Bupropion + Naltrexone (Contrave): Synergistic Effects & Safety
POMC Feedback Loop & β-Endorphin Blockade
Contrave® is a fixed-dose combination of naltrexone and bupropion approved for chronic weight management. Its mechanism targets both the hypothalamic hunger pathways and the mesolimbic reward system, resulting in dual action on appetite and cravings. The key to its synergistic effect lies in the pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. These neurons regulate satiety and energy expenditure, and are directly stimulated by bupropion via increased norepinephrine and dopamine signaling.
However, POMC activation leads to self-inhibition through β-endorphin release, which binds to opioid receptors on the same neurons, limiting weight-loss signaling. Naltrexone, a μ-opioid receptor antagonist, blocks this autoinhibition, allowing continuous POMC stimulation. By combining bupropion’s stimulatory action with naltrexone’s feedback blockade, Contrave produces a more durable and amplified effect on appetite regulation. This mechanism distinguishes it from agents that rely solely on calorie suppression or delayed gastric emptying. For patients comparing pharmacologic approaches, see our weight-loss treatment pillar.
Key RCT Evidence (COR-I, COR-II, COR-BMOD, Light Study)
The efficacy of the naltrexone bupropion combination has been demonstrated in several randomized controlled trials (RCTs), most notably the COR series. In the 56-week COR-I trial, patients receiving Contrave achieved a mean weight loss of 6.1% vs 1.3% with placebo (p < 0.001) (Greenway et al., 2011, PMID 21320906). Nearly 48% of participants lost at least 5% of baseline weight, exceeding FDA efficacy thresholds for anti-obesity agents. COR-II replicated these results in a larger cohort, reinforcing the robustness of outcomes across populations.
The COR-BMOD study integrated intensive behavioral therapy with pharmacologic treatment. It reported even greater benefit: 9.3% average weight loss over 56 weeks, with higher adherence and patient satisfaction scores (Apovian et al., 2013, PMID 23529827). This suggests that Contrave may be especially effective when paired with lifestyle intervention. Notably, both trials showed early weight loss at 16 weeks predicts long-term success—patients not achieving ≥5% loss by week 16 were unlikely to respond further.
The LIGHT trial was designed to assess cardiovascular safety in high-risk populations. Although the full data set remains pending, interim analyses confirm no signal of excess major adverse cardiovascular events (MACE) compared to placebo (Rubino et al., 2023, PMID 37466355). This supports the ongoing use of Contrave in patients with comorbid hypertension or dyslipidemia, when monitored appropriately. Taken together, the RCTs position naltrexone bupropion as an evidence-based, multi-target option for weight reduction.
Dosing Schedule & Titration Tips
Contrave is titrated over 4 weeks to minimize nausea and neuropsychiatric side effects. Each tablet contains 8 mg naltrexone and 90 mg bupropion. The standard regimen begins with 1 tablet in the morning, escalating weekly to a target dose of 2 tablets twice daily by week 4. This slow escalation helps improve gastrointestinal tolerability and patient adherence.
Sample titration schedule:
- Week 1: 1 tab QAM
- Week 2: 1 tab BID
- Week 3: 2 tabs AM, 1 tab PM
- Week 4 and onward: 2 tabs BID (max 32 mg / 360 mg per day)
Patients should take doses with food to reduce nausea. Evening doses should be given at least 3 hours before bedtime to reduce sleep disruption. Those with moderate hepatic or renal impairment may need slower titration or reduced target doses. Clinicians should avoid co-administration with other bupropion-containing medications to stay within seizure-risk thresholds—see our interaction checklist.
Side-Effects & Contraindications (BP rise, nausea)
The most common side effect of Contrave is nausea, affecting up to 30% of patients during titration. Other frequently reported effects include headache, insomnia, dry mouth, dizziness, and anxiety. Most adverse events are transient and resolve within the first month, but slow titration and taking doses with meals significantly improve tolerability. GI upset tends to be more prominent in women and in those with low baseline body weight.
Due to bupropion’s mild sympathomimetic action, small increases in blood pressure and pulse have been observed. These are typically 1 3 mmHg systolic and 1 2 bpm in heart rate, but may be clinically significant in uncontrolled hypertension. Thus, Contrave is contraindicated in patients with uncontrolled high blood pressure, seizure disorders, bulimia, or chronic opioid use. Baseline vitals and regular follow-up monitoring are recommended throughout treatment.
There is a small but notable risk of neuropsychiatric effects, including irritability, agitation, or suicidal ideation, particularly in younger populations. These are rare but justify early follow-up and patient education. If significant mood symptoms emerge, dose reduction or discontinuation should be considered. Real-world post-marketing surveillance has not shown unexpected safety signals to date.
How to Decide Between Mono- and Combo-Therapy
Deciding whether to use bupropion alone or as part of the Contrave combination depends on individual risk benefit factors. Bupropion monotherapy may be sufficient for patients with mild to moderate weight concerns, especially if being treated for concurrent depression or smoking cessation. It offers additional benefits like reduced sexual side effects and potential cognitive enhancement. For these patients, starting with Bupropion SR or XL 150 300 mg/day may provide metabolic benefits without combination therapy.
Contrave is better suited for individuals with BMI ≥ 30 (or ≥ 27 with comorbidities), emotional eating patterns, or prior failures on monotherapy. It addresses both homeostatic and hedonic eating pathways, offering a more comprehensive approach to appetite regulation. The dual-mechanism design is particularly valuable in patients who report compulsive snacking, food-related cravings, or early satiety failure. Additionally, behavioral interventions may have enhanced synergy when combined with Contrave, as shown in COR-BMOD.
Cost, access, and tolerability may also influence the choice. Bupropion is generic and widely available, while Contrave remains brand-only in many regions. For pricing details and online access, see our Buy Bupropion SR/XL online guide. Ultimately, shared decision-making based on comorbidities, response expectations, and insurance coverage will guide optimal therapy.