Naltrexone/Bupropion (Contrave)
A fixed-dose combination of the opioid antagonist naltrexone and the dopamine-noradrenaline reuptake inhibitor bupropion, approved as Contrave (Mysimba in Europe) in 2014 for weight management. It targets appetite and reward pathways, giving modest weight loss with characteristic nausea and a boxed warning around bupropion's psychiatric effects.
01 Overview
Contrave combines sustained-release naltrexone and bupropion. Bupropion stimulates hypothalamic POMC neurons to reduce appetite; naltrexone blocks an opioid-mediated feedback loop that otherwise limits that effect, and the pair also dampens food-reward drive. Trials (COR programme) showed roughly 4-5% placebo-subtracted weight loss.
It is neither the strongest nor the weakest oral option. Nausea is very common, and because bupropion is an antidepressant it carries the class boxed warning for suicidality in younger patients and a seizure risk. It is contraindicated with opioids and in uncontrolled hypertension.
02 Mechanism
Bupropion activates POMC neurons (via dopamine/noradrenaline reuptake inhibition) to suppress appetite; naltrexone blocks beta-endorphin autoinhibition of those neurons, and both reduce reward-driven eating.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Titration | 8–90 mg/day | Oral | Start one tablet (8 mg naltrexone / 90 mg bupropion) daily, escalating weekly. |
| Maintenance dose | 32–360 mg/day | Oral | Two tablets twice daily (32 mg naltrexone / 360 mg bupropion total). |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Weight lossModest weight reduction with reduced appetite and food craving. | ~4-5% vs placebo | Clinical | |
| Reduced food reward/cravingDampened hedonic drive to eat, useful for craving-driven overeating. | moderate | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Nausea and vomitingNausea, constipation and vomiting, the leading cause of discontinuation. | Moderate | Very common | Clinical | |
| Psychiatric effects and seizure riskBupropion carries a suicidality boxed warning and lowers seizure threshold. | Severe | Rare (boxed warning) | Clinical | |
| Blood pressure and heart rate increaseSmall increases in BP and pulse. | Moderate | Common | Clinical |