How Does Mysimba Work? Mechanism of Action & Metabolic Effects
A detailed look at the chemical composition, dual mechanism of action, and metabolic effects of naltrexone and bupropion in Mysimba weight management tablets.
Key Takeaways
- Dual Action: Combines naltrexone (opioid antagonist) with bupropion (dopamine/norepinephrine reuptake inhibitor).
- Brain Targeting: Works on hypothalamus to reduce appetite and increase energy expenditure.
- Synergistic Effect: The combination is more effective than either drug alone for weight management.
- Metabolism: Primarily metabolised in the liver via cytochrome P450 enzymes.
- Clinical Use: Approved for adults with BMI ≥30 or ≥27 with weight-related conditions.
Mysimba provides comprehensive weight management through two distinct but complementary pharmacological pathways, targeting both appetite control and energy expenditure centers in the brain.
Chemical Composition of Mysimba
Mysimba is a prolonged-release tablet containing two active pharmaceutical ingredients (APIs) in a specific formulation designed for sustained effect throughout the day.
| Active Substance | Concentration | Chemical Class & Structure |
|---|---|---|
| Naltrexone Hydrochloride | 8 mg per tablet | Opioid receptor antagonist |
| Bupropion Hydrochloride | 90 mg per tablet | Aminoketone antidepressant (NDRI) |
Excipients (Inactive Ingredients)
- Microcrystalline cellulose: Binder and filler providing tablet structure
- Hydroxypropyl cellulose: Controlled-release polymer matrix
- Lactose anhydrous & monohydrate: Fillers and bulking agents
- Cysteine hydrochloride: Antioxidant stabilising the formulation
- Crospovidone type A: Disintegrant aiding tablet breakdown
- Magnesium stearate: Lubricant for manufacturing
- Hypromellose: Extended-release coating polymer
- Edetate disodium: Chelating agent enhancing stability
- Colloidal silicon dioxide: Anti-caking agent
- Indigo carmine aluminium lake (E132): Blue colourant
Dual Mechanism of Action: Synergistic Appetite Control
Mysimba provides comprehensive weight management through two distinct but complementary pharmacological pathways targeting the hypothalamus - the brain's appetite control center.
Bupropion: The Energy & Reward Modulator
Action: Bupropion is a norepinephrine-dopamine reuptake inhibitor (NDRI).
Effect: It increases levels of dopamine and norepinephrine in the hypothalamus, specifically in the arcuate nucleus. Dopamine activation in the reward pathways reduces food craving, while norepinephrine increases energy expenditure through stimulation of the sympathetic nervous system.
Result: This creates reduced appetite, decreased food cravings, and increased metabolic rate, promoting weight loss through both behavioral and metabolic mechanisms.
Naltrexone: The Opioid Pathway Blocker
Action: Naltrexone is an opioid receptor antagonist.
Effect: It blocks the inhibitory effect of β-endorphin on pro-opiomelanocortin (POMC) neurons. Normally, β-endorphin provides negative feedback to POMC neurons, limiting their activity. By blocking this inhibition, naltrexone enhances POMC neuron firing.
Result: Increased POMC activity leads to enhanced release of α-MSH, which activates melanocortin-4 receptors (MC4R) to further reduce appetite and increase energy expenditure, amplifying bupropion's effects.
Visualizing the Hypothalamic Pathway
Fig 1. Molecular structures of active ingredients in Mysimba
Naltrexone HCl (C20H23NO4·HCl)
O
||
C-C-N
| |
C C (cyclopropyl)
(phenanthrene structure)
Bupropion HCl (C13H18ClNO·HCl)
Cl-C6H4-C(O)-C(CH3)2-NH-C(CH3)3
(tert-butyl group)
Metabolic Pathway & Systemic Effects
Both active ingredients in Mysimba undergo extensive hepatic metabolism, with the prolonged-release formulation designed to maintain stable plasma concentrations while minimizing peak-related side effects.
Bupropion Metabolism
- Primary Pathway: Bupropion is extensively metabolised in the liver by the cytochrome P450 enzyme system (mainly CYP2B6).
- Active Metabolites: It is converted into three active metabolites: hydroxybupropion, threohydrobupropion, and erythrohydrobupropion.
- Excretion: Metabolites are primarily excreted in the urine (87%) with only minimal unchanged bupropion (0.5%).
- Half-life: Bupropion has a half-life of approximately 21 hours, while hydroxybupropion has 20-24 hours.
Naltrexone Metabolism
- Primary Pathway: Naltrexone undergoes rapid and complete metabolism primarily to 6-β-naltrexol.
- Key Enzyme: It is metabolised primarily by reduction rather than cytochrome P450 oxidation.
- Active Metabolite: 6-β-naltrexol is an active metabolite with a longer half-life than the parent drug.
- Excretion: Primarily eliminated via the kidneys with some biliary excretion.
Bupropion is associated with dose-related risk of seizures (approximately 0.1% at 300mg/day and 0.4% at 400mg/day). This risk is increased in patients with eating disorders, those withdrawing from alcohol or benzodiazepines, and those taking other medications that lower seizure threshold. Patients should be closely monitored, particularly during dose escalation.
Clinical Efficacy & Weight Loss Effects
Appropriate Patient Profile
Adults with BMI ≥30 (obesity)
Adults with BMI 27-30 (overweight) with weight-related conditions
Patients committed to reduced-calorie diet and increased physical activity
Treatment Discontinuation Criteria
<5% weight loss after 16 weeks of treatment
Uncontrolled hypertension or significant blood pressure increases
Poor tolerability or safety concerns during treatment
Expected Outcomes
5-10% weight reduction in clinical trials over 1 year
Improved cardiometabolic parameters in responsive patients
Gradual weight loss with maximal effect after 16+ weeks
Clinical Trial Results
| Study Duration | Weight Loss vs Placebo | Responder Rate (>5% weight loss) |
|---|---|---|
| 16 weeks | 4.0-4.8% greater | 48-53% vs 17-20% (placebo) |
| 56 weeks | 4.2-5.2% greater | 46-57% vs 17-25% (placebo) |
FAQs
Why does Mysimba contain two different medications?
Mysimba combines naltrexone and bupropion because they work synergistically on the brain's appetite control centers. Bupropion stimulates POMC neurons to reduce appetite, while naltrexone blocks the natural feedback inhibition that would normally limit this effect. This dual action produces greater weight loss than either medication could achieve alone.
How long does it take for Mysimba to start working for weight loss?
Most patients begin to notice appetite reduction within the first 1-2 weeks, but significant weight loss typically occurs after 4-8 weeks of treatment. The full effect is usually seen after 16 weeks of continuous use. Your doctor will assess your progress after 16 weeks to determine if treatment should continue.
Can Mysimba be taken by patients with diabetes?
Yes, Mysimba can be used by patients with type 2 diabetes who meet the BMI criteria. In fact, overweight patients (BMI 27-30) with type 2 diabetes are specifically indicated for treatment. However, patients using insulin or oral medications that may cause hypoglycemia should be closely monitored as weight loss may affect diabetes control and medication requirements.
What should I do if I experience nausea when taking Mysimba?
Nausea is a common side effect, especially during the first few weeks of treatment. Taking Mysimba with food can significantly reduce nausea. The gradual dose escalation schedule is specifically designed to help your body adjust to the medication. If nausea persists beyond the first month or becomes severe, consult your doctor as they may adjust your dosing schedule or recommend additional management strategies.
Why is blood pressure monitoring important during Mysimba treatment?
Mysimba can cause increases in blood pressure and heart rate in some patients. Regular monitoring is essential, especially during the first 3 months of treatment and after any dose increases. Your doctor will check your blood pressure before starting treatment and periodically throughout therapy. If significant or sustained increases in blood pressure occur, treatment may need to be adjusted or discontinued.
Ready to Start Your Weight Loss Journey?
If you're struggling to lose weight through diet and exercise alone, our UK-registered doctors can help determine if Mysimba Tablets is appropriate for your condition through a confidential online consultation.
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Medical Content Manager
Nabeel is a co-founder and medical content manager of Chemist Doctor. He works closely with our medical team to ensure the information is accurate and up-to-date.
Medical Doctor
Dr. Talal is a GMC registered doctor and medical reviewer at Chemist Doctor. He ensures clinical accuracy and reliability across health content.
Medical Director
Usman is a co-founder and medical director of Chemist Doctor. He leads the organisation's strategic vision, bridging clinical and operational priorities.
Review Date: 18 November 2025
Next Review: 20 May 2026
Published on: 18 November 2025
Last Updated: 19 November 2025
