- Weight loss of about 4.8 percentage points beyond placebo — classified as low-to-moderate potency, below semaglutide (12.0%) and tirzepatide (14.8%).
- In the COR trials average loss was 6% to 9% over 56 weeks; the best result came from the trial with 28 behaviour-modification sessions.
- Acts on the urge to eat (craving, grazing, emotional eating) rather than on physical satiety — a different profile from the GLP-1 pens.
- New in 2026: labels now require reassessment at 16 weeks (previously 12) and a yearly cardiovascular reassessment.
- Sold as Contrave in the United States, Canada and Australia, Mysimba in Europe, Naltreva in Argentina, and under four brand names in Brazil.
Short answer: the combination of naltrexone 8 mg with bupropion 90 mg works, but it is a modest weight-loss drug. Across the four pivotal trials, average weight loss was 5% to 9% over one year, and the difference against placebo was about 4.8 percentage points. The 2026 Brazilian obesity guideline classifies it as low-to-moderate potency — below semaglutide and tirzepatide, in the same band as liraglutide (ABESO, ABESO 2026). In exchange, it is a tablet rather than an injection, it costs less, and it targets something the GLP-1 pens do not reach well: the urge to eat — craving, emotional eating, grazing.
Below is what the trials actually show, what changed in the Brazilian label in June 2026 (a change most pages online have not picked up), and when, in practice, this combination tends to make sense.
What changed in 2026: the Brazilian label approved on 19 June 2026 now requires reassessment at 16 weeks (previously 12) and a yearly cardiovascular reassessment. The Brazilian agency wrote to physicians on 19 May 2026 explaining why: safety data beyond 12 months are still insufficient (bula brasileira, ANVISA 2026; carta da ANVISA, 2026). Europe reached the same conclusion in May 2025 (EMA 2025).
Brand names around the world
The active ingredients are always the same: naltrexone hydrochloride 8 mg + bupropion hydrochloride 90 mg in an extended-release tablet. Only the name on the box changes. Brand names appear here so you can recognise the product on a prescription — this is not a recommendation or advertising, and I have no ties to any manufacturer.
| Country | Brand name | Status |
|---|---|---|
| United States | Contrave | FDA-approved since September 2014 (bula do FDA, 2025) |
| Canada | Contrave | Health Canada, marketed since 2018 |
| Australia | Contrave | Active TGA registration |
| European Union and United Kingdom | Mysimba | EMA-authorised since March 2015 (EMA 2025) |
| Spain | Mysimba | Authorised but not marketed |
| Brazil | Contrave, Sliv, Reduxalt, Bupnal | Registered as an anti-obesity drug; in pharmacies since 2023 |
| Argentina | Naltreva | Authorised in 2023 (ANMAT 2023) |
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One detail that confuses people: the European label says "8 mg naltrexone hydrochloride, equivalent to 7.2 mg naltrexone". It is the same tablet — one figure refers to the salt, the other to the base.
Do not confuse this with low-dose naltrexone. LDN uses naltrexone at 1 to 4.5 mg for a different purpose, and it is not the same as the 8 mg naltrexone in this combination.
How it works in the brain: hunger on one side, wanting on the other
Hunger runs on two different circuits, and this drug was designed to act on both at once.
- BupropionStimulates POMC neurons in the hypothalamus, the cells that signal satiety. It raises available dopamine and noradrenaline.
- NaltrexoneBlocks opioid receptors. When POMC neurons fire they release beta-endorphin, which switches them back off — naltrexone removes that brake.
- TogetherBupropion accelerates, naltrexone prevents the shut-off. That is why the pair does more than either drug alone.
In practice the effect feels less like "a full stomach" and more like less craving: the late-afternoon sweet stops calling, the urge to graze fades. That is different from GLP-1 pens, which mainly slow gastric emptying and increase physical satiety.
How much weight is lost: the COR trials
Four 56-week phase 3 trials underpin the approval. "Main analysis" below counts everyone who took the drug, including those who dropped out; "completers" counts only those who reached the end.
| Trial | Participants | Weight loss on drug | On placebo | Lost ≥5% of body weight |
|---|---|---|---|---|
| COR-I (Greenway et al., Lancet 2010 — COR-I) | 1,742 adults with obesity | −6.1% −8.1% among completers | −1.3% | 48% vs 16% |
| COR-II (Apovian et al., Obesity 2013 — COR-II) | 1,496 adults | −6.4% −8.2% among completers | −1.2% | 50% vs 17% |
| COR-BMOD (Wadden et al., Obesity 2011 — COR-BMOD) | 793 adults, with 28 sessions of behaviour modification | −9.3% −11.5% among completers | −5.1% | more than placebo (p<0.001) |
| COR-Diabetes (Hollander et al., Diabetes Care 2013 — COR-Diabetes) | 505 adults with type 2 diabetes | −5.0% | −1.8% | 45% vs 19% |
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Three honest readings of those numbers:
- The best result came from the trial with intensive support. In COR-BMOD, with 28 behaviour-modification sessions over a year, loss reached 9.3%. Without that support it sat around 6%. The drug on its own delivers considerably less than the drug plus follow-up.
- About half of participants dropped out before one year. That is the biggest weakness of the whole programme, and the European regulator said so explicitly. People who drop out may differ from those who stay.
- In type 2 diabetes the effect was smaller — 5.0% — as happens with every obesity drug. In return, HbA1c fell by 0.6 points (Hollander et al., Diabetes Care 2013 — COR-Diabetes).
When does the effect show up?
The full dose is only reached in week 4. From there the weight curve usually keeps falling until around the sixth to ninth month, then plateaus. That is why the label asks for reassessment at 16 weeks — enough time to know whether your body responded.
How it compares with the other options
The 2026 Brazilian guideline pooled the meta-analyses and ranked the drugs by potency. The figures below are placebo-subtracted weight loss at 52 weeks — the fairest way to compare (ABESO, ABESO 2026).
| Drug | Loss beyond placebo | Potency band | Route |
|---|---|---|---|
| Orlistat | 2.1% | Very low | Capsule, 3×/day |
| Sibutramine | 4.2 kg | Low to moderate | Capsule, once daily |
| Naltrexone + bupropion | 4.8% | Low to moderate | Tablet, up to 4/day |
| Liraglutide | 6.8% | Low to moderate | Daily injection |
| Semaglutide | 12.0% | High | Weekly injection |
| Tirzepatide | 14.8% | High | Weekly injection |
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For scale, in the individual trials: semaglutide 2.4 mg produced −14.9% at 68 weeks (Wilding et al., N Engl J Med 2021 — STEP 1), tirzepatide 15 mg −20.9% at 72 weeks (Jastreboff et al., N Engl J Med 2022 — SURMOUNT-1), and head to head tirzepatide reached −20.2% against −13.7% for semaglutide (Aronne et al., N Engl J Med 2025 — SURMOUNT-5). A 2025 network meta-analysis of 56 trials and more than 60,000 patients reached the same ranking (McGowan et al., Nat Med 2025).
What the guideline recommends: high-potency drugs should be considered whenever possible; low-to-moderate potency drugs "should be preferred when high-potency drugs cannot be used" (ABESO, ABESO 2026). In real life, "cannot be used" includes cost, supply shortages, fear of injections, GLP-1 intolerance and lack of coverage — all legitimate and common reasons.
Who tends to respond best
Not everyone gains weight for the same reason. One study that sorted patients by eating phenotype before choosing the drug achieved 15.9% weight loss in a year, against 9.0% with the usual approach (Acosta et al., Obesity 2021).
Based on the mechanism and on what the trials suggest, naltrexone + bupropion tends to do more for people who recognise themselves here:
- Eat out of wanting rather than hunger — food "calls", even on a full stomach.
- Craving for sweets or ultra-processed food, especially in the afternoon and evening.
- Constant grazing or episodes of binge eating.
- Eat in response to stress, boredom or anxiety.
- Have quit smoking or want to, or have low mood alongside (bupropion is used in both situations).
It tends to do less for people with intense, constant physical hunger, satiety that never arrives and large meal volumes — GLP-1 agonists usually suit that profile better.
How it is taken: dose escalation week by week
The dose never starts full. Titration exists to reduce nausea and, above all, to lower seizure risk (bula brasileira, ANVISA 2026; bula do FDA, 2025).
| Period | Morning | Evening | Total daily dose |
|---|---|---|---|
| Week 1 | 1 tablet | — | 8 mg / 90 mg |
| Week 2 | 1 tablet | 1 tablet | 16 mg / 180 mg |
| Week 3 | 2 tablets | 1 tablet | 24 mg / 270 mg |
| Week 4 onwards | 2 tablets | 2 tablets | 32 mg / 360 mg |
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Rules that genuinely matter:
- Never exceed 4 tablets a day. Bupropion's seizure risk is dose-dependent.
- Never take 2 tablets at once to make up for a missed dose. Skip it and carry on at the next scheduled time.
- Do not split, chew or crush — it is an extended-release tablet.
- Avoid taking it with a high-fat meal: it markedly increases absorption, and with it the seizure risk.
- The evening dose can be taken in the late afternoon to interfere less with sleep.
The 16-week rule
If, after 16 weeks, at least 5% of initial body weight has not been lost, treatment should be stopped — and the need to continue must be reassessed every year (bula brasileira, ANVISA 2026; carta da ANVISA, 2026; EMA 2025). The rule protects both your wallet and your health: it stops someone spending a year on a drug that, in their body, did not work.
Side effects, and what helps
Frequencies from the US label, with 2,545 people on the full dose and 1,515 on placebo (bula do FDA, 2025).
| Effect | On the drug | On placebo | What usually helps |
|---|---|---|---|
| Nausea | 32.5% | 6.7% | Escalate more slowly than the label; take after a light meal; usually settles in 4 to 8 weeks |
| Constipation | 19.2% | 7.2% | Water, fibre, physical activity; sometimes an osmotic laxative |
| Headache | 17.6% | 10.4% | Usually confined to the first weeks |
| Vomiting | 10.7% | 2.9% | If it persists, review the dose with your doctor |
| Dizziness | 9.9% | 3.4% | Stand up slowly; check blood pressure |
| Insomnia | 9.2% | 5.9% | Move the evening dose to late afternoon |
| Dry mouth | 8.1% | 2.3% | Water, sugar-free gum |
| Seizure | about 0.1% | 0% | Respect the maximum dose, the titration and avoid fatty meals |
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24% of people stopped treatment because of a side effect, against 12% on placebo — mostly in the first three months, with nausea the leading cause. In meta-analyses this combination shows one of the highest discontinuation rates among obesity drugs (Khera et al., JAMA 2016; Shi et al., Lancet 2024).
Blood pressure and heart rate rise slightly. In the first 12 weeks the difference against placebo was 1.8 to 2.4 mmHg in systolic pressure and about 2 beats per minute (bula do FDA, 2025). That sounds small, and it is — but it is why uncontrolled hypertension is a contraindication and why blood pressure must be measured before starting and monitored afterwards.
Cardiovascular safety: what LIGHT showed and what it did not
LIGHT was designed to answer whether the combination is safe for the heart: 8,910 people with overweight or obesity and raised cardiovascular risk (Nissen et al., JAMA 2016 — LIGHT). The trial was stopped early — and not because of harm: the sponsor publicly released interim results that were meant to stay confidential, which made continuing impossible.
What remains: at the halfway analysis, rates of major cardiovascular events were similar between groups. No signal of harm appeared, but the trial never proved the safety it set out to prove. The authors themselves wrote that cardiovascular safety remains uncertain. A Brazilian meta-analysis on the topic reached the same conclusion of no clear signal (Sposito et al., Obes Rev 2021).
Regulators remain watchful. In May 2025 Europe concluded a formal review keeping the drug on the market, with mandatory annual reassessment (EMA 2025), and Brazil adopted the same rule in 2026 (carta da ANVISA, 2026). A new cardiovascular trial, INFORMUS, is under way, with results expected around 2028.
Who must not take it
The contraindication list is among the longest of all obesity drugs — the Brazilian guideline itself notes this as a drawback of the combination (ABESO, ABESO 2026). From the label (bula brasileira, ANVISA 2026; bula do FDA, 2025):
- Uncontrolled hypertension
- Epilepsy or any history of seizures
- Known central nervous system tumour
- History of bipolar disorder
- Bulimia or anorexia nervosa
- Chronic opioid use (methadone, buprenorphine, morphine, and also tramadol and codeine) or acute opioid withdrawal
- Abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptics
- Use of any other product containing bupropion or naltrexone
- MAO inhibitors — 14 days must elapse (this includes linezolid and intravenous methylene blue)
- Severe hepatic impairment and end-stage renal disease
- Pregnancy and breastfeeding
- Allergy to any component
Two practical warnings that rarely appear: if you take this drug and need surgery or a strong painkiller, tell the anaesthetist and the surgeon — naltrexone blocks opioids and can make analgesia ineffective. Tramadol and codeine count too.
Can it be combined with semaglutide or tirzepatide?
The Brazilian guideline allows combining drugs when the response has been insufficient, with three caveats (ABESO, ABESO 2026):
- Pairing a GLP-1 agonist with naltrexone + bupropion is among the acceptable combinations, supported by observational data — but the guideline itself records that those data did not hold up in the reanalysis run by the journal that published them. Plausible, not proven.
- Combining sibutramine with naltrexone + bupropion is not recommended.
- Combining two obesity drugs is generally off-label, and should be left to clinicians experienced in treating obesity.
Tirzepatide with naltrexone + bupropion has no trial data at all; anyone doing it must monitor blood pressure and mood closely.
Prescription and access
This is a prescription-only medicine everywhere it is approved, and in several countries — Brazil included — it is subject to special controlled-prescription rules. Availability, brand names and the exact approved wording differ by country, so check your local regulator. Where a reference brand and similar versions both exist, the price difference between them can be substantial, so it is worth asking your doctor and pharmacist whether a similar version fits your prescription.
Frequently asked questions
Does naltrexone with bupropion actually work for weight loss?
Yes, but modestly. Across the four phase 3 trials, average weight loss over 56 weeks was 5% to 9%, and the difference against placebo was around 4.8 percentage points. About half of participants lost at least 5% of their body weight. That is less than semaglutide and tirzepatide, and more than orlistat.
How long does it take to work?
The full dose is only reached in week 4. Weight loss usually continues until the sixth to ninth month and then plateaus. Labels now require reassessment at 16 weeks: if at least 5% of initial weight has not been lost, treatment should stop.
Which is better: naltrexone + bupropion or semaglutide and tirzepatide?
For average weight loss, GLP-1 agonists and tirzepatide are clearly more potent. The tablet has other advantages: it is oral, costs less, and acts on craving and emotional eating. The choice depends on your eating pattern, your contraindications, cost and your preference for tablet or injection.
What is it called in my country?
Contrave in the United States, Canada and Australia; Mysimba in the European Union and the United Kingdom (authorised but not marketed in Spain); Naltreva in Argentina; and Contrave, Sliv, Reduxalt or Bupnal in Brazil. The active ingredients are identical.
What are the main side effects?
Nausea (about one in three people), constipation, headache, vomiting, dizziness, insomnia and dry mouth. Around 24% of people stopped treatment because of a side effect in the trials, mostly in the first three months. Seizure risk is low (about 0.1%) but is the reason behind the dosing rules.
Does it raise blood pressure?
Slightly. In the first 12 weeks the difference against placebo was 1.8 to 2.4 mmHg in systolic pressure and about 2 beats per minute in heart rate. That is why uncontrolled hypertension is a contraindication and blood pressure must be checked before starting and monitored during use.
Who must not take it?
People with uncontrolled hypertension, epilepsy or any seizure history, bipolar disorder, a central nervous system tumour, bulimia or anorexia, chronic opioid use (including tramadol and codeine), abrupt withdrawal from alcohol or benzodiazepines, MAO inhibitor use, pregnancy and breastfeeding, severe liver impairment or end-stage kidney disease.
Can I drink alcohol?
Best avoided. Excess alcohol raises the seizure risk with bupropion, and abruptly stopping heavy drinking is a formal contraindication. Discuss your drinking pattern with your doctor before starting.
Will the weight come back if I stop?
It can, as with any obesity treatment: obesity is a chronic disease, and withdrawing treatment tends to return part of the weight. That is why the decision to continue, switch or stop should be reassessed at least once a year, with follow-up.
Is it the same as low-dose naltrexone (LDN)?
No. LDN uses 1 to 4.5 mg of naltrexone for entirely different purposes. This combination uses 8 mg of naltrexone together with 90 mg of bupropion in an extended-release tablet, and is approved for weight management.
References
- 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 [COR-I]. Lancet. 2010;376(9741):595-605. doi:10.1016/s0140-6736(10)60888-4
- Apovian CM, Aronne L, Rubino D, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity‐related risk factors (COR‐II) [COR-II]. Obesity. 2013;21(5):935-943. doi:10.1002/oby.20309
- 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 [COR-BMOD]. Obesity. 2011;19(1):110-120. doi:10.1038/oby.2010.147
- 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 [COR-Diabetes]. Diabetes Care. 2013;36(12):4022-4029. doi: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 [LIGHT]. JAMA. 2016;315(10):990. doi:10.1001/jama.2016.1558
- Sposito AC, Bonilha I, Luchiari B, et al. Cardiovascular safety of naltrexone and bupropion therapy: Systematic review and meta‐analyses. Obes Rev. 2021;22(6). doi:10.1111/obr.13224
- McGowan B, Ciudin A, Baker JL, et al. A systematic review and meta-analysis of the efficacy and safety of pharmacological treatments for obesity in adults. Nat Med. 2025;31(10):3317-3329. doi:10.1038/s41591-025-03978-z
- Khera R, Murad MH, Chandar AK, et al. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events. JAMA. 2016;315(22):2424. doi:10.1001/jama.2016.7602
- Iannone A, Natale P, Palmer SC, et al. Clinical outcomes associated with drugs for obesity and overweight: A systematic review and network meta‐analysis of randomized controlled trials. Diabetes Obes Metab. 2023;25(9):2535-2544. doi:10.1111/dom.15138
- 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. Lancet. 2024;403(10434):e21-e31. doi:10.1016/s0140-6736(24)00351-9
- Damen JA, Idema DL, Vernooij RW, et al. Benefits and Harms of Pharmacologic Treatments in Adults With Overweight or Obesity: A Living Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med. 2026;179(8):1140-1155. doi:10.7326/annals-24-03764
- Acosta A, Camilleri M, Abu Dayyeh B, et al. Selection of Antiobesity Medications Based on Phenotypes Enhances Weight Loss: A Pragmatic Trial in an Obesity Clinic. Obesity. 2021;29(4):662-671. doi:10.1002/oby.23120
- ABESO. DIRETRIZ BRASILEIRA DE TRATAMENTO FARMACOLÓGICO DA OBESIDADE. ABESO. 2026. doi:10.47626/2026-abeso-0001
- Wilding JP, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity [STEP 1]. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/nejmoa2032183
- Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes [STEP 8]. JAMA. 2022;327(2):138. doi:10.1001/jama.2021.23619
- Wharton S, Freitas P, Hjelmesæth J, et al. Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial [STEP UP]. Lancet Diabetes Endocrinol. 2025;13(11):949-963. doi:10.1016/s2213-8587(25)00226-8
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity [SURMOUNT-1]. N Engl J Med. 2022;387(3):205-216. doi:10.1056/nejmoa2206038
- Aronne LJ, Horn DB, le Roux CW, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity [SURMOUNT-5]. N Engl J Med. 2025;393(1):26-36. doi:10.1056/nejmoa2416394
- ANVISA. Bula do profissional de saúde — CONTRAVE® (cloridrato de naltrexona 8 mg + cloridrato de bupropiona 90 mg). Merck S/A, registro 1.0089.0415. Texto aprovado em 19/06/2026. consultas.anvisa.gov.br/#/bulario/ (buscar "CONTRAVE")
- ANVISA; Merck S/A. Carta aos profissionais de saúde — Contrave® (naltrexona/bupropiona): risco cardiovascular a longo prazo e novas recomendações sobre avaliação anual. 19 de maio de 2026. gov.br/anvisa
- U.S. Food and Drug Administration. CONTRAVE (naltrexone HCl and bupropion HCl) extended-release tablets — prescribing information. NDA 200063, revisão de novembro de 2025. accessdata.fda.gov
- European Medicines Agency. Mysimba (naltrexone/bupropion) — EPAR. EMEA/H/C/003687. Revisão do Artigo 20 concluída pela Comissão Europeia em 22 de maio de 2025. ema.europa.eu
- ANMAT (Argentina). Disposición 7876/2023 — autorização do NALTREVA® (naltrexona/bupropiona), certificado REM 58.766, 21 de setembro de 2023. anmat.gob.ar
Read also
- Weight-loss drugs comparedHow much each one takes off, side by side
- BMI calculatorThe number that defines eligibility for obesity drugs
- Eating behaviour profileMap whether you eat from hunger or from wanting
- Tirzepatide dose calculatorDoses, escalation and equivalences
- Semaglutide dose calculatorPen, insulin syringe and compounded doses
- Cost comparisonWhat each option costs per month
Important: This content is strictly educational and must never be used for self-diagnosis, self-medication or treatment. It does not replace a consultation with a qualified health professional. Responsibility for the use of the information presented here lies entirely with the reader.
I declare, transparently, that I have no conflict of interest with the pharmaceutical companies mentioned in this text. Brand names appear only in an informative context, so that readers can recognise the product on a prescription or at the pharmacy — this is not a recommendation, an endorsement or brand advertising. Availability, brand names and approved indications differ from country to country.
Obesity medicines are prescription only and, in the case of this combination, subject to special control in several countries. Only a doctor who assesses your case can decide whether it is indicated, at what dose and for how long.
All content on my website and social media is meant to inform, educate and clarify — always free of charge. No information shared here should be used as the sole basis for assessment, diagnosis or treatment decisions. Every person is unique and must be assessed individually.
Physician (CRM-SC 32925 | CRM-BA 39586, Brazil). Sees patients by video consultation in Brazil and abroad. This content is educational, reviewed against the cited references, and does not replace a consultation.
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How video consultations workReviewed on November 6, 2026 by Dr. Diegomaier Nunes Neri — CRM-SC 32925 | CRM-BA 39586 (Brazil).