Contrave Review: Efficacy, Side Effects, and Who Should Consider It
A comprehensive, evidence-based review of Contrave (naltrexone/bupropion) for weight loss: how it works, clinical trial results, side effects, and how it compares to GLP-1 medications.
Medically Reviewed
Reviewed by Dr. James Chen, MD, PhD, FACE on March 21, 2026
Our medical review process ensures clinical accuracy and patient safety.
Introduction
Contrave — the brand name for a fixed-dose combination of naltrexone and bupropion — is one of the few FDA-approved medications for chronic weight management that works primarily on brain chemistry rather than gut hormones. Approved in September 2014, it targets the central nervous system pathways that govern hunger, reward-driven eating, and energy balance.
Obesity affects over 42% of U.S. adults, and pharmacotherapy is increasingly recognized as a necessary adjunct to lifestyle changes for many patients. Contrave occupies a distinct niche: it is an oral daily medication with a dual mechanism rooted in addiction neuroscience, offering a non-injectable alternative for patients who cannot or prefer not to use GLP-1 receptor agonists like semaglutide or tirzepatide.
Evidence: "Pooled results from four phase 3 trials reveal placebo-subtracted mean weight loss of 4.7% (range 3.2–5.2%) with naltrexone/bupropion after one year." — Billes SK, et al. Pharmacology & Therapeutics. 2014. PubMed
This review synthesizes the Phase 3 clinical trial data, safety profile, and real-world considerations to help clinicians and patients make an informed decision.
How Contrave Works
Contrave combines two repurposed medications:
- Bupropion (an antidepressant and smoking-cessation drug) stimulates hypothalamic pro-opiomelanocortin (POMC) neurons, which reduce appetite and increase energy expenditure.
- Naltrexone (an opioid receptor antagonist used in addiction treatment) blocks the auto-inhibitory opioid feedback loop on those same POMC neurons, amplifying and sustaining bupropion's effect.
The synergy is the key: bupropion alone produces only modest weight loss because POMC neurons self-limit their firing via opioid receptors. Naltrexone prevents this brake, resulting in more sustained appetite suppression.
Dosing Schedule
Contrave is titrated over four weeks to minimize nausea:
| Week | Morning Dose | Evening Dose | Total Daily |
|---|---|---|---|
| 1 | 1 tablet (8/90 mg) | — | 1 tablet |
| 2 | 1 tablet | 1 tablet | 2 tablets |
| 3 | 2 tablets | 1 tablet | 3 tablets |
| 4+ | 2 tablets | 2 tablets | 4 tablets (maintenance) |
Each tablet contains naltrexone HCl 8 mg / bupropion HCl 90 mg. The maximum dose is 32 mg naltrexone / 360 mg bupropion daily.
Clinical Trial Evidence
Contrave's approval was supported by four large Phase 3 randomized controlled trials — collectively known as the COR program (Contrave Obesity Research).
COR-I: The Pivotal Trial
The COR-I trial enrolled 1,742 adults with BMI ≥30 kg/m² (or ≥27 with a weight-related comorbidity), randomized 1:1:1 to naltrexone 32 mg/bupropion 360 mg, naltrexone 16 mg/bupropion 360 mg, or placebo for 56 weeks.
Evidence: "Participants receiving naltrexone 32 mg/bupropion 360 mg lost significantly more weight than placebo (−6.1% vs. −1.3%; p<0.0001), and 48% achieved ≥5% weight loss compared with 16% on placebo." — Greenway FL, et al. Lancet. 2010;376(9741):595-605. DOI: 10.1016/S0140-6736(10)60888-4
COR-II: Replication and Longer-Term Data
COR-II enrolled 1,496 participants (2:1 active:placebo) with similar inclusion criteria, running for 56 weeks.
Evidence: "At week 56, NB32-treated participants achieved −6.4% weight loss vs. −1.2% for placebo. The proportion achieving ≥5% body weight reduction was 55.6% vs. 17.5%." — Apovian CM, et al. Obesity. 2013;21(5):935-943. DOI: 10.1002/oby.20309
COR-BMOD: Combined with Behavioral Modification
In this 793-participant trial, Contrave was tested as an adjunct to intensive behavioral counseling (28 group sessions over 56 weeks).
Evidence: "NB32 plus intensive behavioral modification produced −9.3% mean weight loss versus −5.1% with placebo plus behavioral modification at week 56 (completers: −11.5% vs. −7.3%)." — Wadden TA, et al. Obesity. 2011;19(1):110-120. DOI: 10.1038/oby.2010.147
COR-DM: Patients With Type 2 Diabetes
Contrave's performance in 505 patients with type 2 diabetes was notably attenuated compared to non-diabetic populations — a pattern seen with most weight loss medications.
Evidence: "In overweight/obese patients with T2DM, NB32 reduced body weight by −5.0% versus −1.8% for placebo, and also significantly improved HbA1c (−0.6% vs. −0.1%)." — Hollander P, et al. Diabetes Care. 2013;36(12):4022-4029. DOI: 10.2337/dc13-0234
Weight Loss Maintenance
A post-hoc analysis of long-term data (including the LIGHT cardiovascular outcomes study, up to 208 weeks) found that early response predicts sustained benefit.
Evidence: "Patients achieving ≥5% weight loss by week 16 were significantly more likely to maintain clinically meaningful weight loss at 1 year; early non-responders had limited benefit from continued therapy." — Fujioka K, et al. eClinicalMedicine (The Lancet). 2022;50:101524. DOI: 10.1016/j.eclinm.2022.101524
Side Effects and Safety Profile
Common Adverse Events
Nausea is the most frequently reported side effect, occurring in up to 33% of Contrave-treated patients versus 7% on placebo. The four-week dose escalation protocol was specifically designed to reduce this. Other common effects include:
| Side Effect | Contrave (%) | Placebo (%) |
|---|---|---|
| Nausea | 33 | 7 |
| Constipation | 19 | 7 |
| Headache | 18 | 11 |
| Vomiting | 11 | 3 |
| Dizziness | 10 | 4 |
| Dry mouth | 8 | 3 |
Most adverse events are dose-dependent, transient, and peak in the first 4 weeks. Discontinuation due to nausea occurred in 4.6–9.6% of participants across trials.
Blood Pressure and Heart Rate
Unlike GLP-1 agonists, which tend to modestly lower blood pressure, Contrave can increase heart rate and blunt blood pressure improvements. In the COR trials, mean systolic blood pressure decreased by −0.86 mmHg in the NB32 group versus −2.33 mmHg in placebo. Monitoring blood pressure at initiation and during the first months of therapy is warranted, particularly in patients with pre-existing hypertension.
Serious Safety Considerations
Black box warning — neuropsychiatric risk and seizure: Bupropion carries a black box warning for increased suicidal ideation in younger patients (a class warning shared with antidepressants) and raises seizure risk in a dose-dependent fashion. Contrave is contraindicated in patients with a seizure disorder.
Black box warning — opioid use: Because naltrexone blocks opioid receptors, Contrave is absolutely contraindicated in patients dependent on opioids or taking chronic opioid medications. It can precipitate acute opioid withdrawal.
Cardiovascular Outcomes
The LIGHT study — a cardiovascular safety outcomes trial enrolling approximately 8,910 patients — was prematurely terminated after a premature data release. Available data showed 2.0% MACE (major adverse cardiovascular events) with NB32 versus 2.3% with placebo, suggesting no increase in cardiovascular risk, but the study was underpowered to reach a definitive conclusion.
Evidence: A systematic literature review found no statistically significant increase in MACE risk with Contrave versus comparators. — Gudzune KA, et al. Pharmacoepidemiology & Drug Safety. 2022. PubMed
Contrave vs. GLP-1 Medications
For patients and clinicians comparing Contrave to newer GLP-1 receptor agonists, the tradeoffs are meaningful:
| Feature | Contrave (NB32) | Semaglutide (Wegovy) | Tirzepatide (Zepbound) |
|---|---|---|---|
| Route | Oral (daily) | Subcutaneous (weekly) | Subcutaneous (weekly) |
| Avg. weight loss | ~5–6% | ~15–17% | ~20–22% |
| Cardiovascular benefit | Neutral/uncertain | Confirmed (CVOT) | Confirmed (SURPASS-CVOT) |
| T2DM benefit | Moderate HbA1c reduction | Strong (also approved for T2DM) | Strong (also approved for T2DM) |
| Common side effects | Nausea, headache, constipation | Nausea, vomiting, diarrhea | Nausea, diarrhea, vomiting |
| Contraindications | Seizure disorder, opioid use | Personal/family MTC, MEN-2 | Personal/family MTC, MEN-2 |
| Monthly cost (cash) | ~$200–300 | ~$1,300–1,500 | ~$1,000–1,200 |
Contrave is meaningfully less effective than GLP-1 medications for weight loss. However, its oral formulation, lower cost, and distinct mechanism make it a reasonable option for patients who cannot tolerate injections, are not candidates for GLP-1 therapy, or prefer a lower-cost alternative.
Who Is Contrave Best For?
Based on the trial data and clinical profile, Contrave may be most appropriate for:
- Adults with BMI ≥30, or ≥27 with at least one weight-related comorbidity
- Patients who prefer an oral medication over weekly injections
- Patients with binge-eating tendencies or reward-driven eating patterns (the dual naltrexone/bupropion mechanism targets craving circuitry)
- Those who cannot use GLP-1 medications due to contraindications (e.g., personal or family history of medullary thyroid carcinoma)
- Patients in whom cost is a barrier to GLP-1 therapy
Contrave Is NOT Appropriate For:
- Patients with a seizure disorder or history of seizures
- Those taking chronic opioid medications or in opioid recovery programs using opioid agonists
- Patients with uncontrolled hypertension
- Pregnant women
- Patients with bulimia nervosa or anorexia nervosa
- Those with abrupt alcohol or benzodiazepine discontinuation (seizure risk)
Conclusion / Key Takeaways
Contrave delivers modest but clinically meaningful weight loss — averaging 5–6% beyond placebo — backed by four large, well-conducted RCTs. Combined with intensive behavioral modification, reductions approaching 9–11% are achievable. Its oral route, tolerable side effect profile (with proper dose escalation), and relatively lower cost differentiate it in a crowded weight-loss pharmacotherapy landscape.
The drug's limitations are real: it underperforms GLP-1 agonists on weight loss magnitude, cannot be used with opioids, and carries black-box warnings that require careful patient selection. Still, for the right patient — particularly those with reward-driven eating, injection aversion, or budget constraints — Contrave remains a guideline-supported, evidence-backed option.
Patients should receive a trial response evaluation at week 12–16: if less than 5% weight loss has been achieved, the benefit-risk calculation shifts and discontinuation should be considered.
References
Greenway FL, 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. Lancet. 2010;376(9741):595-605. DOI: 10.1016/S0140-6736(10)60888-4
Apovian CM, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity. 2013;21(5):935-943. DOI: 10.1002/oby.20309
Wadden TA, et al. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity. 2011;19(1):110-120. DOI: 10.1038/oby.2010.147
Hollander P, 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;36(12):4022-4029. DOI: 10.2337/dc13-0234
Fujioka K, et al. The relationship between early weight loss and weight loss maintenance with naltrexone-bupropion therapy. eClinicalMedicine (The Lancet). 2022;50:101524. DOI: 10.1016/j.eclinm.2022.101524
Gudzune KA, et al. Use of Contrave, naltrexone with bupropion, bupropion, or naltrexone and major adverse cardiovascular events: a systematic literature review. Pharmacoepidemiology & Drug Safety. 2022. PubMed
Billes SK, et al. Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss. Pharmacology & Therapeutics. 2014;143(3):269-281. PubMed
Last updated: 2026-03-21 Medical review: Dr. James Chen, MD, PhD, FACE
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Written By
Dr. Sarah Mitchell
Medical Director, MD, FACP
Dr. Sarah Mitchell is a board-certified internist specializing in metabolic medicine and weight management. With over 15 years of clinical experience, she has helped thousands of patients achieve sustainable weight loss through evidence-based approaches.
Medical Reviewer
Dr. James Chen
Endocrinologist, MD, PhD, FACE
Dr. James Chen is a fellowship-trained endocrinologist with expertise in diabetes, metabolism, and hormone-related weight disorders. His research on GLP-1 receptor agonists has been published in leading medical journals.
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