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Four separate measurements, never averaged. Independent evidence counts only studies with no sponsor attached. Methodology version v2.0-2026-10 · how we grade evidence
Approved as an adjunct to a reduced-calorie diet and increased physical activity, to reduce excess body weight and maintain the reduction long term in adults with obesity, or overweight with at least one weight-related comorbidity. It makes no cardiovascular claim and the label disclaims one: the effect on cardiovascular morbidity and mortality has not been established.
Its own registration trials are positive and modest — a 4.1 percentage-point placebo-adjusted difference by the label’s figures for COR-I, and only 2.0 percentage points in the type 2 diabetes population most likely to be prescribed it. In the 2026 independent network meta-analysis it did not separate convincingly from lifestyle modification alone on body weight at one year, while carrying the worst harm profile of any agent in that analysis.
Two further things sit on the record. The cardiovascular outcomes trial the FDA required, LIGHT, was terminated early and could never formally establish non-inferiority, so that question remains open. And LIGHT is separately the subject of a documented research-conduct case — a research-integrity concern, not a pharmacological safety finding, and it should be read as the former.
At a glance
Bupropion is a weak reuptake inhibitor of dopamine and noradrenaline, proposed to stimulate hypothalamic POMC neurons; naltrexone is an opioid antagonist, proposed to block the β-endorphin-mediated autoinhibitory feedback loop that otherwise limits that stimulation. The combination is claimed to act on both the hypothalamic appetite circuit and the mesolimbic reward pathway. That account is a hypothesis rather than a confirmed human mechanism, and the regulator says so. Section 12.1 of the FDA label states that "the exact neurochemical effects of CONTRAVE leading to weight loss are not fully understood."
Dated determinations, each flagged for whether it is final and whether it covers safety only. A safety review is not an efficacy finding, and most reporting in this category conflates the two.
Issued 15 November 2024. A risk-communication measure about concomitant opioid use; it addresses safety only and makes no statement about efficacy.
Authorised 26 March 2015 for weight management in adults with BMI 30 or above, or 27 to under 30 with a weight-related comorbidity. The product is under additional monitoring, and is contraindicated or restricted in severe renal or hepatic impairment, uncontrolled hypertension, a history of seizures, certain psychiatric conditions, brain tumour, and alcohol or drug withdrawal. A referral procedure is listed on the EPAR.
The path to approval was prolonged: NDA submitted 31 March 2010, a positive advisory committee vote on 8 December 2010, then a complete response letter — i.e. not approved — on 1 February 2011, resubmission on 11 December 2013 and approval on 10 September 2014. The indication is to reduce excess body weight and maintain the reduction long term in adults with obesity, or overweight with at least one weight-related comorbid condition. The label carries explicit limitations of use: the effect on cardiovascular morbidity and mortality has not been established. Co-administration with other naltrexone-containing products is not recommended and with other bupropion-containing products is contraindicated.
The product is not approved for major depressive disorder or any other psychiatric disorder, and patients of all ages must be monitored for the emergence of suicidal thoughts and behaviours. Labelled Warnings and Precautions also cover neuropsychiatric adverse events and suicide risk in smoking-cessation treatment, seizures, patients receiving opioid analgesics, increases in blood pressure and heart rate, allergic reactions, hepatotoxicity, activation of mania, angle-closure glaucoma, and hypoglycaemia risk in type 2 diabetes on antidiabetic therapy. A safety warning says nothing about whether the drug works.
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