mysimba
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Mysimba represents one of the more interesting pharmacological approaches to weight management we’ve seen in recent years. Unlike single-agent therapies, it combines two established medications—naltrexone and bupropion—in an extended-release formulation specifically designed to target the central nervous system’s regulation of appetite and food reward pathways. What’s fascinating clinically isn’t just the dual mechanism, but the specific ratio—8 mg naltrexone to 90 mg bupropion—which appears critical for the synergistic effect. I’ve been prescribing this for about three years now, initially with some skepticism given the checkered history of weight loss medications.
1. Introduction: What is Mysimba? Its Role in Modern Medicine
Mysimba (known as Contrave in some markets) is a prescription-only combination medication approved for chronic weight management in adults with obesity or overweight with at least one weight-related comorbidity. Classified as a schedule 3 controlled drug in many jurisdictions due to its bupropion component, it represents a shift from purely behavioral interventions toward neurobiological approaches to obesity treatment. The fundamental premise behind Mysimba is that obesity involves dysregulation in brain reward pathways and hunger signaling—not simply a lack of willpower. This understanding has transformed how we approach pharmacological management of this complex condition.
2. Key Components and Bioavailability Mysimba
The formulation contains two active pharmaceutical ingredients with distinct pharmacokinetic profiles:
Naltrexone HCl (8 mg)
- Opioid receptor antagonist with high oral bioavailability (5-40%)
- Peak plasma concentration: 1 hour post-dose
- Half-life: approximately 4 hours
- Hepatic metabolism via dihydrodiol dehydrogenase
Bupropion HCl (90 mg)
- Aminoketone class, atypical antidepressant
- Bioavailability: approximately 5-20% in animals (human data limited)
- Peak plasma concentration: 3 hours
- Half-life: 21 hours (primary metabolites active)
- Hepatic metabolism via CYP2B6
The extended-release formulation uses a proprietary multiparticulate technology that allows for once-daily dosing after the titration period. The specific 1:11.25 ratio of naltrexone to bupropion was determined through extensive phase 2 testing to maximize the synergistic effect on hypothalamic feeding centers and mesolimbic reward pathways while minimizing adverse effects.
3. Mechanism of Action Mysimba: Scientific Substantiation
The therapeutic effect emerges from the interaction between two distinct CNS pathways:
Hypothalamic Hunger Regulation Bupropion stimulates pro-opiomelanocortin (POMC) neurons in the arcuate nucleus, increasing α-MSH release which activates melanocortin-4 receptors (MC4R) downstream. This creates an anorexigenic (appetite-suppressing) signal. However, POMC neurons also release β-endorphin which auto-inhibits them through μ-opioid receptors—this is where naltrexone comes in, blocking this feedback inhibition and amplifying the bupropion effect.
Mesolimbic Reward Pathway Modulation Both medications affect dopamine signaling in the nucleus accumbens, though through different mechanisms. Bupropion inhibits dopamine reuptake while naltrexone blocks opioid-mediated reward signaling from palatable foods. The combination appears to reduce the hedonic drive to eat—what patients often describe as “food noise” decreasing.
We initially thought the mechanism was straightforward appetite suppression, but the reality appears more nuanced. The reduction in food cravings, particularly for high-fat and high-sugar foods, suggests significant impact on reward processing beyond simple hunger signaling.
4. Indications for Use: What is Mysimba Effective For?
Mysimba for Chronic Weight Management
Approved for adults with BMI ≥30 kg/m² or ≥27 kg/m² with at least one weight-related comorbidity (hypertension, type 2 diabetes, or dyslipidemia). Clinical trials demonstrated 5-10% total body weight loss in approximately 42-48% of participants versus 17-23% with placebo.
Mysimba for Reduction of Food Cravings
Multiple studies using the Food Craving Inventory and craving questionnaires showed significant reductions in cravings for sweets, carbohydrates, and fast-food fats. This effect typically emerges within 2-4 weeks of reaching maintenance dosing.
Mysimba for Weight Maintenance After Initial Loss
The COR-II extension trial demonstrated maintained weight loss over 56 weeks in responders, with significantly fewer regaining >25% of lost weight compared to placebo (18% vs 43%).
Mysimba for Polycystic Ovary Syndrome (PCOS)
Off-label use shows promise for improving weight parameters in PCOS, with one open-label study demonstrating 7.3% weight reduction at 24 weeks alongside improvements in insulin sensitivity.
5. Instructions for Use: Dosage and Course of Administration
The dosing schedule requires careful titration to minimize initial adverse effects:
| Treatment Week | Morning Dose | Evening Dose | Total Daily Naltrexone/Bupropion |
|---|---|---|---|
| 1 | 1 tablet | None | 8 mg/90 mg |
| 2 | 1 tablet | 1 tablet | 16 mg/180 mg |
| 3 | 2 tablets | 1 tablet | 24 mg/270 mg |
| 4 onward | 2 tablets | 2 tablets | 32 mg/360 mg |
Administration should occur with food to reduce nausea incidence. The medication should be swallowed whole—not crushed, chewed, or divided. If patients miss a dose, they should not double the next dose.
We typically assess response after 12 weeks at maintenance dose—patients who haven’t lost at least 5% of baseline body weight are unlikely to benefit from continued treatment and should be discontinued.
6. Contraindications and Drug Interactions Mysimba
Absolute Contraindications:
- Uncontrolled hypertension
- Seizure disorders or history of seizures
- Concomitant MAO inhibitors
- Chronic opioid use or opioid dependence
- Pregnancy or breastfeeding
- Bulimia or anorexia nervosa (current or history)
- Severe hepatic impairment
- Concomitant bupropion-containing products
Significant Drug Interactions:
- CYP2B6 inhibitors (e.g., clopidogrel, ticlopidine): Increase bupropion exposure
- CYP2B6 inducers: Decrease bupropion efficacy
- Drugs lowering seizure threshold: Antipsychotics, antidepressants, tramadol
- Antihypertensives: May require dose adjustment
- Alcohol: Increases seizure risk; contraindicated
The bupropion component carries a black box warning for suicidal ideation in young adults, though the weight management trials didn’t show increased incidence.
7. Clinical Studies and Evidence Base Mysimba
The COR (Contrave Obesity Research) program formed the basis for regulatory approval:
COR-I (NEJM 2010)
- 1,742 participants, 56 weeks
- Placebo-subtracted weight loss: 4.2%
- 55% achieved ≥5% weight loss vs 17% placebo
COR-II (Obesity 2013)
- 1,496 participants with type 2 diabetes
- Placebo-subtracted weight loss: 2.0%
- HbA1c reduction: 0.5% vs 0.1% placebo
COR-BMOD (Obesity 2014)
- Intensive behavior modification plus Mysimba vs BMOD alone
- Weight loss: 9.3% vs 5.1% with BMOD alone
The LIGHT trial examining cardiovascular outcomes was terminated early after demonstrating non-inferiority for major adverse cardiovascular events.
What the published data doesn’t fully capture is the heterogeneity of response—we’ve found approximately one-third of patients are “super-responders” losing >15% body weight, while another third have minimal response despite adequate dosing and adherence.
8. Comparing Mysimba with Similar Products and Choosing a Quality Product
Versus GLP-1 receptor agonists (liraglutide, semaglutide):
- Mysimba: Oral administration, lower cost, different mechanism
- GLP-1s: Injectable, superior efficacy (10-15% weight loss), gastrointestinal side effects
Versus phentermine-topiramate:
- Mysimba: Lower blood pressure effects, cognitive side effect profile
- Phentermine-topiramate: Superior weight loss efficacy, more metabolic side effects
Versus orlistat:
- Mysimba: Central mechanism, better tolerability
- Orlistat: Peripheral mechanism, gastrointestinal adverse effects
When selecting patients for Mysimba, we consider:
- Preference for oral versus injectable
- Comorbid depression (bupropion may help)
- Contraindications to GLP-1 agonists
- Response to previous weight loss medications
- Cardiovascular risk profile
9. Frequently Asked Questions (FAQ) about Mysimba
What is the recommended course of Mysimba to achieve results?
Treatment should be evaluated at 12-16 weeks—if <5% weight loss is achieved, discontinuation is recommended. Responders typically continue for 6-12 months with periodic evaluation.
Can Mysimba be combined with GLP-1 receptor agonists?
Limited data exists, though some practices use sequential therapy. Concurrent use isn’t well-studied and may increase adverse effect risk.
How long do Mysimba side effects typically last?
Most gastrointestinal and CNS effects (nausea, headache, insomnia) diminish within 2-4 weeks of dose stabilization.
Is weight regain common after stopping Mysimba?
Like most anti-obesity medications, discontinuation typically leads to gradual weight regain unless significant lifestyle changes are maintained.
Can Mysimba be used in patients with binge eating disorder?
Limited evidence exists—naltrexone/bupropion combinations show promise but aren’t first-line. Comprehensive eating disorder evaluation is essential.
10. Conclusion: Validity of Mysimba Use in Clinical Practice
Mysimba occupies a specific niche in the obesity treatment arsenal—particularly valuable for patients with co-occurring depression or binge eating tendencies, those preferring oral administration, and individuals who haven’t responded adequately to lifestyle interventions alone. The risk-benefit profile favors patients without contraindications who demonstrate early response. While not the most potent weight loss agent available, its unique mechanism and generally manageable side effect profile make it a useful option in appropriately selected patients.
I remember particularly one patient—Sarah, a 42-year-old teacher with BMI 38 and prediabetes—who’d failed multiple previous attempts. She had this pattern of restrictive dieting followed by what she called “cupboard clearing” binge episodes, especially with sweet foods. We started Mysimba with modest expectations, but by week 8 she reported something interesting: “The cookies in the staff room just don’t call to me anymore.” Not that she’d lost her sweet tooth entirely, but the compulsive quality had diminished significantly. Her weight loss was steady rather than dramatic—about 7% at 16 weeks—but what struck me was her comment: “For the first time, I feel like I’m in charge of what I eat rather than food being in charge of me.”
We’ve had our share of failures too—probably 30-40% of patients either don’t respond or can’t tolerate the initial side effects. The nausea in the first few weeks is real, and I’ve had several patients discontinue despite my warnings to push through. There was Mark, the 55-year-old with severe osteoarthritis, who had to stop after two weeks due to dizziness and insomnia that didn’t resolve. We switched him to liraglutide with better results.
The manufacturing process had its own challenges initially—I recall the early supply issues and the peculiar batch that seemed to have different dissolution properties based on some pharmacy reports. Our hospital’s pharmacy team actually worked with the manufacturer to adjust storage recommendations after we noticed higher nausea rates with medication that had been stored in warmer conditions.
What’s become clear over time is that the patients who do best with Mysimba are those with significant hedonic eating components to their obesity, rather than purely metabolic drivers. We’ve started using brief craving questionnaires as part of our baseline assessment, and the responses correlate reasonably well with eventual outcomes. The 18-month follow-up data from our clinic shows maintained >5% weight loss in about 60% of initial responders—not spectacular, but meaningful considering the chronic relapsing nature of obesity.
Sarah recently came for her 2-year follow-up—she’s maintained a 9% total body weight loss, her HbA1c is back in normal range, and she’s off her antihypertensive medication. When I asked what made the difference this time, she said “It wasn’t the medication alone—it was that the medication gave me the mental space to actually build new habits without constantly fighting my brain.” That, to me, captures the real clinical value of this approach.