Efficacy of naltrexone and bupropion combination in patients with binge eating disorder: a systematic review and meta-analysis

Abstract

Purpose

Binge Eating Disorder (BED) is a prevalent condition with limited evidence-based treatments. Naltrexone and Bupropion Combination (NB) targets neurobiological pathways implicated in BED. The Objective of this paper is to evaluate the efficacy of NB for BED in adults through a systematic review and meta-analysis.

Methods

Following PRISMA guidelines, we searched major databases and trial registries (up to Feb 2025) for randomized controlled trials (RCTs) comparing NB to placebo or usual care in adults with BED. The primary outcome was binge eating frequency; secondary outcomes included weight loss and BMI. Risk of bias (ROB2) and certainty of evidence (GRADE) were assessed. A fixed-effects meta-analysis was performed.

Results

Four RCTs (n = 444 participants) met inclusion criteria. Meta-analysis of three studies indicated NB did not significantly reduce binge eating frequency compared to controls (Mean Difference [MD] − 1.49, 95% CI − 3.63 to 0.64, p = 0.17). However, NB significantly reduced weight (MD -3.57 kg, 95% CI − 4.86 to − 2.27, p < 0.001) and BMI (MD − 1.24 kg/m², 95% CI − 1.79 to − 0.70, p < 0.001). The certainty of evidence was assessed as moderate for binge frequency and low for weight and BMI outcomes.

Conclusion

NB aids weight reduction in adults with BED, but current evidence is insufficient to confirm its efficacy for reducing binge eating frequency. Further high-quality RCTs are warranted.

Level of evidence

Level I, systematic reviews and meta-analyses.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40519-025-01786-5.

Introduction

Binge eating disorder (BED) is characterized by recurrent episodes of excessive food consumption that are accompanied by a feeling of loss of control, setting it apart from other eating disorders [1]. It is the most prevalent eating disorder, impacting approximately 1–2% of the global population, and is linked to significant psychological distress as well as metabolic complications [2]. Neurobiological research indicates shared mechanisms with substance use disorders, such as dysregulated reward processing and impulsivity [3]. Despite the substantial burden on public health, there is a limited availability of evidence-based treatments, highlighting the urgent need for targeted therapeutic strategies [4].

Naltrexone, an opioid receptor antagonist primarily used for treating opioid and alcohol use disorders, inhibits the binding of β-endorphin at μ-opioid receptors. This mechanism leads to the disinhibition of proopiomelanocortin neurons, which enhances signaling related to satiety [5]. Bupropion, a dopamine and norepinephrine reuptake inhibitor approved for the treatment of depression and smoking cessation, may reduce appetite by modulating neural reward circuits and increasing energy expenditure through the activation of melanocortin. Together, these agents target complementary pathways—hedonic and homeostatic—thereby providing synergistic benefits for weight regulation [6].

The combination of naltrexone and bupropion (NB), marketed under the name Contrave®, is primarily approved for the chronic management of weight in adults who are obese or overweight, and it should be used in conjunction with diet and exercise [7, 8]. Additionally, this medication functions to modulate opioidergic and dopaminergic pathways, helping to reduce appetite and enhance feelings of fullness [9]. Although primarily studied for its weight loss benefits, emerging trials also suggest its potential in addressing compulsive behaviors, albeit with evidence that remains in the preliminary stages [10]. Clinical recommendations stress the importance of sustained administration to uphold therapeutic effects, and safety profiles generally remain consistent across diverse populations [7, 9]. This review aims to evaluate the efficacy of the NB combination on binge eating behavior in adults, bridge current knowledge gaps by synthesizing recent evidence, and outline essential tracks for future investigation.

Methods

Data sources and search strategy

The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [11]. To identify the most relevant studies, a comprehensive search was conducted in February 2025 across various databases, including Scopus, Web of Science, Cochrane Library, and Medline through PubMed. Additionally, the WHO International Clinical Trials Registry Platform (ICTRP) and clinicaltrials.gov were investigated to ensure a thorough coverage of pertinent studies. To further enhance the strategy, both included studies and comparable reviews were screened for backward and forward citations. The search strategy was refined using Medical Subject Headings (MeSH). The search terms employed included (Details available in supplementary materials): ("BED" OR "Binge eat*" OR "Binge-eat*") AND ((("Amfebutamone" OR "Bupropion" OR "Zyban" OR "Wellbutrin" OR "Quomen" OR "Zyntabac") AND ("Trexan" OR "Antaxone" OR "Celupan" OR "ReVia" OR "Nalorex" OR "Nemexin" OR "Naltrexone" OR "Depade" OR "Vivitrol")) OR ("Contrave" OR "Mysimba")).

Inclusion and exclusion criteria

Inclusion criteria for this systematic review presented using the PICO (Participant, Intervention, Control, Outcome) framework; The randomized controlled trials (RCTs) involved Participants who had to be at least 18 years old, evaluated for BED using conventional methods, and treated in cases where their Body Mass Index (BMI) was greater than 30 (or greater than 27 if they also had a comorbidity). Eligible Interventions encompassed the utilization of oral NB combination therapy, with no restrictions imposed on the duration of treatment or the prescribed dosage. The Control group of included studies should receive a placebo or non-pharmacological interventions. The primary Outcome was the effect of NB on binge eating behavior in patients with BED, assessed by the frequency (reported number of episodes), or the severity (evaluated by scores) on validated scales, both compared between baseline and post-treatment. Secondary outcomes included weight loss and changes in weight-related measures, specifically in BMI, assessed at baseline and post-treatment using validated measurement tools. Conversely, studies were excluded if they did not assess BED or did not utilize NB as the intervention. Additionally, review articles, case reports, case series, meta-analyses, pilot studies, and study protocols were excluded.

Study selection and data extraction

After removing duplicate studies from the initial search results, two researchers (F.M. and S.E.) examined the titles, abstracts, and keywords to identify and exclude irrelevant articles. Subsequently, they conducted a comprehensive review of the full texts of the selected studies, focusing on study design, interventions, and outcomes to determine eligibility. The same authors independently gathered specific data from the included studies, which included details such as study design, sample size, interventions, follow-up periods, weight loss, BMI, medication dosage, and eating disorder scores measured both pre- and post-intervention. Any discrepancies in the data collection were resolved with the assistance of a third reviewer (M.S.).

Risk of bias and certainty assessment

In evaluating the quality of the studies included in this review, we utilized the revised Cochrane risk of bias tool for randomized trials (ROB2) quality assessment checklist to assess the risk of bias [12]. Two authors (F.M. and S.E.) independently conducted the risk of bias assessment for each study using the ROB2 checklist, with a third reviewer (M.S.) intervening to resolve any disagreements. Each study was thoroughly examined across multiple domains, including bias, blinding, follow-up, measurement, analysis, and design and overall assessment.

To perform a certainty assessment, we employed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, which aided in evaluating the confidence level in the synthesized findings [13]. Two reviewers (F.M. and S.E.) separately rated each domain for every comparison and addressed any discrepancies with the help of a third reviewer (M.S.). Each comparison and outcome was classified as 'high', 'moderate', 'low', or 'very low, ' taking into account the risk of bias, inconsistency, indirectness, publication bias, and imprecision.

Statistical analysis

In this study, a meta-analysis of quantitative data was conducted using Stata v17 [14]. As the outcome indicators were all continuous variables and the evaluation tools for each detection indicator were the same, we used the mean difference (MD) and 95% confidence interval (CI) to estimate the intervention. The primary outcome was Binge Eating Frequency; the secondary outcomes were Weight Loss and Body Mass Index (BMI).

The statistical heterogeneity of the included studies was evaluated using statistics and p-values. Low, medium, and high heterogeneity were defined as values of 25%, 50%, and 75%, respectively (Higgins et al., 2003). Fixed-effects model was utilized for analysis. The analysis was reported as a forest plot, and due to the low number of included trials, we could not estimate potential publication bias using a funnel plot for outcomes. A p < 0.05 was considered statistically significant.

Results

Search results and study characteristics

After eliminating duplicates, a total of 116 articles were screened based on their titles, abstracts, and keywords. Nine articles were subsequently evaluated for full-text availability, and their content was assessed against additional eligibility criteria. Five studies were excluded for various reasons: three lacked a randomized or placebo-controlled design, one involved an inappropriate intervention, and one was a pilot study. In the end, four studies were included in the review (Fig. 1) [15–18]. One study was excluded from the quantitative meta-analysis because its data for binge eating frequency was not reported in a format amenable to statistical pooling [18].

Fig. 1.

PRISMA Flow Diagram. Flow diagram outlining the systematic review process, including identification, screening, eligibility assessment, and final inclusion of studies

The included studies comprised a total of 444 participants, with sample sizes ranging from 66 to 153. These studies were all conducted in the USA, primarily by the same research group. Participants generally had a mean age in their mid-40 s, with varying gender distributions. Treatment durations ranged from 12 to 26 weeks. Further comprehensive details on the characteristics of each study, including specific medication dosages, gender distribution, mean age, and detailed assessment instruments, are provided in Table 1.

Table 1.

Study characteristics

Study	Country	intervention types		Medication dosage	Sample size		Gender (%Males)		Age (Mean (SD))		Duration (week)	Instruments used to assess binge eating	Weight measurement method	Summary of the results
		Int	Con		Int	Con	Int	Con	Int	Con
Grilo n2023 (November) [15]	USA	NB	Placebo	naltrexone-sustained-release (32 mg/day) combined with bupropion-sustained-release (360 mg/day)	43	46	25.6%	28.3%	45.30 (14.01)	46.02 (13.16)	12	EDE; 16th edition	Weight assessed at 2 weeks, 1 month, 2 month, and post-treatment	NB was not effective in reducing binge eating compared to placebo NB was effective in reducing weight in patients with BED
Grilo j2023 (June) [16]	USA	NB	Placebo	Two capsules, each containing 8 mg naltrexone and 90 mg bupropion, were taken twice daily	32	34	9.4%	17.6%	50.4 (11.7)	43.6 (11.8)	16	EDE; 16th edition	Weight measured at 2 weeks, monthly, post-treatment (Digital scale)	Maintenance treatment with NB is recommended for adults with BED and obesity who respond well to acute treatment
Grilo 2022 [17]	USA	NB	Placebo	NB comprised naltrexone-sustained-release (32 mg/day) combined with bupropion-sustained-release (360 mg/day)	32	34	15.6%	17.6%	46.03 (11.95)	46.94 (12.57)	16	EDE; 16th edition And EDE-Q	Measured monthly and at study end	Both BWL and NB improved BED symptoms, with BWL showing superior outcomes compared to no-BWL
		BWL  +  NB	BWL  +  Placebo		35	35	14.3%	17.1%	46.00 (11.87)	46.99 (12.98)
Halseth 2018 [18]	USA	NB  +  CLI	UC	32 mg naltrexone sustained release (SR)/360 mg bupropion SR in conjunction with a CLI program, or UC (diet and exercise education from the study site)	71	82	20%	13%	48 (9)	48 (10)	26	Binge Eating Scale (BES)	Weight assessed at baseline, week 16, and week 26	NB + CLI led to greater improvements in weight-related quality of life, eating behavior control, and sexual functioning compared to usual care

Summary of included randomized controlled trials evaluating the efficacy of NB in adults with binge eating disorder (BED). Details include country, intervention type, dosage, sample size, gender distribution, mean age, duration, and key outcomes.

NB naltrexone and bupropion Combination, BWL behavioral weight loss, CLI comprehensive lifestyle intervention, UC usual care, EDE Eating Disorder Examination-Interview, EDE-Q Eating Disorder Examination-Questionnaire

Risk of bias

The ROB2 tool was used to assess the risk of bias in each study, and the results were shown in Figs. 2. For the randomization process, all studies were rated as having "low risk," indicating adequate random sequence generation and allocation concealment [15–18]. In the domain of deviations from intended interventions, two studies were rated as "low risk" [15, 16]; and two as having "some concerns," reflecting potential issues with blinding or adherence to the intervention protocols [17, 18]. For missing outcome data, two studies were judged to have "low risk" [15, 17]; and two as having "some concerns," due to possible attrition or incomplete reporting [16, 18]. In terms of measurement of the outcome, three studies were rated as "low risk," [15–17]; and one study had "some concerns," suggesting that most studies used valid and reliable outcome measurements with minimal risk of bias [18]. For selection of the reported result, all studies were rated as having "some concerns," [15–18]. Overall, two studies were judged to have "low risk" of bias [15, 16], one had "some concerns" [17], and one was rated as "high risk" [18].

Fig. 2.

Risk of Bias Assessment (ROB2). Summary of risk of bias across included studies using the Cochrane ROB2 tool. Domains include randomization, deviations from intended interventions, missing outcome data, outcome measurement, and selective reporting

Binge eating frequency

A fixed-effects inverse-variance meta-analysis was performed to evaluate the impact of NB on binge eating frequency among individuals with BED (Fig. 3). This analysis included four comparisons across three studies, with one study providing two independent groups (NB vs. placebo and NB + BWL vs. placebo + BWL) [15–17]. The pooled mean difference was -1.49 (95% CI: -3.63 to 0.64), which was not statistically significant (p = 0.17). Additionally, heterogeneity was low (I² = 4.63%). Notably, Halseth et al. reported a significant reduction in BED scores between the intervention and control groups [18].

Fig. 3.

Meta-Analysis: Binge Eating Frequency. Forest plot showing pooled mean difference in binge eating frequency between NB and control groups

Weight loss and BMI

A fixed-effects inverse-variance meta-analysis was performed to evaluate the impact of NB on weight loss in individuals diagnosed with BED (Fig. 4a). This analysis included four comparisons derived from three studies, with one study providing two independent groups (NB vs. placebo and NB + BWL vs. placebo + BWL) [15–17]. The pooled mean difference for weight loss was − 3.57 kg (95% CI: − 4.86 to − 2.27), which was statistically significant (p < 0.001). No heterogeneity was detected (I² = 0.00%), indicating a high level of consistency across the studies. In the study conducted by Halseth et al., the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) was assessed, revealing a significant improvement in the total IWQOL-Lite score accompanying greater weight loss in the intervention group [18].

Fig. 4.

a Meta-Analysis: Weight Loss. Forest plot displaying the pooled mean difference in weight loss (kg) between NB and control groups. b Meta-Analysis: BMI Reduction. Forest plot illustrating the pooled mean difference in BMI (kg/m²) between NB and control groups

The analysis evaluated the impact of NB on BMI reduction, encompassing two studies (Fig. 4b) [15, 16]. The combined mean difference in BMI indicated a significant advantage for the treatment group, revealing a statistically significant decrease of 1.24 kg/m² (95% CI: − 1.79 to − 0.70; p < 0.001). There was no observed heterogeneity (I² = 0.00%), suggesting consistent results across the studies. Both studies demonstrated noteworthy reductions in BMI for the treatment group compared to the placebo group.

Certainty assessment

The certainty of evidence regarding outcomes was assessed and rated from high to low. This evaluation was downgraded due to serious Indirectness observed in the weight loss and BMI analysis. Additionally, serious imprecision was noted in the all analysis. The rationale for these decisions across each domain is summarized in Table 2.

Table 2.

Certainty assessment (GRADE)

Certainty assessment							№ of patients		Effect		Certainty	Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	naltrexone and bupropion Combination	Placebo or usual care	Relative (95% CI)	Absolute (95% CI)
Binge eating frequency
3	Randomised trials	Not serious	Not serious	Not serious	Seriousa,b	None	123	128	–	MD 1.49 lower (3.63 lower to 0.64 higher)	⨁⨁⨁◯ Moderatea,b
Weight loss
3	Randomised trials	Not serious	Not serious	Seriousc	Seriousa,b	None	120	124	–	MD 3.57 lower (4.86 lower to 2.27 lower)	⨁⨁◯◯ Lowa,b,c
Body Mass Index (BMI)
2	Randomised trials	Not serious	Not serious	Seriousc	Seriousa,b	None	69	65	–	MD 1.24 lower (1.79 lower to 0.7 lower)	⨁⨁◯◯ Lowa,b,c

Grading of Recommendations, Assessment, Development and Evaluations (GRADE) summary for primary and secondary outcomes. Ratings consider risk of bias, inconsistency, indirectness, imprecision, and other factors. Outcomes include binge eating frequency, weight loss, and BMI reduction.

CI confidence interval, MD mean difference, BMI body mass index

^aLow number of included studies

^bSame authors (same locations, same culture, etc.)

^cWeight loss and BMI might not directly reflect changes in the frequency of binge eating, as these outcomes can be influenced by medications and lifestyle choices

Discussion

This systematic review and meta-analysis sought to assess the effectiveness of NB combination therapy for adults with BED. The findings indicated that NB treatment led to statistically significant reductions in both body weight and BMI when compared to control conditions. However, the primary outcome of binge eating frequency did not demonstrate a statistically significant decrease in the pooled analysis.

The significant impact of NB on weight loss and BMI is consistent with the established use of this combination therapy for chronic weight management in individuals with obesity or overweight. The mechanisms underpinning this effect likely involve NB's dual action on modulating opioidergic and dopaminergic pathways involved in appetite regulation, reward processing, and potentially energy expenditure [19, 20]. The observed mean weight loss of approximately 3.57 kg and BMI reduction of 1.24 kg/m² suggest a clinically relevant effect for weight management within the BED population, which often presents with comorbid obesity. Furthermore, one study included in the review reported significant IWQOL-Lite associated with NB treatment, highlighting potential broader benefits beyond weight metrics alone [18].

Conversely, the meta-analysis did not demonstrate a statistically significant effect of NB on reducing the frequency of binge eating episodes. This finding contrasts with the theoretical rationale suggesting NB might target the reward dysregulation and compulsive behaviors characteristic of BED [21]. Several factors could contribute to this non-significant result. Firstly, the overall evidence base is limited, with only three studies contributing to the meta-analysis for this outcome. Although statistical heterogeneity was low, the small number of studies limits the power to detect a potential effect and contributes to the 'serious imprecision' identified in the GRADE assessment, resulting in moderate certainty for this outcome. It is also possible that the duration of the included trials (ranging from 12 to 26 weeks) was insufficient to observe significant changes in entrenched binge eating patterns. Additionally, while one study did report a significant reduction in BED scores descriptively [18]; variations in measurement tools and specific study populations across the included trials might obscure an overall effect. The focus of NB's mechanism on homeostatic and hedonic appetite control might also impact weight more directly than the complex psychological components driving binge episodes themselves.

Several empirically supported treatment frameworks are available for adults with BED. First-line interventions for those with mild-to-moderate symptom severity include cognitive-behavioral therapy (CBT), which targets maladaptive cognitions and irregular eating patterns, as well as interpersonal psychotherapy (IPT), which focuses on resolving affective and relational triggers for binge episodes [22, 23]. While CBT has shown partial efficacy, especially in short-term outcomes, its theoretical underpinnings may overlook the chronicity and severity aspects of BED [24]. This gap underscores the importance of evaluating pharmacologic interventions like NB in conjunction with psychotherapeutic approaches, especially for patients with more severe or treatment-resistant forms of BED.

Strengths of this study include its rigorous adherence to PRISMA guidelines, comprehensive search strategy across multiple databases and registries, and the application of robust methodological tools such as the Cochrane ROB2 and GRADE frameworks. This approach ensured systematic appraisal and transparent grading of the certainty of evidence. Additionally, the inclusion of only RCTs enhances the internal validity and relevance of the findings to clinical practice. By focusing on both behavioral (binge frequency) and somatic (weight and BMI) outcomes, the review offers a multifaceted assessment of NB’s therapeutic role in BED.

This review has several limitations that must be acknowledged. At the process level, the review protocol was not prospectively registered, and the literature search did not include the Embase database, while the grey literature search was confined to trial registries. To mitigate these search limitations, we supplemented our electronic search with extensive forward and backward citation tracking. The primary limitation of the evidence itself is the small number of eligible trials, which were predominantly from the same research group, potentially limiting generalizability. This small sample size restricted the robustness of the meta-analytical findings and precluded a formal assessment of publication bias. Furthermore, the risk of bias assessment revealed some concerns, particularly regarding deviations from intended interventions and selective reporting, with one study rated as high risk overall. Consequently, the certainty of evidence for key outcomes like weight loss and BMI was downgraded to 'low' due to serious indirectness and imprecision.

Based on current evidence, NB appears effective for promoting weight loss and reducing BMI in adults with BED, particularly relevant given the high rates of obesity in this population. However, there is insufficient evidence from this meta-analysis to conclude that NB significantly reduces binge eating frequency. Clinicians might consider NB for patients with BED and comorbid obesity, managing expectations regarding its direct impact on binge episodes. Future research should prioritize larger, high-quality RCTs with extended follow-up periods to definitively assess NB’s effect on binge eating frequency as a primary outcome. Investigating optimal dosing, treatment duration, patient characteristics predicting response, and the potential synergistic effects of combining NB with psychotherapies like BWL are crucial next steps to clarify the therapeutic role of NB in managing BED.

In conclusion, this systematic review and meta-analysis synthesized evidence on the efficacy of NB for treating BED in adults. The findings indicate that NB significantly reduces body weight and BMI in this population, suggesting a potential benefit for managing the common comorbidity of obesity. However, based on the limited number of available studies, the meta-analysis did not find a statistically significant reduction in the frequency of binge eating episodes. While NB shows promise for weight management in individuals with BED, the current evidence, rated as moderate certainty for binge frequency and low certainty for weight outcomes, is insufficient to confirm its effectiveness for the core behavioral symptom of binge eating. Further large-scale, high-quality randomized controlled trials are necessary to definitively establish the role of NB in the treatment landscape for BED.

What is already known on this subject?

• BED is a prevalent and impairing condition, often comorbid with obesity, and associated with compulsive overeating and impaired reward regulation.

• NB, a combination pharmacotherapy approved for obesity, targets both homeostatic and hedonic pathways and has been hypothesized to reduce binge behaviors.

• Prior studies have shown NB’s effectiveness for weight loss; however, evidence regarding its impact on core binge eating symptoms has remained limited and inconclusive.

What this study adds

• NB was found to significantly reduce body weight and BMI, confirming its utility in weight management within the BED population.

• However, the meta-analysis did not find a statistically significant reduction in binge eating frequency, highlighting a disconnect between weight loss effects and direct behavioral symptom improvement.

• The findings underscore the need for future trials to account for BED severity, chronicity, and the potential benefit of combining NB with psychotherapeutic interventions.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

The authors confirm contribution to the paper as follows: study conception and design: SNR.; data extraction: FM, SE, MS; analysis and interpretation of results: MS; draft manuscript preparation: All authors. All authors reviewed the results and approved the final version of the manuscript.

Funding

This research received no specific grant from any funding agency in the public.

Data availability

The data supporting this research are available from the author(s) on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.