Disorders of gut-brain interaction (DGBIs), previously called functional gastrointestinal (GI) disorders, are a group of disorders with chronic symptoms relating to motility disturbance, visceral hypersensitivity and altered CNS processing, as well as probable altered gut mucosal and immune function and altered gut microbiota, in the absence of structural and inflammatory causes. Examples of DGBIs include irritable bowel syndrome (IBS), functional dyspepsia (FD), and its subtypes postprandial distress syndrome and epigastric pain syndrome.^1,2 Despite advances in understanding of DGBIs, there is a need for novel therapies, particularly for upper GI DGBIs such as FD.³

Buspirone is an azapirone that acts as a partial agonist at the post-synaptic serotonin 5-hydroxytryptamine 1a receptor. It also exerts weak antagonist effects at pre-synaptic dopamine D2 auto-receptors and partial agonist effects at α-1 noradrenergic receptors.⁴ It has known benefit for depression and anxiety, believed to be primarily via its central serotonergic effects.^5,6 In recent years, buspirone has also shown promise as a treatment for DGBIs, with beneficial effects on fundal accommodation and improved symptoms of FD.⁷ Buspirone is particularly promising given the increasingly clear role of visceral hypersensitivity in patients diagnosed with either FD or gastroparesis,⁸ as well as the limitations of prokinetic therapies.³ To date, however, there has been no meta-analysis testing the effect of buspirone on FD or other DGBIs.

In this systematic review and meta-analysis, we analyzed the specific effects of buspirone on upper GI DGBIs, such as FD. The secondary aim was to establish the effect of anxiety and depression symptoms in patients with DGBIs.

The development of this systematic review was directed by the standards of the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Statement.⁹ Studies were analyzed to ensure that they met the review criteria, and randomized controlled trials (RCTs) that had adequate data were pooled for meta-analysis.

Study Selection

Studies that met the following criteria were included: (1) participants had a diagnosis of an upper GI DGBI according to Rome criteria; (2) study type was RCT, non-RCT, case-control study, prospective and retrospective observational study, case series, or case report; (3) participants were prescribed buspirone (at any dose) in the study; and (4) the effect on GI symptoms was evaluated using a validated questionnaire.

The exclusion criteria for the studies analysed were: (1) study examined the effect of buspirone on healthy volunteers only; (2) study analysed the effect of buspirone on animal models; (3) study recruited a paediatric population, defined as participant age < 18 years; and (4) study was a review article and did not exhibit original data.

Study Extraction

The following databases were systematically searched for studies published from inception to 15th September 2023: Cochrane, PubMed, Scopus, and American Psychological Association PsycInfo. The text ‘Buspirone AND’ followed by the following GI phrases were entered into the search box: ‘vomiting,’ ‘dyspepsia,’ ‘nausea,’ ‘globus,’ ‘dysphagia,’ ‘gastroparesis,’ ‘belching,’ ‘irritable bowel,’ ‘constipation,’ ‘diarrhoea,’ ‘bloating,’ ‘abdominal pain,’ ‘faecal incontinence,’ ‘anorectal pain,’ and ‘abdominal migraine.’

The literature search was carried out by 2 authors (Z.M. and C.D.M.) and any disparities in studies regarding inclusion and exclusion settled through discussion. The titles and abstracts identified during the search were also separately vetted to ensure eligibility for this review. Data extraction was carried out once studies that were to be included were selected.

Data Extraction

The following data was extracted for each study: author name, year of study, country of study, study setting, study type, average age of participants, total number of participants, total number in buspirone group, DGBI type, concomitant medication, control medication, baseline psychiatric status, buspirone dose, duration of buspirone treatment, post-treatment scores for GI symptoms/depression/anxiety, P-values for post-treatment between-group comparisons, as well as frequencies of incident adverse events.

Risk of Bias Assessment

Study quality was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group (CCDAN) instrument.¹⁰ The scale consists of 23 items, each scored 0-2 and each contributing equally to a final score between 0 and 46, higher scores indicating higher quality. The CCDAN covers aspects of both internal validity (or control of bias) and external validity. A cut-off score of more than 20 has been suggested to identify high-quality studies.¹¹ We modified item 10, “Outcome Measures”, as follows: 0 = no Rome DGBI diagnosis; 1 = Rome DGBI diagnosis but no severity scale; and 2 = Rome DGBI diagnosis and severity scale.

Outcomes

The primary outcome was the effect of buspirone on upper GI symptoms. The secondary outcomes were anxiety and depression symptoms, as well as incident adverse events.

Measures of Effect

The effect size estimates for each study were calculated using the standardized mean difference (SMD) in GI symptoms after treatment between buspirone treatment and control treatment. Negative SMDs favored buspirone, whereas positive SMDs favored controls. The same was done for our secondary outcomes of depression and anxiety symptoms.

Statistical Methods

We performed separate meta-analyses for any specific DGBI (eg, FD) that was analysed by at least 2 comparable studies. Studies were weighted using an inverse-variance method, where studies with larger precision are afforded greater weight. Pooled effect estimates were calculated using a random-effects model.¹² Analyses were performed using STATA version 18.0 (StataCorp LLC, College Station, TX, USA). Poor quality studies were not included in meta-analysis.

Heterogeneity

Heterogeneity between studies was quantified by calculating the I²-statistic, I² between 25%, 50%, and 75% suggesting low, moderate, and high heterogeneity, respectively.¹³ Moderate and high heterogeneity were explored using subgroup analysis by treatment duration (≥ 4 weeks only), buspirone daily dose (total ≥ 30 mg/day only) and type of controls (placebo only). We did not assess for publication bias due to the small number of studies in the meta-analyses.

An initial total of 472 studies were retrieved from the initial database searches. After screening the titles for relevance and excluding duplicates, 92 full-text articles were reviewed, of which 10 articles (n = 283 patients total) were included (Table 1). Figure 1 shows the PRISMA flow diagram of the search.

Figure 1. PRISMA flow diagram outlining the systematic review stages. DGBI, disorder of gut–brain interaction; GI, gastrointestinal; RCTs, randomized controlled trials.

Table 1 . Summary Characteristics of Included Studies

Author year	Country	Setting	Study type	Average age of participants (yr)	Total No.	Total No. in buspirone group	GI condition	Control	Concomitant medication	Baseline psychiatric status
Aggarwal, 2018	USA	OP	Double-blind RCT (crossover)	52.7 (9.3)	10	10 (crossover study)	Functional dysphagia/IEM	Matched placebo		NR
Alianova, 2019	Ukraine	OP	Unblinded RCT	NR (range 18-45)	63	34	PDS (subtype of FD) and all H.pylori positive	H.pylori eradication therapy both groups		No selection: 40% had clinically significant anxiety
Ambros, 2023	Brazil	OP	N-of-1 trial	36	1	1	Gastric glitch (proposed new subtype of FD)	Prucalopride and placebo (compared individually)		NR
Caviglia, 2017	Italy	OP	Real world study with patients retrospectively recruited	49.9 (NR)	59	32	FD	3 separate treatment groups: buspirone vs amitriptyline vs debopride		NR
Parkman, 2023	USA	OP	Double-blind RCT		96	47	Symptoms of gastroparesis with at least moderately severe symptoms of early satiation and/or postprandial fullness; normal upper GI endoscopy; could have normal or delayed gastric emptying	Matched placebo	72% taking PPI, 26% prokinetics, 51% antiemetics, 45% antidepressants, 63% other neuromodulators (regular opiate users excluded)	No selection: 39% had major depression or anxiety
Radetic, 2019	USA	OP	Case report	60	1	1	FD with rapid gastric emptying	Nil		NR
Singh, 2021	USA	OP	Case series	61.0 (17.1)	5 (1 per case)	5 (1 per case)	EPS (n = 1), PDS (n = 2) or mixed (n = 2) - all post-fundoplication	None	1 amitriptyline 10 mg, 1 mirtazapine 15 mg	1 reported anxiety
Sadiku, 2020	USA	IP	Case report	58	1	1	FD/gastroparesis	Metoclopramide 5 mg QDS, ondansetron 4 mg QDS, famotidine 20 mg BD		NR
Tack, 2012	Belgium	OP	Double-blind RCT (crossover)	38.5 (2.4)	17	17 (crossover study)	FD	Matched placebo		Excluded if current anxiety or depression or treated with antipsychotics or antidepressants during last 6 weeks
Taghvaei, 2021	Iran	OP	Double-blind RCT	NR	30	18	FD	Matched placebo		No selection: baseline HADS score 22.11 in buspirone group, 25.23 in placebo (no significant difference)

GI, gastrointestinal; USA, United States of America; OP, outpatient; RCT, randomized controlled trial; NR, not reported; IEM, ineffective esophageal motility; PDS, post-prandial distress syndrome; FD, functional dyspepsia; EPS, epigastric pain syndrome; H. pylori; Helicobacter pylori; OD, once daily; BD, twice daily; PPI, proton pump inhibitor; HADS, Hospital Anxiety and Depression Scale.

Data are presented as mean (SD) or n.

Randomized Controlled Trials

Five RCTs were included.^7,14-17 Of these, 4 were placebo-controlled,^7,14,16,17 whilst 1 study was controlled with Helicobacter pylori eradication therapy in both groups.¹⁵ All recruited patients with persistent upper GI symptoms, of which 2 recruited participants with FD,^7,17 1 both FD and ineffective esophageal motility,¹⁴ and 1 moderate-to-severe early satiation and postprandial fullness along with other symptoms suggestive of a gastric origin (nausea, fullness, bloating, and epigastric pain) for at least 3 months (Table 1).¹⁶ Treatment duration was generally limited: only 1 study treated for longer than 4 weeks.¹⁷ Findings were mixed: 2 found significant benefit of buspirone over controls,^7,15 and 3 found no benefit for primary symptom outcomes (Table 2).^14,16,17

Table 2 . Summary of Treatment and Outcomes for Included Studies

Study	Buspirone dose	Duration of treatment	Between group comparisons (mean ± SD, P-value for between-group differences)	Effect on psychiatric outcomes	Adverse effects reported
Aggarwal, 2018	10 mg TDS	2 weeks	Compared to placebo, buspirone did not improve dysphagia severity score (2.9 ± 0.99 vs 2.6 ± 0.7, P = 0.28); Dysphagia frequency score (3.9 ± 1.9 vs 3.9 ± 1.1, P = 0.72) or GERD-HRQL score (26.4 ± 22.2 vs 20.3 ± 16.6, P = 0.30)	NR	Mild nausea that resolved after 3 days (n = 1)
Alianova, 2019	10 mg TDS	14 days	Buspirone produced 85.2% reduction of post-prandial heaviness vs 34.5% in controls (no P-value). Rate of symptom recurrence at 30 days was 13.8% in buspirone group vs 80% in controls (P < 0.001).	82.3% decrease in anxiety level in buspirone group vs 20.6% in controls (P < 0.001)	NR
Ambros, 2023	10 mg TDS	63 days but given only 5 times in study before wine challenges	Borderline significant improvement in mean pain score after wine challenges in buspirone group vs controls (2.2 [0.6-3.7] vs 4.8 [2.1-7.4], P = 0.051); no difference between prucalopride and placebo (P = 0.091)	NR	Nausea, diarrhoea, drowsiness on 1st administration but no significant association when compared to placebo
Caviglia, 2017	10 mg BD	3 months	Compared to placebo, lower number of patients reporting severe early satiation (50% pre-treatment to 6.3% after treatment, P < 0.001) but no difference in post-prandial fullness (P = 0.16), epigastric pain (P = 0.41) or epigastric burning (P = 0.21)	NR	Dizziness (6.3%)
Parkman, 2023	10mg TDS	4 weeks	Compared to placebo, no difference in GCSI ES/PPF subscore (–1.03 ± 1.19 vs –1.16 ± 1.25, P = 0.69) (primary outcome); Compared to placebo, buspirone improved ANMS Gastroparesis Cardinal Symptom Index Daily Diary improvement in feeling excessively full after meals (–0.82 ± 1.03 vs –0.31 ± 0.84, P = 0.01) but no difference in early satiation/postprandial fullness (–0.71 ± 1.03 vs –0.39 ± 0.71, P =0.10) or feeling unable to finish a normal-sized meal (–0.62 ± 1.10 vs –0.46 ± 0.76, P = 0.43), nor in PAGI-SYM items of stomach fulness (P = 0.76), excessive fullness after a meal (P = 0.64), inability to finish meal (P = 0.66) or loss of appetite (P = 0.70)
Radetic, 2019	10 mg TDS	1 week	Subjective complete resolution of nausea, vomiting, early satiation and diarrhoea	NR	NR
Sadiku, 2020	10 mg TDS	3 days	Improvement in vomiting, nausea and epigastric after 3 days of buspirone but not quantified	NR	NR
Singh, 2021	10 mg OD	2-5 years	Subjective improvement in pain, nausea or bloating in 3/5 patients	Not quantified though 1 reported improvement in anxiety	NR
Taghvaei, 2021	5 mg TDS 1 month, 10 mg TDS 2nd month	2 months	SF-LDQ score 5.72 ± 5.16 buspirone vs 5.33 ± 7.30 placebo (P = 0.86)	HADS depression score 6.05 ± 4.59 vs 7.16 ± 5.13 (P = 0.54); HADS anxiety score 7.72 ± 4.87 vs 9.58 ± 3.70 (P = 0.27)	In buspirone group, increased appetite (15%), drowsiness (20%), and fatigue (5%). In placebo group, increased appetite (10%) and dry mouth (10%)
Tack, 2012	10 mg TDS	4 weeks (crossover study)	Compared to placebo, buspirone improved DSS score (7.5 ± 5.4 vs 9.5 ± 4.5, P = 0.05), post-prandial fullness (1.3 ± 1.2 vs 1.9 ± 0.8, P < 0.05), total meal-related symptom score (67 ± 17 vs 97 ± 15, ) P < 0.01); meal-related postprandial fullness (23 ± 20.6 vs 14 ± 20.6, P < 0.05) and upper abdominal bloating (22 ± 20.6 vs 14 ± 16.5, P < 0.05)	NR – study excluded patients with depression or anxiety or psychiatric background by doing SCL-90R scores at baseline, these scores not repeated post-buspirone treatment	No significant adverse effect compared to placebo - comparable, specific adverse effects not mentioned

TDS, 3 times daily; BD, twice daily; OD, once daily; GERD-HRQL score, Gastroesophageal Reflux Disease–Health-related Quality of Life score; GCSI, Gastroparesis Cardinal Symptom Index; ES/PPF subscore, early satiety/postprandial fullness subscore; SF-LDQ score, Short-Form Leeds Dyspepsia Questionnaire score; DSS score, Dyspepsia Symptom Severity score; NR, not reported; HADS, Hospital Anxiety and Depression Scale; SCL-90R score, Symptom Checklist 90 score (questionnaire to screen for range of psychological symptoms).

Of these 5 RCTs, data from 3 good-quality studies (see below for quality assessment) contributed to meta-analysis.^7,16,17 We performed meta-analysis of functional dyspepsia symptoms based on 3 studies, 2 of which defined FD using Rome IV criteria,^7,17 and 1 recruited patients with gastroparesis symptoms with or without delayed gastric emptying.¹⁶ In random-effects meta-analysis of these studies, buspirone produced a non-significant improvement in FD/gastroparesis symptoms compared to placebo (SMD = –0.14; 95% CI, –0.44 to 0.17; P = 0.39; I² = 0%) (Fig. 2). All studies used the same dose of buspirone (30 mg/day) and all treated for at least 4 weeks. Of the individual symptoms reported quantitatively by more than 1 study, buspirone improved bloating severity more than placebo (SMD = –0.41; 95% CI, –0.77 to –0.04; P = 0.03; I² = 0%; N_studies = 2) (Fig. 3A) but did not improve post-prandial fullness (SMD = –0.25; 95% CI, –0.66 to –0.16; P = 0.24; I² = 23%; N_studies = 2) (Fig. 3B) or nausea severity (SMD = –0.06; 95% CI, –0.44 to 0.31; P = 0.75; I² = 0%; N_studies = 2) (Fig. 3C). Only 1 study reported data on early satiation, such that meta-analysis could not be performed.

Figure 2. Forest plot showing post-treatment differences between buspirone and placebo in functional dyspepsia/gastroparesis symptoms.

Figure 3. Forest plots showing post-treatment differences between buspirone and placebo in individual upper gastrointestinal symptoms: (A) bloating severity, (B) postprandial fullness, and (C) nausea severity. REML, restricted maximum likelihood.

Secondary Outcomes

One RCT found no difference between buspirone and placebo for post-treatment depression or anxiety symptoms.¹⁷ Data on secondary outcomes were insufficient for meta-analysis.

Risk of Bias

Of the 5 RCT’s, the 3 with sufficient data for meta-analysis were all good quality. As such, none were excluded from meta-analysis (Table 3).

Table 3 . Modified Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group Scores for Included Trials

	Item	Aggarwal 2018	Alianova 2019	Parkman 2023	Tack 2012	Taghvaei 2021
1	Objectives	2	2	2	2	2
2	Adequate sample size	0	0	0	0	0
3	Appropriate duration of follow-up	0	0	0	0	0
4	Power calculation	2	0	2	2	1
5	Method of allocation	2	1	2	1	2
6	Concealment of allocation	0	1	2	0	2
7	Clear description of treatment	1	1	2	1	1
8	Blinding of subjects	1	0	1	1	1
9	Source of subjects and recruitment	0	1	1	0	1
10	Use of diagnostic criteria	1	1	0	2	2
11	Record of exclusion criteria	1	1	1	1	1
12	Description of sample demographics	0	1	2	0	2
13	Blinding of assessor	1	0	1	1	1
14	Assessment of compliance	2	0	2	0	0
15	Details on side-effects	2	0	2	0	1
16	Record of withdrawals	2	0	2	2	2
17	Outcome measures	2	2	2	2	2
18	Comparability and adjustment for differences	2	2	2	2	2
19	Intention-to-treat analysis	2	0	2	0	0
20	Presentation of results	2	1	2	2	2
21	Appropriate statistical analysis	1	1	2	1	1
22	Conclusions justified	2	2	2	2	2
23	Declaration of interests	2	0	2	2	2
Total score (/46)		30	17	36	24	30
		65%	37%	78%	52%	65%

Non-randomized or Open-label Trials

In an N-of-1 double-blind clinical trial in a patient with FD,¹⁸ pain scores were assessed during a wine challenge after administration of buspirone or placebo. The authors reported borderline significant benefits of buspirone for pain compared to placebo. Our secondary outcomes were not assessed.

Cohort Studies

A cohort study looking at patients with FD found there was a significant improvement in early satiation scores after treatment with buspirone,¹⁹ but no significant improvement was found for post-prandial fullness, epigastric pain, or epigastric burning.

Case Series and Reports

We included 1 case series with 5 patients all post-fundoplication, of whom 1 had epigastric pain syndrome, 2 had postprandial distress syndrome and 2 had mixed symptoms. All were treated with buspirone for a period of 2-5 years.²⁰ This series found that 3 out of the 5 patients found an improvement in GI symptoms (pain, nausea, epigastric fullness, and bloating). In addition, we included 2 case reports. In 1 case of FD and rapid gastric emptying,²¹ treatment with buspirone led to complete resolution of nausea, vomiting, early satiety and diarrhea after 1 week. In a case of FD,²² short-term treatment with buspirone improved vomiting, nausea and epigastric pain.

Tolerability

Reported adverse effects with buspirone included nausea and vomiting, diarrhoea, drowsiness, headache, vertigo, dizziness, abdominal pain, increased appetite, and fatigue. However, out of the 5 studies that reported adverse effects, 3 found no significant difference in adverse effects when compared to controls,^7,18,23 and another was in only 1 patient out of 59 (dizziness).¹⁹

In this systematic review of buspirone for upper GI DGBIs, we analyzed data from 10 studies. In a meta-analysis, we found that buspirone did not consistently improve functional dyspepsia/gastroparesis symptoms. There was a specific symptom benefit for bloating, though this was measured by only 2 studies. Tolerability of buspirone was generally good. Treatment duration was typically only 4 weeks, whilst studies were generally under-powered to detect clinical effects.

There is bidirectional communication between the CNS and gut via shared neurotransmitters and receptors at both central and peripheral levels, which forms the part of the gut–brain axis. Abnormalities in these brain-gut neural pathways are important in the pathogenesis of DGBIs. In the upper GI tract, altered neural signaling can impair gastric accommodation, meaning the upper stomach is less able to act as a reservoir for ingested food, such that food transit into the distal stomach is excessively rapid.²⁴ This contributes to symptoms of early satiation in both functional dyspepsia and idiopathic gastroparesis.^25,26

Buspirone is a promising candidate for treating DGBI, particularly in the upper GI tract, in view of its favorable effects on neural signaling across the gut–brain axis. In the gut, buspirone has been found to increase esophageal peristalsis and improve lower esophageal sphincter function.²⁷ In healthy volunteers, buspirone has also been found to reduce post-prandial GI symptoms and nausea,²⁸ as well as relaxing the proximal stomach in the fasting state.²⁹ In the brain, buspirone has established anxiolytic effects––although these can take 6 weeks to emerge⁵––and has some direct anti-emetic effects. Interest in buspirone for DGBI has increased as the overlap between FD and gastroparesis has become better understood,⁸ along with the limitations of prokinetic treatments.³ Indeed, the Rome consortium recommends buspirone as a potential treatment for early satiety, fullness, and nausea.²

In this context, our findings are disappointing in showing that buspirone did not significantly improve upper GI symptoms more than placebo. Several factors could underpin our negative findings. There was heterogeneity in the phenotype of DGBI included, meaning a limited number of studies could be included in each meta-analysis. With potential benefit seen for bloating, more precise selection of cases––for example recruiting patients with severe bloating, an established fundal accommodation defect or even high levels of anxiety––could increase its efficacy. The largest trial, which was negative, recruited patients with functional dyspepsia and gastroparesis. Although it is possible that selection of purely patients with functional dyspepsia could enhance the benefit of buspirone, functional dyspepsia and gastroparesis are known to be overlapping syndromes, in which patients switch between the 2 diagnoses over time.⁸ For most studies, duration of treatment was short, which is notable because the benefits of buspirone for anxiety can take 6 weeks or more to be realized.⁵

In principle, buspirone could also have a role in treating lower GI DGBIs. Notably, 5-hydroxytryptamine 1A receptors are found in the myenteric and submucosal plexuses of the enteric nervous system, including in the ileum, and their activation may regulate a range of downstream effects on GI motility and nociception.^30,31 Furthermore, buspirone has known efficacy for anxiety in general, and 39.1% of patients with IBS have clinically significant anxiety.³² One case report found dramatic benefit of buspirone in a patient with refractory IBS.³³ Whether by acting directly on the gut or by downstream effects of reduced anxiety, buspirone therefore has potential to improve DGBI in patients with IBS, and further clinical evaluation of such effects is warranted.

Our review has several limitations beyond those discussed above. In particular, all included studies were modest in size, leading to underpowering for clinical benefit. Furthermore, we accepted non-RCTs in our synthesis, such as case reports and case series, but ensured the robustness of our statistical analysis by including only good-quality RCTs in the meta-analyses.

In conclusion, in this systematic review and meta-analysis, we found that buspirone did not improve overall functional dyspepsia/gastroparesis symptoms compared to controls, though included studies were small in sample size and short in treatment duration. Buspirone had a benefit for bloating severity, though this was based on only 2 studies. Future clinical trials of buspirone are warranted in better defined groups, such as patients with predominant bloating or fundal accommodation deficits, and over longer treatment duration.

Calum D Moulton is supported by an NIHR Advanced Fellowship.

Calum D Moulton has given paid educational talks for AbbVie, Dr Falk, Takeda, Ferring Pharmaceuticals, and Lilly.

Zahra Momedali, Gehanjali Amarasinghe, and Calum D Moulton conceived the manuscript; Zahra Mohamedali, Calum D Moulton, and Christopher W P Hopkins performed data analysis. All authors revised the manuscript for important intellectual content.