Naltrexone-bupropion
In phase 3 trials, naltrexone-bupropion cut body weight by about 5 to 9% against 1 to 5% on placebo at 56 weeks. Pooled estimates range from 2.5 to 5.0 kg more than placebo. Nausea affected about 3 in 10. Serious adverse events and stopping for side effects rose. A heart outcome trial ended early without an answer.
Add to Bio HackChecked 2026-11-09
- Status
- Prescription drug in the US. FDA-approved as Contrave (extended-release tablet) for chronic weight management in adults. The label carries a boxed warning on suicidal thoughts and behaviors.
- Also called
- Contrave, Mysimba, naltrexone/bupropion, NB32, naltrexone SR/bupropion SR
- Taken for
- weight loss, cravings, appetite, emotional eating, binge eating
Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on
Shown to help2
Reported risks5
- StrongShown to raise nausea to about 27 to 30% against 5% on placebo, with more headache, constipation, dizziness, vomiting and dry mouth.Very common
- LimitedThe label states bupropion can cause seizures, with dose-related risk. Trials found seizures in about 0.1% against 0% on placebo.Uncommon
- ModerateShown to raise serious adverse events about 70%, one extra for every 21 people treated, and to roughly double stopping for side effects.How often is not known
- LimitedThe label carries a boxed warning on suicidal thinking from the antidepressant class. In weight trials, depression and suicidality did not rise over placebo.How often is not known
- LimitedThe label states it can raise blood pressure and heart rate, and lists chronic opioid use as a contraindication. One trial saw a brief 1.5 mmHg rise.How often is not known
What people take it for, and what was found
Shown to help2
Weight loss
Shown to cut about 2.5 to 5 kg more weight than placebo over a year in adults with overweight or obesity, depending on the analysis.
The numbers and sources
- How common
- Very common: more than 1 in 10 people.
- Effect
- At 56 weeks, weight changed by -1.3% on placebo, -5.0% on naltrexone 16 mg with bupropion and -6.1% on naltrexone 32 mg with bupropion. A loss of 5% or more occurred in 16%, 39% and 48% [1]. With intensive behavior therapy, weight fell 9.3% on the combination and 5.1% on placebo [2]. Across trials of at least a year, the combination produced 5.0 kg (95% CrI 3.96 to 5.94) more loss than placebo [3]. A meta-analysis built from the unpublished clinical study reports of 4 pivotal trials found 2.53 kg (95% CI 1.85 to 3.21) more loss than placebo, with GRADE certainty rated low [4].
- Population
- 1,742 adults with BMI 27 to 45 [1]; 793 adults, mean BMI 36.5 [2]; 28 RCTs with 29,018 adults [3]; 4 trials with 4,536 participants [4].
- Sources
- [1], [2], [3], [4]
- Caveats
- The pooled estimates disagree, 2.53 kg [4] against 5.0 kg [3], in part because [4] used the full clinical study reports. Half of COR-I participants completed 56 weeks, and the analysis carried the last observation forward [1]. COR-I was funded by Orexigen Therapeutics, the developer [1].
Weight and blood sugar in type 2 diabetes
One trial found more weight loss, 5.0% against 1.8%, and a larger HbA1c drop than placebo in adults with type 2 diabetes.
The numbers and sources
Not shown to help1
Heart attack, stroke and cardiovascular death
One trial stopped early: an early drop in major cardiovascular events did not hold at the later analysis, and cardiovascular safety remains uncertain.
The numbers and sources
- Effect
- At the 25% interim analysis, major cardiovascular events occurred in 1.3% on placebo and 0.8% on the combination (HR 0.59, 95% CI 0.39 to 0.90). At 50% of planned events the figures were 2.3% and 2.0% (HR 0.88, adjusted 99.7% CI 0.57 to 1.34). The trial was stopped early after the sponsor publicly released confidential interim data, and the authors state that cardiovascular safety remains uncertain [6].
- Population
- 8,910 adults with overweight or obesity at raised cardiovascular risk, mean age 61, 85.2% with diabetes [6].
- Sources
- [6]
- Caveats
- The trial ended before it could test its planned noninferiority margin. The early interim result did not hold at the later analysis [6].
- Why limited
- This rests on one trial, of 8,910 people. Strength counts independent studies that agree, so one trial is limited at any size.
Doses studied
The phase 3 trials and the cardiovascular trial used sustained-release naltrexone 32 mg per day with sustained-release bupropion 360 mg per day. COR-I also had an arm of naltrexone 16 mg per day with bupropion 360 mg per day [1][2][5][6].
Risks
Reported risks5
Nausea and other gastrointestinal effects
Shown to raise nausea to about 27 to 30% against 5% on placebo, with more headache, constipation, dizziness, vomiting and dry mouth.
The numbers and sources
- How common
- Very common: more than 1 in 10 people.
- Effect
- Nausea occurred in 29.8% on naltrexone 32 mg with bupropion, 27.2% on naltrexone 16 mg with bupropion and 5.3% on placebo. Headache, constipation, dizziness, vomiting and dry mouth were also more frequent than on placebo [1]. In type 2 diabetes, nausea occurred in 42.3% against 7.1%, vomiting in 18.3% against 3.6% and constipation in 17.7% against 7.1% [5]. In the cardiovascular trial, gastrointestinal events occurred in 14.2% against 1.9% [6].
- Population
- Trial participants in [1], [5] and [6].
- Sources
- [1], [5], [6]
- Caveats
- Rates differ across trials with how events were collected.
Seizures
The label states bupropion can cause seizures, with dose-related risk. Trials found seizures in about 0.1% against 0% on placebo.
The numbers and sources
- How common
- Uncommon: between 1 in 1,000 and 1 in 100 people.
- Effect
- The label states bupropion can cause seizures, with dose-related risk. Seizure incidence in Contrave trials was about 0.1% against 0% on placebo. It is contraindicated with a seizure disorder [8].
- Population
- Contrave trial participants, summarized in the label [8].
- Sources
- [8]
- Caveats
- Few events.
Serious adverse events and stopping treatment
Shown to raise serious adverse events about 70%, one extra for every 21 people treated, and to roughly double stopping for side effects.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- From clinical study reports, the combination raised adverse events (RR 1.11, 95% CI 1.05 to 1.18), serious adverse events (RR 1.70, 95% CI 1.38 to 2.10) and discontinuation for adverse events (RR 1.92, 95% CI 1.65 to 2.24). One extra serious adverse event occurred for every 21 people treated [4]. In the network meta-analysis, odds of stopping for adverse events were 2.64 (95% CrI 2.10 to 3.35) times those of placebo [3]. A second network meta-analysis found odds of 2.69 (95% CI 2.10 to 3.44) against lifestyle change alone [7].
- Population
- 4,536 participants in 4 pivotal trials [4]; 28 RCTs [3]; 132 RCTs with 48,209 adults [7].
- Sources
- [4], [3], [7]
- Caveats
- [4] rated certainty for serious adverse events as moderate.
Suicidal thoughts and mood (boxed warning)
The label carries a boxed warning on suicidal thinking from the antidepressant class. In weight trials, depression and suicidality did not rise over placebo.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- The label carries a boxed warning on suicidal thinking and behavior, based on antidepressant use in children, adolescents and young adults [8]. In COR-I, the combination was not associated with more depression or suicidality events than placebo [1]. In type 2 diabetes, depression and suicidal ideation did not differ between groups [5]. In the cardiovascular trial, central nervous system symptoms occurred in 5.1% against 1.2% [6].
- Population
- Label class warning for bupropion [8]; trial participants in [1], [5] and [6].
- Sources
- [8], [1], [5], [6]
- Caveats
- The boxed warning comes from the antidepressant class, not from a signal in the weight trials.
Blood pressure, heart rate and opioid interaction
The label states it can raise blood pressure and heart rate, and lists chronic opioid use as a contraindication. One trial saw a brief 1.5 mmHg rise.
The numbers and sources
- How common
- How often is not known: the sources give no rate.
- Effect
- In COR-I, mean systolic and diastolic blood pressure rose about 1.5 mm Hg at first, then fell about 1 mm Hg below baseline [1]. The label states the drug can raise blood pressure and resting heart rate. It is contraindicated with chronic opioid use and uncontrolled hypertension, because naltrexone blocks opioids and can precipitate withdrawal [8].
- Population
- 1,742 adults [1]; label [8].
- Sources
- [1], [8]
- Caveats
- The label states the clinical significance of the blood pressure and heart rate changes is unclear [8].
Claims tested and not found
- That naltrexone-bupropion reduces binge eating. In 3 placebo-controlled trials with 177 people with binge eating disorder, binge eating frequency did not differ from placebo (MD -1.25, 95% CI -5.61 to 3.11), nor did BMI or depression scores [9]. In a network meta-analysis of 12 trials of three drugs with 1,988 adults, naltrexone-bupropion did not reduce binge frequency against placebo (MD -2.07, 95% CI -4.45 to 0.31) [10].
Sources
- Greenway FL, Fujioka K, Plodkowski RA, et al. Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2010. https://doi.org/10.1016/S0140-6736(10)60888-4
- Wadden TA, Foreyt JP, Foster GD, et al. Weight Loss With Naltrexone SR/Bupropion SR Combination Therapy as an Adjunct to Behavior Modification: The COR-BMOD Trial. Obesity. 2011. https://doi.org/10.1038/oby.2010.147
- Khera R, Murad MH, Chandar AK, et al. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events. JAMA. 2016. https://doi.org/10.1001/jama.2016.7602
- Onakpoya IJ, Lee JJ, Mahtani KR, et al. Naltrexone-bupropion (Mysimba) in management of obesity: A systematic review and meta-analysis of unpublished clinical study reports. British Journal of Clinical Pharmacology. 2020. https://doi.org/10.1111/bcp.14210
- Hollander P, Gupta AK, Plodkowski R, et al. Effects of Naltrexone Sustained-Release/Bupropion Sustained-Release Combination Therapy on Body Weight and Glycemic Parameters in Overweight and Obese Patients With Type 2 Diabetes. Diabetes Care. 2013. https://doi.org/10.2337/dc13-0234
- Nissen SE, Wolski KE, Prcela L, et al. Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial. JAMA. 2016. https://doi.org/10.1001/jama.2016.1558
- Shi Q, Wang Y, Hao Q, et al. Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of randomised controlled trials. The Lancet. 2024. https://doi.org/10.1016/S0140-6736(24)00351-9
- U.S. Food and Drug Administration. CONTRAVE (naltrexone hydrochloride and bupropion hydrochloride) extended-release tablets, prescribing information. 2025. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=485ff360-32c8-11df-928b-0002a5d5c51b
- Marçal JBC, Sobral MVS, Ellwanger MP, Rister GP. Naltrexone-bupropion for the treatment of binge eating disorder: a systematic review and meta-analysis. Brazilian Journal of Psychiatry. 2025. https://doi.org/10.47626/1516-4446-2025-4258
- Hodrob T, Ismail I, Abusalameh A, et al. Efficacy and Safety of Lisdexamfetamine Versus Topiramate Versus Naltrexone/Bupropion in Individuals With Binge Eating Disorder: A Network Meta-Analysis. European Eating Disorders Review. 2026. https://doi.org/10.1002/erv.70035