Medications · Metabolic & weight

Naltrexone-Bupropion Combination

Compounded alternative to FDA-approved Contrave.

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Naltrexone-Bupropion Combination molecular structure (Norepinephrine-dopamine reuptake inhibitor + opioid antagonist)

Why this needs to be personal

Why Personalized Naltrexone-Bupropion

Contrave's fixed 8 mg naltrexone / 90 mg bupropion sustained-release tablet was titrated up to four tablets a day in the COR program because that ratio was tractable to manufacture and tolerable across the average phase III enrollee. It was not chosen for the patient who got craving suppression from low-dose naltrexone at 3 or 4.5 mg and wants that anchored to a bupropion dose, the patient already stabilized on bupropion 150 or 300 mg for depression who needs naltrexone added without doubling their bupropion exposure, the patient whose seizure-threshold history makes 360 mg of bupropion a day a non-starter, or the patient sensitive to the lactose, microcrystalline cellulose, or FD&C dyes in the branded tablet. The fixed ratio also fails the patient who simply cannot get Contrave because of a manufactured-product backorder.

Compounding decouples the two molecules. A prescriber who knows the chart can ask for 4.5 mg naltrexone with 75 mg bupropion, or 25 mg naltrexone with 150 mg bupropion, or a naltrexone-forward ratio when craving is the dominant target and the bupropion is doing supporting work. The actives are the same naltrexone HCl and bupropion HCl the FDA reviewed in their respective monographs. What changes is the strengths, the excipients, the capsule format, and the ability to fill when Contrave is unavailable. None of that is possible inside a fixed-dose commercial tablet.

This is the older arrangement. A prescriber writes for a named patient, a pharmacist compounds it, the label carries that patient's name. Modern state licensure, USP-compliant facilities, and recall infrastructure keep it honest.

In brief

Naltrexone-Bupropion Explained

Naltrexone-bupropion is a prescription weight-loss pill. The brand-name version is Contrave, the FDA approved it in 2014. RonanRx can also make a custom-compounded version when the brand pill isn't right for you (an allergy to an ingredient, a different dose, or it's out of stock).

It works by quieting hunger and food cravings 9. The two ingredients team up: one nudges the brain's appetite controls, the other keeps that effect from wearing off too fast. Used alongside diet and exercise, most people lose 4, 5% of their body weight over a year 1.

At a glance

Quick Facts About Naltrexone-Bupropion

Category
Combination weight-management therapy
Active ingredients
Naltrexone HCl (opioid receptor antagonist) + bupropion HCl (norepinephrine-dopamine reuptake inhibitor)
FDA-approved branded form
Contrave (naltrexone HCl 8 mg / bupropion HCl 90 mg sustained-release tablet); FDA-approved September 2014 for chronic weight management
Routes studied in humans
Oral (sustained-release tablet for the manufactured product; compounded oral capsules where dispensed)
Evidence posture
Pivotal phase III evidence (COR-I, COR-II, COR-BMOD, COR-Diabetes) supports manufactured Contrave; the compounded preparation has no separate efficacy program
FDA-approval status
Manufactured Contrave is FDA-approved for chronic weight management as adjunct to reduced-calorie diet and increased physical activity. Compounded variants are not FDA-approved.
Compounded under
503A, patient-specific prescription only, where the manufactured FDA-approved product is not clinically appropriate
Important compounding caution
Per FDA guidance, compounded versions of an FDA-approved drug are generally permissible only when the manufactured product cannot meet the patient's medical need (e.g., excipient sensitivity, dose individualization, manufactured-product unavailability). Routine compounding of essentially-a-copy preparations is restricted.

Prescription review

Patient-Specific Prescription Only

Naltrexone-Bupropion Combination on this page is a 503A compounded preparation. Every dose is made on a prescription, for a named patient, by a licensed pharmacist. It is not a stocked, mass-manufactured product.

  • Made to order, not off a shelf. No batch sits in a warehouse waiting for buyers. Your prescription is what triggers the prep.
  • Named-patient label. The bottle carries your name. The batch records carry your prescription.
  • Dose, strength, and route chosen for you. A prescriber who knows your chart decides what gets compounded, not a manufacturer who set the strength for a trial population.
  • Licensed pharmacist on the hook. A real person, with a license that can be pulled, signs off on every prep. State inspectors check the facility.
  • Compounded drugs are not FDA-approved. They should not be evaluated using branded-drug trial data. Availability varies by state and prescribed medication.
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Real medicine, not gray market

How This Differs from a Research-Use-Only Website

A research-use-only website ships a vial from a warehouse. There is no prescription, no pharmacist, no facility inspection, and no way to recall the product if something is wrong with it. If the vial is mislabeled, contaminated, or under-potent, there is nobody whose license is at stake.

A 503A compounding pharmacy is the other thing. Your doctor writes the prescription. A licensed pharmacist, whose name is on the label, prepares the medicine in a facility the state inspects. If something goes wrong, there is a person and a license on the hook, and a documented chain of custody on every lot. That accountability is what makes it safe.

What it is

What is Naltrexone-Bupropion?

Naltrexone-bupropion is a combination of two long-established active ingredients with different individual indications, formulated together for chronic weight management. Bupropion HCl (originally introduced for major depressive disorder in 1985 and later for smoking cessation) is a norepinephrine-dopamine reuptake inhibitor. Naltrexone HCl (introduced 1984) is a competitive antagonist at mu- and kappa-opioid receptors used in opioid-use and alcohol-use disorders.

The combination was developed on the rationale that naltrexone removes a beta-endorphin-mediated negative feedback signal that otherwise limits bupropion's effect on hypothalamic POMC neurons 9. This was demonstrated preclinically by Greenway and colleagues and supported the design of the phase III COR program in human obesity 6.

The resulting branded product, Contrave, was FDA-approved in September 2014 as an adjunct to lifestyle modification in adults with body mass index ≥30 kg/m² (obesity) or ≥27 kg/m² with at least one weight-related comorbidity such as hypertension, type 2 diabetes, or dyslipidemia.

How it works

How Naltrexone-Bupropion Works

Class
Norepinephrine-dopamine reuptake inhibitor + opioid antagonist
First studied
Combination approved 2014
Common forms
Compounded capsule
Compounding category
503A, patient-specific prescription

Bupropion stimulates POMC (pro-opiomelanocortin) neurons in the hypothalamic arcuate nucleus through inhibition of norepinephrine and dopamine reuptake. POMC neurons release α-MSH, which activates MC4 receptors that drive satiety and reduced food intake. Bupropion alone produces modest weight reduction, but its effect is self-limiting because POMC neurons co-release beta-endorphin that feeds back through mu-opioid receptors on the same neurons to inhibit further firing.

Naltrexone blocks that beta-endorphin autoinhibitory loop by antagonizing mu-opioid receptors on POMC neurons. With the brake removed, bupropion's stimulatory effect on POMC neurons is sustained and amplified, yielding greater weight loss in combination than either drug alone 73.

Beyond appetite, the combination also engages mesolimbic reward circuits implicated in food craving 6. Reduction in hedonic eating and craving has been observed in functional imaging and behavioral measures from the COR-BMOD subset analyses.

Research history

Naltrexone-Bupropion Research History

Bupropion's anti-obesity effect as monotherapy was characterized in the late 1990s and early 2000s, with Anderson and colleagues (2002) reporting modest but sustained weight reduction in a 48-week placebo-controlled trial 8. The bupropion sustained-release formulation later combined with naltrexone had been validated in the smoking-cessation pivotal trial 20, and bupropion's pharmacokinetic disposition was characterized by Hsyu and colleagues in 1997 24. Concurrently, naltrexone's PK profile (parent half-life ~4 h, 6β-naltrexol metabolite ~13 h) had been mapped by Verebey and colleagues a decade earlier 25, and naltrexone monotherapy at moderate doses had been examined for obesity in the 1980s with limited individual benefit but documented effects on food intake and palatability 18. Naltrexone's foundational efficacy in alcohol-use disorder 19 had established the molecule's clinical activity at mu-opioid receptors and informed dose selection for the combination. Parallel work by Wang, Volkow and colleagues had implicated striatal dopamine D2-receptor availability and mesolimbic reward circuits in human obesity 27, framing the reward-circuit rationale for engaging both catecholamine and opioid systems together 35.

Greenway and colleagues published the rational-design rationale for combining the two in 2009 6, articulating the POMC autoinhibition hypothesis built on preclinical catecholamine-reuptake data 7. A phase 2 RCT comparing combined bupropion + naltrexone to monotherapy and placebo, also led by Greenway, confirmed the combination's superiority over either component alone before pivotal trials began 23. The phase III clinical development program, COR-I 1, COR-II 2, COR-BMOD 3, and COR-Diabetes 4, followed across 2010, 2013, demonstrating consistent placebo-adjusted weight loss of approximately 4, 5% in the combined-therapy arms 34.

After the LIGHT cardiovascular outcomes trial was terminated early in 2013 over disclosure controversy, post-hoc analyses through 2016 5 did not establish a cardiovascular benefit and did not exclude harm. Contrave's FDA approval in September 2014 was conditional on a continuing post-marketing cardiovascular outcomes commitment. Independent reviews from Caixàs 12, Sherman 13, Apovian 14, Tek 29, and Velazquez & Apovian 36 consolidated the efficacy/safety package. Functional imaging by Wang and colleagues subsequently demonstrated that combined naltrexone-bupropion modulated brain functional connectivity in regions implicated in food reward, providing in-vivo human evidence consistent with the rational-design hypothesis 28. Systematic and network meta-analyses from Khera 15, Singh 31, and Onakpoya 30 placed the combination mid-pack among approved obesity pharmacotherapies; major society guidelines from the Endocrine Society 32 and AACE 33 incorporated naltrexone-bupropion into recommended pharmacotherapy algorithms 3534. Long-term real-world evidence remains limited, though Ard and colleagues (2024) reported 12-month telehealth-cohort outcomes for FDA-approved anti-obesity medications including the combination 37.

Timeline

Naltrexone-Bupropion Timeline

  1. 1976 Verebey et al 25. characterize naltrexone pharmacokinetics (parent t½ ~4 h, 6β-naltrexol metabolite t½ ~13 h), foundational PK still cited in modern labeling
  2. 1984 Naltrexone HCl receives FDA approval for opioid use disorder
  3. 1985 Bupropion HCl receives FDA approval for major depressive disorder
  4. 1989 Davidson reports elevated seizure rate with original immediate-release bupropion at higher doses; FDA tightens dose ceilings 17
  5. 1992 Volpicelli et al 19. demonstrate naltrexone efficacy in alcohol dependence, establishes mu-opioid antagonism as a clinical lever for reward-related behavior
  6. 1996 Bupropion HCl approved for smoking cessation as Zyban; sustained-release (SR) and extended-release (XL) formulations follow
  7. 1997 Hurt et al 20. publish New England Journal of Medicine pivotal trial of sustained-release bupropion for smoking cessation
  8. 1997 Hsyu et al 24. characterize bupropion pharmacokinetics and metabolite profile (hydroxybupropion, threohydrobupropion, erythrohydrobupropion) via CYP2B6, establishes the drug-interaction footprint carried into Contrave labeling
  9. 1997 Yeomans & Gray characterize naltrexone's effect on food intake and palatability in humans, linking endogenous opioid tone to appetite 18
  10. 2001 Wang & Volkow et al 27. (Lancet) report inverse correlation between striatal dopamine D2-receptor availability and BMI in severe obesity, frames dopaminergic reward-circuit basis for catecholamine-targeted obesity pharmacotherapy
  11. 2002 Anderson et al 8. publish 48-week placebo-controlled trial showing bupropion-induced weight loss in obesity
  12. 2002 Pesola & Avasarala emergency-department case-series review reaffirms bupropion's disproportionate contribution to drug-related new-onset generalized seizures, supports the dose ceiling carried into Contrave 26
  13. 2004 Stahl et al 16. publish comprehensive review of bupropion's dual norepinephrine-dopamine reuptake inhibition mechanism
  14. 2008 Billes & Cowley demonstrate the catecholamine reuptake inhibition mechanism of weight loss in preclinical models 7
  15. 2009 Greenway et al 6. publish the rational-design rationale for combining naltrexone with bupropion based on the POMC autoinhibition hypothesis
  16. 2009 Greenway et al 23. (J Clin Endocrinol Metab) publish phase 2 RCT showing combined bupropion + naltrexone superior to either monotherapy or placebo over 24 weeks, selects doses for COR phase III
  17. 2010 COR-I phase III trial published (Greenway et al., Lancet) 1
  18. 2011 COR-BMOD phase III trial published (Wadden et al.) 3
  19. 2013 COR-II and COR-Diabetes phase III trials published (Apovian et al.; Hollander et al.) 24
  20. 2014 FDA approves naltrexone-bupropion as Contrave for chronic weight management 9
  21. 2014 Caixàs et al 12. publish a clinical review of naltrexone SR/bupropion SR data through approval
  22. 2014 Yanovski & Yanovski (JAMA) publish systematic review of long-term obesity pharmacotherapy contextualizing naltrexone-bupropion alongside orlistat, phentermine-topiramate, and lorcaserin 34
  23. 2015 Endocrine Society clinical practice guideline (Apovian et al., J Clin Endocrinol Metab) incorporates naltrexone-bupropion among recommended chronic-weight-management pharmacotherapies 32
  24. 2015 EMA grants marketing authorization for the combination as Mysimba in the European Union
  25. 2016 Nissen et al 5. publish JAMA analysis of the LIGHT cardiovascular outcomes trial (terminated early); CV benefit not established
  26. 2016 Khera et al 15. publish JAMA network meta-analysis of pharmacological treatments for obesity
  27. 2016 AACE/ACE comprehensive clinical practice guidelines for medical care of patients with obesity (Garvey et al., Endocr Pract) include naltrexone-bupropion in recommended pharmacotherapy options 33
  28. 2016 Sherman et al., Apovian, and Tek publish post-approval clinical reviews summarizing efficacy, safety, and patient-selection considerations 131429
  29. 2017 Heymsfield & Wadden (NEJM) review mechanisms, pathophysiology, and management of obesity, placing naltrexone-bupropion within the broader pharmacotherapy landscape 35
  30. 2018 Wang et al 28. publish first fMRI evidence that combined naltrexone-bupropion alters resting-state functional connectivity in hypothalamus and reward-circuit regions, in-vivo human confirmation of the rational-design hypothesis
  31. 2018 Velazquez & Apovian publish updated review of pharmacological management of obesity 36
  32. 2020 Singh et al 31. and Onakpoya et al 30. publish systematic reviews/meta-analyses (the latter incorporating unpublished clinical study reports) confirming COR-program effect sizes and adverse-event patterns
  33. 2024 Ard et al 37. (Obesity) publish 12-month real-world telehealth-cohort outcomes for FDA-approved anti-obesity medications including naltrexone-bupropion
  34. 2018 Currax Pharmaceuticals acquires Contrave from Orexigen Therapeutics (chapter 11 reorganization)

Natural role

Biological Role of Naltrexone-Bupropion

The naltrexone-bupropion combination acts on two endogenous regulatory systems that govern appetite, food reward, and energy balance: the central catecholamine pathways (norepinephrine and dopamine) that drive POMC neuron activity in the hypothalamic arcuate nucleus, and the endogenous opioid system whose mu-opioid receptors normally provide feedback inhibition on those same neurons 7.

POMC (pro-opiomelanocortin) is a precursor protein cleaved into multiple bioactive peptides including α-MSH (which activates MC4 receptors and suppresses appetite) and beta-endorphin (which acts on mu-opioid receptors). Beta-endorphin co-released from POMC neurons binds mu-opioid receptors on those neurons in an autoinhibitory loop. Naltrexone, a competitive mu-opioid antagonist with a long history of use in opioid- and alcohol-use disorders, blocks that autoinhibition.

Bupropion, originally introduced as an antidepressant and later for smoking cessation, increases synaptic norepinephrine and dopamine availability via reuptake inhibition 16. In the arcuate nucleus this stimulates POMC firing. The combination therefore engages both an excitatory drive (bupropion) and disinhibition (naltrexone) on the same satiety-driving neurons, producing a sustained increase in α-MSH release and reduced food intake that exceeds either drug's individual effect 61819.

Clinical contexts studied

Clinical Contexts for Naltrexone-Bupropion

Chronic weight management in adults with obesity (BMI ≥30 kg/m²) fda approved

FDA-approved indication for the manufactured combination.

Contrave is FDA-approved as an adjunct to reduced-calorie diet and increased physical activity in adults with BMI ≥30 kg/m² 9. COR-I 1 reported approximately 6.1% placebo-adjusted weight loss at 56 weeks in the highest-dose arm. Approximately 48% of completers in the combined-therapy arm achieved ≥5% weight loss vs 16% on placebo.

Branded product: Contrave (naltrexone HCl 8 mg / bupropion HCl 90 mg ER tablet, Currax Pharmaceuticals, formerly Orexigen)

Chronic weight management in adults with overweight (BMI ≥27 kg/m²) plus weight-related comorbidity fda approved

FDA-approved indication for the manufactured combination.

Same FDA-approved indication extends to BMI ≥27 with at least one weight-related comorbidity (hypertension, type 2 diabetes, or dyslipidemia). COR-II 2 replicated the COR-I efficacy signal in a similar adult population over 56 weeks 9.

Branded product: Contrave

Weight management in patients with type 2 diabetes well studied

Studied in a dedicated phase III trial; included in the FDA label population.

COR-Diabetes 4 randomized 505 overweight or obese patients with type 2 diabetes to combined therapy or placebo over 56 weeks. Mean weight loss was 5.0% with combined therapy vs 1.8% on placebo, and HbA1c reduction averaged 0.6% vs 0.1%, supporting metabolic benefit beyond weight loss alone.

Weight management as adjunct to intensive behavior modification well studied

Evaluated in a dedicated phase III trial; consistent with FDA-label adjunctive framing.

COR-BMOD 3 randomized participants enrolled in a 56-week intensive behavior-modification program to combined therapy or placebo. The combined-therapy arm achieved approximately 9.3% mean weight loss vs 5.1% with placebo, indicating additive benefit beyond behavioral intervention.

FDA-approved use

FDA-Approved Uses of Naltrexone-Bupropion

BrandIndicationYearRoute
Contrave Chronic weight management in adults (BMI ≥30, or ≥27 with weight-related comorbidity) as adjunct to reduced-calorie diet and increased physical activity 2014 Oral, sustained-release tablet

The FDA-approved branded form is Contrave (naltrexone HCl 8 mg / bupropion HCl 90 mg sustained-release tablet), approved September 10, 2014 9. Approval was based on the COR phase III program (COR-I, COR-II, COR-BMOD, COR-Diabetes), which demonstrated 4, 5% placebo-adjusted weight reduction in adults with obesity or overweight-plus-comorbidity.

The label includes a Boxed Warning regarding suicidal thoughts and behaviors associated with bupropion-containing products, and contraindications including uncontrolled hypertension, seizure disorder, eating disorders, chronic opioid use, and pregnancy. Cardiovascular safety is qualified, the LIGHT outcomes trial was terminated early and did not establish a CV benefit 5.

Compounded use

Compounded Naltrexone-Bupropion (503A)

Compounded naltrexone-bupropion is dispensed under 503A only when the prescribing clinician documents a patient-specific need that the manufactured Contrave product cannot meet. Common documented needs include excipient sensitivity (the manufactured tablet contains specific dyes, lactose, and microcrystalline cellulose), dose individualization outside the fixed 8/90 mg ratio (for example, separate titration of components for a patient who tolerates one but not the other), or a confirmed supply interruption of the manufactured product.

Per FDA guidance for industry on compounding under 503A, a compound that is essentially a copy of a commercially available drug is generally restricted unless a prescriber has determined a clinical difference for the identified patient 1011. RonanRx's pharmacist review evaluates each prescription against this criterion before dispensing and does not fill prescriptions for compounded naltrexone-bupropion that read as routine substitution for Contrave.

Compounded variants are typically dispensed as oral capsules with custom strengths matched to the patient's clinical profile. The manufactured tablet's sustained-release matrix cannot be replicated identically in compounded capsules; clinicians and patients should understand that PK/PD profiles of a compounded preparation may differ from Contrave's published characteristics.

Formulations and routes

Naltrexone-Bupropion Formulations and Routes

FormConcentrationDescription
Oral capsule (compounded combination) Custom (commonly naltrexone 4, 8 mg + bupropion 45, 90 mg per capsule) Two-component capsule prepared under USP <795> non-sterile compounding standards. Dose individualized by the prescribing clinician; not bioequivalent to Contrave's sustained-release manufactured tablet.
Oral capsule (separated components, twice-daily) Custom strengths per component When a patient requires asymmetric titration of one component, naltrexone and bupropion may be dispensed as separate compounded capsules so doses can be titrated independently.

Routes used in published literature: oral.

Dosing

Naltrexone-Bupropion Dosing

RoutePopulationRangeDurationStudy type
Oral Adults with obesity or overweight + comorbidity (FDA-label population) Titration over 4 weeks: week 1, naltrexone 8 mg + bupropion 90 mg every morning; week 2, twice daily; week 3, two tablets AM + one tablet PM; week 4+, two tablets twice daily (target 32 mg / 360 mg per day) Indefinite while clinically beneficial; reassess at 16 weeks per FDA-label criterion (discontinue if <5% weight loss from baseline) FDA-approved labeled regimen; mirrored by compounded preparations unless prescriber documents patient-specific reason for variance9
Oral Adults with renal impairment (moderate to severe; eGFR <60) Reduced maintenance: 1 tablet (8/90 mg) AM and PM (16 mg / 180 mg per day); not recommended in end-stage renal disease Indefinite while clinically beneficial FDA-label population-specific guidance9
Oral Adults with hepatic impairment Reduced maintenance: 1 tablet (8/90 mg) every morning only (8 mg / 90 mg per day); not recommended in severe hepatic impairment Indefinite while clinically beneficial FDA-label population-specific guidance9
Oral Adults concomitantly taking strong CYP2B6 inhibitors Maximum daily dose limited to 1 tablet AM + 1 tablet PM (16 mg / 180 mg per day) due to elevated bupropion exposure While concomitant therapy continues FDA-label drug-interaction guidance9
Oral (bupropion monotherapy reference) Adults, bupropion as antidepressant or smoking-cessation precedent Bupropion HCl SR 150 mg twice daily for major depressive disorder; XL 150, 300 mg once daily; smoking cessation 150 mg BID; doses above 450 mg/day carry markedly increased seizure risk Per indication Approved labeling for bupropion components; informs the bupropion ceiling in combination therapy201617
Oral (naltrexone monotherapy reference) Adults, naltrexone in opioid-use and alcohol-use disorders Naltrexone HCl 50 mg orally once daily for alcohol dependence (Volpicelli regimen); 380 mg long-acting injection monthly for opioid use disorder Per indication; alcohol dependence often 12+ weeks Long-established labeled regimens that pre-date the obesity combination; component safety database1918

Doctor-prescribed and titrated. The Contrave label-defined four-week escalation balances tolerability (especially nausea, headache, insomnia) against time-to-target. Most adverse-event-driven discontinuations in the COR trials occurred during the first 4, 8 weeks; titration pacing is the primary tolerability lever.

Compounded preparations should not exceed the FDA-label maximum daily dose of naltrexone 32 mg + bupropion 360 mg in routine prescribing 9. Higher doses of either component carry component-specific risks (bupropion seizure risk above 450 mg/day; naltrexone hepatotoxicity at very high chronic doses) and have not been studied in combination.

Doses listed are literature context, not patient instructions. Dosing decisions are made by the prescribing doctor and tailored to the individual patient.

Safety

Naltrexone-Bupropion Safety

Safety overview

Naltrexone-bupropion safety reflects the safety profiles of both components plus a small number of combination-specific signals 1. The most common adverse events in the COR program were nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea, the majority of which were mild to moderate and concentrated in the titration period. Independent reviews summarize the same tolerability pattern, and Onakpoya and colleagues' analysis of unpublished clinical study reports 30 reproduces the published adverse-event profile 24.

The Contrave label 9 carries a Boxed Warning regarding suicidal thoughts and behaviors, derived from class-wide bupropion-containing antidepressant labeling. Bupropion also lowers seizure threshold, Davidson's 1989 review of bupropion seizure risk 17 drove the dose ceiling that the combination still observes, and Pesola & Avasarala's ED case-series review 26 reaffirmed bupropion's disproportionate contribution to drug-related new-onset generalized seizures 12. Naltrexone-bupropion is contraindicated in patients with seizure disorder, bulimia or anorexia nervosa, chronic opioid use, abrupt discontinuation of alcohol or sedatives, and uncontrolled hypertension 132936.

Cardiovascular safety remains qualified. The LIGHT outcomes trial 5 was terminated early; published interim data did not demonstrate a cardiovascular benefit and did not exclude harm. A continuing post-marketing cardiovascular safety commitment was a condition of approval. Major society guidelines 3233 reflect this qualification when recommending the combination among chronic-weight-management options 3.

Contraindications

Naltrexone-bupropion is contraindicated in: uncontrolled hypertension; seizure disorder or history of seizures; current or past bulimia nervosa or anorexia nervosa; chronic opioid use, opioid agonist use (e.g., methadone), or acute opioid withdrawal; abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs; concomitant use of MAO inhibitors (within 14 days); known allergy to bupropion or naltrexone; and pregnancy 9.

Drug interactions

Bupropion is a strong CYP2D6 inhibitor; concomitant use with CYP2D6 substrates (many antidepressants, antipsychotics, beta-blockers, and Type 1C antiarrhythmics) can raise plasma levels of those substrates substantially. Dose reductions of CYP2D6 substrates may be required 9.

Bupropion is metabolized primarily by CYP2B6; strong CYP2B6 inducers (e.g., ritonavir, efavirenz, carbamazepine) can decrease bupropion exposure, while CYP2B6 inhibitors (e.g., ticlopidine, clopidogrel) can increase it 249. The maximum daily dose of the combination is reduced by half in patients on concomitant strong CYP2B6 inhibitors.

Naltrexone blocks the analgesic effect of opioid medications. Patients requiring acute opioid analgesia (postoperative, trauma) should not be on naltrexone-bupropion; naltrexone should be discontinued in advance per surgical-clearance protocols 925.

Adverse events

Across the COR phase III program (combined N >4,500), the most common adverse events with combined therapy vs placebo were nausea (32% vs 7%), constipation (19% vs 7%), headache (18% vs 11%), vomiting (11% vs 3%), dizziness (10% vs 3%), insomnia (9% vs 6%), and dry mouth (8% vs 2%) 1. Adverse-event-driven discontinuation rates ranged from approximately 24, 28% with combined therapy across the four trials, vs 12, 14% with placebo 34. Onakpoya and colleagues' independent analysis of clinical study reports reproduces these adverse-event frequencies 30.

Serious adverse events were uncommon. Seizure rates in the combined COR development program were approximately 0.06% in the active arm, consistent with bupropion's labeled seizure risk 1726 and lower than older immediate-release bupropion formulations 2. Reported suicidal-ideation rates did not differ statistically from placebo in the combined COR program but the Boxed Warning is class-wide 9. Real-world tolerability and discontinuation patterns under telehealth-driven prescribing have been documented at 12 months by Ard and colleagues 37.

Monitoring

Monitoring Naltrexone-Bupropion Therapy

Baseline assessment should include blood pressure, heart rate, complete medication review focused on opioid use and CYP2D6/CYP2B6 substrates, screening for seizure history and eating disorders, and a structured suicidal-ideation screen consistent with bupropion-containing-product labeling.

On therapy: blood pressure and heart rate at the next clinical visit and periodically thereafter; reassessment of weight loss at 16 weeks (label criterion: discontinue if <5% weight loss from baseline at 16 weeks); ongoing monitoring for mood changes, sleep disturbance, and tolerability 9.

Evidence quality

Naltrexone-Bupropion Evidence Quality

Evidence supporting the manufactured Contrave is strong: a phase 2 dose-finding RCT 23 followed by four phase III randomized double-blind placebo-controlled trials (COR-I 1, COR-II 2, COR-BMOD 3, COR-Diabetes 4) totaling over 4,500 participants, plus a partial cardiovascular outcomes trial (LIGHT 5) terminated early. Effect sizes for weight loss are consistent across trials (4, 5% placebo-adjusted at 56 weeks) and consistent with mechanism 21. Independent network meta-analyses by Khera and colleagues (28 RCTs, 29,018 patients) 15 and Singh and colleagues 31 place naltrexone-bupropion mid-pack among approved obesity pharmacotherapies for absolute weight loss, behind liraglutide and phentermine-topiramate but ahead of orlistat and lorcaserin (since withdrawn) 12. Onakpoya and colleagues' 2020 systematic review of unpublished clinical study reports reached similar effect-size conclusions and also documented adverse-event patterns consistent with the published trial reports 30 3435.

Major society guidelines incorporate naltrexone-bupropion: the Endocrine Society's 2015 clinical practice guideline 32 and the AACE/ACE 2016 comprehensive clinical practice guidelines for medical care of patients with obesity 33 both include the combination among recommended pharmacotherapy options for chronic weight management 12. Broad reviews of the obesity-pharmacotherapy field place naltrexone-bupropion in context relative to the broader class. Real-world evidence beyond the registration trials is limited but emerging: Ard and colleagues' 2024 telehealth-cohort analysis reported 12-month weight-loss outcomes for FDA-approved anti-obesity medications including naltrexone-bupropion under contemporary prescribing patterns 37. In-vivo functional MRI data from Wang and colleagues provide mechanistic confirmation in humans of altered reward-circuit connectivity on therapy 28 36.

Evidence specifically supporting the compounded preparation is absent, there is no parallel efficacy program for compounded oral capsules. Compounded use is therefore an extrapolation from the manufactured-product evidence base, justified case by case by patient-specific clinical factors that the manufactured product cannot accommodate. The component drugs themselves have decades of safety data: bupropion since 1985 in MDD and 1997 for smoking cessation 20, with PK characterized in detail 24 and a well-documented dose-related seizure-risk profile 1726; naltrexone since 1984 in opioid-use disorder and the early-1990s alcohol-use disorder approval 19, with PK characterized in the foundational Verebey work 25 12.

Major studies

Major Naltrexone-Bupropion Clinical Studies

StudyDesignParticipantsDurationFinding
COR-I (Greenway 2010, Lancet) Phase III, randomized, double-blind, placebo-controlled 1742 56 weeks 6.1% mean weight loss (high-dose combined therapy) vs 1.3% placebo; 48% vs 16% achieved ≥5% weight loss 1
COR-II (Apovian 2013) Phase III, randomized, double-blind, placebo-controlled 1496 56 weeks 6.4% mean weight loss vs 1.2% placebo; replicated COR-I efficacy 2
COR-BMOD (Wadden 2011) Phase III, randomized, double-blind, placebo-controlled with intensive behavioral modification arm 793 56 weeks 9.3% mean weight loss with combined therapy + BMOD vs 5.1% with placebo + BMOD 3
COR-Diabetes (Hollander 2013) Phase III, randomized, double-blind, placebo-controlled in adults with T2D 505 56 weeks 5.0% mean weight loss vs 1.8% placebo; HbA1c reduction 0.6% vs 0.1% 4
LIGHT (Nissen 2016) Cardiovascular outcomes RCT terminated early; published interim analysis — Interim follow-up (terminated early) No statistically significant cardiovascular benefit established in interim data; trial did not exclude harm 5
Anderson et al. (2002, Obesity Research) Bupropion monotherapy, 48-week double-blind placebo-controlled trial in obese adults 327 48 weeks Bupropion SR 300 mg/day produced 7.2% weight loss vs 5.0% placebo; 46% vs 30% achieved ≥5% weight loss, established the bupropion-monotherapy effect that motivated the combination 8
Khera et al. (2016, JAMA) Network meta-analysis of pharmacological treatments for obesity 28 RCTs, 29,018 patients ≥1 year Naltrexone-bupropion produced ~5.0 kg placebo-adjusted weight loss; placed mid-pack among approved obesity pharmacotherapies (liraglutide and phentermine-topiramate produced larger effects) 15
Caixàs et al. (2014, Drug Des Devel Ther) Comprehensive clinical review of all naltrexone SR/bupropion SR data through FDA approval — Pooled phase II, III data Consistent 4, 5% placebo-adjusted weight reduction across the COR program; tolerability profile dominated by nausea (most concentrated in titration weeks) 12
Volpicelli et al. (1992, Arch Gen Psychiatry) Foundational RCT of naltrexone in alcohol use disorder 70 12 weeks Naltrexone 50 mg/day reduced alcohol-relapse rate vs placebo, established naltrexone's clinical activity at the mu-opioid receptor and the dose precedent later carried into the combination 19
Hurt et al. (1997, NEJM) Pivotal RCT of sustained-release bupropion for smoking cessation 615 7 weeks treatment, 1 year follow-up Bupropion SR 100, 300 mg/day produced dose-dependent quit-rate increases, established the bupropion SR formulation later combined with naltrexone 20
Greenway et al. (2009, J Clin Endocrinol Metab), phase 2 RCT Randomized, double-blind, placebo-controlled phase 2 comparing combined bupropion + naltrexone to each monotherapy and placebo 419 24 weeks Combined bupropion (400 mg/day) + naltrexone produced significantly greater weight loss than either monotherapy or placebo, with the largest effect at the bupropion-400 + naltrexone-32 mg dose; supported dose selection for COR phase III 23
Wang et al. (2018, Int J Obes), fMRI mechanism Randomized double-blind placebo-controlled fMRI study of combined naltrexone + bupropion vs placebo 40 4 weeks Combined therapy altered resting-state functional connectivity in hypothalamus and reward-circuit regions in directions consistent with reduced food-cue reactivity, in-vivo human confirmation of the rational-design hypothesis 28
Wang & Volkow et al. (2001, Lancet) PET imaging of striatal dopamine D2-receptor availability in adults with severe obesity vs lean controls 20 Cross-sectional Striatal D2-receptor availability inversely correlated with BMI in severely obese adults, established the dopamine reward-circuit deficit that informed the rationale for catecholamine-modulating obesity pharmacotherapy 27
Singh et al. (2020, Expert Rev Clin Pharmacol) Systematic review and meta-analysis of RCTs of pharmacotherapy in obesity Multiple RCTs across all approved AOMs ≥12 months follow-up Confirmed naltrexone-bupropion produces 4, 5% placebo-adjusted weight loss; GLP-1 receptor agonists and phentermine-topiramate produced larger absolute effects 31
Onakpoya et al. (2020, Br J Clin Pharmacol) Systematic review and meta-analysis using unpublished clinical study reports Four phase III RCTs (COR program) Up to 56 weeks Confirmed published weight-loss effect sizes from clinical study reports; also documented adverse-event rates and discontinuation patterns consistent with published trial reports 30
Hsyu et al. (1997, J Clin Pharmacol), bupropion PK Single- and multiple-dose pharmacokinetic study of bupropion and its metabolites in smokers and nonsmokers 24 Single-dose and 14-day multiple-dose phases Characterized bupropion's primary metabolic disposition via CYP2B6 to hydroxybupropion (longer half-life than parent), threohydrobupropion, and erythrohydrobupropion, informed the combination's drug-interaction labeling 24
Verebey et al. (1976, Clin Pharmacol Ther), naltrexone PK Pharmacokinetic and pharmacodynamic study of naltrexone after acute and chronic oral dosing Healthy and former opioid-dependent volunteers Acute single-dose and chronic dosing Characterized naltrexone disposition: oral bioavailability with extensive first-pass conversion to 6β-naltrexol; parent half-life ~4 h and 6β-naltrexol half-life ~13 h sustains receptor occupancy across the dosing interval 25
Pesola & Avasarala (2002, J Emerg Med), bupropion seizure risk Emergency department case series and review of new-onset and drug-related generalized seizures — ED case series review Bupropion was a disproportionately represented drug-related cause of new-onset generalized seizures presenting to the ED, supports the seizure-risk dose ceiling carried into the naltrexone-bupropion combination 26
Apovian et al. (2015, J Clin Endocrinol Metab), Endocrine Society guideline Clinical practice guideline using GRADE methodology — N/A Endocrine Society recommends pharmacotherapy (including naltrexone-bupropion) as adjunct to lifestyle modification in adults with BMI ≥30 or ≥27 with weight-related comorbidity; outlines selection considerations across approved agents 32
Garvey et al. (2016, Endocr Pract), AACE/ACE guidelines Comprehensive clinical practice guideline (AACE/ACE) — N/A AACE/ACE comprehensive obesity-management guidelines include naltrexone-bupropion as one of the recommended chronic weight-management pharmacotherapies, with selection guided by comorbidity profile and tolerability 33
Yanovski & Yanovski (2014, JAMA) Systematic and clinical review of long-term obesity pharmacotherapy — Reviewed long-term RCT evidence Reviewed efficacy and safety of long-term obesity drug treatment including naltrexone-bupropion and contextualized effect sizes against orlistat, phentermine-topiramate, and lorcaserin 34
Heymsfield & Wadden (2017, NEJM) Narrative review of mechanisms, pathophysiology, and management of obesity — N/A Placed naltrexone-bupropion within the broader pharmacotherapy landscape and detailed the POMC-arcuate mechanism that underpins the combination 35
Ard et al. (2024, Obesity), real-world telehealth cohort Retrospective real-world analysis of a telehealth obesity-treatment provider using FDA-approved AOMs — 12 months Documented 12-month weight-loss outcomes across FDA-approved anti-obesity medications including naltrexone-bupropion in contemporary telehealth prescribing, first large real-world AOM cohort to include the combination 37
Tek (2016, Patient Prefer Adherence) Clinical review of naltrexone-bupropion focused on patient selection and persistence — N/A Reviewed the COR-program persistence and tolerability data; emphasized titration pacing as the primary lever for first-month tolerability and adherence 29

Mechanism detail

Detailed Mechanism of Naltrexone-Bupropion

POMC neurons in the hypothalamic arcuate nucleus integrate peripheral metabolic signals (leptin, insulin, ghrelin) and project to second-order neurons in the paraventricular nucleus that govern food intake. Activation of POMC neurons cleaves α-MSH from the POMC precursor, which binds MC4 receptors to suppress appetite. POMC neurons also co-release beta-endorphin, which binds mu-opioid receptors on the same neurons in an autoinhibitory feedback loop that limits sustained firing, the mechanistic vulnerability that the naltrexone-bupropion combination was designed to exploit 6.

Bupropion, through inhibition of norepinephrine and dopamine reuptake, increases monoamine availability in the arcuate, depolarizing POMC neurons and increasing α-MSH release. The dual NE/DA reuptake-inhibition mechanism of bupropion was characterized comprehensively by Stahl and colleagues across both the depression and weight-management literatures 16; weight-loss-specific catecholamine effects in preclinical models were dissected by Billes and Cowley 7. Beyond the hypothalamus, bupropion's dopaminergic action engages mesolimbic reward circuits that govern food palatability, circuits independently implicated in human obesity by Wang, Volkow and colleagues, who reported reduced striatal dopamine D2-receptor availability in patients with obesity 27.

Naltrexone, a competitive mu-opioid antagonist, blocks beta-endorphin's autoinhibitory effect on POMC neurons. The opioid system's role in food reward and palatability had already been established by Yeomans and colleagues, who showed that naltrexone alone reduces palatability-driven food intake in humans 18. The combination produces a sustained increase in POMC firing and α-MSH output that exceeds either drug's individual effect. This was demonstrated in a human phase 2 RCT in which combined bupropion + naltrexone produced greater weight loss than either monotherapy or placebo 23. Functional MRI work by Wang and colleagues showed that 4 weeks of combined naltrexone-bupropion altered resting-state functional connectivity in the hypothalamus and reward-circuit regions in ways consistent with reduced food-cue reactivity 28.

Naltrexone's parent compound has a relatively short plasma half-life (~4 h), but its active metabolite 6β-naltrexol has a longer half-life (~13 h) and contributes meaningfully to sustained mu-opioid receptor occupancy across the dosing interval, a PK property characterized in the foundational Verebey work 25. Bupropion's metabolism by CYP2B6 to hydroxybupropion and other active metabolites was mapped by Hsyu and colleagues 24, and explains both the prolonged effective half-life (~21 h with metabolites) and the substantial cytochrome-mediated drug-interaction profile that shapes the combination's labeling.

Pharmacology

Naltrexone-Bupropion Pharmacokinetics & Pharmacodynamics

Pharmacokinetics

Manufactured Contrave is formulated as sustained-release tablets 9. Bupropion Tmax approximately 3 hours; naltrexone Tmax approximately 2 hours. Bupropion half-life approximately 21 hours (with active metabolites contributing) 24; naltrexone half-life approximately 4, 5 hours for the parent and ~13 hours for the active metabolite 6β-naltrexol 25.

Both components are extensively metabolized: bupropion primarily by CYP2B6 to the active metabolite hydroxybupropion (longer half-life than parent) and to threohydrobupropion and erythrohydrobupropion as characterized by Hsyu and colleagues 24; naltrexone primarily by dihydrodiol dehydrogenase to 6β-naltrexol as characterized by Verebey and colleagues 25. Renal excretion of metabolites predominates for both. Steady-state is reached after approximately 7 days at maintenance dosing 9.

Compounded immediate-release oral capsules will not replicate the sustained-release PK of the manufactured tablet. Cmax with compounded capsules is expected to be higher and Tmax shorter; this affects both efficacy timing and tolerability profile and should inform titration decisions.

Pharmacodynamics

Pharmacodynamic effects are dominated by sustained suppression of appetite signaling and reduction in food craving, particularly for highly palatable foods. Behavioral measures from COR-BMOD subset analyses showed reductions in self-reported food craving and binge-eating tendencies that paralleled weight loss in the combined-therapy arm 3.

Cardiovascular pharmacodynamics include modest sustained increases in heart rate (approximately 1 bpm) and blood pressure (approximately 1 mmHg systolic) in pooled COR data, attributed to the bupropion component's noradrenergic activity 9. These effects warrant baseline and on-therapy blood-pressure monitoring.

Comparative formulations

Comparing Naltrexone-Bupropion Formulations

The manufactured Contrave tablet is a sustained-release matrix engineered to deliver naltrexone and bupropion in a controlled-release profile that supports twice-daily dosing at steady state 9. This formulation has been the subject of all phase III efficacy and safety data.

Compounded immediate-release oral capsules differ pharmacokinetically. They produce higher peak concentrations and shorter dosing intervals are needed to maintain steady-state. Patients switched from manufactured to compounded preparations (or vice versa) should be re-evaluated for dose titration and tolerability; equivalence cannot be assumed.

RonanRx-compounded preparations are dispensed only when the manufactured product is not appropriate for the identified patient. The pharmacist review documents the patient-specific clinical reason and the resulting formulation difference is noted on dispensing.

Storage

Naltrexone-Bupropion Storage and Handling

Compounded oral capsules are stored at controlled room temperature (USP definition: 20, 25°C, with allowed excursions 15, 30°C) in tightly closed light-resistant containers. Beyond-use date is established per USP <795> for non-sterile compounding, typically up to 180 days for solid oral formulations from non-sterile components, subject to formulation-specific stability data 22.

Manufactured Contrave is similarly stored at 20, 25°C with excursions permitted to 15, 30°C. Both bupropion and naltrexone are stable as their HCl salts at room temperature; no refrigeration is required for compounded oral capsules 9.

RonanRx operations

Naltrexone-Bupropion Compounding & Operations

503A compounding

Compounded naltrexone-bupropion is prepared under 503A on patient-specific prescriptions in state-licensed compounding pharmacies. RonanRx prepares non-sterile oral capsules per USP General Chapter <795>, the official compendial standard for non-sterile pharmaceutical compounding, with documented active ingredient sourcing (USP/NF grade where available), gravimetric verification, and finished-product quality checks per the pharmacy's quality-management system 1122.

Beyond-use dating, ingredient identity verification, and stability assessment follow USP <795> requirements. Each compounded batch is documented per state board of pharmacy retention rules with full traceability from API lot through dispensing.

Pharmacist review

Each prescription for compounded naltrexone-bupropion undergoes pharmacist review prior to dispensing. The review confirms: a documented patient-specific clinical reason that the manufactured Contrave is not appropriate (excipient sensitivity, dose individualization, supply gap, or other documented factor); absence of contraindications (seizure disorder, eating disorder, chronic opioid use, uncontrolled hypertension, pregnancy); and the prescribed regimen aligns with FDA-label dose ceilings.

RonanRx does not fill prescriptions that read as routine substitution of compounded for manufactured product without documented clinical rationale, consistent with FDA guidance on compounded copies of commercially available drugs 10.

Quality and traceability

Active pharmaceutical ingredients are sourced from FDA-registered facilities with documented certificates of analysis. Each batch is recorded with lot numbers traceable to API source, compounding date, beyond-use date, and dispensing pharmacist of record. Finished product lot records are retained per state board of pharmacy retention requirements.

Cold chain

Compounded oral capsules of naltrexone-bupropion are not cold-chain products. They are stable at controlled room temperature and shipped in standard pharmacy-grade packaging. Patients should store at room temperature in tightly closed containers away from heat and humidity, consistent with the manufactured Contrave label.

FAQ

Frequently Asked Questions About Naltrexone-Bupropion

Is compounded naltrexone-bupropion the same as Contrave?

No. Contrave is the FDA-approved manufactured product (naltrexone 8 mg / bupropion 90 mg sustained-release tablet) 9. Compounded preparations are pharmacy-prepared on a patient-specific prescription and are not bioequivalent to Contrave. Compounded drugs are not FDA-approved 11.

When is a compounded version appropriate?

Per FDA guidance, a compounded version of an FDA-approved drug is generally restricted unless the prescriber documents a patient-specific clinical need that the manufactured product cannot meet, for example, excipient sensitivity, dose individualization outside the manufactured strength, or a documented manufactured-product supply gap 10.

How well does naltrexone-bupropion work for weight loss?

In the manufactured-product COR phase III program, mean placebo-adjusted weight loss was 4, 5% at 56 weeks 123. Approximately 48% of completers in the combined-therapy arm of COR-I achieved ≥5% body-weight loss vs 16% on placebo. Effect sizes are similar across the four trials and consistent across populations including type 2 diabetes 4.

What are the most common side effects?

Nausea, constipation, headache, vomiting, dizziness, and insomnia, mostly mild to moderate and concentrated in the first 4, 8 weeks of titration. Approximately 24, 28% of patients in the COR program discontinued for adverse events vs 12, 14% on placebo 12.

Who should not take naltrexone-bupropion?

Contraindicated in seizure disorder, current or past bulimia or anorexia, chronic opioid use, abrupt discontinuation of alcohol or sedatives, uncontrolled hypertension, MAO-inhibitor use within 14 days, pregnancy, and known allergy to either component. Patients requiring acute opioid analgesia (e.g., postoperative) should not be on therapy 9.

Does RonanRx sell compounded naltrexone-bupropion directly to patients?

No. Compounded naltrexone-bupropion requires a patient-specific prescription written by a licensed doctor for an identified patient with a documented clinical reason that the manufactured Contrave is not appropriate, plus pharmacist review before dispensing 10. RonanRx is not a direct-to-consumer storefront 11.

Clinician resource

Download the Naltrexone-Bupropion Clinical Monograph (PDF)

The full white paper covers every section on this page plus chemical identity, evidence grading, indication-by-indication summaries, research gaps, and reference appendix. Suitable for sharing with prescribing doctors and pharmacist reviewers.

Download information packet ↓

References

References

  1. [greenway2010] Greenway FL, Fujioka K, Plodkowski RA, Mudaliar S, Guttadauria M, Erickson J, Kim DD, Dunayevich E; COR-I Study Group. 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. PMID 20673995. (accessed 2026-05-08)
  2. [apovian2013] Apovian CM, Aronne L, Rubino D, Still C, Wyatt H, Burns C, Kim D, Dunayevich E; COR-II Study Group. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity (Silver Spring). 2013. PMID 23408728. (accessed 2026-05-08)
  3. [wadden2011] Wadden TA, Foreyt JP, Foster GD, Hill JO, Klein S, O'Neil PM, Perri MG, Pi-Sunyer FX, Rock CL, Erickson JS, Maier HN, Kim DD, Dunayevich E. Weight loss with naltrexone SR/bupropion SR combination therapy as an adjunct to behavior modification: the COR-BMOD trial. Obesity (Silver Spring). 2011. PMID 20559296. (accessed 2026-05-08)
  4. [hollander2013] Hollander P, Gupta AK, Plodkowski R, Greenway F, Bays H, Burns C, Klassen P, Fujioka K; COR-Diabetes Study Group. 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. PMID 24144653. (accessed 2026-05-08)
  5. [nissen2016] Nissen SE, Wolski KE, Prcela L, Wadden T, Buse JB, Bakris G, Perez A, Smith SR. Effect of Naltrexone-Bupropion on Major Adverse Cardiovascular Events in Overweight and Obese Patients With Cardiovascular Risk Factors: A Randomized Clinical Trial. JAMA. 2016. PMID 26954408. (accessed 2026-05-08)
  6. [greenway2009] Greenway FL, Whitehouse MJ, Guttadauria M, Anderson JW, Atkinson RL, Fujioka K, Gadde KM, Gupta AK, O'Neil P, Schumacher D, Smith D, Dunayevich E, Tollefson GD, Weber E, Cowley MA. Rational design of a combination medication for the treatment of obesity. Obesity (Silver Spring). 2009. PMID 18997675. (accessed 2026-05-08)
  7. [billes2008] Billes SK, Cowley MA. Catecholamine reuptake inhibition causes weight loss by increasing locomotor activity and thermogenesis. Neuropsychopharmacology. 2008. PMID 17687262. (accessed 2026-05-08)
  8. [anderson2002] Anderson JW, Greenway FL, Fujioka K, Gadde KM, McKenney J, O'Neil PM. Bupropion SR enhances weight loss: a 48-week double-blind, placebo- controlled trial. Obesity Research. 2002. PMID 12105285. (accessed 2026-05-08)
  9. [fda_label_contrave] U.S. Food and Drug Administration. Contrave (naltrexone HCl and bupropion HCl) extended-release tablets — FDA Prescribing Information. FDA Drug Approval Package. 2014. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf (accessed 2026-05-08)
  10. [fda_essentially_a_copy] U.S. Food and Drug Administration. Compounded Drug Products That Are Essentially Copies of Approved Drug Products Under Section 503A of the Federal Food, Drug, and Cosmetic Act — Guidance for Industry. FDA Guidance for Industry. 2018. https://www.fda.gov/media/98973/download (accessed 2026-05-08)
  11. [fda503a] U.S. Food and Drug Administration. Compounding Laws and Policies — Section 503A of the Federal Food, Drug, and Cosmetic Act. FDA Drug Compounding. 2024. https://www.fda.gov/drugs/human-drug-compounding/compounding-laws-and-policies (accessed 2026-05-08)
  12. [caixas2014] Caixàs A, Albert L, Capel I, Rigla M. Naltrexone sustained-release/bupropion sustained-release for the management of obesity: review of the data to date. Drug Design, Development and Therapy. 2014. PMID 25258511. (accessed 2026-05-09)
  13. [sherman2016] Sherman MM, Ungureanu S, Rey JA. Naltrexone/Bupropion ER (Contrave): Newly Approved Treatment Option for Chronic Weight Management in Obese Adults. P&T. 2016. PMID 26957883. (accessed 2026-05-09)
  14. [apovian2016] Apovian CM. Naltrexone/bupropion for the treatment of obesity and obesity with Type 2 diabetes. Future Cardiology. 2016. PMID 26679384. (accessed 2026-05-09)
  15. [khera2016] Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, Loomba R, Camilleri M, Singh S. Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis. JAMA. 2016. PMID 27299618. (accessed 2026-05-09)
  16. [stahl2004] Stahl SM, Pradko JF, Haight BR, Modell JG, Rockett CB, Learned-Coughlin S. A Review of the Neuropharmacology of Bupropion, a Dual Norepinephrine and Dopamine Reuptake Inhibitor. Primary Care Companion to The Journal of Clinical Psychiatry. 2004. PMID 15361919. (accessed 2026-05-09)
  17. [davidson1989] Davidson J. Seizures and bupropion: a review. Journal of Clinical Psychiatry. 1989. PMID 2500425. (accessed 2026-05-09)
  18. [yeomans1997] Yeomans MR, Gray RW. Effects of naltrexone on food intake and changes in subjective appetite during eating: evidence for opioid involvement in the appetizer effect. Physiology & Behavior. 1997. PMID 9226337. (accessed 2026-05-09)
  19. [volpicelli1992] Volpicelli JR, Alterman AI, Hayashida M, O'Brien CP. Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry. 1992. PMID 1345133. (accessed 2026-05-09)
  20. [hurt1997] Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, Croghan IT, Sullivan PM. A comparison of sustained-release bupropion and placebo for smoking cessation. New England Journal of Medicine. 1997. PMID 9337378. (accessed 2026-05-09)
  21. [saunders2016] Saunders KH, Kumar RB, Igel LI, Aronne LJ. Pharmacologic Approaches to Weight Management: Recent Gains and Shortfalls in Combating Obesity. Current Atherosclerosis Reports. 2016. PMID 27181165. (accessed 2026-05-09)
  22. [usp_795] United States Pharmacopeia. USP General Chapter <795> Pharmaceutical Compounding — Nonsterile Preparations. USP Compounding Compendium. 2024. https://www.usp.org/compounding/general-chapter-795 (accessed 2026-05-09)
  23. [greenway2009_phase2] Greenway FL, Dunayevich E, Tollefson G, Erickson J, Guttadauria M, Fujioka K, Cowley MA; NB-201 Study Group. Comparison of combined bupropion and naltrexone therapy for obesity with monotherapy and placebo. Journal of Clinical Endocrinology & Metabolism. 2009. PMID 19846734. (accessed 2026-05-11)
  24. [hsyu1997] Hsyu PH, Singh A, Giargiari TD, Dunn JA, Ascher JA, Johnston JA. Pharmacokinetics of bupropion and its metabolites in cigarette smokers versus nonsmokers. Journal of Clinical Pharmacology. 1997. PMID 9378846. (accessed 2026-05-11)
  25. [verebey1976] Verebey K, Volavka J, Mulé SJ, Resnick RB. Naltrexone: disposition, metabolism, and effects after acute and chronic dosing. Clinical Pharmacology & Therapeutics. 1976. PMID 954353. (accessed 2026-05-11)
  26. [pesola2002] Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. Journal of Emergency Medicine. 2002. PMID 11932084. (accessed 2026-05-11)
  27. [wang2001] Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS. Brain dopamine and obesity. Lancet. 2001. PMID 11210998. (accessed 2026-05-11)
  28. [wang2018_fmri] Wang GJ, Zhao J, Tomasi D, Kojori ES, Wang R, Wiers CE, Caparelli EC, Volkow ND. Effect of combined naltrexone and bupropion therapy on the brain's functional connectivity. International Journal of Obesity. 2018. PMID 29535451. (accessed 2026-05-11)
  29. [tek2016] Tek C. Naltrexone HCI/bupropion HCI for chronic weight management in obese adults: patient selection and perspectives. Patient Preference and Adherence. 2016. PMID 27217728. (accessed 2026-05-11)
  30. [onakpoya2020] Onakpoya IJ, Lee JJ, Mahtani KR, Aronson JK, Heneghan CJ. Naltrexone-bupropion (Mysimba) in management of obesity: A systematic review and meta-analysis of unpublished clinical study reports. British Journal of Clinical Pharmacology. 2020. PMID 31918448. (accessed 2026-05-11)
  31. [singh2020] Singh AK, Singh R. Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs. Expert Review of Clinical Pharmacology. 2020. PMID 31770497. (accessed 2026-05-11)
  32. [apovian2015_guideline] Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, Ryan DH, Still CD; Endocrine Society. Pharmacological management of obesity: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology & Metabolism. 2015. PMID 25590212. (accessed 2026-05-11)
  33. [garvey2016_aace] Garvey WT, Mechanick JI, Brett EM, Garber AJ, Hurley DL, Jastreboff AM, Nadolsky K, Pessah-Pollack R, Plodkowski R; Reviewers of the AACE/ACE Obesity Clinical Practice Guidelines. American Association of Clinical Endocrinologists and American College of Endocrinology Comprehensive Clinical Practice Guidelines for Medical Care of Patients With Obesity. Endocrine Practice. 2016. PMID 27219496. (accessed 2026-05-11)
  34. [yanovski2014] Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. JAMA. 2014. PMID 24231879. (accessed 2026-05-11)
  35. [heymsfield2017] Heymsfield SB, Wadden TA. Mechanisms, Pathophysiology, and Management of Obesity. New England Journal of Medicine. 2017. PMID 28099824. (accessed 2026-05-11)
  36. [velazquez2018] Velazquez A, Apovian CM. Pharmacological management of obesity. Minerva Endocrinologica. 2018. PMID 28462579. (accessed 2026-05-11)
  37. [ard2024_realworld] Ard JD, Hong YR, Foster GD, et al.. Twelve-month analysis of real-world evidence from a telehealth obesity-treatment provider using antiobesity medications. Obesity (Silver Spring). 2024. PMID 39478294. (accessed 2026-05-11)

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