Non‐Chinese herbal medicines for functional dyspepsia

Germán Báez; Camila Vargas; Marcelo Arancibia; Cristian Papuzinski; Juan VA Franco

doi:10.1002/14651858.CD013323.pub2

. 2023 Jun 15;2023(6):CD013323. doi: 10.1002/14651858.CD013323.pub2

Non‐Chinese herbal medicines for functional dyspepsia

Germán Báez ¹, Camila Vargas ², Marcelo Arancibia ³, Cristian Papuzinski ^4,⁵, Juan VA Franco ^6,^✉

Editor: Cochrane Gut Group

PMCID: PMC10267606 PMID: 37323050

Abstract

Background

One‐third of people with gastrointestinal disorders, including functional dyspepsia, use some form of complementary and alternative medicine, including herbal medicines.

Objectives

The primary objective is to assess the effects of non‐Chinese herbal medicines for the treatment of people with functional dyspepsia.

Search methods

We searched the following electronic databases on 22 December 2022: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Allied and Complementary Medicine Database, Latin American and Caribbean Health Sciences Literature, among other sources, without placing language restrictions.

Selection criteria

We included RCTs comparing non‐Chinese herbal medicines versus placebo or other treatments in people with functional dyspepsia.

Data collection and analysis

Two review authors independently screened references, extracted data and assessed the risk of bias from trial reports. We used a random‐effects model to calculate risk ratios (RRs) and mean differences (MDs). We created effect direction plots when meta‐analysis was not possible, following the reporting guideline for Synthesis without Meta‐analysis (SWiM). We used GRADE to assess the certainty of the evidence (CoE) for all outcomes.

Main results

We included 41 trials with 4477 participants that assessed 27 herbal medicines. This review evaluated global symptoms of functional dyspepsia, adverse events and quality of life; however, some studies did not report these outcomes.

STW5 (Iberogast) may moderately improve global symptoms of dyspepsia compared with placebo at 28 to 56 days; however, the evidence is very uncertain (MD ‐2.64, 95% CI ‐4.39 to ‐0.90; I² = 87%; 5 studies, 814 participants; very low CoE). STW5 may also increase the improvement rate compared to placebo at four to eight weeks' follow‐up (RR 1.55, 95% CI 0.98 to 2.47; 2 studies, 324 participants; low CoE). There was little to no difference in adverse events for STW5 compared to placebo (RR 0.92, 95% CI 0.52 to 1.64; I² = 0%; 4 studies, 786 participants; low CoE). STW5 may cause little to no difference in quality of life compared to placebo (no numerical data available, low CoE).

Peppermint and caraway oil probably result in a large improvement in global symptoms of dyspepsia compared to placebo at four weeks (SMD ‐0.87, 95% CI ‐1.15 to ‐0.58; I² = 0%; 2 studies, 210 participants; moderate CoE) and increase the improvement rate of global symptoms of dyspepsia (RR 1.53, 95% CI 1.30 to 1.81; I² = 0%; 3 studies, 305 participants; moderate CoE). There may be little to no difference in the rate of adverse events between this intervention and placebo (RR 1.56, 95% CI 0.69 to 3.53; I² = 47%; 3 studies, 305 participants; low CoE). The intervention probably improves the quality of life (measured on the Nepean Dyspepsia Index) (MD ‐131.40, 95% CI ‐193.76 to ‐69.04; 1 study, 99 participants; moderate CoE).

Curcuma longa probably results in a moderate improvement global symptoms of dyspepsia compared to placebo at four weeks (MD ‐3.33, 95% CI ‐5.84 to ‐0.81; I² = 50%; 2 studies, 110 participants; moderate CoE) and may increase the improvement rate (RR 1.50, 95% CI 1.06 to 2.11; 1 study, 76 participants; low CoE). There is probably little to no difference in the rate of adverse events between this intervention and placebo (RR 1.26, 95% CI 0.51 to 3.08; 1 study, 89 participants; moderate CoE). The intervention probably improves the quality of life, measured on the EQ‐5D (MD 0.05, 95% CI 0.01 to 0.09; 1 study, 89 participants; moderate CoE).

We found evidence that the following herbal medicines may improve symptoms of dyspepsia compared to placebo: Lafonesia pacari (RR 1.52, 95% CI 1.08 to 2.14; 1 study, 97 participants; moderate CoE), Nigella sativa (SMD ‐1.59, 95% CI ‐2.13 to ‐1.05; 1 study, 70 participants; high CoE), artichoke (SMD ‐0.34, 95% CI ‐0.59 to ‐0.09; 1 study, 244 participants; low CoE), Boensenbergia rotunda (SMD ‐2.22, 95% CI ‐2.62 to ‐1.83; 1 study, 160 participants; low CoE), Pistacia lenticus (SMD ‐0.33, 95% CI ‐0.66 to ‐0.01; 1 study, 148 participants; low CoE), Enteroplant (SMD ‐1.09, 95% CI ‐1.40 to ‐0.77; 1 study, 198 participants; low CoE), Ferula asafoetida (SMD ‐1.51, 95% CI ‐2.20 to ‐0.83; 1 study, 43 participants; low CoE), ginger and artichoke (RR 1.64, 95% CI 1.27 to 2.13; 1 study, 126 participants; low CoE), Glycyrrhiza glaba (SMD ‐1.86, 95% CI ‐2.54 to ‐1.19; 1 study, 50 participants; moderate CoE), OLNP‐06 (RR 3.80, 95% CI 1.70 to 8.51; 1 study, 48 participants; low CoE), red pepper (SMD ‐1.07, 95% CI ‐1.89 to ‐0.26; 1 study, 27 participants; low CoE), Cuadrania tricuspidata (SMD ‐1.19, 95% CI ‐1.66 to ‐0.72; 1 study, 83 participants; low CoE), jollab (SMD ‐1.22, 95% CI ‐1.59 to ‐0.85; 1 study, 133 participants; low CoE), Pimpinella anisum (SMD ‐2.30, 95% CI ‐2.79 to ‐1.80; 1 study, 107 participants; low CoE). The following may provide little to no difference compared to placebo: Mentha pulegium (SMD ‐0.38, 95% CI ‐0.78 to 0.02; 1 study, 100 participants; moderate CoE) and cinnamon oil (SMD 0.38, 95% CI ‐0.17 to 0.94; 1 study, 51 participants; low CoE); moreover, Mentha longifolia may increase dyspeptic symptoms (SMD 0.46, 95% CI 0.04 to 0.88; 1 study, 88 participants; low CoE).

Almost all the studies reported little to no difference in the rate of adverse events compared to placebo except for red pepper, which may result in a higher risk of adverse events compared to placebo (RR 4.31, 95% CI 1.56 to 11.89; 1 study, 27 participants; low CoE). With respect to the quality of life, most studies did not report this outcome.

When compared to other interventions, essential oils may improve global symptoms of dyspepsia compared to omeprazole. Peppermint oil/caraway oil, STW5, Nigella sativa and Curcuma longa may provide little to no benefit compared to other treatments.

Authors' conclusions

Based on moderate to very low‐certainty evidence, we identified some herbal medicines that may be effective in improving symptoms of dyspepsia. Moreover, these interventions may not be associated with important adverse events. More high‐quality trials are needed on herbal medicines, especially including participants with common gastrointestinal comorbidities.

Keywords: Humans, Complementary Therapies, Dyspepsia, Dyspepsia/drug therapy, Plant Extracts, Quality of Life

Plain language summary

What are the effects of non‐Chinese herbal medicines for people with functional dyspepsia?

Key results

We identified multiple herbal medicines that were effective in improving symptoms and well‐being in people with functional dyspepsia. Also, they may not be associated with important unwanted events compared to sham treatment. However, we found little evidence on the comparative effectiveness of herbal medicines and other treatments.

The effect of herbal medicines may need to be compared to common medical treatments for functional dyspepsia to assess their relative effectiveness. More high‐quality trials are needed for functional dyspepsia, especially with people with common gastrointestinal comorbidities.

Background

What is functional dyspepsia?

Functional dyspepsia is a frequent problem among adults. It is characterized by pain and discomfort in the stomach. However, unlike organic dyspepsia, these symptoms can not be blamed on ulcers or other lesions in the stomach or intestines.

How is functional dyspepsia treated?

The treatments for this include drug and non‐drug approaches, but it is not known how well they work. A variety of herbal products have been tested, to an extent, as possible treatments for this condition.

What did we want to find out?

In this review, we looked at all available studies on this subject to find out if any of these herbs can improve symptoms and well‐being, and if they are safe.

Study characteristics

What did we do?

We searched for studies investigating non‐Chinese herbal medicines compared with usual treatment or other treatments in people with functional dyspepsia. We compared and summarized their results about symptoms, well‐being, and unwanted effects, and rated our confidence in the evidence according to study methods and the numbers of people in the studies.

Summary of results

What did we find?

We found 41 studies of 4477 people with functional dyspepsia that assessed 27 herbal products. Most of them compared herbal products against placebo (dummy tablets), although some studies compared them against drugs like omeprazole, H pylori treatment, or other treatments. The duration of the studies varied from 15 days to 12 weeks. The studies were conducted in many countries around the world; 12 of them took place in Iran. The pharmaceutical industry provided funds for 14 studies, government institutions funded eight, a medical association funded one study and the rest did not state how they were funded.

Main results

STW5 (known commercially as Iberogast because one of the herbs it contains is Iberis amara L.) may reduce global symptoms of dyspepsia compared with placebo in one or two months. SWT5 may not be more effective than placebo in improving the well‐being, but only one small study measured this. In terms of safety, unwanted effects may be similar when compared to placebo.

Peppermint and caraway oil probably result in a moderate to a large reduction in global symptoms of dyspepsia and improved well‐being compared to a simulated treatment at one month. However, there may be little to no difference in the rate of unwanted effects between this intervention and the placebo.

Curcuma longa probably reduces global symptoms of dyspepsia and improves well‐being compared to placebo at four weeks. There is probably little to no difference in the rate of unwanted effects between this intervention and placebo.

We found evidence that the following herbal medicines may improve symptoms of dyspepsia compared to placebo: Lafonesia pacari, Nigella sativa, artichoke, Boensenbergia rotunda, Pistacia lenticus, Enteroplant, Ferula asafoetida, ginger and artichoke, Glycyrrhiza glabra, OLNP‐ 06, red pepper, Cuadrania tricuspidata, jollab, and Pimpinella anisum. Mentha pulegium and cinnamon oil may provide little to no difference compared to placebo; moreover, Mentha longifolia may increase dyspeptic symptoms. Almost all the studies reported little to no difference in the rate of unwanted effects compared to placebo, except for red pepper, which may result in a higher risk of unwanted effects compared to placebo. Most studies did not report on participants' well‐being.

When compared to other drugs, we only found that a combination of essential oils seems to provide superior relief of symptoms compared to omeprazole.

Certainty of the evidence

What are the limitations of the evidence?

We have little confidence in the evidence, as we found few trials for each herbal medicine, few participants for each comparison, and few head‐to‐head comparisons. In addition, most studies had limitations in their design. Besides, many studies did not clearly state how they diagnosed functional dyspepsia.

How up to date is this evidence?

The evidence is current to 22 December 2022.

Summary of findings

Summary of findings 1. STW5 (Iberogast) compared to placebo for functional dyspepsia.

STW5 compared to placebo for functional dyspepsia
Patient or population: participants with functional dyspepsia Setting: outpatient clinics Intervention: STW5 (Iberogast) Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with STW5
Global symptoms of dyspepsia Assessed with: GIS Range 0 to 40 Follow‐up: 28 to 56 days	The mean global symptoms of dyspepsia (continuous) was 5 points.	MD 2.64 lower (4.39 lower to 0.90 lower)	‐	814 (5 RCTs)	⊕⊝⊝⊝ VERY LOW^a,b,c	Higher scores mean worse symptoms.
Global symptoms of dyspepsia (responders) Assessed with: > 20% improvement GIS scores Follow‐up: 4 to 8 weeks	Study population		RR 1.55 (0.98 to 2.47)	324 (2 RCT)	⊕⊕⊝⊝ LOW^d,e	Higher number of responders indicates a beneficial effect.
	418 per 1000	648 per 1000 (410 to 1000)
Adverse events Assessed clinically Follow‐up: 28 to 56 days	Study population		RR 0.92 (0.52 to 1.64)	786 (4 RCTs)	⊕⊕⊝⊝ LOW^b,e
	57 per 1000	53 per 1000 (30 to 93)
Quality of life Assessed with: NDI Follow‐up: 4 weeks	Not available		‐	52 (1 RCT)	⊕⊕⊝⊝ LOW^d,f	The study stated that "differences between treatment groups did not yield significance."
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; GIS: Gastrointestinal Symptom Score; NDI: Nepean Dyspepsia Index; RR: risk ratio.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Peppermint/caraway oil compared to placebo for functional dyspepsia
Patient or population: participants with functional dyspepsia Setting: outpatient clinics Intervention: peppermint/caraway oil Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Peppermint/caraway oil
Global symptoms of dyspepsia Assessed with: SMD Follow‐up: 4 weeks	The mean global symptoms of dyspepsia (continuous) was 2.96 points.	SMD 0.87 lower (1.15 lower to 0.58 lower)	‐	210 (2 RCTs)	⊕⊕⊕⊝ MODERATE^a	Indicates a moderate to large benefit.
Global symptoms of dyspepsia (responders) Assessed with: clinical improvement Follow‐up: 4 weeks	Study population		RR 1.53 (1.30 to 1.81)	305 (3 RCTs)	⊕⊕⊕⊝ MODERATE^a	Higher number of responders indicates a beneficial effect.
	537 per 1000	821 per 1000 (698 to 972)
Adverse events Assessed clinically Follow‐up: 4 weeks	Study population		RR 1.56 (0.69 to 3.53)	305 (3 RCTs)	⊕⊕⊝⊝ LOW ^a,b
	141 per 1000	220 per 1000 (97 to 498)
Quality of life Assessed with: NDI Follow‐up: 4 weeks	The mean quality of life was 218.3 points.	MD 131.4 lower (193.76 lower to 69.04 lower)	‐	99 (1 RCT)	⊕⊕⊕⊝ MODERATE^a	Lower scores indicate better quality of life.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; MD: mean difference; NDI: Nepean Dyspepsia Index; RR: risk ratio; SMD: standardized mean difference
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Curcuma longa compared to placebo for functional dyspepsia
Patient or population: participants with functional dyspepsia Setting: outpatient clinics Intervention:Curcuma longa Comparison: placebo
Outcomes	*Anticipated absolute effects^ (95% CI)**		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with Curcuma longa
Global symptoms of dyspepsia Assessed with: Severity of Dyspepsia Assessment Follow‐up: 4 weeks	The mean decrease in global symptoms of dyspepsia (continuous) was 10.94 points.	MD 3.33 lower (5.84 lower to 0.81 lower)	‐	110 (2 RCTs)	⊕⊕⊕⊝ MODERATE^a	Lower scores indicates fewer symptoms.
Global symptoms of dyspepsia (responders) Assessed with: clinical improvement Follow‐up: 1 week	Study population		RR 1.5 (1.06 to 2.11)	76 (1 RCT)	⊕⊕⊝⊝ LOW ^a,b
	526 per 1000	789 per 1000 (558 to 1000)
Adverse events Assessed clinically Follow‐up: 4 weeks	Study population		RR 1.26 (0.51 to 3.08)	89 (1 RCT)	⊕⊕⊕⊝ MODERATE^a
	200 per 1000	252 per 1000 (102 to 616)
Quality of life Assessed with: EuroQoL EQ‐5D (range 0 to 1) Follow‐up: 4 weeks	The mean quality of life was 0.92 points.	MD 0.05 higher (0.01 higher to 0.09 higher)	‐	89 (1 RCT)	⊕⊕⊕⊝ MODERATE^a	Higher scores indicate better quality of life.
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; MD: mean difference; RR: Risk ratio.
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Herbal preparation	Study	n	Global symptoms (continuous)	Global symptoms (dichotomous)	Adverse Events	Quality of life
Studies at low risk of bias
Lafoensia pacari	Da Mota Menezes 2006	97	NR	▲	⯇⯈	NR
Mentha pulegium	Khonche 2017	100	⯇⯈	NR	⯇⯈	▲
Nigella sativa	Mohtashami 2015	70	▲	⯇⯈	⯇⯈	NR
Nigella sativa	Alizadeh‐Naini 2020	51	NR	NR	⯇⯈	NR
Studies at unclear risk of bias
Artichoke	Holtmann 2003	244	▲	NR	⯇⯈	▲
Astaxanthin	Kupcinskas 2008	131	NR	NR	⯇⯈	NR
Boesenbergia rotunda (fingerroot)	Chitapanarux 2020	160	▲	NR	▲	NR
Pistacia lentiscus (Chios mastic gum/oil)	Dabos 2010	148	▲	NR	⯇⯈	NR
Pistacia lentiscus (Chios mastic gum/oil)	Sattarzadeh 2021	63	NR	NR	⯇⯈	NR
Enteroplant	Sun 2016	198	▲	NR	⯇⯈	⯇⯈
Ferula asafoetida	Mala 2018	43	▲	NR	⯇⯈	▲
Ginger (Zingiber officinalis) and artichoke (Cynara cardunculus)	Giacosa 2015	126	NR	▲	⯇⯈	NR
Glycyrrhiza glabra (Gutcard)	Allan 2012	50	▲	NR	⯇⯈	▲
Mentha longifolia	Babaeian 2017	88	▼	NR	⯇⯈	NR
OLNP‐06	Panda 2020	48	NR	▲	⯇⯈	NR
Pistacia atlantica	Eftekharafzali 2018	119	NR	NR	⯇⯈	NR
Red pepper	Bortolotti 2002	27	▲	NR	▼	NR
Studies at high risk of bias
Apium graveolens and Trachyspermum copticom	Azimi 2017	92	NR	NR	⯇⯈	▲
Cinnamon oil	Zobeiri 2021	51	⯇⯈	NR	⯇⯈	NR
Cuadrania tricuspidata	Shin 2021	83	▲	NR	⯇⯈	▲
Jollab	Pasalar 2015	133	▲	NR	⯇⯈	NR
Pimpinella anisum	Ghoshegir 2015	107	▲	NR	⯇⯈	NR

Herbal preparation	Comparison	Study	n	Global symptoms(continous)	Global symptoms (dichotomous)	Adverse Events	Quality of life
Studies at low risk of bias
Curcuma longa	Omeprazole	Yongwatana 2022	88	⯇⯈	NR	⯇⯈	⯇⯈
Curcuma longa	Omeprazole	Puttapitakpong 2016	22	⯇⯈	NR	NR	NR
Studies at unclear risk of bias
Curcuma longa	Flatulence	Thamlikitkul 1989	68	NR	⯇⯈	NR	NR
Peppermint oil/caraway oil	Cisapride	Madisch 1999	118	⯇⯈	NR	⯇⯈	NR
STW5 (Iberogast)	Cisapride	Rosch 2002	137	⯇⯈	NR	⯇⯈	NR
STW5 (Iberogast)	Proton pump inhibitor	Holtmann 2013	57	NR	⯇⯈	NR	NR
Trachyspermum ammi L., Anethum graveolens L., and Zataria multiflora Boiss herbal oils vs omeprazole	Omeprazole	Bordbar 2020	57	▲	NR	⯇⯈	▲
Studies at a high risk of bias
Apium graveolens and Trachyspermum copticom	Omeprazole	Azimi 2017	100	NR	NR	⯇⯈	⯇⯈
Nigella sativa at different doses: 1, 2 and 3 g	Clarithromycin, amoxicillin, and omeprazole	Salem 2010	88	NR	⯇⯈	⯇⯈	NR
Pudin hara pearls	Pudin hara liquid	Sastry 2016	79	⯇⯈	NR	⯇⯈	NR

Functional dyspepsia	Rome I (Talley 1991)	Rome II (Talley 1999)	Rome III (Tack 2006)	Rome IV (Stanghellini 2016)
Main criteria	Pain or discomfort centered in the upper abdomen with no evidence of organic disease	Persistent or recurrent symptoms (pain or discomfort centered in the upper abdomen) AND No evidence that dyspepsia is exclusively relieved by defecation or associated with the onset of a change in stool frequency or stool form (exclude irritable bowel syndrome and exclude reflux)	≥ 1 symptoms need to be present: • Bothersome postprandial fullness • Early satiation • Epigastric pain • Epigastric burning AND No evidence of structural disease, including the use of upper endoscopy, that is likely to explain the symptoms. Criteria should be fulfilled for at least 3 months with symptom onset at least 6 months previously.	≥ 1 symptoms need to be present: • Bothersome postprandial fullness • Bothersome early satiation • Bothersome epigastric pain • Bothersome epigastric burning AND No evidence of structural disease, including the use of upper endoscopy, that is likely to explain the symptoms. Must fulfill criteria for a) postprandial distress syndrome or b) epigastric pain syndrome, or both. Criteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 Global symptoms of dyspepsia (continuous)	5	814	Mean Difference (IV, Random, 95% CI)	‐2.64 [‐4.39, ‐0.90]
1.2 Global symptoms of dyspepsia (responders)	2	324	Risk Ratio (M‐H, Random, 95% CI)	1.55 [0.98, 2.47]
1.3 Adverse events	4	786	Risk Ratio (M‐H, Random, 95% CI)	0.92 [0.52, 1.64]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Global symptoms of dyspepsia (continuous)	2	210	Std. Mean Difference (IV, Random, 95% CI)	‐0.87 [‐1.15, ‐0.58]
2.2 Global symptoms of dyspepsia (responders)	3	305	Risk Ratio (M‐H, Random, 95% CI)	1.53 [1.30, 1.81]
2.3 Adverse events	3	305	Risk Ratio (M‐H, Random, 95% CI)	1.56 [0.69, 3.53]
2.4 Quality of life	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Global symptoms of dyspepsia (continuous)	2	110	Mean Difference (IV, Random, 95% CI)	‐3.33 [‐5.84, ‐0.81]
3.2 Global symptoms of dyspepsia (responders)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.3 Adverse events	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
3.4 Quality of life	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 Global symptoms of dyspepsia (continuous)	14		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.1 Mentha longifolia	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.2 Chios mastic gum	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.3 Artichoke	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.4 Mentha pulegium	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.5 Red pepper	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.6 Enteroplant	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.7 Jollab	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.8 Ferula asafoetida	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.9 Nigella sativa	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.10 Glycyrrhiza glabra (Gutcard)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.11 Boesenbergia rotunda (fingerroot)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.12 Pimpinella anisum	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.13 Cinnamon oil	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.1.14 Cudrania tricuspidata	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.2 Global symptoms of dyspepsia (responders)	3		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.2.1 Lafoensia pacari	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.2.2 Ginger (Zingiber officinalis) and Artichoke (Cynara cardunculus)	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.2.3 OLNP‐06	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
4.3 Quality of life	8		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.1 Enteroplant	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.2 Artichoke	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.3 Mentha pulegium	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.4 Ferula asafoetida	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.5 Glycyrrhiza glabra (Gutcard)	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.6 Apium graveolens and Trachyspermum copticom	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.7 Curcuma longa	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.3.8 Cudrania tricuspidata	1		Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
4.4 Adverse events	22		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
4.4.1 Mentha pulegium	1	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.4.2 Mentha longifolia	1	88	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.06, 15.49]
4.4.3 Pistacia lentiscus (Chios mastic gum)	1	148	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.24, 102.40]
4.4.4 Glycyrrhiza glabra	1	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.4.5 Artichoke	1	244	Risk Ratio (M‐H, Random, 95% CI)	1.44 [0.84, 2.44]
4.4.6 Pistacia atlantica	1	119	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.14, 6.53]
4.4.7 Ferula asafoetida	1	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.4.8 Jollab	1	133	Risk Ratio (M‐H, Random, 95% CI)	2.39 [0.48, 11.89]
4.4.9 Fingerroot	1	160	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.17, 3.24]
4.4.10 Ginger and artichoke	1	0	Risk Ratio (M‐H, Random, 95% CI)	Not estimable
4.4.11 OLNP‐06	1	50	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.15, 6.55]
4.4.12 Pimpinella Anisum	1	107	Risk Ratio (M‐H, Random, 95% CI)	0.25 [0.01, 5.17]
4.4.13 Nigella sativa	2	121	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.53, 1.88]
4.4.14 Red pepper	1	27	Risk Ratio (M‐H, Random, 95% CI)	4.31 [1.56, 11.89]
4.4.15 Lafoensia pacari	1	100	Risk Ratio (M‐H, Random, 95% CI)	1.52 [0.66, 3.49]
4.4.16 Enteroplant	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.09, 10.58]
4.4.17 Apium Graveolence and Trachyspermum Copticum	1	92	Risk Ratio (M‐H, Random, 95% CI)	0.18 [0.01, 3.57]
4.4.18 Astaxanthin	1	131	Risk Ratio (M‐H, Random, 95% CI)	1.23 [0.55, 2.74]
4.4.19 Cinnamon oil	1	51	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.14, 4.12]
4.4.20 Cudrania tricuspidata	1	100	Risk Ratio (M‐H, Random, 95% CI)	0.80 [0.42, 1.53]
4.4.21 Curcuma longa	1	89	Risk Ratio (M‐H, Random, 95% CI)	1.26 [0.51, 3.08]

Outcome or subgroup title	No. of studies	Statistical method	Effect size
5.1 Global symptoms of dyspepsia (continuous)	6	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.1 Trachyspermum ammi L., Anethum graveolens L., and Zataria multiflora Boiss herbal oils vs omeprazole	1	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.2 Pudin hara pearls vs pudin hara liquid	1	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.3 STW5 vs cisapride	1	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.4 Peppermint oil/caraway oil vs cisapride	1	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.1.5 Curcuma longa vs omeprazole	2	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.2 Global symptoms of dyspepsia (responders)	3	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.2.1 Curcuma longa vs flatulence	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.2.2 STW5 vs proton pump inhibitor	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.2.3 Nigella sativa and Omeprazol vs Triple therapy	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.3 Quality of life	3	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.3.1 The Trachyspermum ammi L. (TA), Anethum graveolens L. (AG), and Zataria multiflora Boiss (ZM) herbal oils vs Omeprazole	1	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.3.2 Apium graveolens and Trachyspermum copticom vs omeprazole	1	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.3.3 Curcuma longa vs omeprazole	1	Std. Mean Difference (IV, Random, 95% CI)	Totals not selected
5.4 Adverse events	6	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.1 Pepermint/caraway oil vs cisapride	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.2 STW5 I‐II vs Cisapride	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.3 The Trachyspermum ammi L. (TA), Anethum graveolens L. (AG), and Zataria multiflora Boiss (ZM) herbal oils vs Omeprazole	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.4 Pudin hara	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.5 Apium Graveolence and Trachyspermum Copticum vs omeprazole	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
5.4.6 Curcuma longa vs omeprazole	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

*Study characteristics*
Methods	Study design: randomized, double‐blind, placebo‐controlled clinical trial Study dates: 2017 to 2018 Setting and number of centres: outpatient, national Country: Iran
Participants	Inclusion criteria: patients diagnosed with ROME III and with H pylori infection. Exclusion criteria: patients who had a history of gastric cancer or gastric surgery, active gastrointestinal bleeding and Intense gastritis, inflammatory and chronic diseases such as kidney and liver diseases, inflammatory bowel disease, heart ischaemia, diabetes mellitus, lung disease, asthma, cancer, HIV infection, and systemic inflammation, patients who were pregnant or lactating, those having body mass index greater than 30 kg/m², taking any antibiotics or bismuth 6 weeks before the study, getting any medication for H pylori eradication prior to the onset of the study, drinking alcohol or using narcotics Sample size: 51 randomized Withdrawals Group 1: 2 were excluded because of their intolerance to quadruple therapy. Group 2: 3 were excluded, one who did not adhere to the study protocol, one who got out of reach, and one who was not willing to continue the study. Age (mean ± SD years) Group 1 (40.61 ± 2.15); Group 2 (40.12 ± 2.15) Ethnicity by group: not stated. Sex (M/F) Group 1 (Study); 10 M/16 F Group 2 (Control) 6 M/19 F Symptom severity at baseline: not available.
Interventions	Group 1 (n = 26):N sativa powder 2 grs. 2 capsules twice daily 30 min after the meal Group 2 (n = 25): coloured pharmaceutical starch 2 grs. 2 capsules twice daily 30 min after the meal Co‐interventions: 500 mg metronidazole twice daily, 1000 mg amoxicillin twice daily, 240 mg bismuth subcitrate twice daily, and 40 mg omeprazole twice daily for 2 weeks.
Outcomes	Adverse events How measured: by phone call Time points measured: every 7 days Time points reported: end of study Subgroups: no Quality of life How measured: Short‐ form 36 (SF‐36) Time points measured: at the beginning and at the end of 8 weeks of intervention. Time points reported: end of weeks 1, 2, and cumulative incidence of the remaining 6 weeks Subgroups: none Other outcomes reported in the review Global symptoms of dyspepsia were not measured. The study reported each symptom separately (using ROME III). Hs‐CRP serum levels, serum level of malondialdehyde (MDA), IL‐8 (pg/ml).
Funding	Financially supported (grant no #95‐01‐84‐13771) by the Vice Chancellery of Research and Technology in Shiraz University of Medical Sciences, Shiraz, I.R. Iran.
Declaration of interest	The authors declare no conflicts of interest.
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"block randomization using random allocation software".
Allocation concealment (selection bias)	Low risk	“N. sativa and placebo capsules were completely similar in color, size, and smell to blind the participants, gastroenterology clinic staff, and the researcher to group allocation”.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“N. sativa and placebo capsules were completely similar in color, size, and smell to blind the participants, gastroenterology clinic staff, and the researcher to group allocation”.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	“N. sativa and placebo capsules were completely similar in color, size, and smell to blind the participants, gastroenterology clinic staff, and the researcher to group allocation”.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are available for nearly all participants (with the exception of five withdrawals) for all results.
Selective reporting (reporting bias)	Low risk	All outcomes in the protocol (en.irct.ir/trial/27133) are reported in the study.
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: parallel‐group randomized trial Study dates: December 2009 to March 2010 Setting and number of centres: inpatients in two centres Country: India
Participants	Sample size: 50 Inclusion criteria: Rome‐III criteria Exclusion criteria: Age less than 18 years or over 65 years, advanced chronic illness that would impair follow‐up or monitoring, pregnancy or breastfeeding, previous surgery for ulcers, people with a previous history of gastroesophageal reflux, people with concomitant symptoms of the irritable bowel syndrome, drug and alcohol abuse, mental illness or dementia Withdrawals: none Age (mean ± SD years) Group 1 (Study); mean age 38.12 ± 1.84 Group 2 (Control) mean age of 45.16 ± 2.06 Ethnicity by group: not stated Sex (M/F) Group 1 (Study); 15 M/10 F Group 2 (Control) 16 M/9 F Symptom severity at baseline: total symptoms scores of dyspepsia Group1 (Study) 29.96 ± 0.55 Group 2 (Control) 28.68 ± 0.62
Interventions	Group 1 (n = 25 ): Glycyrrhiza glabra (GutGard) (75 mg twice daily) for 30 days after meals (morning and night) with a glass of water. GutGard has following phytochemical specifications, namely, glabridin (≥ 3.5% w/w), glabrol (≥ 0.5% w/w), eicosanyl caffeate (≥ 0.1% w/w), docosyl caffeate (≥ 0.1% w/w), glycyrrhizin (≤ 0.5% w/w), and total flavonoids (≥ 10% w/w). Group 2 (n = 25): placebo twice a day for 30 days Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: list of 10 gastrointestinal symptoms (7‐point Likert scale) Time points measured: baseline, after 15 days and after a month. Time points reported: baseline, after 15 days and after a month Subgroups: none Adverse events How measured: reported by participants when they attended the centre. Time points measured: Day 15 and 30 Time points reported: cumulative incidence Subgroups: none Quality of life How measured: Nepean Dyspepsia Index (NDI) Time points measured: Days 0, 15 and 30 Time points reported: Days 0, 15 and 30 Subgroups: none Other outcomes reported in the review: laboratory investigations
Funding	Not available
Declaration of interest	Not available
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A list of unique integer random numbers considered as patient code (i.e., random allocation sequence) was generated using a computer‐aided programme” “randomization sequence was developed at Natural Remedies Pvt. Ltd., Bangalore, India, and forwarded to study centre. The entire process was performed in a confidential manner and all the concerned in study centre namely, investigators, patients, and other supportive staff were unaware of the random allocation sequence”
Allocation concealment (selection bias)	Low risk	“As per the random allocation sequence, the containers (either placebo or GutGard capsules) were labeled with unique random numbers.” ‐ central allocation (pharmacy)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“The investigators, patients, and pharmacist dispensing the interventions were all concealed to group assignment. The blinding process was maintained till all the data were compiled and verified for accuracy and then forwarded for statistical analysis”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	“The investigators, patients, and pharmacist dispensing the interventions were all concealed to group assignment. The blinding process was maintained till all the data were compiled and verified for accuracy and then forwarded for statistical analysis”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Nearly complete data for every outcome were reported. No participant was lost.
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	Low risk	We did not identify other sources of bias.

*Study characteristics*
Methods	Study design: 3 arms ‐ RCT Study dates: 2015 to 2016 Setting and number of centres: outpatient, national, single centre Country: Iran
Participants	Inclusion criteria: aged 18 to 60 years old, diagnosed according to ROME III criteria. Exclusion criteria: pregnancy, breastfeeding, convulsion, active urinary tract infection, any severe side effects possibly relating to the drug, simultaneous use of other chemical or herbal drugs related to symptoms of FD, intake anticoagulants, digestive ulcers or reflux, Irritable Bowel Syndrome (IBS), serious diseases like diabetes and cardiovascular diseases, oesophagus and gastrointestinal surgery, severe mental retardation, drug abuse, patient’s unwillingness to continue the project, not filling out the consent form, and the emergence of warning symptoms including sudden severe weight loss, anaemia, blood in the stool, dysphagia. Sample size: 150 randomized Withdrawals: 13 (group 1: after 2 weeks because not regularly using (1); group 2: because not regularly used (2), drug intolerance (1) and using other drugs (2); group 3: not regularly using (2), drug intolerance (2), using other drugs (2) and wanted to be pregnant (1)) Age (years): ages are expressed in age subgroups for each group. Group 1 (Study): 18 to 30 (15), 31 to 45 (23), and 46 to 60 (11); Group 2 (Placebo): 18 to 30 (12), 31 to 45 (19), and 46 to 60 (11) Group 3 (Omeprazol): 18 to 30 (16), 31 to 45 (18), and 46 to 60 (11). Ethnicity by group: not stated. Sex (M/F) Group 1 (Study); 16 M/32 F Group 2 (Placebo) 17 M/28 F Group 3 (Omepraol) 16 M/27 F Symptom severity at baseline: Stangellini’s symptom severity and ROME III. The symptom severity questionnaire includes 8 items with the final score ranging between 8 and 32. The symptom frequency questionnaire is comprised of 8 items with the final score ranging between 8 and 48.
Interventions	Group 1 (n = 50): capsule with Apium graveolence (herbarium number of KF1447) 250 mg and Trachyspermum copticum 250 mg (herbarium number of KF1138), twice daily (after breakfast and another one after dinner) Group 2 (n = 50): capsule of omeprazole 20 mg before breakfast daily Group 3 (n=50): placebo cornstarch, 500 mg, twice daily (after breakfast and another one after dinner) Co‐interventions: none
Outcomes	Adverse events How measured: questionnaire at follow‐up Time points measured: at baseline, 4 and 8 weeks Time points reported: at baseline, 4 and 8 weeks Subgroups: none Quality of life How measured: Nepean Dyspepsia Index (NDI) short questionnaire Time points measured: at baseline, 4 and 8 weeks Time points reported: at baseline, 4 and 8 weeks Subgroups: none Other outcomes reported in the review: Global symptoms of dyspepsia were not measured. The study reported each symptom separately (using Stangellini’s symptom severity and ROME III) measured at the baseline, 2, 4 and 8 weeks.
Funding	Non‐reported
Declaration of interest	The authors declare no conflicts of interest.
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"Randomization was performed by minimisation, in which 15 patients were divided into three intervention groups by randomizing the numbers 1, 2, and 3, and their multiples, to the subjects. The patients were then intentionally placed into these groups based on potential confounders, namely age and sex, to match these three groups with respect to the factors mentioned." There is no explanation on how data were handled nor the use of software.
Allocation concealment (selection bias)	Low risk	"Drugs were identically packaged and coded in the Pharmacognosy Department of Kerman University of Medical Sciences. The person who did the coding was not involved in the study." ‐ Central allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"This study was conducted in the double‐blinded" "The person who coded the drugs did not have any role until the end of the intervention. Without any knowledge of the study objectives, the second person divided the patients into the three groups purposefully based on each patient’s basic information"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The patient’s information was analyzed by a fourth person blind about grouping and drugs coding."
Incomplete outcome data (attrition bias) All outcomes	High risk	Unbalanced attrition: 7/50 in the placebo group, 1/50 in the herbal therapy group, 5/50 in the omeprazole group.
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: parallel‐group randomized trial. Study dates: not available. Setting and number of centres: single‐centre, outpatient. Country: Iran
Participants	Inclusion criteria: age 18 to 65 years and a diagnosis of postprandial distress syndrome according to the ROME III criteria. Exclusion criteria: pregnancy, breastfeeding, peptic ulcer, gastroesophageal reflux disease, dysphagia, celiac sprue, gastrointestinal surgery, irritable bowel syndrome, abdominal pain, night diarrhoea, greasy or black stool, blood in stool, mental retardation, immune system disorders, severe recent weight loss, cancer, renal disorders, and the current need for or use of the following medications: antibiotics, proton pump inhibitors, H2 blockers, bismuth, metoclopramide, domperidone, lactulose, non‐steroidal anti‐inflammatory drugs, corticosteroids, and herbal medicines Sample size: 100 participants allocated equally to each group Withdrawals: 12 in total (4 because of the lack of regular use of the medication, this happened equally in both groups; 6 due to drug intolerance, 5 of them were in the intervention branch; and 2 due to adverse events, 1 in each branch; 1 participant of the placebo group was lost for other reasons). Age (mean ± SD years) Group 1 (43 ± 12.3); Group 2 (42.8 ± 14) Ethnicity by group: not stated Sex (M/F) Group 1 (Study); 10 M/40 F Group 2 (Control) 10 M/40 F Symptom severity at baseline: evaluated with the FD severity scale. All symptoms were distributed similarly between the two groups. Group 1: 13.9 ± 7.60 Group 2: 14.2 ± 7.23 No significant difference was seen in different symptoms of postprandial distress syndrome in the two groups (13.9 ± 7.60 vs. 14.2 ± 7.23, P = 0.84).
Interventions	Group 1 (n = 50): 750 mg Mentha longifollia 3 times a day for 4 weeks (each pill contains 250 mg + 250 of cornstarch) Group 2 (n = 50): placebo 500 mg of cornstarch Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: validated scale using Likert rating (‐2 to +2). Range ‐32 to 32 (higher scores indicate fewer symptoms of discomfort/bloating/pain/fullness/burning, preprandial and postprandial nausea and epigastric pain, night epigastric pain, morning nausea, vomiting, retching, belching, loss of appetite, and early satiety were assessed) Time points measured: end of weeks 2, 4 and 12 Time points reported: end of weeks 2, 4 and 12 Subgroups: none Adverse events How measured: any side effects from their medications were recorded at each follow‐up. Time points measured: end of weeks 2, 4 and 12 Time points reported: cumulative incidence of events Subgroups: none Quality of life How measured: QOL was evaluated with Persian version of the Short Form‐36 (SF36) questionnaire (higher scores indicate better quality of life) Time points measured: baseline and end of week 12 Time points reported: baseline and end of week 12 Subgroups: none Other outcomes reported in the review: epigastric discomfort/bloating/pain/fullness/burning, preprandial and postprandial nausea and epigastric pain, night epigastric pain, morning nausea, vomiting, retching, belching, loss of appetite, and early satiety were assessed individually as well.
Funding	None
Declaration of interest	The authors declare no conflicts of interest
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Randomization and enrollment of the patients in the MLE and placebo groups were done by the gastroenterologist equally and alternatively using permuted random blocks with a block size of two”
Allocation concealment (selection bias)	Low risk	“The MLE and placebo were packaged and alphabetically labeled with the same appearance. An independent pharmacist set the codes on the drug or placebo packets using a confidential list that contained the secret codes and was kept in sealed, opaque envelopes until the end of the study and until they were needed.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“The current study was a double‐blind, randomized clinical trial study. The gastroenterologist, patients, and outcome assessor were not informed which participants had received the drug and which had been given the placebo”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	“The gastroenterologist, patients, and outcome assessor were not informed which participants had received the drug and which had been given the placebo.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Nearly complete data for every outcome were reported. 12/100 patients were excluded (six in each group, balanced attrition).
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	Low risk	No other sources of bias were identified.

*Study characteristics*
Methods	Study design: parallel‐group placebo‐controlled Study dates: not available Setting and number of centres: outpatient, multicentre, national Country: Germany
Participants	Inclusion criteria: aged 18 to 85 years, diagnosed with FD according to the Rome II criteria, 3 or more items on a GIS Profile had to be judged at least moderate (grade 2), determination of the status of H pylori. Exclusion criteria: people with endoscopically proven oesophageal erosions, Barrett’s, oesophagus, gastroduodenal ulcers or erosions (have had to be ruled out by an abdominal ultrasound examination and an oesophagogastroduodenoscopy within the preceding 3 months), diabetes mellitus, a history of abdominal surgery (apart from appendectomy and cholecystectomy) or predominant gastro‐oesophageal reflux disease were not eligible for the study. Sample size: 103 participants enrolled: 93 randomized, 86 in results (7 participants unclear) Withdrawals: withdrawals of consent (n = 6) new intercurrent diseases (n = 2), a violation of in‐/exclusion criteria (n = 1) or for other reasons (n = 1) Age (mean ± SD years): Group 1 (45.9 ± 15.2); Group 2 (48.6 ± 17.3) Ethnicity by group: not available. Sex (M/F): Group 1 (Study); 10 M/16 F Group 2 (Control) 6 M/19 F Group 1 (14 (31.8%)); Group 2 (12 (28.6%)) Symptom severity at baseline: Gastrointestinal symptoms score (GIS). Each symptom was graded on a validated five‐point Likert scale, ranging from 0 (no problem) to 4 (very severe problem, markedly influencing daily activities or requiring rest). Max score: 40 points, minimum for inclusion greater than or equal to 6 points. Group 1: 11.6 ± 4.4 Group 2: 12.0 ± 4.7
Interventions	Group 1 (n = 44 ): Intervention. STW 5 tincture 20 drops 3 times a day for 28 days Group 2 (n = 42 ): Placebo. Liquid placebo 20 drops 3 times a day for 28 days. Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: Gastrointestinal symptoms score (GIS) Time points measured: Start of treatment (visit 2) and end of treatment (visit 3) Time points reported: Total score start of treatment (visit 2) and end of treatment (visit 3) Subgroups: none Adverse events How measured: Cumulative incidence Time points measured: At complete follow‐up Time points reported: Narratively Subgroups: none Other outcomes reported in the review: 13C octanoic acid breath test (13C‐OBT) for the assessment of gastric emptying, Infection with H. pylori, laboratory parameters and global assessment of efficacy.
Funding	Not available
Declaration of interest	Dr Vinson is an employee of the Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany. The other authors (B.B., W.C., N.B., A.S.) do not have conflicts of interest to declare.
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method used to generate the random sequence is not described
Allocation concealment (selection bias)	Unclear risk	The methods for allocation concealment are not described.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	It was only mentioned in the article that it was double blind. It is unclear whether personnel was blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants were blinded by the use of placebo (patient‐reported outcome)
Incomplete outcome data (attrition bias) All outcomes	Low risk	Seven participants were not included in the analysis (7/93) without explaining the reasons for withdrawal.
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: randomized double‐blind placebo‐controlled trial Study dates: 2004 Setting and number of centres: outpatient, national, single centre Country: Brazil
Participants	Inclusion criteria: 18 years or older, dyspeptic complaints and positive for H pylori, detected by a rapid urease test. Exclusion criteria: patients who received any medication containing nonsteroidal anti‐inflammatory drugs, antibiotics, or gastric antisecretory agents in the last 3 weeks; gastrectomized and vagotomized patients, and individuals with a history of stenosis, perforation, or digestive haemorrhage in the last 2 months prior to inclusion in the study; patients with any malignancy; pregnant patients; patients who did not agree to sign the informed consent form. Sample size: 100 randomized Withdrawals: 3 (1 for allergic reaction and 2 for being prescribed an eradicating drug by the assistant physician) Loss to follow‐up: 4 (2 participants reported improvement of symptoms) Non‐adherent: 1 Age (years and SD): all participants 47 (15.6) Ethnicity by group: not stated Sex (M/F): all participants (36M/64F) Symptom severity at baseline: not available
Interventions	Group 1 (n = 55): capsule with 500 mg powder of 20% methanolic extract of Lafoensia pacari, obtained after drying, orally, twice a day. Group 2 (n = 45): capsule with 500 mg of inert material (placebo), orally, twice a day. Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: “Overall Treatment Evaluation” Time points measured: end of week 2. Time points reported: end of week 2. Subgroups: none Adverse events How measured: “Self‐Evaluation” card Time points measured: end of week 2. Time points reported: end week 2. Subgroups: none Other outcomes reported in the review: total blood count with platelet count, alkaline phosphatase, GOT, GPT, urea, creatinine, and total cholesterol.
Funding	Not available
Declaration of interest	Not available
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomization.
Allocation concealment (selection bias)	Low risk	"130 identical cards were numbered, from 001 to 130, and each card was placed in one of the 130 identical brown envelopes which were sealed. After selecting the patients the attending physician took one of the sealed envelopes, opened it, and removed the card with a number corresponding to the bottle to be given to the patient”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Todos os participante‐médico assistente, endoscopista, farmacêutico, patologista, pacientes e pesquisado resestavam “cegos” durante todo o processo" (All the participant‐attending physicians, endoscopist, pharmacist, pathologist, patients and researchers "blind" during all process)
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants were blinding using placebo.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are available for nearly all participants (with the exception of 8 withdrawals/100 participants) for all results.
Selective reporting (reporting bias)	Low risk	The outcomes match the protocol (available in the full thesis document).
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: double‐blind randomized clinical trial Study dates: 2013 to 2014 Setting and number of centres: outpatient, national, single centre Country: Iran
Participants	Inclusion criteria: participants aged 18 to 65 years and diagnosed with postprandial distress syndrome (PDS) according to Rome III criteria Exclusion criteria: pregnancy, breastfeeding, peptic ulcer, gastroesophageal reflux disease, dysphagia, coeliac, GI surgery, irritable bowel syndrome, abdominal pain, night diarrhoea, greasy or black stool, blood in stool, mental retardation, immune system disorders, major depression, bipolar disorder and psychosomatic disorders, severe recent weight loss, cancer, renal disorders, current use of antibiotics, proton pump inhibitors, H2 blockers, bismuth, metoclopramide, domperidone, lactulose, nonsteroid anti‐inflammatory drugs, corticosteroids, herbal medicines and drug abuse. Sample size: 180 enrolled; 107 randomized Withdrawals: 8 (intervention: 2 not regularly using the medication; 1 wanted to be pregnant; 1 drug intolerance; 1 medication administration/ placebo: 2 not regularly using the medication; 2 drug intolerance). Age (years): Group 1 (45.5 ±15.5); Group 2 (41 ±11.7) Ethnicity by group: not stated. Sex (M/F) Group 1 (Study) 26 M/21 F Group 2 (Control) 28 M/32 F Symptom severity at baseline: FD severity scale with 4‐item Likert scale was employed to answer the questions (16). Total score (good) 0 to 64 (bad); Each participant's total score was between 0 and 48. Group 1: 10.6 Group 2: 10.96
Interventions	Group 1 (n = 47): anise powder, 3 g after each meal (3 times/day) for 4 weeks (This plant specimen was kept in their herbarium with number 1697). Group 2 (n = 60): corn starch powder, 3 g after each meal (3 times/day) for 4 weeks. Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: FD severity scale with 4‐item Likert scale was employed to answer the questions. Time points measured: at baseline and end of weeks 2, 4 and 12 Time points reported: none Subgroups: none Adverse events How measured: questionnaire Time points measured: possibly at complete follow‐up Time points reported: narratively. Subgroups: none Quality of life How measured: Persian version SF‐36 Time points measured: at baseline and at the end of week 12 Time points reported: at baseline and at the end of week 12 Subgroups: none Other outcomes reported in the review: none
Funding	Not available
Declaration of interest	The authors declare no conflicts of interest.
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors do not explain how the randomization was performed ("They were randomized by simple randomization method into intervention and placebo groups").
Allocation concealment (selection bias)	Unclear risk	Authors do not explain how the randomization was performed or the manner of concealment.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Doctors and patients were blind to the assigned treatments". "The placebo were packed similar to anise powder in shape, color and size. Both powders were prepared in similar packages"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Doctors and participants were blind to the assigned treatments.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are available for nearly all participants (with the exception of eight withdrawals from 107 randomized participants) for all results.
Selective reporting (reporting bias)	High risk	The study protocol points out the assessment of the severity of the disorder, quality of life (primary outcomes) and side effects (secondary outcome), but quality of life and side effects were not reported.
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: parallel‐group: randomized trial Study dates: 2012 Setting and number of centres: outpatients, 2 centres Country: Italy
Participants	Inclusion criteria: patients with functional dyspepsia According to Rome II criteria. Exclusion criteria: patients with relevant gastroesophageal reflux symptoms (retrosternal pain, burning, or regurgitation) as well as patients with clear evidence of irritable bowel syndrome, patients with a previous diagnosis of cancer or with previous surgery of the upper gastrointestinal tract or of the biliopancreatic system (except for cholecystectomy) and patients with active HP infection or with gastric or duodenal ulcer, as well as pregnant women, were excluded. Sample size: 126 Withdrawals: none Age (mean ± SD years): Group 1 (Study): 45.85 ± 16.61; Group 2 (Control) 48.05 ± 17.02 Ethnicity by group: not reported Sex (M/F): Group 1 (Study): 19 M/46 F; Group 2 (Control) 20 M/41 F Symptom severity at baseline: only homogenous allocation by dyspepsia typology is reported. Ulcer‐like FD Group 1: 5; Group 2: 6. Dysmotility‐like FD Group 1: 39; Group 2: 33. Unspecified FD Group 1: 21; Group 2:22
Interventions	Group 1 (n =65 ): 100 mg of artichoke and 20 mg of ginger extracts in hard gelatin capsules twice a day before starting lunch and dinner for 30 days. Group 2 (n = 61): placebo twice a day before starting lunch and dinner for 30 days. Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: intensity of functional dyspepsia as defined by patient’s rating. Patient’s ratings were ascribed to 1 of 4 categories (0: not improved or worsened, 1: slightly improved, 2: markedly improved, and 3: completely improved). Time points measured: Day 0, after 2 and 4 weeks Time points reported: Day 0, after 2 and 4 weeks Subgroups: ulcer‐like FD, dysmotility‐like and unspecified FD Study (0 to 3 rating, 0 means without improvement, 3 completely improved) Adverse events How measured: unwanted adverse events, tolerability, vital signs, and clinically significant modifications in laboratory values were monitored in each visit. Time points measured: Day 0, after 2 and 4 weeks Time points reported: not reported. Subgroups: none Other outcomes reported in the review: intensity of 6 dyspeptic symptoms, epigastric fullness, bloating, early satiety, nausea, vomiting, and epigastric pain
Funding	Not available
Declaration of interest	The authors declare no conflicts of interest.
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Patients who met the admission criteria and who signed the informed consent to the study have been assigned consecutive and growing numbers of randomization, starting with number 1, according to a 1: 1 ratio”
Allocation concealment (selection bias)	Low risk	Central allocation: “Identical and odorless capsules for each treatment group (intervention and placebo) were assigned according to a randomization code. Both products (active supplement and placebo) were provided free of charge by Indena (Milan) in packaging specifically designed for this study”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“Investigators were blinded to the randomization table.” “Identical and odorless capsules for each treatment group (intervention and placebo) were assigned according to a randomization code. Both products (active supplement and placebo) were provided free of charge by Indena (Milan) in packaging specifically designed for this study”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants were blinded with the use of placebo.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Nearly complete data for every outcome were reported.
Selective reporting (reporting bias)	Unclear risk	Protocol was not available. Adverse events were measured but not reported.
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: randomized placebo‐controlled clinical trial Study dates: December 2015 to March 2016 Setting and number of centres: outpatient, national, single centre Country: Iran
Participants	Inclusion criteria: participants aged 20 to 80 fulfilling Rome III for functional dyspepsia. Exclusion criteria: patients with peptic ulcer disease, inflammatory bowel disease, irritable bowel syndrome, pure gastro‐oesophagal reflux disease, biliary motility disorder and any organic gastrointestinal disease; patients with a history of H pylori infection eradicating drugs use within the past 3 months; patients with a history of gastrointestinal system surgery; patients with background systemic diseases such as diabetes mellitus, heart failure, hepatic failure, renal failure, asthma, chronic obstructive pulmonary disease, neoplasms and severe psychiatric diseases; patients addicted to alcohol and opium; patients using cardiac, antihypertensive, antipsychotic, antianxiety, antibiotic and corticosteroid drugs and iron and calcium; patients with a history of discontinuing prescribed pharmacotherapy and incomplete treatment; pregnant women; women planning pregnancy; breast‐feeding women. Sample size: 103 participants randomized. Withdrawals: ‐ Loss to follow‐up: 3 (they did not come for a monthly visit due to personal reasons) Age (mean ± SD years): Group 1 (38.31 ± 12.57); Group 2 (42.87 ± 13.33) Ethnicity by group: not stated Sex (M/F): Group 1 (25/25); Group 2 (23/27) Symptom severity at baseline: the Hong Kong dyspepsia index Group 1: 27.79 ± 7.32; Group 2: 24.91 ± 6.10
Interventions	Group 1 (n = 52): intervention, Mentha pulegium capsule (drug extract ratio: 15.9:1, extraction solvent: 70% v/v aqueous ethanol). 330 mg (dosage regimen for the extract was empirically determined) 3 times daily taken for 8 weeks. Group 2 (n = 51): placebo, capsule (roasted powder) 3 times a day orally for 8 weeks. Co‐interventions: Famotidine 40 mg tablet per day for 8 weeks
Outcomes	Global symptoms of dyspepsia How measured: The Hong Kong Dyspepsia Index Time points measured: before and after 2, 4 and 8 weeks of intervention Time points reported: before and after 2, 4 and 8 weeks of intervention (reported in table 2 and 3) Subgroups: none Adverse events How measured: as related to the intervention Time points measured: possibly at complete follow‐up Time points reported: narratively Subgroups: none Quality of life How measured: SF‐36 Health Survey scores Time points measured: before and after 2, 4 and 8 weeks of intervention Time points reported: before and after 2, 4 and 8 weeks of intervention (reported in table 4) Subgroups: none Other outcomes reported in the review: infection with H pylori, complete blood cell count and the blood levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen and creatinine
Funding	Possibly by the Institute of Medicinal Plants (Karaj, Iran) and Baqiyatallah University of Medical Sciences (Tehran, Iran)
Declaration of interest	The authors declare no conflicts of interest.
Notes	Phenolics, flavonoids, quercetin, rosmarinic acid, chlorogenic acid and antioxidant activity were quantified in the M. pulegium extract.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Block randomization with computer generated random number table and sequentially numbered containers each representing a block consisting of two patients was used for the treatment allocation.”
Allocation concealment (selection bias)	Low risk	"Three different persons generated the random allocation sequence, enrolled the patients and assigned them to interventions. These persons, care‐providers and patients were blinded to interventions."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Care providers and patients were blinded to interventions.” "The M. pulegium and placebo capsules were identical in all respects (to make the placebo capsules smell like the M. pulegium, essential oil was put in the placebo capsules containers)."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"Care providers and patients were blinded to interventions.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are available for nearly all participants (with the exception of 3 withdrawals from 103 randomized patients) for all results.
Selective reporting (reporting bias)	Low risk	The outcomes shown in the study protocol were reported in the article.
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: RCT Study dates: not available Setting and number of centres: outpatient, national Country: Lithuania
Participants	Inclusion criteria: non‐lactating and non‐pregnant, aged 18 to 70 years. Symptoms of functional dyspepsia were defined as per the Rome II. Exclusion criteria: patients with predominant reflux symptoms were considered to have non‐erosive gastroesophageal reflux disease (NERD), clinically relevant abnormalities in physical examination or laboratory screening tests with a history of peptic ulcer and/or reflux‐esophagitis at endoscopy or any evidence of significant hematological, hepatic, renal, cardiac, pulmonary, metabolic, and other structural diseases. Sample size: 132 randomized. Withdrawals: 16 (5 per each group prematurely withdrawn and 1 group 2 not treatment) Age (mean ± SD years): Group 1 (45.7 ± 11,9); Group 2 (42.9 ± 13); Group 3 (43.2 ± 14) Ethnicity by group: not stated. Sex (M/F) Group 1 (Control): 5 M/39 F Group 2 (Low dose): 4 M/39 F Group 3 (High dose): 9 M/35 F) Symptom severity at baseline: Gastrointestinal Symptom Rating Scale (GSRS) 15 questions using a scale from 1 (no discomfort at all) to 7 (very severe discomfort) Group 1: 2.61 ± 1.45 Group 2: 2.27 ± 1.09 Group 3: 2.66 ± 1.38
Interventions	Group 1 (n = 44): 40 mg astaxanthin: 5 capsules twice daily for 4 weeks Group 2 (n = 43): 16 mg astaxanthin: 5 capsules twice daily for 4 weeks Group 3 (n = 44): placebo. 5 capsules placebo twice daily for 4 weeks Co‐interventions: none
Outcomes	Adverse events How measured: as related to the intervention Time points measured: at complete follow‐up Time points reported: at complete follow‐up Subgroups: none Quality of life How measured: SF‐36 Healthy Survey (by sub‐item) Time points measured: weeks 0, 4, and 8 Time points reported: weeks 0, 4, and 8 Subgroups: none Other outcomes reported in the review: urea breath test by H pylori Global symptoms of dyspepsia were not measured: The study reported each symptom separately (using GSRS score) at baseline, week 4 and week 8. Divided results in abdominal pain, indigestion syndrome, reflux syndrome.
Funding	AZT Grant from Lund University (Grant 16x‐04723)
Declaration of interest	Dr. Ake Lignell was the representative of the sponsor, AstaReal AB. Other authors declare that the answer to the question on competing interest is No and therefore have nothing to declare. No dependence from funders to researchers occurred
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A computer‐generated random list with permuted blocks."
Allocation concealment (selection bias)	Low risk	"The patient number assigned corresponded to the treatment given and also appeared on the medication container and ran through numbers 001–132."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Intervention and placebo capsules were elaborated with identical characteristics. It is unclear if personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants were blinded with the use of placebo.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Data are available for almost all participants (with the exception of 16 withdrawals from 131 randomized patients) for all outcomes.
Selective reporting (reporting bias)	Unclear risk	Protocol not available.
Other bias	Low risk	The study does not appear to be affected by other sources of bias.

*Study characteristics*
Methods	Study design: parallel group randomized trial Study dates: not available Setting and number of centres: multicentre, outpatients, national Country: Germany
Participants	Inclusion criteria: participants aged 21 to 70 years; endoscopically confirmed functional dyspepsia with at least 6 months of persistent or recurrent symptoms (ulcer‐type and/or dysmotility‐type dyspepsia); no organic findings following upper GI endoscopy, abdominal sonography (both in preceding 6 weeks), and routine blood count and blood chemistry analysis; a baseline of at least 3 moderate to very severe dyspeptic symptoms Exclusion criteria: History of peptic ulcer disease and GERD; predominant symptoms of irritable bowel syndrome; predominant symptoms of GERD; any alarm symptoms (e.g. weight loss, black stool, dysphagia); cardiac, pulmonary, liver or kidney disease; surgical procedures in the gastrointestinal tract, excluding appendectomy, carried out more than 6 months previously; pregnancy or breastfeeding; current alcoholism or drug abuse; current intestinal or extraintestinal organic disease (e.g. cholangitis, pancreatitis, enteropathy, etc.); severe organic or psychiatric illness; allergies to one of the component substances in the trial medication (active medication); intake of any medication influencing the gastrointestinal tract; participation in another clinical trial less than 3 months previously; HIV positive status; malabsorption, maldigestion Sample size: 120 participants Withdrawals: 8 in total, Group 1 STW 5‐ll for 8 weeks = 0 Group 2 STW 5‐ll for 4 weeks followed by placebo = 4 in total, 2 due to no compliance, 1 because of a personal wish, 1 discontinued treatment due to insufficient efficacy. Group 3 4 weeks of placebo followed by STW 5‐ll = 3 in total, 1 due to adverse events, 1 discontinued treatment because of insufficient efficacy, and 1 because of complete relief of symptoms. Group 4 placebo for eight weeks = 1 in total discontinued treatment because of insufficient efficacy Age (mean ± SD years): Group 1 (STW 5‐ll): 44.1 ± 13.0; Group 2 (STW 5‐ll and placebo): 45.5 ± 13.2; Group 3 (placebo and STW 5‐ll): 43.8 ± 12.6; Group 4 (placebo): 45.2 ± 13.0 Ethnicity by group: not available Sex (M/F) Group 1 (STW 5‐ll): 21 F/9 M Group 2 (STW 5‐ll and placebo: 19 F/11 M Group 3 (placebo and STW 5‐ll): 24 F/6 M Group 4 (placebo): 21 F/9 M Symptom severity at baseline: GIS at baseline (mean ± SD): Group 1 (STW 5‐ll): 12.3 ± 4.7; Group 2 (STW 5‐ll and placebo): 12.1 ± 4.6; Group 3 (placebo and STW 5‐ll): 12.4 ± 3.8; Group 4 (placebo): 12.2 ± 3.9
Interventions	Treatment during the final 4‐week period was based upon the investigators’ judgements of treatment efficacy during the second 4‐week period of randomized treatment. In patients with appropriate control of symptoms, treatment with the compound they had received during the preceding 4 weeks was continued Group 1 (n = 30 ): STW 5‐ll =15 ml of Iberis amara totalis (1:2, 50% v/v ethanol), 30 ml of matricaria flower (1:3, 30% v/v ethanol), Liquiritiae radix, 10 ml and Melissae folium 15 ml, peppermint leaves (Menthae piperitae folium, 10 ml), caraway (Carvi fructus, 20 ml), and lemon balm (Melissae folium, 15 ml) per 100 ml (3 x 20 drops daily prior to meal) for 8 weeks. Group 2 (n =30 ): STW 5‐ll for 4 weeks followed by placebo Group 3 (n =30 ): placebo for 4 weeks followed by STW 5‐ll Group 4 (n =30 ): placebo for 8 weeks Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: GIS and Likert scale of each symptom (absent, 0; mild, 1; moderate, 2; severe, 3; very severe, 4) Time points measured: baseline, 4, 8 and 12 weeks. Time points reported: baseline, 4, 8 and 12 weeks. Subgroups: none Adverse events How measured: reported in follow‐ups. Time points measured: baseline, 4, 8 and 12 weeks. Time points reported: cumulative incidence Subgroups: none Other outcomes reported in the review: VAS used to determine the participant's global judgement of intensity of discomfort (ranging from 0 (no complaints) to 10 (most intense complaints) by diary cards.
Funding	Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
Declaration of interest	Not available
Notes	This study had a component of cross‐over. For the purpose of this review we included the first part of the randomization.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“A random code based on the method of permuted blocks, with a block size of four, was prepared in advance for each study center.”
Allocation concealment (selection bias)	Low risk	“Investigators had only numbered bottles and no allocation lists. Thus, patients, investigators and study centers maintained strict blinding.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“Investigators had only numbered bottles and no allocation lists. Thus, patients, investigators and study centres maintained strict blinding.”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	It is not clearly stated whether the clinicians who assessed the outcomes were blind.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Nearly complete data were available (8/120 patients were lost).
Selective reporting (reporting bias)	Unclear risk	Study protocol/registry unavailable.
Other bias	Low risk	No other sources of bias were identified.

*Study characteristics*
Methods	Study design: parallel‐group single‐blind randomized trial Study dates: not available Setting and number of centres: not available Country: not available
Participants	Inclusion criteria: symptom of dyspepsia and underwent esophagogastroduodenoscopy which revealed no ulcer or lesion explain the symptoms. Exclusion criteria: not available Sample size: 34 randomized Withdrawals: (number and reasons): not available Age (years): not available Ethnicity by group: not available Sex (M/F): not available Symptom severity at baseline: not available
Interventions	Group 1 (n = 12):Curcuma longa Group 2 (n = 10): omeprazole Group 3 (n=9): placebo Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: severity of dyspepsia assessment Time points measured: at baseline, 2 weeks and 6 weeks Time points reported: at baseline, 2 weeks and 6 weeks Subgroups: unclear Adverse events How measured: not available Quality of life How measured: not measured Other outcomes reported in the review: satisfaction score and pain score.
Funding	Not available
Declaration of interest	Not available
Notes	Abstract only.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not available ‐ abstract only
Allocation concealment (selection bias)	Unclear risk	Not available ‐ abstract only
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Not available ‐ abstract only
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Not available ‐ abstract only
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Not available ‐ abstract only
Selective reporting (reporting bias)	Unclear risk	Not available ‐ abstract only
Other bias	Unclear risk	Not available ‐ abstract only

*Study characteristics*
Methods	Study design: factorial parallel‐group randomized trial Study dates: February 1997 to June 1999 Setting and number of centres: multicentre, national, outpatient Country: Germany
Participants	Inclusion criteria: male or female outpatients, 21 to 70 years old; clinical diagnosis of functional dyspepsia of the dysmotility type, relapsing or with symptoms for over 6 months; 2 or more of the symptoms of the Gastrointestinal Symptom Score (GIS) had to be classified as moderate or more (exclusive the symptoms ‘acidic eructation/heartburn’ and ‘retrosternal pain’); echosonography of upper abdomen and endoscopy of the upper gastrointestinal tract did not show relevant disorders; written informed consent of the participant Exclusion criteria: known organic disease which could have explained the dyspeptic symptoms; reflux esophagitis, gastrointestinal tumours or findings suspicious of tumours, gastric or duodenal ulcer, acute erosive gastritis/duodenitis with more than 5 erosions; Whipple’s disease, diverticulitis, polyposis coli, ulcerative colitis, Crohn’s disease, diabetic or infectious enteropathy, food allergies, malabsorption, maldigestion; bulbus scars as signs of chronic ulcer; predominance of symptoms of an irritable bowel disease; relevant defecation frequency anomalies; mesenteric vascular disorders; cholecystitis, cholangitis; pancreas tumours, pancreatitis; thyroid disorders; relevant hepatic disea; diseases of the urogenital system; history of abdominal surgery (with exception of appendectomy, hysterectomy or cholecystectomy, when at least 6 months before study start, without complications and without connection to dyspeptic symptoms); history of gastrointestinal ulcers; abuse of laxatives, regular intake of NSAIDs; concomitant medication influencing the gastrointestinal tract Sample size: 186 Withdrawals: 10 STW‐5 group: adverse event (2) STW 5‐II group: participant's request (1); personal reasons (1) Cisapride group: participant's request (2); adverse event (3); lost to follow‐up (1) Age (mean, SD years) Group 1 (STW‐5): 44.2 ± 14.3; Group 2 (STW 5‐II): 42.9 ± 13.2; Group 3 (Cisapride): 47.9 ± 15.2 Ethnicity by group: not stated Sex (M/F): Group 1 (STW‐5): 29/32; Group 2 (STW 5‐II): 24/37; Group 3 (Cisapride): 24/37 Symptom severity at baseline: GIS sum score Group 1 (STW‐5): 14.3 ± 4.9; Group 2 (STW 5‐II): 13.9 ± 4.0; Group 3 (Cisapride): 14.0 ± 4.1
Interventions	Group 1 STW‐5 (n = 61): 20 drops of STW 5 plus cisapride‐placebo 3 times a day. STW‐5 composition: contains alcoholic extracts of Iberis amara, Angelicae radix, Cardui mariae fructus, Chelidonii herba, Liquiritiae radix, Matricariae flos, Melissae folium, Carvi fructus, and Menthae piperitae. Group 2 TW 5‐II (n = 61): 20 drops of STW 5‐ll plus cisapride‐ placebo 3 times a day. STW‐ll composition: Does not contain Angelicae radix, Cardui mariae fructus, and Chelidonii herba. Contains higher concentrations of the other plant extracts. Group 3 Cisapride (n = 61): tablet containing 10 mg cisapride plus 20 drops STW 5/5‐II‐placebo 3 times a day. Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: GIS Time points measured: day –7, Day 0, Day 14 and Day 28 Time points reported: day –7, Day 0, Day 14 and Day 28 Subgroups: “STW 5 and STW 5‐II showed a trend towards a higher efficacy than cisapride in the patients with a family history of functional dyspepsia” Adverse events How measured: adverse effects were assessed in each of the first 4 visits. Time points measured: Day –7, Day 0, Day 14 and Day 28 Time points reported: cumulative incidence Subgroups: none Other outcomes reported in the review: global efficacy evaluations by investigator and participant.
Funding	Steigerwald Arzneimittelwerk GmbH, Darmstadt.
Declaration of interest	Not available
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“A random code based on the method of permuted blocks with a block size of three was prepared in advance. This code allocated the patients randomly and symmetrically to the three treatment groups (STW 5, STW 5‐II, cisapride).”
Allocation concealment (selection bias)	Low risk	“Because STW 5 and STW 5‐II are liquid preparations and cisapride was only available as tablets, in this study a double‐dummy method was used. The placebos used were identical in appearance to the corresponding active medication and could not be distinguished from it.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“Patients, investigators, and study centres maintained strict blinding throughout the study."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	“Patients, investigators, and study centres maintained strict blinding throughout the study. The random code was not known and could not be accessed by anyone involved in study performance, study management, or data analysis”
Incomplete outcome data (attrition bias) All outcomes	Low risk	Nearly complete data for every outcome were reported; 10/186 participants were lost.
Selective reporting (reporting bias)	Unclear risk	Every outcome was reported. However, certain subgroup analyses were not reported. Registry was unavailable.
Other bias	Low risk	No other sources of bias were identified.

*Study characteristics*
Methods	Study design: multicentre, randomized, double‐blind trial. Study dates: September 1987 to May 1988. Setting and number of centres: outpatient, multicentre (1 provincial hospital and 5 community hospitals in various parts of Thailand) Country: Thailand
Participants	Inclusion criteria: 12 years old or older and inflicted with dyspepsia syndrome, acid dyspepsia, flatulent dyspepsia, or atonic dyspepsia Exclusion criteria: pregnant, had gut obstruction or severe abdominal pain, gastrointestinal infection, cholecystitis, hepatitis, pancreatitis, appendicitis, or peritonitis. Sample size: 116 included in the study. Loss to follow‐up: Group 1 3/39; Group 2/36 6; Group 3 1/41 Age (mean years): Group 1 (42); Group 2 (48); Group 3: (41) Ethnicity by group: not available Sex (M/F): Group 1 (18/21); Group 2 (19/17); Group 3: (22/19) Symptom severity at baseline: not available.
Interventions	Group 1 (n = 39):Curcuma longa (Curcuma domestica val) (powder form of dried rhizome, 250 mg, containing 0.02 ml of volatile oil and 0.024 g of total curcuminoids per capsule) 2 capsules 4 times a day for 7 days. Group 2 (n = 36): flatulence (cascara dry extract 65 mg, nux vomica dry extract 16 mg, asofoetida tincture 0.325 mg, capsicum powder, 8 mg, ginger powder 48 mg and diastase 3 mg) for 7 days. Group 3: (n = 41): placebo (starch powder) 2 capsules 4 times a day for 7 days Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: not mentioned how global symptomatology was measured, even though the results are according to response (cured, improved, not improved, worse). Time points measured: daily by self‐report (postcard) for 7 days Time points reported: end of treatment (7 days) Subgroups: none Adverse events How measured: unclear Time points measured: daily by self‐report (postcard) for 7 days Time points reported: end of treatment Subgroups: none Other outcomes reported in the review: satisfaction and compliance of treatment
Funding	German agency for technical cooperation (GTZ)
Declaration of interest	not available
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Participants were assigned by simple randomization (no other details provided).
Allocation concealment (selection bias)	Unclear risk	No details on allocation concealment were mentioned in the article.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	It was only mentioned that all medications were in identical capsules.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants were blinded using placebo.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The study results of the 106 participants with complete follow‐up are shown (116 randomized).
Selective reporting (reporting bias)	Unclear risk	No protocol available.
Other bias	Unclear risk	The article does not mention how the outcomes were measured.

PERMALINK

Non‐Chinese herbal medicines for functional dyspepsia

Germán Báez

Camila Vargas

Marcelo Arancibia

Cristian Papuzinski

Juan VA Franco

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Summary of findings 1. STW5 (Iberogast) compared to placebo for functional dyspepsia.

Summary of findings 2. Peppermint/caraway oil compared to placebo for functional dyspepsia.

Summary of findings 3. Curcuma longa compared to placebo.

Summary of findings 4. Other herbal medicines compared to placebo.

Summary of findings 5. Herbal medicines compared to other treatments.

Background

Description of the condition

Description of the intervention

1. Herbal medicinal products for treatment of dyspepsia.

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Assessment of bias in conducting the systematic review

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Reaching conclusions

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

Included studies

Study design and setting

Country of origin

Participants

Interventions

Comparisons

Outcomes

Funding

Excluded studies

Studies awaiting classification

Ongoing studies

Risk of bias in included studies

2.

Allocation

Random sequence generation

Allocation concealment

Blinding

Performance bias

Detection bias

Incomplete outcome data

Selective reporting

*Study characteristics*
Methods	Study design: double‐blind, randomized, multicentre trial Study dates: unknown Setting and number of centres: multicentre, outpatient Country: Germany
Participants	Inclusion criteria: FD according to ROME criteria Exclusion criteria: not available Sample size: 272, no information regarding sample size calculation is available Withdrawals: not available Age (mean ± SD years) Not available. Text only mentions that both groups are comparable. Ethnicity by group Not stated Sex (M/F) Not stated. Text only mentions that both groups are comparable. Symptom severity at baseline: GIS (mean ± SD) Group 1: (11.9 ± 3.66) Group 2: 12.1 ± 4.0
Interventions	Group 1: 3 x 20 drops/day of STW 5‐II Group 2: same posology of placebo Co‐interventions: none
Outcomes	Global symptoms of dypepsia How measured: Gastrointestinal Symptom Score (GIS) Time points measured: not available Time points reported: 8 weeks Adverse events How masured: narratively Time points measured: not available Time points reported: possibly at complete follow‐up
Funding	Unknown
Declaration of interest	Unknown
Notes	Only congress abstract is available
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No informartion (only abstract available).
Allocation concealment (selection bias)	Unclear risk	No informartion (only abstract available).
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Text only states that this is a double‐blinded study (only abstract available).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Text only states that this is a double‐blinded study (only abstract available).
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Only abstract is available; therefore, complete outcome data are not published.
Selective reporting (reporting bias)	Unclear risk	Protocol not available (only abstract available).
Other bias	Unclear risk	Only abstract available.

*Study characteristics*
Methods	Study design: parallel‐group randomized trial Study dates: not available Setting and number of centres: multicentre, outpatients, national Country: Germany
Participants	Inclusion criteria: presence of “moderate” as the degree of severity for at least 3 Gastrointestinal Symptom (GIS) score, epigastric pain or discomfort was required to have persisted in a permanent or recurrent form for a minimum period of 12 wk before the initial examination. Exclusion criteria: esophagogastroduodenoscopy and other routine examinations which indicate any clinically relevant organic disease; the relief of dyspeptic symptoms exclusively through evacuation or in relation to change in stool frequency or form permitted as a clinical sign of irritable bowel syndrome. Sample size: 315 Withdrawals: 46; 15 due to adverse effects, 8 in the study group and 7 in the control group. 6 because of lack of compliance, 2 in the study group and 4 in the control group. 5 due to private reasons, 3 in the study group and 2 in the other. 12 for other reasons, 7 in the study branch and 5 in the control one. Another 8 participants were lost in the follow‐up of the last visit, 4 in each branch. Age (mean, SD, years): Group 1 (Study): 49.3 ± 15.2; Group 2 (Control): 48.9 ± 15.9 Ethnicity by group: not reported Sex (M/F): Group 1 (Study): 52/105; Group 2 (Control): 51/100 Symptom severity at baseline: GIS sum score Group 1 (Study): 11.6 ± 3.5; Group 2 (Control): 11.9 ± 4.3
Interventions	Group 1 (n = 158 ): 3 x 20 drops daily of STW5 for 8 weeks. Every 100 ml: alcoholic fresh plant extract (extraction agent 50% ethanol by volume) from Iberis amara totalis 1 : 2 15.0 mL alcoholic drug extracts (extraction agent 30% ethanol by volume) from Angelicae radix 1 : 3 10.0 mL Cardui mariae fructus 1 : 3 10.0 mL Carvi fructus 1 : 3 10.0 mL Chelidonii herba 1 : 3 10.0 mL Liquiritiae radix 1 : 3 10.0 mL Marticariae flos 1 : 3 20.0 mL Melissae folium 1 : 3 10.0 mL Menthae piperitae folium 1: 3 5.0 mL Group 2 (n = 157): Placebo, drops for 20 weeks. Co‐interventions: none
Outcomes	Global symptoms of dyspepsia How measured: GIS Time points measured: baseline and after 14, 28, and 56 days. Also after 8 months. Time points reported: baseline and after 14, 28, and 56 days. Also after 8 months. Subgroups: none Quality of life Not measured Adverse events How measured: any side effects from their medications were recorded at each follow‐up. Time points measured: baseline and after 14, 28, and 56 days. Also after 8 months. Time points reported: cumulative incidence Subgroups: none Other outcomes reported in the review: secondary target variables comprised the overall efficacy and tolerability of the 8‐wk treatment with STW 5 or the placebo, assessed by investigator and participant using a 6‐point Likert scale ranging from very good (1) to very poor (6)
Funding	Steigerwald Arzneimittelwerke GmbH, Darmstadt, Germany.
Declaration of interest	Dr Bettina Vinson is an employee of Steigerwald Arzneimittelwerke GmbH, Darmstadt, Germany
Notes	None
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Block randomization was performed over all centers without stratification. The randomization list for the study with a parallel‐group design with two independent treatment groups was elaborated using the randomization program IDVRANCODE 3.6. Block size was 4”
Allocation concealment (selection bias)	Low risk	“For blinding, an alcoholic tincture identical to the verum drug in organoleptic properties was manufactured. Organoleptic means that color, smell, taste, viscosity, and alcohol content are identical in the STW 5 preparation and placebo”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“This is the largest double‐blind, randomized, placebo‐controlled multicenter study with STW 5 in F” “For blinding, an alcoholic tincture identical to the verum drug in organoleptic properties was manufactured”
Blinding of outcome assessment (detection bias) All outcomes	Low risk	“The investigator’s allocation of study medication was blind, being supervised by Harrison Clinical Research GmbH, Munich.”
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Most of the data for each outcome were reported. There were 46/315 dropouts
Selective reporting (reporting bias)	Unclear risk	Every outcome was reported that was declared in the method, but the protocol was unavailable.
Other bias	Low risk	No other sources of bias were detected.

Study	Reason for exclusion
ACTRN12619001236189	Ineligible population: participants with gastrointestinal symptoms in general (not restricted to dyspepsia).
ACTRN12621000116820	Ineligible study population: healthy volunteers
Arai 2011	Ineligible intervention: Kampo herbal medicine
Arai 2012	Ineligible intervention: Kampo herbal medicine
Asha 2017	Ineligible study design: non‐randomised trial
Asif 2015	Ineligible population: people with no functional dyspepsia
Aydin 1997	Ineligible study design: non‐randomised trial
Barnick 1990	Ineligible population: people with no functional dyspepsia
Bekar 2011	Ineligible intervention: triple therapy for the erradication of Helicobacter pylori
Bommer 2013	Ineligible study design: single‐arm trial of Boldocynara (a proprietary combination product consisting of artichoke leaves, milk thistle fruits, dandelion herb and root, and boldo leaves).
Choi 2011	Ineligible intervention: Korean herbal medicine
Choi 2020	Ineligible intervention: Chinese herbal medicine ("crude medicine for abdominal symptoms in East Asia since the Ming Dynasty of China")
CTRI/2022/03/041419	Wrong patient population: diabetic gastroparesis.
Di 2007	Ineligible study design: single‐arm study
Dimitrov 1983	Ineligible population: people with no functional dyspepsia
Dos 2010	Ineligible population: people with no functional dyspepsia
Du 2014	Ineligible intervention: Chinese herbal medicine
Eady 2019	Ineligible population: people with no functional dyspepsia
Fuhrer 2011	Ineligible study design: this study tested capsaicin as a diagnostic test for people with dyspepsia.
Gao 2007	Ineligible intervention: Chinese herbal medicine
Gasbarrini 2010	Ineligible intervention: cold dessert
Gong 2019	Ineligible intervention: teprenone (antiinflammatory drug)
Guo 2011	Ineligible intervention: Chinese herbal medicine
Guo 2014	Ineligible intervention: Chinese herbal medicine
Hajiaghamohammadi 2016	Ineligible population: people with no functional dyspepsia
Hashem‐Dabaghian 2016	Ineligible study design: non‐randomised trial
IRCT20110310006026N9	Randomised clinical trial protocol with an ineligible population (people with Helicobater pylori but with no functional dyspepsia)
IRCT2017022332738N1	Randomised clinical trial protocol with a Chinese herbal medicine
IRCT20170317033107N3	Randomised clinical trial protocol which only includes people with migraine associated with functional dyspepsia
IRCT20200128046288N3	Randomised clinical trial protocol which only assesses reflux related symptoms
Ivashkin 2022	Ineligible patient population: case mix with IBS (no dissagregated data for functional dyspepsia).
Kammerer 2001	Ineligible study design: narrative review
KCT0003761 2019	Randomised clinical trial protocol which assesses a Chinese yam extract
KCT0004085 2019	Randomised clinical trial protocol which assesses a Chinese herbal medicine
KCT0005265 2020	Randomised clinical trial protocol which assesses a Chinese herbal medicine
Kelber 2017	Ineligible study design: systematic review
Kim 2010	Ineligible intervention: Chinese herbal medicine
Labenz 2023	Ineligible patient population: only people with heartburn.
Lacy 2022	Ineligible study design: observational study of caraway oil and L‐menthol.
Lee 2020	Ineligible population: people with no functional dyspepsia
Lopresti 2018	Ineligible population: participants with gastrointestinal complaints (not functional dyspepsia)
Marakis 2002	Ineligible population: healthy people with dyspeptic complaints (not functional dyspepsia)
Meier 2005	Ineligible study design: non‐randomised trial
Metugriachuk 2008	Ineligible study design: the study refers to randomisation but there is no control group (they used a matched control group of healthy individuals)
Mihai 2019	Ineligible intervention: probiotic
Muss 2013	Ineligible population: participants had irritable bowel syndrome (not functional dyspepsia)
NCT04593836	Randomised clinical trial protocol with an ineligible population
Nili‐Ahmadabadi 2017	Ineligible population: people with no functional dyspepsia
Pasalar 2015a	Ineligible study design: the objective of the study was to assess the effect of the drug on depressive symptoms
Shim 2015	Ineligible intervention: Korean herbal medicine
Shim 2019	Ineligible population: people with no functional dyspepsia
Wang 2017	Ineligible intervention: Chinese herbal medicine
Xiao 2013	Ineligible population: children

Methods	Parallel group randomized trial
Participants	Not available
Interventions	Not available
Outcomes	Not available
Notes	Neither the full text nor the abstract are available.

Methods	Randomized, paralle‐group, active‐controlled trial
Participants	People with functional dyspepsia and people with gastro‐esophageal reflux disease with esophagitis
Interventions	Pudin hara antacid suspension
Outcomes	Any improvement or relief from clinical symptoms related to acidity at the end of 2 weeks and 4 weeks or by the resolution of symptoms whichever stands early. 2 and 4 weeks.
Notes

Methods	Not available.
Participants	Not avaialable.
Interventions	Red pepper, no details of the interventions or groups are available.
Outcomes	Not available.
Notes	Neither the full text nor the abstract are available.

Methods	Study design: controlled clinical trial Study dates: not available Setting and number of centres: unknown Country: India
Participants	Not available.
Interventions	Group 1 (study): garlic‐omeprazole combined therapy Group 2 (control): standard quadruple therapy Co‐interventions: omeprazole
Outcomes	Not available.
Notes	Neither the full text nor the abstract are available. The main outcome was most likely erradication of H pylori.

Methods	Study design: clinical study Study dates: not available. Setting and number of centres: not available Country: not available
Participants	Sample size: 553; there was no information available regarding the reason for the sample size.
Interventions	Group 1 (study): artichoke (Cynara scolymus)
Outcomes	Not available
Notes	Neither the full text nor the abstract are available. No information on what the comparison was, or if this was a one‐branch study.

Methods	Randomized, double‐blind, placebo‐controlled clinical trial
Participants	Helicobacter pylori as the cause of diseases classified elsewhere
Interventions	Intervention 1: Intervention group: routine treatment (Omeprazole 20 mg + Amoxicillin 1 g+ Clarithromycin 500 mg BID) + herbal soft capsule containing essential oil of Satureja hortensis BID for two weeks orally. Intervention 2: Control group: routine treatment (Omeprazole 20 mg + Amoxicillin 1 g + Clarithromycin 500 mg BID) + placebo soft capsule BID for two weeks orally.
Outcomes	Clinical signs. Timepoint: before the intervention, two weeks after the initial intervention. Method of measurement: questionnaire. The eradication rate of Helicobacter pylori. Timepoint: 1 month after the end of treatment. Method of measurement: stool antigen for Helicobacter pylori
Notes

Methods	Randomized controlled trial
Participants	Inclusion: People aged 18 to 60 years, with functional dyspepsia (based on ROME IV syndrome) Exclusion: history of a gastrointestinal ulcer or reflux disease with natural endoscopy without specific pathologic findings, underlying diseases including heart failure, hypertension, renal failure and uremic disease, cirrhosis; history of abdominal surgery; any malignancy or individuals NSAIDs are used, having a history of chemotherapy and radiotherapy or exposure to radiation. Use of any other herbal medicine; pregnancy and lactation; positive urea breath test for Helicobacter pylori infection
Interventions	Intervention group: capsules containing Ghors‐Vard 3 times daily (after meals) for 1 month. Control group: placebo capsules 3 times daily (after meals) for 1 month.
Outcomes	Clinical symptoms of people with functional dyspepsia
Notes	The status of the trial and the components of the intervention (the polyherbal preparation) are unclear.