137 C.E.),
another prominent scientist and physician in the medieval era in The Treasure of the Khwarazm Shah, which
is now regarded as the largest Persian medical encyclopedia, explained the use of herbal medicines, such as
Pistacia lentiscus and Coriander Triphala, for treating esophagus and stomach diseases. In Storehouse of
Medicaments (a pharmacopoeia by Mohammad Hosein Aghili Shirazi; 1670–1747 C.E.), a complete
description of 1,700 monographs, including Pistacia lentiscus, Phyllanthus emblica, Terminalia belerica,
Terminalia chebula, and Coriandrum sativum, was provided.

2. REVIEW doi: 10.12032/TMR20200929200
Submit a manuscript: https://www.tmrjournals.com/tmr TMR | November 2020 | vol. 5 | no. 6 | 465
Abstract
Background: Pyrosis and regurgitation are the cardinal symptoms of gastroesophageal reflux disease. Several
herbs have been used for treating gastrointestinal disorders worldwide. This systematic review was conducted to
investigate the effects of medicinal herbs on gastroesophageal reflux disease and adverse events. Methods:
MEDLINE (via PubMed; The United States National Library of Medicine, USA), Scopus, ScienceDirect,
Cochrane Central Register of Controlled Trials, Web of Science, Magiran, and Scientific Information Database
were systematically searched for human studies, without a time frame, using medical subject heading terms such as
“gastroesophageal reflux disease”, “reflux”, “esophagitis” and “herbs”. Manual searches completed the electronic
searches. Results: Thirteen randomized controlled trials were identified, including 1,164 participants from 1,509
publications. In comparing herbal medicine to placebo, there were no significant differences in terms of heartburn
(P = 0.23 and 0.48), epigastric or abdominal pain (P = 0.35), reflux syndrome (P = 0.12), and effective rate (P =
0.60), but there was a significant difference in terms of acid regurgitation (P = 0.01). In comparing herbal medicine
to drugs, there was a significant difference in terms of effective rate (P = 0.001), and there was one trial that
reported a significant difference in terms of epigastric pain (P = 0.00001). Also, in comparing herbal medicine to
drugs, there were no significant differences in terms of acid regurgitation (P = 0.39). Conclusion: This
meta-analysis showed that herbal medicines are effective in treating gastroesophageal reflux disease. Further
standardized researches with a large-scale, multicenter, and rigorous design are needed.
Keywords: Herbal medicine, Gastroesophageal reflux disease, Randomized controlled trial, Acid regurgitation,
Effective rate, Epigastric pain
Author contributions:
Study concept and design: Laleh Khodaie, Seyed Mohammad Bagher Fazljou, Bita Sepehri, and Fariba Sadeghi.
Analysis and interpretation of data: Fariba Sadeghi, Mojgan Mirghafourvand, and Hassan Monirifar. Drafting
and revision of the manuscript: Fariba Sadeghi, Mojgan Mirghafourvand, Laleh Khodaie, and Hassan Monirifar.
Statistical analysis: Hassan Monirifar.
Acknowledgments:
The authors are thankful to Dr. Hamideh Sedighzadeh, from USA for comments that significantly improved the
manuscript editing. We would like also to show our gratitude to Mona Nasir Zonouzi, Optometry Graduate
Students Association, Canada for sharing her pearls of wisdom with us through the progress of this study.
Abbreviations:
GERD, gastroesophageal reflux disease; PPIs, proton pump inhibitors; RKT, Rikkunshito; RCTs, randomized
controlled trials; RPZ, rabeprazole; MD, mean difference; SMD, standardized mean difference; CI, confidence
interval; FSSG, frequency scale for symptoms of gastroesophageal reflux disease; GERD-HRQL,
gastroesophageal reflux disease-health-related quality of life; TJG, Tongjiang granule; WCYT, Wuchuyu soup;
PTM, Persian traditional medicine.
Competing interests:
The authors declare that there is no conflict of interest.
Citation:
Fariba Sadeghi, Seyed Mohammad Bagher Fazljou, Bita Sepehri, et al. Effects of herbal medicine in
gastroesophageal reflux disease symptoms: a systematic review and meta-analysis. Traditional Medicine
Research 2020, 5 (6): 464–475.
Executive editor: Jing-Na Zhou.
Submitted: 18 June 2020, Accepted: 9 September 2020, Online: 27 October 2020

3. REVIEW
doi: 10.12032/TMR20200929200
Submit a manuscript: https://www.tmrjournals.com/tmr
TMR | November 2020 | vol. 5 | no. 6 | 466
Background
About 8% to 30% of Asians and 8.5% of Iranians
suffer from uninvestigated dyspepsia [1, 2]. The
prevalence of gastroesophageal reflux disease (GERD)
is estimated to be 10%–20% in Western countries
and 3%–7% in Asians [3–5]. In southern Iran, the
prevalence of regurgitation, heartburn, and concurrent
symptoms were reported to be 52%, 32%, and 24.4%,
respectively [6]. The prevalence of GERD symptoms
at least weekly was reported to be 10% to 25% in
western countries [7–9].
Proton pump inhibitors (PPIs) are used as an
essential and custom cure for GERD. Although PPIs
change the pH of the refluxrate, they do not stop reflux
due to a mechanically or functionally incompetent
lower esophageal sphincter [10]. PPIs may cause side
effects. Because GERD is persistent and progressive,
many patients prefer to use traditional medicine [11].
Classic herbs in Persian medicine have been used in
treating GERD. The first recorded prescription of
Pistacia lentiscus (mastaki or mastic) and Coriander
Triphala (Itrifal Gheshnizi) for treating gastrointestinal
disorders was in Liber Medicinalis Almansoris [12]. It
was compiled by Abu Bakr Muhammad ibn Zakariyya
al-Razi (865–925 C.E.), known to the Latin world as
Rhazes, an Iranian scientist. Then, Abu Rayhan
al-Biruni (973–1048 C.E.), another Iranian scientist, in
his Book on the Pharmacopoeia of Medicine and his
contemporary Abu Ali Sina (980–1032 C.E.), famed as
Avi-cenna in Europe, in his Canon of Medicine
described the use of single and combined forms of
Pistacia lentiscus and Coriander Triphala for treating
various disorders such as gastralgia, reflux, and
dyspepsia [14]. Jorjani (1042–1137 C.E.), another
prominent scientist and physician in the medieval era
in The Treasure of the Khwarazm Shah, which is now
regarded as the largest Persian medical encyclopedia,
explained the use of herbal medicines, such as Pistacia
lentiscus and Coriander Triphala, for treating
esophagus and stomach diseases [15]. In Storehouse of
Medicaments (a pharmacopoeia by Mohammad
Hosein Aghili Shirazi; 1670–1747 C.E.), a complete
description of 1,700 monographs, including Pistacia
lentiscus, Phyllanthus emblica, Terminalia belerica,
and Terminalia chebula, was provided [16]. The World
Health Organization has reported that the use of herbal
remedies has increased twofold to threefold compared
to conventional drugs worldwide [17, 18]. In the
primary healthcare system in developing countries,
about 80% of patients continue to use traditional
medicine. About 25% of drugs in the United States
contain at least one herbal substance [19]. The World
Health Organization encourages all countries to
develop their complementary and traditional medicines
and reinforces practitioners to follow that path [20].
Meta-analyses and systematic reviews have been
conducted to evaluate the effects of herbal medicines
on gastrointestinal diseases [11, 19, 21–24]. For
example, Salehi et al. reviewed the effects of herbal
medicines on the treatment for GERD in human and
animal studies [19]. They found that medicinal plants
were more effective in treating GERD and helped
manage histopathological changes related to GERD.
Dai et al. evaluated the safety and efficacy of modified
Chinese medicine preparation Banxia Xiexin
decoction in treating GERD in adults [11]. They
mentioned the potential effects of modified Banxia
Xiexin decoction on the treatment for GERD. Teschke
et al. studied the efficacy of different traditional
Chinese medicine preparations [24]. They concluded
that there was no sufficient available evidence to
support the equivalency of herbal traditional Chinese
medicine preparations to conventional GERD. Ling et
al. reported that clsssical Chinese medicine preparation
Wendan decoction had a consistent therapeutic
efficacy on bile reflux gastritis and GERD [22].
Mogami et al. indicated that Rikkunshito (RKT) could
improve adverse effects caused by various western
drugs and achieve better results, not influencing the
efficacy and bioavailability of western drugs [23].
In this meta-analysis, all randomized controlled
trials (RCTs) were reviewed. The role of herbal
medicine in the management of GERD symptoms in
humans and their adverse effects (if any) are
presented.
Methods
Objective
The objective of this review was to determine the
effects (benefits and harms) of herbal medicines on the
treatment of adult patients with GERD and compare
them to those prescribed with placebo or conventional
western drugs.
Database and search strategies
Literature search. MEDLINE (via PubMed; The
United States National Library of Medicine, USA),
Scopus, ScienceDirect, Cochrane Central Register of
Controlled Trials, Web of Science, and Persian
databases (e.g., Magiran and Scientific Information
Database), without a time frame, were searched. In this
review, all RCTs that studied the efficacy of herbal
medicine in patients 18 years and older and evaluated
placebo or conventional therapy, both written in
English and Persian, were enrolled. Searches were
based on specified controlled terms, focusing mostly
on “GERD” and relevant words, including medical
subject heading terms when possible. Moreover, the
variation of the words’ root, the related keywords, and
Persian synonyms were searched. Traditional medicine
references (Ayurveda, Persian, Chinese, etc.) were not
searched independently. The searched terms were used
individually or in combination with the title, abstract,

4. REVIEW doi: 10.12032/TMR20200929200
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and keywords, such as (“gastroesophageal reflux
disease” OR “gastroesophageal reflux” OR “reflux”
OR “esophagitis” OR “gerd” OR “heartburn”) AND
(“herbal” OR “herbs” OR “phytotherapy” OR “herbal
medicine” OR “extract”) AND (“randomized
controlled trials” OR “clinical trials”).
Manual searches of the related literature completed
the electronic searches. Also, clinical trial registries,
such as the Iranian Registry of Clinical Trials, were
searched to find unpublished studies. The references of
the included articles were also assessed for relevant
studies.
Inclusion and exclusion criteria
Population, intervention, comparison, and outcome.
The population, intervention, comparison, and
outcome for this review was defined as follows.
Types of participants. The participants were adult
men and women 18 years and older who had classic
symptoms (heartburn and regurgitation) of GERD.
Types of intervention. Herbal medicines were
provided for the intervention group. Publications that
have used herbal medicine as intervention were
included in this study.
Types of control. Placebo or conventional Western
drugs (omeprazole, pantoprazole, rabeprazole (RPZ),
mosapride, and alginic acid) were provided for the
control group.
Types of outcome. The improvement of GERD
symptoms was the primary outcome (scores, reflux,
heartburn, non-cardiac chest pain, effective rate, etc.),
and adverse event was the secondary outcome.
Exclusion criteria. Patients less than 18 years old,
infants, pregnant and nursing women, and patients
with severe disease were excluded from this study.
Study selection and data extraction
All trials that assessed GERD symptoms were
reviewed. Also, an adverse event was the secondary
outcome in this systematic review. A two-stage
screening process was carried out by two researchers
independently (F.S. and M.M.). At first, titles and
abstracts were screened for eligibility. Then, data were
extracted from all included studies (Table 1). One
author extracted the data, and another author
reassessed each included study and assayed the
findings. Any disagreement was resolved by
consensus.
Assessment of risk of bias
The Cochrane Collaboration tool was applied to assess
the risk of bias in six domains in the included studies
[25]. Each domain was evaluated in high, unclear, and
low risks of bias. Two authors independently assessed
the risk of bias in the included studies and
disagreement cases, and a third person who was
specialized in this field helped them.
Data synthesis and analysis
The Review Manager Software version 5.3 (Cochrane
Collaboration, Europe) was used to pool effect sizes.
The mean difference (MD) or standardized mean
difference (SMD), odds ratio, and 95% confidence
interval (95% CI) were calculated for the reporting of
meta-analysis results. The I2
index was used for the
evaluation of heterogeneity in meta-analysis [26]. The
random-effect model was used instead of the
fixed-effect model when heterogeneity existed [27].
Table 1 Characteristics of the studies
Study ID (first
author year)
Sample size Age (years) Duration Intervention*
Mechanism (EG) Results
CG M/F EG M/F CG EG
Treat
ment
Follow-
up
CG EG
Shuang 2011
[29]
55 30/25 57 30/27
46.86 ±
14.22
50.91 ±
10.47
4W –
Mosapride and
TJG dummy
(placebo)
TJG and
mosapride
dummy
(placebo)
Harmonize stomach and
liver function, inhibit
gastric acid, relieve pain,
increase the motilin
plasma level, and
promote gastric
emptying
TJG improves
NERD and quality
of life
Tominaga 2012
[36]
48 20/30 51 17/34 63.6 64.5 4W – RKT + RPZ
(10 mg)
RKT + RPZ (20
mg)
Decrease acid exposure
time, enhance
esophageal clearance,
and prokinetic agents
RKT + standard
dose RPZ therapy
may be useful
Di Pierro 2013
[30]
29
B:
15/14
29
A:
11/18
B: 47.3
± 12.6
A: 52.9
± 15.2
8W –
B:
Pantoprazole
and alginic acid
then crossover
to alginic acid
A: Pantoprazole
and Mirgeal
Sachet then
crossover to the
multi-ingredient
formula
Anti-inflammatory,
cytoprotective, and
antiulcer activities by
prostaglandins E2 and
F2α
Improve
symptoms in
patients
Tominaga 2014
[37]
109 28/80 109 35/74 59.4 62.1 8W – RPZ + placebo
RPZ + RKT (7.5
g/t.i.d.)
Prokinetic agents,
increase esophageal
clearance, and decrease
esophageal acid
exposure
No significant
difference in the
improvement of
GERD symptoms
in patients

5. REVIEW
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Table 1 Characteristics of the studies (continued)
Study ID (first
author year)
Sample size Age (years) Duration Intervention*
Mechanism (EG) Results
CG M/F EG M/F CG EG
Treat
ment
Follow-
up
CG EG
Sakata 2014
[33]
43 8/35 52 17/35
73.4
(65–83)
72.1
(65–85)
8W – RPZ + placebo RPZ + RKT
Prokinetic agents and
improve emptying and
accommodation
Improvement in
abdominal
bloating, heavy
feeling in the
stomach, sick
feeling, and
heartburn after
meals
Alecci 2016
[28]
53 28/31 55 28/31
50.05 ±
5.5
51.01 ±
7.6
2M – Placebo
Mucosave
Sachet
Gastroprotective;
prevent the experimental
formation of gastric
lesions
Reduce the
frequency and
intensity of
symptoms
Moeini 2016
[32]
41 25/16 39 18/21 20–60 20–60 4W – Placebo Hawthorn Gastroprotective
Alleviate
heartburn and
regurgitation
Zohalinezhad
2016 [38]
13 6/7
14
15
4/10
4/11
35.38 ±
6.50
34.64 ±
7.28
35.73 ±
9.73
6W – B (omeprazole)
A (Myrtle
berries); C (A
and B)
Anti-H. pylori and
anti-inflammatory
activities
Significant
changes observed
in FSSG;
symptoms of
dysmotility and
acid reflux; no
significant
difference in all
groups in the final
total score of
FSSG
Salehi 2017
[34]
37 19/18 38 20/18
39.88 ±
9.24
41.24 ±
9.48
6W 2W
Omeprazole
and placebo
Omeprazole 20
mg with myrtle
Relieving; improve
histopathology
symptoms; carminative,
analgesic, antiseptic, and
anti-inflammatory
activities, strengthen the
stomach; reduce
constipation and ulcer
index, total acidity, and
gastric juice volume;
increase gastric pH and
gastric wall mucus
Lower recurrence
of symptoms;
significant delay
in the onset of
symptoms
Faghihi 2018
[39]
18 11/7 21 12/9
36.06 ±
9.24
38.29 ±
13.29
4W – Placebo-cornst
arch
Satureja.
hortensis L.
Carminative,
antispasmodic,
anti-inflammatory,
anti-diarrheal,
pain-relieving,
antibacterial, antiviral,
and antioxidant activities
Decrease in FSSG,
dysmotility-like
symptoms, and
acid reflux
Karkon 2018
[31]
36 2/29 32 8/24
42.79 ±
11.57
42.28 ±
12.04
4W – Placebo Amla
Antisecretory, antiulcer,
cytoprotective activities
Reduction in
regurgitation and
heartburn
frequency and
severity
Shih 2018 [35] 37 20/17 40
14/
26
46.95 ±
13.42
46.03 ±
13.88
4W –
Omeprazole +
WCYT
(placebo)
Omeprazole
(placebo) +
WCYT
Anti-inflammatory,
analgesic, and
gastroprotective
activities
Omeprazole and
WCYT for 4
weeks reduce
RDQ and GERDQ
scores with similar
rates of adverse
events
Sadeghi 2020
[40]
25 47/43 32
11/
14
42.48 ±
15.07
33.65 ±
11.18
4W – Omeprazole
and placebo
Coriander
Triphala capsule
Gastroprotective,
anti-inflammatory
activities
Reduction in
FSSG score after 4
weeks of
intervention
CG, control group; EG, experimental group; M, male; F, female; D, days; W, weeks; M, months; GERD, gastroesophageal reflux disease; NERD, non-erosive
reflux disease; RKT, Rikkunshito; RPZ, rabeprazole; TJG, Tongjiang granule; TJG, Tongjiang Granule; FSSG, Frequency Scale for Symptoms of
gastroesophageal reflux disease; RDQ, reflux diagnostic questionnaire; GERDQ, gastroesophageal reflux disease questionnaire; –, not mentioned.
*Details of interventions:
TJG, Tongjiang granule, contains Caulis Perillae (Perilla stem), Rhizoma Cyperi, Os Sepiellae, Radix Glycyrrhizae, maltodextrin.
WCYT, Wuchuyu soup, contains Evodia rutaecarpa (Juss) Benth, Panax ginseng C.A. Meyer, Zingiber officinale Rose, Ziziphus jujuba Mill.
Mucosave sachet contains sodium alginate, Mucosave (verum), sodium bicarbonate.
Mirgeal sachet contains alginic acid, glycyrrhetinic acid, vaccinium myrtillus extract.
Coriander Triphala capsule contains Ziziphus jujuba Mill, Zingiber officinale Rose, Phyllanthus emblica L. (Amla), Terminalia belerica Retz, Coriandrum
sativum.

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Results
Study selection
A total of 1,509 records were achieved according to a
systematic search. After screening, 13 studies (n =
1,164) had eligibility criteria and were included in this
review [28–40]. Data of one study could not be
included in the meta-analysis. The authors emailed to
access the study data but did not receive any response
[28]. Based on the objective, ultimately, 12 studies (n
= 1,056) were entered into the meta-analysis (Figure
1).
Study characteristics
In all studies, symptomatic GERD response was
evaluated. The sample size ranged from 15 to 109 [37,
38]. The therapy period lasted from 4 weeks to 2
months in the included studies. The minimum age of
the patients was 18 years old. The features of the
included studies are available in Table 1.
Risk of bias in the included studies
In all 13 included studies, there was no significant
difference in terms of baseline characteristics between
the intervention and control groups. Eleven trials were
described as double-blind, and one study was
described as open-labeled [30]. Random sequence
generation (selection bias) in two studies was unclear
[32, 39]. Four studies had high-risk allocation
concealment [30, 32, 33, 39]. Unclear allocation
concealment (selection bias) was identified in two
studies [29, 35]. Blinding of personal information and
participants (performance bias) in five studies was a
high risk [28, 30, 32–34]. Detection bias was low risk
in two studies [26, 32]. Unclear attrition bias and
high-risk reporting bias were other criteria for
evaluating the risk of bias [28, 30, 33, 34, 38, 39].
Intention-to-treat analysis was performed in four
studies, and three studies reported full analysis set [28,
29, 31, 33, 34, 37, 40]. One study reported an
all-patient-treated analysis and a pre-protocol set
analysis [29]. The randomization techniques used in
the included RCTs were simple randomization,
random number table, blokes of size 3 and 6, SAS and
NCSS statistics software. In contrast, the other two
studies did not report the specific randomization
techniques [32, 38] (Figure 2 and Figure 3).
Primary outcomes
The primary outcomes were the scores of GERD
symptoms. In various studies, different questionnaires
have been used [28–40].
Alecci et al. used the gastroesophageal reflux
disease-health-related quality of life (GERD-HRQL)
and GERD symptom assessment scale questionnaires
[28]. The GERD-HRQL questionnaire assesses
heartburn severity in nine questions on a scale of 0 (no
symptoms) to 5 (incapacitating). This validated
instrument includes six heartburn-related items and
questions relating to other GERD symptoms,
medication use, and satisfaction with the present
condition. The total GERD-HRQL score ranges from 0
to 50, with a higher score indicating more severe
symptoms. The GERD symptom assessment scale is a
self-administered questionnaire that asks the patient to
report the frequency, severity, and degree of bother for
Figure 1 Flow chart of the included eligible studies
in the systematic review

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15 specific symptoms. Shuang et al. used “total score
of symptoms” and “score of major symptoms” and
“domain of SF-36” the previous week for the
evaluation of the improvement of GERD [29]. The
major symptoms referred to the reflux diagnostic
questionnaire, which included retrosternal burning
feeling or heartburn, chest pain, acid or bitter in the
mouth, and uncomfortable nausea. Scores were given
as 0, 1, 2, 3, 4, and 5. The minor symptoms contained
abdominal distension, acid reflux, belching, poor
appetite, gastric upset, emotional irritability or
depression, blocked sensation in the throat, stomach
pain or bloating, and satiety and were scored as 0, 1, 2,
and 3. Di Pierro et al. used a visual analog scale (0–10)
for assessing the symptoms [30]. Karkon et al.
measured on a frequency and severity scale the
symptoms of GERD according to the quality of life in
a reflux-associated disease questionnaire [31]. Salehi
et al. used the Mayo Clinic standardized questionnaire
[34]. Moeini et al. used a validated questionnaire to
detect the severity of symptoms [32]. Shih et al.
assessed the primary objectives using the reflux
disease questionnaire and GERD questionnaire scores
[35]. Six trials used the frequency scale for symptoms
of GERD (FSSG) score to evaluate the intervention
[33, 36–40]. The scores were calculated according to
the frequency of the symptoms: 0, never; 1,
occasionally; 2, sometimes; 3, often; and 4, always.
Tominaga et al. assessed the symptoms in two domains:
reflux symptom and acid-related dysmotility symptom
domains; the total score was given by the sum of the
two domains [36]. Sadeghi et al. assessed only the
reflux symptom domain [40].
Despite different questionnaires, common outcomes,
including total score, effective rate, regurgitation,
heartburn, epigastric pain, and reflux syndrome, were
used.
In 13 included studies, 1,164 participants (618 in the
experimental groups and 546 in the control groups)
were evaluated. In the included trials, PPIs,
omeprazole, rabeprazole, pantoprazole, and other
drugs, including mosapride, were used. The
components of the prescriptions used in each literature
are listed in Table 1.
This review carried out two categories as trials, such
as herbal medicine versus placebo and herbal medicine
versus classic drugs.
Figure 2 Risk of bias graph
Figure 3 Risk of bias summary
Total scores of symptoms. In the trials that compared
the herbal medicines to drugs, six studies reported
symptom scores. One of those was “total score of
symptoms”, and the other three were “FSSG score”
[29, 36, 38, 40]. One trial used GERD questionnaire,
and another study used “mean global score” [30, 35].
A random-effect model (P < 0.001, I2
= 95%) and
SMD were performed. Therefore, there was no
statistically significant difference in the improvement
of total score between the experimental and control
groups (SMD = −0.99, 95% CI = −1.99 to 0.00; P =
0.05) (Figure 4).
Acid regurgitation. Two studies evaluated the
improvement of acid regurgitation [30, 40]. Di Pierro
et al. showed a statistically significant difference
between Mirgeal + pantaprazole and drug
(pantaprazole + alginic acid; P = 0.001) [30]. However,

8. REVIEW doi: 10.12032/TMR20200929200
Submit a manuscript: https://www.tmrjournals.com/tmr TMR | November 2020 | vol. 5 | no. 6 | 471
no significant difference was observed between groups.
Therefore, there was no statistically significant
difference between the experimental and control
groups in the improvement of acid regurgitation (MD
= −1.02; 95% CI = −3.32 to 1.29; P = 0.39).
In the herbal medicine versus placebo group, two
studies that evaluated the improvement of acid
regurgitation using hawthorn and Myrtus communis
showed significant (P = 0.02) and insignificant (P =
0.26) difference, respectively [32, 34]. Because the
data were dichotomous, the odds ratio was calculated.
The reduction of regurgitation score showed a
statistically significant difference between the
experimental and control groups (odds ratio = 0.22;
95% CI = 0.07 to 0.70; P = 0.01).
In the herbal medicine versus placebo group with
continuous data, three studies evaluated the
improvement of acid regurgitation using Amla, RKT,
and Satureja hortensis L. [31, 33, 39]. Due to
significant heterogeneity in the heartburn score (P <
0.001, I2
= 89%), a random-effect model was
performed. Therefore, there was no statistically
significant difference between the experimental and
control groups in the improvement of acid
regurgitation (MD = −0.37; 95% CI = −1.78 to 1.03; P
= 0.60) (Figure 5)
Heartburn (epigastric burning). Two studies
reported heartburn [30, 40]. Di Pierro et al. showed a
statistically significant difference between Mirgeal +
pantaprazole and drug (pantaprazole + alginic acid) on
the improvement of score (P = 0.0005) [30]. The
results prompted that there was no significant
difference between the Coriander Triphala and
omeprazole groups in the improvement of epigastric
burning (P = 0.58) [40].
In the herbal medicine versus placebo group, two
studies reported epigastric burning (Myrtus communis
and hawthorn) [30, 34]. Due to heterogeneity, a
random-effect model was used (P = 0.05, I2
= 74%).
No significant difference was observed between the
experimental and control groups in the improvement
of epigastric burning (odds ratio = 0.32; 95% CI =
0.05 to 2.03; P = 0.23).
In the herbal medicine versus placebo group with
continuous data, four studies reported epigastric
burning (Amla, RKT, and Satureja hortensis) [31, 33,
37, 39]. Due to significant heterogeneity in the
regurgitation and heartburn score (P < 0.001, I2
=
93%), a random-effect model was performed. There
was no statistically significant difference between the
experimental and placebo groups in the improvement
of epigastric burning (MD = −0.57; 95% CI = −2.15 to
1.01; P = 0. 48).
Abdominal (epigastric, chest) pain. For the
abdominal (epigastric, chest) pain, two trials were
included [3, 33]. Both trials used RPZ + RKT as
intervention, and RPZ + placebo was used as control.
Because there was no significant heterogeneity (P =
0.77, I2
= 0%), a fixed-effect model was applied.
Therefore, there was no statistically significant
difference between the experimental and control
groups in the improvement of abdominal (epigastric,
chest) pain (MD = −0.11; 95% CI = −0.35 to 0.13; P =
0.35). Di Pierro et al. showed a statistically significant
Figure 4 Forest plot of comparison: effect of herbal therapy versus drugs on total scores. CI, confidence
interval; SD, standard deviation.
Figure 5 Forest plot of comparison: effect of herbal therapy versus placebo on acid regurgitation. CI,
confidence interval; SD, standard deviation.

9. REVIEW
doi: 10.12032/TMR20200929200
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TMR | November 2020 | vol. 5 | no. 6 | 472
difference between Mirgeal + pantaprazole and drug
(pantaprazole + alginic acid) in the improvement of
abdominal pain score (P = 0.00001) [30].
Effective rate. In the herbal medicine versus placebo
group for effective rate, four trials were included [31,
33, 37, 39]. Amla, pantaprazole + RKT, pantaprazole +
RKT, and Satureja hortensis L. were used as
intervention, and placebo, pantaprazole + placebo,
pantaprazole + placebo, and placebo were used as
control, respectively. Due to significant heterogeneity
(P < 0.001, I2
= 89%), a random-effect model was
applied. Therefore, there was no statistically
significant difference between the experimental and
control groups in effective rate (MD = −0.37; 95% CI
= −1.78 to 1.03; P = 0.60) (Supplementary Figure 1).
In the herbal medicine versus classic drugs group
for effective rate, six trials were included [29, 30, 35,
36, 38, 40]. Due to significant heterogeneity (P =
0.0006, I2
= 77%), a random-effect model was applied.
Therefore, there was no statistically significant
difference between the experimental and control
groups in the improvement of effective rate (MD =
0.18; 95% CI = 0.19 to −0.24 to 0.59; P = 0.40)
(Supplementary Figure 2).
Reflux syndrome. For reflux syndrome, three trials
were included [33, 37, 39]. In the three trials,
pantaprazole + RKT, pantaprazole + RKT, and
Satureja hortensis L. were used as intervention, and
pantaprazole + placebo, pantaprazole + placebo, and
placebo were used as control, respectively. Because
there was no significant heterogeneity (P = 0.21, I2
=
36%), a fixed-effect model was applied. Therefore,
there was no statistically significant difference
between the experimental and control groups in the
improvement of reflux syndrome (MD = 0.44; 95% CI
= −0.12 to 1.00; P = 0.12) (Supplementary Figure 3).
In the herbal medicine versus classic drugs group
for reflux syndrome, six trials were included [29, 30,
35, 36, 38, 40]. Tongjiang granule (TJG), Mirgeal,
Wuchuyu soup, RKT + RPZ 20 mg, and Myrtus
communis L., Coriander Triphala were used for the
experimental group, and mosapride citrate, alginic acid,
omeprazole, RKT + RPZ 10 mg, omeprazole, and
omeprazole were used as control, respectively. Due to
significant heterogeneity (P < 0.001, I2
= 94%), a
random-effect model was applied. Therefore, there
was no statistically significant difference between the
experimental and control groups in the improvement
of reflux syndrome (MD = 0.27; 95% CI = −2.50 to
3.03; P = 0.85) (Supplementary Figure 4).
Secondary outcome
Adverse events. Of all included RCTs, seven studies
reported adverse reactions during the treatment period
[29, 31, 32, 34, 35, 37, 40]. Overall, two trials
mentioned no adverse events [28, 30]. In four articles,
there were no discussions about adverse effects [33, 36,
38, 39]. The adverse effects are presented in
Supplementary Table 1.
Discussion
Possible explanation of the findings
PPIs and histamine 2 receptor blockers are used in
treating GERD [36]. However, the daily use of a
standard dose of PPIs has not been able to clinically
eliminate GERD symptoms in 20% to 30% of patients
[4, 37]. Furthermore, many patients should receive
these medications in the long term or even lifetime,
which causes side effects such as Clostridium difficile
infections, kidney problems, hip fractures, and
respiratory infections, and the symptoms easily relapse
after stopping PPIs [41–47]. As conventional
treatments often remain unsatisfactory, a growing
interest has been developed in herbal medicine, and up
to 50% of patients seek other therapies, such as
complementary and alternative medicine [48–50].
Of the 13 included RCTs, the efficacy of herbal
medicine in treating GERD symptoms was compared
to PPIs in 6 trials [30, 34–36, 38, 40]. In all 6 RCTs,
herbal medicines were at least as effective as or even
superior to PPIs.
In the placebo group, Sakata et al. reported that the
degree of improvement of total and acid reflux disease
scores of FSSG after 8-week treatment was
significantly greater in the RKT group (RPZ 10 mg/q.d.
+ RKT 7.5 g/t.i.d.) than in the placebo (RPZ + placebo)
group [33].
Various herbal medicines can play an important role
in Helicobacter pylori eradication. Only one trial
discussed Helicobacter pylori [33]. In this review, two
herbal medicines, Myrtus communis L. (Mirgeal) and
hawthorn, were significantly effective in the
amelioration of some GERD symptoms [30, 32].
Mirgeal was effective in the improvement of
abdominal pain. Myrtus communis L. and hawthorn
were effective in the improvement of acid
regurgitation.
Coriander Triphala is composed of the fruits of
three herbal plant trees: Phyllanthus emblica L.
(Amla), Terminalia belerica Retz., and Terminalia
chebula Retz. [51]. Triphala possesses
anti-inflammatory, antimicrobial, antiulcer, antiviral,
and antibacterial properties [52–55]. Although
Triphala has a long history in many different
therapeutic applications in Persian traditional medicine
(PTM) and Ayurvedic medicine, such as the treatment
for digestive disorders, its combination with coriander
(as Coriander Triphala) is unique to PTM. Sadeghi et
al. observed 80% and 83.33% improvement in reflux
symptom and FSSG scores, respectively, in patients
who received Coriander Triphala as an intervention
[40]. Patients in this group showed a significant
decrease in heartburn and acid in the throat after
treatment with Coriander Triphala.
In one study, the effectiveness of Satureja hortensis

10. REVIEW doi: 10.12032/TMR20200929200
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as an anti-inflammatory factor, as well as an antifungal,
pain-relieving, carminative, antibacterial,
anti-diarrheal, antiviral, and antioxidant medication,
has been shown [39].
RKT, which has prokinetic properties, has been
shown to improve gastric fundus relaxation, which
increases gastric storage capacity. Also, it facilitates
the emptying of the stomach [33]. It acts through
nitrergic and serotonergic pathways. In the
hypothalamic-pituitary-adrenal axis, RKT suppresses
the secretion of adrenocorticotropic hormone, and
therefore cortisol plasma levels under stress conditions,
and reverses the increases of the neuropeptide Y
plasma level, a neurotransmitter in the brain and
autonomic nervous system [36, 37, 56]. Myrtus
communis L. (myrtle) has anti-Helicobacter pylori and
anti-inflammatory activities [38]. Myrtle acts as a
carminative, analgesic, astringent, and demulcent
agent; it possesses anti-inflammatory and antiseptic
properties. Based on PTM texts, myrtle reinforces the
stomach and improves the LES. Constipation
exacerbates reflux, and myrtle reduces constipation
[34].
The functions of TJG are inhibiting gastric acid, and
relieving pain. TJG can enhance the motilin plasma
level, decrease the gastric acid level, and improve
gastric emptying [29].
Glycyrrhiza glabra extract has anti-inflammatory,
cytoprotective, and antiulcer properties. Licorice
causes potassium loss and weight gain and increases
blood pressure. All its side effects are due to the
increase of sodium retention induced by glycyrrhetinic
acid. It prolongs the presence of prostaglandins E2 and
F2α on the gastric mucosa [30].
Flavonoids, procyanidins, anthocyanidins, and
phenolic acids are effective chemical compounds of
hawthorn fruit [32]. Moreover, the doses of the
medicines and the frequencies and methods of
administration were different among these trials.
Quality of the evidence
Single center, small sample size, short duration of
treatment and follow-up, attrition bias, missing data,
and various interventions are the limitations of this
review. Follow-up visits (2 weeks) have been reported
in only one trial [34]. The treatment courses in the 13
studies ranged from 4 to 8 weeks. Dropouts in three
trials were unexplained [30, 33, 38]. Missing data were
not evaluated by intention-to-treat analysis in seven
trials [30, 32, 33, 35, 36, 38, 39]. Furthermore, herbs
under consideration are not available in other
countries.
Conclusion
Herbal medicines have been used to manage different
diseases worldwide since ancient times. The results of
the clinical trials confirmed the effect of herbal
medicines for treating GERD symptoms. Evidence
from this review showed that herbal medicines in
simple and combined forms have a positive efficacy in
the treatment and relief of GERD symptoms.
Therefore, medicinal plants can be used as a large
source of medications independently or as an
additional agent in managing gastrointestinal diseases.
However, due to the poor methodological quality and
small sample size of the included studies, further
multicenter, large-scale, and large-sample-size
investigations should be done.
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13. 1
Supplementary Materials
Table 1 Summary of adverse events in 13 included RCTs
No First author & year Adverse events
1 Shuang 2011 [29] In the experimental group: cold (n = 1).
2 Tominaga 2012 [36] Unexplained.
3 Di Pierro 2013 [30] Adverse events (n = 0).
4 Tominaga 2014 [37]
Rikkunshito group: n = 19, placebo group: n = 11, nausea, mild cough,
dizziness, diarrhea.
5 Sakata 2014 [33] Unexplained.
6 Alecci 2016 [28] Adverse events (n = 0).
7 Moeini 2016 [32] In the experimental group: n = 2, nausea, exacerbation of bloating.
8 Salehi 2017 [34] Diarrhea grade 1 (n = 1).
9 Shih 2018 [35]
Right knocking pain, dysuria, vomiting, gastritis and gastroduodenitis,
urinary tract infection, occasional constipation, fatigue, periodic abdominal
pain, palpitation, increase of liver enzymes, worsening of acid reflux, fever
sensation, skin rash, paralytic ileus and intermittent epigastric pain.
10 Faghihi 2018 [39] Unexplained.
11 Karkon 2018 [31] Placebo group: worsening of heartburn (n = 1).
12 Zohalinezhad 2016 [38] Unexplained.
13 Sadeghi 2020 [40] Itching, abdominal pain (n = 1).
Figure1 Forest plot of comparison: effect of herbal therapy versus placebo on effective rate. CI, confidence
interval; SD, standard deviation.
Figure 2 Forest plot of comparison: effect of herbal therapy versus drugs on effective rate. CI, confidence
interval; SD, standard deviation.
Figure 3 Forest plot of comparison: effect of herbal therapy versus placebo on reflux syndrome. CI,
confidence interval; SD, standard deviation.

14. 2
Figure 4 Forest plot of comparison: effect of herbal therapy versus drugs on reflux syndrome. CI, confidence
interval; SD, standard deviation.