Medicinal Plants for Management of Gastroesophageal Reflux Disease: A Review of Animal and Human Studies

Abstract

Objectives:

Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disease that causes troublesome symptoms and/or complications. The major therapeutic strategy for GERD focuses mainly on symptom alleviation using proton pump inhibitors (PPIs), which does not produce a perfect response in all patients. An approach with new therapeutic agents for GERD seems to be essential. The aim of this study was to review animal and human studies investigating the effect of medicinal plants in GERD as well as mechanisms underlying their therapeutic effects.

Methods:

Medline, Scopus, and Cochrane Central Register of Controlled Trials were searched for animal or human studies. The data collected covered January 1966–October 2015.

Results:

A total of 22 studies were included in this review, of which nine were animal studies and 13 were human studies. Ceratonia siliqua as a medicinal plant and rikkunshito as a multicomponent herbal preparation were the most frequently studied herbal medicines in GERD. Antioxidant and anti-inflammatory activities were the main mechanisms demonstrated in animal studies for ameliorating the effects of medicinal plants in GERD. Other mechanisms include downregulation of genes encoding inflammatory proteins, improvement of barrier function and gastric mucus, a decrease in gastric acid, and induction of tonic contractions of the lower esophageal sphincter. All herbal preparations used in human studies have led to the alleviation of symptoms related to GERD. Myrtus communis and Cydonia oblonga showed marked reduction in GERD symptoms comparable to omeprazole. The therapeutic effect of Cydonia oblonga persisted after discontinuation of the drug. Tongjlang and rikkunshito showed therapeutic effects for non-erosive reflux disease (NERD) where PPIs failed to show a promising effect. Studies on Ceratonia siliqua have been solely focused on regurgitation in infants, and a remarkable decrease in the number of regurgitations was demonstrated.

Conclusion:

The multiple mechanisms of action of medicinal plants in GERD other than anti-secretory properties appear to provide more efficient treatment and helped to manage the histopathological changes associated with this disorder. Further studies are needed to understand the effects of medicinal plants on GERD better.

Introduction

Gastroesophageal reflux disease (GERD) develops when the stomach contents reflux into the esophagus, causing troublesome symptoms and/or complications.¹ It is a common disorder with a prevalence of 10–20% in the West, defined as heartburn and/or acid regurgitation occurring at least weekly. In Asia, the occurrence is lower (<5%).^2
–4 Although GERD occurs frequently in Western countries, recent epidemiological studies suggest that the incidence of the disease is increasing in Asian populations.^5
–7 GERD manifests as a range of symptoms, such as heartburn, acid regurgitation, chest pain, and organic manifestations, including esophagitis, esophageal stricture and ulceration, Barrett's esophagus, and esophageal adenocarcinoma.^7,8

The main pathophysiology of GERD is reflux of the gastric contents, including gastric acid, followed by esophageal mucosal injury or acid stimulation of the esophageal mucosa, even without injury.^9,10 In recent years, the accelerated pace of life, increasing work pressure, and changes in diet have increased the incidence of GERD,¹¹ and this has a considerable negative impact on patient quality of life.^12

–15

A major therapeutic strategy for GERD is inhibition of acid secretion by using proton pump inhibitors (PPIs).^16
–18 However, in clinical practice, troublesome GERD symptoms persist in 20–30% of patients, despite daily treatment with a standard PPI dose.¹⁹ Discovery of new pharmacological agents for GERD appears to be necessary. One invaluable source for the discovery of novel drugs is medicinal plants. The World Health Organization (WHO) reports that the use of herbal remedies worldwide exceeds that of conventional drugs by two- to threefold.^20,21

About 80% of people in developing countries continue to rely on traditional medicine based largely on species of plants for their primary healthcare. At present, about 25% of pharmaceutical prescriptions in the United States contain at least one plant-derived ingredient.²² Gastrointestinal disease, including inflammatory bowel disease, irritable bowel syndrome, and peptic ulcer, are among the disorders that are frequently treated using medicinal plants.^23
–25 The present study is a review of animal and human studies investigating the effect of medicinal plants used for the management of GERD and the mechanisms underlying their therapeutic effects.

Methods

Medline, Scopus, and the Cochrane Central Register of control trials were searched for all animal or human studies that examined the effect of any herbal preparation on GERD, as well as investigating their possible mechanisms in this disease. With regard to human studies, any uncontrolled or controlled study that investigated the effects of any herbal preparation alone or compared to placebo or conventional therapies in any outcomes related to GERD was included. Unpublished works, non-English articles, and studies investigating complementary medicines rather than herbal medicines were excluded. Data were collected for the period January 1966–October 2015. The search terms were “gastroesophageal reflux” in the title and abstract and “plant,” “extract,” or “herb” in the body of the text.

The results of the primary search were screened by two independent investigators. The references of the retrieved articles were also evaluated for relevant studies. The articles were reviewed to extract plant, scientific names, complete ingredients of the product (in combined preparations), the part and extract of the plants, active components (if mentioned), model for animal investigations, and type for human studies. The results were abstracted in Tables 1 and 2.

Table 1.

Animal Studies on Use of Herbal Medicines for Management of GERD

Scientific name	Part/extract	Active component	Model	Animal	Results	References
Artemisia asiatica	Extract	—	Duodenogastroesophageal reflux	Male Sprague-Dawley rats	↓ thickness of esophageal wall ↓ mean score of extent of mucosal ulceration ↓ mean inflammation score ↑ regeneration ↓ MDA ↑ GSH ↓ NF-kB-DNA binding ↓ COX-2 ↓ iNOS ↑ IkBa protein	37
Curcuma longa	Rhizome	Curcumin	Acute and chronic acid reflux esophagitis	Male Wistar-strain rats	Effect of curcumin on acute acid reflux esophagitis: • ↓ incidence of perforation • ↓ incidence or severity of esophageal ulcer • ↓ gastric acidity without affecting pepsin activity Effect of curcumin on chronic acid reflux esophagitis: • no reduction in mortality rate or severity of esophagitis Effect of curcumin on mixed reflux esophagitis: • no change in the incidence and the severity of papillomatosis formation on top of esophagus • ↓ incidence and severity of neutrophil infiltration into muscularis externa and adventitia No significant change in incidence of red blood cells in lamina propria and submucosal layers	39
Lonicera Japonica	Flower	—	Reflux esophagitis induced by pylorus and fore-stomach ligation	Female Sprague-Dawley rats	↓ esophageal lesion scores ↓ infiltration of inflammatory cells ↓ hemorrhage depth in stomach ↓ thicknesses of esophageal tissue ↑ mucosal thickness ↓ MDA ↑ GSH ↑ SOD ↑ catalase activity ↓ MPO ↓ level of collagen	40
Morus alba	Ethyl acetate fraction of Morus alba leaves	Flavonoids.	Acute reflux esophagitis	Sprague-Dawley rats of either sex	↑ gastric wall mucus level ↓ plasma histamine ↓ H+-K+-ATPase ↓ lipid peroxidation ↑ catalase ↑ GSH	41
Panax quinquefolium	Root	—	Acute reflux esophagitis	Female Sprague-Dawley rats	↓ severity of macroscopic signs of RE-induced tissue damage ↓ MDA ↑ GSH/GSSG ↓ MPO activity ↓ gene expression of CINC-2 and ICAM-1 No change in MCP-1 gene	42
Rikkunshito	Polyherbal formula containing: Pinellia ternate rhizome, Poria cocos sclerotia, Glycyrrhiza uralensis root, Panax ginseng root, Citrus reticulate peel, Atractylodes macrocephala rhizome, Polygala tenuifolia root, Zingiber officinale rhizome	—	Chronic acid reflux esophagitis	8-week-old male Wistar rats	No change in average total area of erosive lesions in esophageal mucosa ↓ dilation from stratum spinosum to stratum basale No effect on claudin-3 mRNA level ↓ levels of NP-40-soluble claudin-1, -3 and -4 protein ↑ level of NP-40- insoluble claudin-3 protein ↑ voluntary movement of rats	53
Rubus spp.	Fruit	—	Esophagoduodenal anastomosis model	Male Sprague-Dawley rats	No alteration in grade of esophagitis, induction of BE, cellular antioxidant enzymes (MnSOD, CAT, and GPX), levels of lipid peroxidation (MDA concentration) compared to control diet	43
Salvia miltiorrhiza	Ethanol extract of dried roots	—	Ex vivo	Male Sprague-Dawley rats	↑ tonic contraction of LES ↑ extracellular Ca²⁺ entry into smooth-muscle cells ↑ intracellular Ca²⁺ release	44
STW 5	Hydroethanolic extracts of nine herbs, including Iberis amara, Angelica archangelica root, Matricaria chamomilla flower, Mentha piperita leaves, Carum carvi fruits, Silybum marianum fruits, Melissa officinalis leaves, Chelidonium majus, and Glycyrrhiza glabra root	—	Acute reflux esophagitis	Adult male Wistar rats	No effect on esophageal pH ↓ area and depth of lesions ↓ perforations ↓ MPO ↓ TBARS ↓ TNF-α ↓ IL-1β Normalization of histopathological changes (extensive epithelial defects, leukocyte infiltrates in lamina propria, sub-mucosa, and edema)	45

GERD, gastroesophageal reflux disease; ↓, decrease; ↑, increase; MDA, Malondialdehyde; GSH, glutathione; SOD, superoxide dismutase; MPO, myeloperoxidase; GSSG, oxidized glutathione; MnSOD, manganese superodxide dismutase; GPX, gluatathione peroxidase; CAT, catalase; LES, lower esophageal sphincter; TBARS, thiobarbituric acid-reactive substance; TNF-α, tumor necrosis factor alpha; IL-1β, interleukin-1 beta; ICAM-1, intercellular adhesion molecule-1; CINC-2, cytokine-induced neutrophil chemoattractant-2; MCP-1, monocyte chemotactic protein-1.

Table 2.

Human Studies on Use of Herbal Medicines for Management of GERD

Scientific name	Part/extract	Patients	Study design	Intervention	Duration	Results	Jadad score	References
Acidinol syrup	Polyherbal formula containing: Glycyrrhiza glabra, Tinospora cordifolia, Trichosanthes dioica, Emblica offcinalis, Terminalia bellirica, Terminalia chebula, Fumeria indica, Adhatoda vasica, Azadirachta indica, Swertia chirata, Berberis aristata, Plumbago zeylanica, Holarrhena antidysenterica, Asparagus racemosus, Fagonia arabica	Adult patients with chronic heartburn	Prospective, observational, non-comparative, open-label, single-center study	1–2 tsp of syrup 3 to 4 times a day after meals	4 weeks	↓ heartburn ↓ abdominal pain ↓ bloating ↓ loss of appetite ↓ nausea due to heartburn ↓ dyspepsia	1	34
Ceratonia siliqua (carob bean)	Seed gum	Infants with regurgitation	Crossover trial design	Group A: cow's milk formula containing carob bean gum Group B: cow's milk formula	2–4 weeks	↓ symptoms of vomiting ↑ weight gain per week No change in gastric emptying times ↓ night coughing ↓ crying No change in symptoms of colic	1	31
		Infants with regurgitation	Double-blind prospective study	Group A: cow's milk formula containing carob bean gumGroup B: cow's milk formula	1 week	↓ number of regurgitation in both groups without significant difference↓ percentage of time that esophageal pH was <4.0 in gum groupno significant improvement in duration of longest reflux episode and in number of reflux episodes lasting >5 min; improvement in reflux index	3	30
		Infants with regurgitation or vomiting	Randomized controlled crossover clinical trial	Group A: infants fed with cow's milk formula containing carob bean gum (350 g/100 mL) for first week, and with control milk containing carob bean gum (0 g/100 mL) the following weekGroup B: infants fed with control milk containing carob bean gum (0 g/100 mL) for first week, and with cow's milk formula containing carob bean gum (350 g/100 mL) the following week	2 weeks	↓ regurgitation episodes with gum-containing formulaNo significant difference in feeding volume and time, body weight gain, and gastric emptying rate between two groups↑ number of bowel movements with gum-containing formula	2	36
		Babies 6–8 weeks old with clinical GERD pathology	Uncontrolled clinical trial	30 bottle-fed babies 6–8 weeks old with clinical GERD pathology. 24-hour esophageal monitoring done before and after study. Infants had to have been vomiting for >2 weeks, more than 6 times a day.	—	Improvement in symptoms (regurgitation and emesis)↓ number of reflux episodes in pH monitoring↑ duration of longest reflux episode in pH monitoring	0	35
		Infants with recurrent regurgitation	Randomized placebo-controlled crossover study	Group A: fed alternately (A-B-A-B-A-B) with thickened (A) and non-thickened (B) but otherwise identical formulaGroup B: fed with non-thickened formula	During six feeding intervals	↓ frequency of regurgitation↓ amount of regurgitationNo change in the mean GER duration and the frequency of acid (pH <4) GER	5	29
Cydonia oblonga (quince)	Syrup containing 600 mg of dried aqueous fruit extract/mL	Children with GERD	Double-blind randomized controlled parallel treatment clinical trial	Group A: quince syrup 0.3 mL/kg twice a day, after lunch and dinner, for 4 weeksGroup B: omeprazole syrup 1 mL/kg/day (each mL of liquid concentrate for oral administration contained 2 mg of omeprazole)	4 weeks	↓ symptoms (vomiting/regurgitation, refusal to eat/refusal to feed, difficulty swallowing/irritability or fussiness, choking when eating/hiccup episodes, burping or belching/choking or gaging, abdominal or belly pain/arching back, chest pain/heartburn, nausea) from baseline in each treatment group without statistically significant differences between groups	5	28
Myrtus communis	Freeze-dried aqueous extract of fruit	Adult aged 18–60 years.Patients with confirmed symptomatic GERD	Double-blind randomized controlled clinical trial	Group A: freeze-dried aqueous extract of fruit 1000 mg/dayGroup B: omeprazol capsules 20 mg/dayGroup C: freeze-dried aqueous extract of fruit 1000 mg/day + omeprazol capsules 20 mg/day	4 weeks	↓ reflux and dyspeptic scores in all groups without significant difference between groups	4	27
Olea europea	Oil	Adult patients with duodeno-gastro-oesophageal reflux	Case series	7 (5 men/2 women) postgastrectomy patients with severe symptomatic duodenogastroesophageal reflux who did not respond to conventional therapy: treated with a spoonful (15 mL) of olive oil 4 to 6 times per day after meals	6 months	3 patients were symptom free, and 4 patients showed a significant improvement in symptoms	—	32
Rikkunshito	Polyherbal formula containing: Glycyrrhiza uralensis root, Zingiber officinale rhizome, Atractylodes macrocephala rhizome, Ziziphus jujuba fruit, Citrus aurantium peel, Panax ginseng root, Pinellia ternate tuber, and Pachyma hoelen	Elderly patients with PPI-refractory NERD	Prospective, multicenter randomized parallel comparative study	Group A: rikkunshito (7.5 g/day) + rabeprazole (10 mg/day)Group B: rabeprazole 20 mg/day	4 weeks	↓ scale for symptoms of GERD	4	9
		Children with symptomatic GERD	Uncontrolled clinical trial	Rikkunshito (0.3 g/kg/day) orally or via nasogastric tubes in three divided doses before meals	1 week	↓ frequency of emesis, nausea, hematemesis, and stridor↓ percentage time of esophageal pH <4.0↓ esophageal acid clearance timeNo change in number of acid reflux per hour	1	33
		Adult patients with PPI-refractory NERD	Prospective multicenter randomized double-blind paralleled comparative study	Group A: rabeprazole (10 mg once daily) + rikkunshito (7.5 g/day 3 times) (rikkunshito group)Group B: RPZ (10 mg once daily) + placebo (7.5 g/day 3 times) (placebo group)	8 weeks	↓ scale for the symptoms of GERD↓ abdominal bloating↓ heavy feeling in stomach↓ sick feeling after meals↓ heartburn after meals↓ acid regurgitation↓ abdominal distension↓ constipation	4	19
Tongjlang granules	Polyherbal formula containing: Perilla frutesces, Cyperus rotundus rhizome, Sepia esculenta, and Glycyrrhiza uralensis root	Adult patients with NERD	Randomized controlled double-blind double-dummy method	Group A: Tongjlang granules (10 g)30–60 min after meals + dummy Mosapride citrate (5 mg) 15–20 min before meals, 3 times a dayGroup B: Mosapride citrate (5 mg)15–20 min before meals + dummy tongjlang granules (10 g) 30–60 min after meals 3 times a day	4 weeks	Total score of symptom and major symptoms after treatment were better than those before treatment in both groups. Improvement in total score of symptom and major symptoms in experiment group was better than that in the control groupMajor symptoms (retrosternal burning feeling of heartburn, chest pain, acid or bitter taste in mouth, and uncomfortable feeling of nausea)Minor symptoms (abdominal distension, acid reflux, belching, poor appetite, gastric upset, emotional irritability or depression, blocked sensation in throat, stomach pain or bloating, satiety);experiment group had more effective rates than control group;↑ quality of life	5	11

RE, reflux esophagitis; NERD, non-erosive reflux disease; PPI, proton pump inhibitor, ↓, decrease in; ↑, increase in.

The quality of animal studies was determined according to Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines,²⁶ and this is represented in Table 3.

Table 3.

Quality Assessment of Animal Studies According to ARRIVE Guidelines

	Validity	Ethical statement	Animals	Experimental procedures	Housing and husbandry	Numbers analyzed
Oh et al.³⁷	−	−	+	+	−	+
Mahattanadul et al.³⁹	−	+	+	+	+	+
Ku et al.⁴⁰	−	+	−	+	+	+
Gupta et al.⁴¹	−	+	+	+	+	−
Singh et al.⁴²	−	+	+	+	+	+
Miwa et al.⁵³	−	+	+	+	+	−
Aiyer et al.⁴³	−	−	+	+	+	+
Tsai et al.⁴⁴	−	+	+	+	−	−
Abdel-Aziz et al.⁴⁵	−	+	+	+	+	−

+, meet the mentioned criteria; −, doesn't meet the mentioned criteria; ARRIVE, Animal Research: Reporting of In Vivo Experiments.

In human studies, the study design, number of patients, intervention, duration of treatment, Jadad score, and the efficacy and tolerability of the herbal treatment were also recorded. The Jadad score rates the quality of the study based on its description of randomization, blinding, and dropouts (withdrawals), and was used to assess the methodological quality of trials. The quality scale ranged from 0 to 5 points. A score of ≤2 was considered low quality, and a score of ≥3 was considered high quality. The risk of bias for the human studies was determined according to Cochrane Collaboration's tool for assessing the risk of bias, and this is demonstrated in Table 4.

Table 4.

Risk Bias of Human Studies on GERD Determined According to Cochrane Collaboration's Tool for Assessing Risk of Bias

References	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data
Nautiyal et al.³⁴	+	+	+	+	?
Vivatvakin et al.³¹	?	?	?	?	−
Vandenplas et al.³⁰	?	?	−	?	−
Miyazawa et al.³⁶	−	?	+	+	−
Vandenplas et al.³⁵	+	+	+	+	?
Wenzl et al.²⁹	−	?	−	?	−
Zohalinezhad et al.²⁸	?	?	?	?	−
Zohalinezhad et al.²⁷	?	?	?	?	−
Karamanolis et al.³²	+	+	+	+	+
Tominagaet al.⁹	?	−	?	?	−
Kawahara et al.³³	+	+	+	+	−
Sakata et al.¹⁹	?	?	?	?	−
Li et al.¹¹	?	?	−	−	−

+, sign of bias; −, no sign of bias; ?, judgment unclear.

Findings and Results

The electronic search yielded 639 items (Fig. 1): 70 from Medline, 567 from Scopus, and two from Cochrane Central Register of control trials. Of these, 23 reports were excluded because they duplicated findings, 39 because they were opinions, and 473 on the basis of title and abstract. A total of 104 papers were retrieved, and 82 were excluded. Of these, 19 were excluded because they studied non-herbal drugs in combination with plants or other types of complementary medicine, 53 because they were about GERD but were non-interventional, one because it was not in English, and nine because the treatment exacerbated GERD. Of the 22 studies included in this review, nine were animal-based and the rest were human studies. Most animal studies met all criteria for quality assessment according to ARRIVE guidelines, except for validity (Table 3). From 13 human studies, seven obtained Jadad scores of ≥3^{9,11,19,27–30} and six obtained a Jadad score of <3^31–36 (Table 2). In human studies, the most risk of bias was observed for uncontrolled studies (Table 4).

Fig. 1.

Flow diagram of study design.

Animal studies

Artemisia asiatica

Pretreatment with extract of Artemisia asiatica (DA-9601) decreased the overall thickness of the esophageal wall and extent of ulceration over the ranitidine group. Ranitidine failed to decrease the severity of reflux esophagitis (RE). Only DA-9601 pretreatment showed a statistically significant decrease in mean score for extent of mucosal ulceration and mucosal inflammation. The mean inflammation score of the DA-9601-treated groups was significantly lower than those of the ranitidine-pretreated group. Esophageal mucosa showed excellent regeneration in the DA-9601 pretreatment groups, whereas no or scant evidence of regeneration was observed using ranitidine.³⁷ The possible mechanisms of action of DA-9601 in attenuating RE are antioxidant and decrease in inflammatory factors, including NF-kB and COX-2, as well as a decrease in iNOS expression.^37,38 Ranitidine did not affect oxidative stress in the esophageal mucosa.³⁷

Curcuma longa

Curcumin is a compound isolated from the rhizome of Curcuma longa and plays a preventive role in the formation of acute acid RE. It was not effective in prevention of chronic acid RE. However, its combination with dimethyl sulfoxide as an antioxidant agent reduced the mortality rate and severity of the esophagitis ulcer index to approximately that of lansoprazole. Intraduodenal administration of curcumin also markedly prevented the formation of acute mixed RE and reduced neutrophil infiltration. By contrast, lansoprazole tended to increase the severity of all histopathological changes over the control and curcumin-treated groups. The antioxidant and anti-inflammatory activity of curcumin seemed to play a crucial role in its beneficial effects on GERD.³⁹

Lonicera japonica

Pretreatment of rats with Lonicera japonica flowers inhibited the induction of RE in rats and was probably mediated by antioxidant activity that was similar to alpha-tocopherol.⁴⁰

Morus alba

Treatment with Morus alba leaf extract in rats prior to induction of GERD increased the gastric wall mucus. The level of plasma histamine and H+-K+-ATPase decreased significantly. Morus alba extract demonstrated antioxidant activity by inhibition of lipid peroxidation and an increase in the level of antioxidant enzymes.⁴¹

Panax quinquefolium

Pretreatment of rats with Panax quinquefolium significantly attenuated the severity of RE-induced tissue damage and caused a dose-dependent reduction in lipid peroxidation and increase in antioxidant status. By contrast, omeprazole, although effectively improving mucosal damage, failed to show antioxidant activity. Panax quinquefolium also significantly downregulated the genes encoding proteins that play a role in acute inflammation, including intercellular adhesion molecule 1 (ICAM-1) and cytokine-induced neutrophil chemoattractant 2 (CINC-2) expression. It showed no effect on monocyte chemotactic protein 1(MCP-1), a marker of chronic inflammation.⁴²

Rubus spp. (black raspberry)

Dietary supplementation of black raspberry did not alter the levels of cellular antioxidant or lipid peroxidation compared to the control diet in a short-term study of gastroesophageal reflux (GER) induction in an esophagoduodenal anastomosis animal model. Moreover, it did not alter or ameliorate the grade of esophagitis or the induction of Barrett's esophagus.⁴³

Salvia miltiorrhiza

Salvia miltiorrhiza appears beneficial for the management of GERD by inducing tonic contraction of the lower esophageal sphincter (LES) of rats. The extracellular Ca (2+) influx pathway was revealed to be an underlying mechanism of this contractile effect.⁴⁴

STW 5

STW 5 (Iberogast) is a multicomponent herbal medicine composed of hydroethanolic extracts of nine herbs and is prepared for functional gastrointestinal disorders, including GERD and irritable bowel syndrome.^24,45 STW 5 did not affect esophageal pH in an acute model of RE in rats, but dose dependently reduced the severity of esophageal lesions and normalized the deranged level of proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β).⁴⁶ It normalized changes in the level of oxidative stress markers for myeloperoxidase (MPO) and thiobarbituric acid-reactive substances (TBARS) ⁴⁵. It was also shown to improve gastric accommodation,^46,47 reduce visceral hypersensitivity,^48,49 and increase the tonic contractions of the LES,⁵⁰ all of which are factors that play an important role in the pathogenesis of GERD.⁵¹

Human studies

Acidinol syrup

Administration of acidinol syrup, a polyherbal formulation, for 4 weeks to patients with chronic complaints of heartburn or acid regurgitation resulted in relief from the symptoms of general heartburn, abdominal pain, bloating, loss of appetite, nausea caused by heartburn, and dyspepsia in a significant percentage of patients. The ingredients are reported to act as PPIs and reduce gastric secretion in the stomach.³⁴

Ceratonia siliqua

The gum obtained from the seeds of Ceratonia siliqua is commonly known as locust bean or carob bean gum. Results of human trials showed that infant milk containing carob bean gum ameliorated the clinical symptoms of regurgitating infants, such as vomiting and weight loss, and significantly decreased the percentage of time with an esophageal pH of <4.0, but did not significantly alter gastric emptying time.^30,31

Another clinical trial revealed a significant effect for carob bean gum combined with milk on a decrease in the frequency³⁶ and amount of regurgitation by decreasing the number of nonacid (pH >4) GER episodes and the mean reflux height reached in the esophagus, but the frequency of acid GER did not decrease.²⁹ Another clinical trial demonstrated that milk containing carob bean gum may be clinically effective for infant GERD, it but can lead to occult episodes of GER of long duration, possibly increasing the risk for esophagitis or respiratory dysfunction.³⁵

Cydonia oblonga (quince)

Administration of a syrup derived from the fruit of Cydonia oblonga to children with GERD resulted in a significant decrease in symptoms compared with before treatment. However, compared to the control group, the decrease was not significant. Despite the use of omeprazole, quince syrup remained effective for 2 weeks after its discontinuation.²⁸

Myrtus communis

In a randomized controlled trial, administration of aqueous extract of Myrtus communis fruit significantly decreased reflux and dyspeptic scores.²⁷ The protective effect of different fruit extracts were shown for gastric ulcers in rats. Moreover, the extracts reduced gastric juice volume and total acidity.⁵²

Olea europea

Administration of olive oil for 2–6 months to postgastrectomy patients with severe symptomatic duodenogastroesophageal reflux who did not respond to conventional therapies resulted in the patients being symptom free or caused a significant improvement in symptoms.³²

Rikkunshito

Administration of rikkunshito, a traditional Japanese multiherbal medicine, combined with rabeprazole, to patients with GERD for 4 weeks significantly decreased the frequency of GERD symptoms.⁹ Similar intervention in elderly PPI-refractory NERD patients with acid-related dysmotility symptoms caused significant improvement in GERD symptoms, particularly abdominal bloating, feeling of heaviness in the stomach, and feeling ill after meals.¹⁹ The effects of rikkunshito have been also evaluated for children with GERD. The frequency of GERD symptoms decreased in these patients after 7 days of administration. Furthermore, the percentage time for which esophageal pH <4.0 was recorded and the mean duration of reflux decreased markedly. The number of acid reflux episodes per hour did not change significantly.³³

Possible mechanisms of the action for rikkunshito have been investigated in RE models in rats, and these indicate that rikkunshito did not reduce the average total area of erosive lesions in the esophageal mucosa. Rikkunshito significantly suppressed intercellular space dilation and significantly increased the level of NP-40-insoluble claudin 3, but had no affect at the mRNA level, suggesting that it promotes tight junction formation by facilitating translocation of proteins.⁵³ Moreover, rikkunshito ameliorated the symptoms of RE by improving the barrier function of esophageal mucosa⁵³ and gastric emptying.¹⁹

Tongjlang granules

Administration of a multiherbal Chinese medicine, tongjlang granules, to patients with NERD for 4 weeks improved symptoms and their quality of life. No adverse event was found during the study.¹¹

Discussion

This study reviewed in vitro animal and clinical studies focusing on medicinal plants for the management of GERD. All the studies are summarized in Tables 1 and 2. The most frequently studied simple and compound herbal medicines were Ceratonia siliqua and rikkunshito, respectively. All herbal preparations used in human studies have led to the alleviation of symptoms related to GERD. In two human studies, one on Myrtus communis ²⁷ and another on Cydonia oblonga,²⁸ the effect of herbal preparation was compared to a conventional drug, omeprazole. Both of these studies showed marked reduction in GERD symptoms comparable to that of omeprazole. However, in one of these studies investigating the effect of Cydonia oblonga,²⁸ the relapse rate in the Cydonia oblonga group was significantly lower than omeprazole 2 weeks after drug discontinuation.

Two human studies, one on tongjlang granules¹¹ and another on rikkunshito,^9,19 have examined the effect of herbal preparations on PPI-refractory NERD. Both of the mentioned preparations could alleviate symptoms of GERD in comparison to placebo and even PPI.

Studies on one of the medicinal plants, Ceratonia siliqua, have been solely focused on infant regurgitation, and its bean gum has been administered as an additive to cow's milk. All of these studies showed a remarkable decrease in regurgitation. Only in one study was the decrease in regurgitation not significant. However, a marked reduction was shown in the reflux index.

The major underlying mechanisms for the effect of medicinal plants on GERD are antioxidant and anti-inflammatory activity. The medicinal plants and herbal preparations that act by these mechanisms are Artemisia asiatica, Curcuma longa, Panax quinquefolium, Lonicera japonica, and STW 5. Other mechanisms include downregulation of the genes encoding proteins that play role in acute inflammation, including ICAM-1 and CINC-2 (Panax quinquefolium), improving the barrier function and gastric mucus (Morus alba, rikkunshito, Curcuma longa, STW 5), decreasing gastric acid (Curcuma longa, Morus alba, acidinol syrup, tongjlang granules), increasing of tonic contractions of the LES (Salvia miltiorrhiza, STW 5), and inhibiting the proinflammatory cytokines TNF-α and IL-1 β (STW 5).

The pathophysiology of GERD is multifactorial.⁵⁴ Oxidative stress, inflammation, and acid secretion are pathophysiologic factors that contribute to GERD.^37,41,55,56 Anti-secretory treatment alone has not been effective in attenuating inflammation or the degree of RE and thus does not promote complete healing.^37,57 For example, omeprazole is an anti-secretory drug that improves mucosal damage. However, it failed to attenuate RE-associated changes in oxidative stress and inflammatory parameters significantly.⁴² Most medicinal plants investigated for GERD show anti-inflammatory and antioxidant activity rather than anti-secretory properties. One advantage of medicinal plants over conventional anti-secretory agents is their promising effect on NERD, an area for which PPIs do not show potential effect. Moreover, medicinal plants appear to have a longer-lasting therapeutic effect than conventional anti-secretory agents have. For example, Cydonia oblonga was still effective 2 weeks after discontinuation.

Some studies reported a meta-analysis of the efficacy of Chinese herbal compounds on GERD. A Chinese compound called vendan that contains Pinellia ternate rhizomes, Zingiber officinale rhizomes, fruit exocarp of Citrus grandis, Citrus aurantium flowers, Phyllostachys nigra stems, and Glycyrrhiza uralensis root was effective for bile reflux gastritis and GERD. It alleviated symptoms significantly, and the relapse rate was markedly lower than that of conventional therapies.⁵⁸ A meta-analysis on a compound medicine called si-ni-san (SNS) that combines Bupleurum falcatum root, Paeonia lactiflora root, Citrus aurantium flowers, and Glycyrrhiza uralensis root showed that it had a better effect on duodenogastric reflux and GERD than conventional therapies.⁵⁹

One limitation of this review was the insufficient number of studies on the effect on reflux of each plant investigated. The number of human studies was few, and their sample sizes were low. It is suggested to conduct further clinical studies with larger sample sizes on the efficacy and safety of medicinal plants for GERD. Symptom alleviation was investigated in most studies, but the underlying mechanisms were not considered. Thus, it would be beneficial to design studies to investigate the mechanisms of action of medicinal plants for GERD.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

References

Vakil

, van Zanten

, Kahrilas

, et al. The Montreal definition and classification of gastroesophageal reflux disease: A global evidence-based consensus. Am J Gastroenterol, 2006; 101:1900–1920.

Wang

J-H

, Luo

J-Y

, Dong

, et al. Epidemiology of gastroesophageal reflux disease: A general population-based study in Xi'an of Northwest China. World J Gastroenterol, 2004; 10:1647–1651.

El-Serag

, Sweet

, Winchester

, et al. Update on the epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut, 2014; 63:871–880.

Dent

, El-Serag

, Wallander

, et al. Epidemiology of gastro-oesophageal reflux disease: A systematic review. Gut, 2005; 54:710–717.

Watanabe

, Urita

, Sugimoto

, et al. Gastroesophageal reflux disease symptoms are more common in general practice in Japan. World J Gastroenterol, 2007; 13:4219–4223.

Jung

H-K

. Epidemiology of gastroesophageal reflux disease in Asia: A systematic review. J Neurogastroenterol Motil, 2011; 17:14–27.

Malfertheiner

, Hallerbäck

. Clinical manifestations and complications of gastroesophageal reflux disease (GERD). Int J Clin Pract, 2005; 59:346–355.

Katz

, Gerson

, Vela

. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol, 2013; 108:308–328.

Tominaga

, Iwakiri

, Fujimoto

, et al. Rikkunshito improves symptoms in PPI-refractory GERD patients: A prospective, randomized, multicenter trial in Japan. J Gastroenterol, 2012; 47:284–292.

10.

Nahata

, Muto

, Oridate

, et al. Impaired ghrelin signaling is associated with gastrointestinal dysmotility in rats with gastroesophageal reflux disease. Am J Physiol Gastrointest Liver Physiol, 2012; 303:G42–53.

11.

, Li

, Tang

, et al. A randomized, controlled, double-blinded and double-dummy trial of the effect of tongjiang granule on the nonerosive reflux disease of and Gan-Wei incoordination syndrome. Chin J Integr Med, 2011; 17:339–345.

12.

Yang

, Jiang

, Hou

, Song

. Anxiety and depression in patients with gastroesophageal reflux disease and their effect on quality of life. World J Gastroenterol, 2015; 21:4302–4309.

13.

Revicki

, Wood

, Maton

, et al. The impact of gastroesophageal reflux disease on health-related quality of life. Am J Med, 1998; 104:252–258.

14.

Talley

, Fullerton

, Junghard

, et al. Quality of life in patients with endoscopy-negative heartburn: Reliability and sensitivity of disease-specific instruments. Am J Gastroenterol, 2001; 96:1998–2004.

15.

Coron

, Hatlebakk

, Galmiche

. Medical therapy of gastroesophageal reflux disease. Curr Opin Gastroenterol, 2007; 23:434–439.

16.

Forgacs

, Loganayagam

. Overprescribing proton pump inhibitors. BMJ, 2008; 336:2–3.

17.

. Proton pump inhibitors: Uncommon adverse effects. Aust Fam Physician, 2011; 40:705.

18.

Fock

, Poh

. Gastroesophageal reflux disease. J Gastroenterol, 2010; 45:808–815.

19.

Sakata

, Tominaga

, Kato

, et al. Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito. BMC Gastroenterol, 2014; 14:116.

20.

Pal

, Shukla

. Herbal medicine: Current status and the future. Asian Pac J Cancer Prev, 2003; 4:281–288.

21.

Thavorn

, Mamdani

, Straus

. Efficacy of turmeric in the treatment of digestive disorders: A systematic review and meta-analysis protocol. Syst Rev, 2014; 3:71.

22.

Verma

, Singh

. Current and future status of herbal medicines. Vet World, 2008; 1:347–350.

23.

Farzaei

, Shams-Ardekani

, Abbasabadi

, et al. Scientific evaluation of edible fruits and spices used for the treatment of peptic ulcer in traditional Iranian medicine. ISRN Gastroenterol, 2013; 2013:136932.

24.

Rahimi

, Abdollahi

. Herbal medicines for the management of irritable bowel syndrome: A comprehensive review. World J Gastroenterol, 2012; 18:589–600.

25.

Farzaei

, Rahimi

, Abdollahi

. The role of dietary polyphenols in the management of inflammatory bowel disease. Curr Pharm Biotechnol, 2015; 16:196–210.

26.

McGrath

, Lilley

. Implementing guidelines on reporting research using animals (ARRIVE etc.): New requirements for publication in BJP. Br J Pharmacol, 2015; 172:3189–3193.

27.

Zohalinezhad

, Hosseini-Asl

, Akrami

, et al. Myrtus communis L. Freeze-dried aqueous extract versus omeprazol in gastrointestinal reflux disease: A double-blind randomized controlled clinical trial. J Evid Based Complementary Altern Med, 2016; 21:23–29.

28.

Zohalinezhad

, Imanieh

, Samani

, et al. Effects of Quince syrup on clinical symptoms of children with symptomatic gastroesophageal reflux disease: A double-blind randomized controlled clinical trial. Complement Ther Clin Pract, 2015; 21:268–276.

29.

Wenzl

, Schneider

, Scheele

, et al. Effects of thickened feeding on gastroesophageal reflux in infants: A placebo-controlled crossover study using intraluminal impedance. Pediatrics, 2003; 111:e355–e359.

30.

Vandenplas

, Hachimi-Idrissi

, Casteels

, et al. A clinical trial with an “anti-regurgitation” formula. Eur J Pediatr, 1994; 153:419–423.

31.

Vivatvakin

, Buachum

. Effect of carob bean on gastric emptying time in Thai infants. Asia Pac J Clin Nutr, 2003; 12:193–197.

32.

Karamanolis

, Polymeros

, Triantafyllou

, et al. Olive oil for symptomatic relief of duodeno-gastro-oesophageal reflux after gastrectomy. Eur J Gastroenterol Hepatol, 2006; 18:1239.

33.

Kawahara

, Kubota

, Hasegawa

, et al. Effects of rikkunshito on the clinical symptoms and esophageal acid exposure in children with symptomatic gastroesophageal reflux. Pediatr Surg Int, 2007; 23:1001–1005.

34.

Nautiyal

, Maniar

. Efficacy study of ACIDINOL syrup in patients with acid peptic disorders. Asian J Pharm Clin Res, 2013; 6:274–276.

35.

Vandenplas

, Sacre

. Milk-thickening agents as a treatment for gastroesophageal reflux. Clin Pediatr, 1987; 26:66–68.

36.

Miyazawa

, Tomomasa

, Kaneko

, et al. Effect of formula thickened with reduced concentration of locust bean gum on gastroesophageal reflux. Acta Paediatr, 2007; 96:910–914.

37.

, Lee

, Ahn

, et al. Oxidative damages are critical in pathogenesis of reflux esophagitis: Implication of antioxidants in its treatment. Free Radic Biol Med, 2001; 30:905–915.

38.

Seol

, Kim

, Ryu

, et al. DA-9601 for erosive gastritis: Results of a double-blind placebo-controlled phase III clinical trial. World J Gastroenterol, 2004; 10:2379–2382.

39.

Mahattanadul

, Radenahmad

, Phadoongsombut

, et al. Effects of curcumin on reflux esophagitis in rats. J Nat Med, 2006; 60:198–205.

40.

S-K

, Seo

B-I

, Park

J-H

, et al. Effect of Lonicerae Flos extracts on reflux esophagitis with antioxidant activity. World J Gastroenterol, 2009; 15:4799–4805.

41.

Gupta

, Rajesh Kumar

, Sharma

, et al. Effects of flavonoids from Morus Alba leaves extract on experimentally induced gastroesophageal reflux disease (GERD) in rats. Res J Pharm Biol Chem Sci, 2014; 5:1021–1030.

42.

Singh

, Singh

, Sengupta

, et al. Ameliorative effects of Panax quinquefolium on experimentally induced reflux oesophagitis in rats. Indian J Med Res, 2012; 135:407–413.

43.

Aiyer

, Li

, Liu

, et al. Dietary freeze-dried black raspberry's effect on cellular antioxidant status during reflux-induced esophagitis in rats. Nutrition, 2011; 27:182–187.

44.

Tsai

, Chang

, Huang

, et al. Salvia miltiorrhiza induces tonic contraction of the lower esophageal sphincter in rats via activation of extracellular Ca2+ influx. Molecules, 2015; 20:14504–14521.

45.

Abdel-Aziz

, Zaki

, Neuhuber

, et al. Effect of an herbal preparation, STW 5, in an acute model of reflux oesophagitis in rats. J Pharmacol Sci, 2010; 113:134–142.

46.

Pilichiewicz

, Horowitz

, Russo

, et al. Effects of Iberogast^® on proximal gastric volume, antropyloroduodenal motility and gastric emptying in healthy men. Am J Gastroenterol, 2007; 102:1276–1283.

47.

Hohenester

, Rühl

, Kelber

, et al. The herbal preparation STW5 (lberogast^®) has potent and region‐specific effects on gastric motility. Neurogastroenterol Motil, 2004; 16:765–773.

48.

Müller

, Liu

C-Y

, Glatzle

, et al. STW 5 (Iberogast^®) reduces afferent sensitivity in the rat small intestine. Phytomedicine, 2006; 13:100–106.

49.

Liu

, Müller

, Glatzle

, et al. The herbal preparation STW 5 (Iberogast^®) desensitizes intestinal afferents in the rat small intestine1. Neurogastroenterol Motil, 2004; 16:759–764.

50.

Schemann

, Krüger

, Gruber

, et al. Action profile of the phytomedicine STW 5 suggests novel indications. Neurogastroenterol Motil, 2008; 20:95.

51.

Kahrilas

. GERD pathogenesis, pathophysiology, and clinical manifestations. Cleve Clin J Med, 2003; 70:S4.

52.

Sumbul

, Ahmad

, Asif

, et al. Evaluation of Myrtus communis Linn. berries (common myrtle) in experimental ulcer models in rats. Hum Exp Toxicol, 2010; 29:935–944.

53.

Miwa

, Koseki

, Oshima

, et al. Rikkunshito, a traditional Japanese medicine, may relieve abdominal symptoms in rats with experimental esophagitis by improving the barrier function of epithelial cells in esophageal mucosa. J Gastroenterol, 2010; 45:478–487.

54.

Herbella

, Patti

. Gastroesophageal reflux disease: From pathophysiology to treatment. World J Gastroenterol, 2010; 16(30):3745–3749.

55.

, Lee

, Ahn

, et al. Oxidative stress is more important than acid in the pathogenesis of reflux oesophagitis in rats. Gut, 2001; 49:364–371.

56.

Yoshida

. Inflammation and oxidative stress in gastroesophageal reflux disease. J Clin Biochem Nutr, 2007; 40:13.

57.

Farré

. Pathophysiology of gastro-esophageal reflux disease: A role for mucosa integrity?. Neurogastroenterol Motil, 2013; 25:783–799.

58.

Ling

, Huang

, Xu

, et al. Consistent efficacy of wendan decoction for the treatment of digestive reflux disorders. Am J Chin Med, 2015; 43:893–913.

59.

Ling

, Li

, Jiang

, et al. Common mechanism of pathogenesis in gastrointestinal diseases implied by consistent efficacy of single Chinese medicine formula. Medicine (Baltimore), 2015; 94:e1111.