For an otherwise healthy overweight adult without opioid use, hepatic impairment, pregnancy, or breastfeeding, is low‑dose naltrexone (4.5 mg daily) an effective first‑line treatment for weight loss?

Naltrexone for Weight Loss: Not Recommended as Monotherapy

Low-dose naltrexone (4.5 mg daily) as monotherapy is not an effective first-line treatment for weight loss in otherwise healthy overweight adults. The FDA-approved formulation is naltrexone-bupropion extended-release combination therapy (32 mg naltrexone/360 mg bupropion daily), which produces modest but clinically meaningful weight reduction when added to lifestyle interventions. 1

Why Naltrexone Alone Does Not Work

• Naltrexone monotherapy has weak anorectic effects because β-endorphin exerts auto-inhibitory activity on hypothalamic anorexigenic neurons; naltrexone blocks this inhibition but requires bupropion to activate the neurons in the first place. 1
• The synergistic mechanism requires bupropion to activate pro-opiomelanocortin (POMC) neurons while naltrexone antagonizes opioid-mediated feedback inhibition—neither component is effective alone for weight loss. 2

Evidence for the FDA-Approved Combination

• The naltrexone-bupropion ER combination produces 3.01% additional total body weight loss compared to placebo plus lifestyle intervention (moderate-certainty evidence from 5 RCTs including 12,659 patients). 1
• 48–55% of treated patients achieve ≥5% weight loss versus 17–30.6% with placebo, meeting the threshold for clinically meaningful cardiovascular risk reduction. 2
• This magnitude of benefit is substantially less than semaglutide 2.4 mg (10.76% additional weight loss) or phentermine-topiramate ER (8.45% additional weight loss), but superior to orlistat (2.6–4.8%). 23

Dosing Protocol for the Approved Combination

• Week 1: One tablet (8 mg naltrexone/90 mg bupropion) once daily in the morning. 1
• Week 2: One tablet twice daily. 1
• Week 3: Two tablets in the morning, one tablet in the afternoon. 1
• Week 4 onward: Two tablets twice daily (maintenance dose = 32 mg naltrexone/360 mg bupropion total daily). 12
• Discontinue after 12 weeks if the patient has not lost 5% of total body weight on the maintenance dose, as they are likely a poor responder. 12

Absolute Contraindications

• Current or anticipated opioid use (risk of precipitated withdrawal or reduced analgesic efficacy). 12
• Uncontrolled hypertension (bupropion can raise blood pressure and heart rate). 2
• History of seizures or conditions lowering seizure threshold (brain tumor, stroke, head trauma, eating disorders). 2
• Recent monoamine oxidase inhibitor use (within 14 days). 2
• End-stage renal disease. 12
• Pregnancy or inadequate contraception (potential teratogenicity). 2

Dose Adjustments for Organ Impairment

• Moderate-to-severe renal impairment (eGFR <90 mL/min): Maximum one tablet twice daily. 2
• Moderate-to-severe hepatic impairment: Maximum one tablet once daily. 12

Monitoring Requirements

• Cardiovascular: Measure blood pressure and heart rate at baseline and periodically during the first 12 weeks, as bupropion may cause elevations most prominently in the first 8 weeks. 12
• Neuropsychiatric: Assess for suicidal ideation, agitation, and behavioral changes weekly during the first month, especially in adults <24 years. 2
• Procedural planning: Discontinue before procedures requiring opioid analgesia (e.g., endoscopy with fentanyl) to avoid reduced analgesic efficacy. 1

Adverse Event Profile

• Treatment discontinuation due to adverse events occurs in 129 additional patients per 1,000 treated compared to placebo—the highest rate among FDA-approved anti-obesity medications. 12
• Most common side effects: Nausea (most reported), constipation, headache, dizziness, insomnia, and dry mouth. 24
• Serious adverse events: Potentially severe neuropsychiatric disorders (aggressiveness, depression, suicidal ideation, seizures, cognitive impairment, psychotic symptoms), allergic reactions including Stevens-Johnson syndrome, and cardiac arrhythmias. 54
• Nausea affects 23.5% during titration and can be minimized by gradual dose escalation over 4 weeks. 6

Real-World Effectiveness and Tolerability

• In a 2025 real-world cohort of 98 patients, mean total weight loss was 7.9% at 3 months, 10.3% at 6 months, and 11.5% at 12 months when combined with lifestyle intervention. 6
• Treatment discontinuation within 12 months occurred in 52.7% of patients due to side effects and other reasons, highlighting the importance of careful patient selection and monitoring. 6

Clinical Bottom Line

• Do not prescribe low-dose naltrexone (4.5 mg) monotherapy for weight loss—it lacks efficacy and FDA approval for this indication.
• The FDA-approved naltrexone-bupropion ER combination is a conditional recommendation for adults with BMI ≥30 kg/m² or BMI ≥27 kg/m² with weight-related complications, when added to lifestyle interventions. 11
• Ideal candidates include patients describing food cravings, hedonic eating behaviors, concomitant depression, or those attempting smoking cessation. 2
• Avoid in patients requiring opioid therapy, with seizure history, uncontrolled hypertension, or end-stage renal disease. 12
• Expect modest weight loss (3–5% additional reduction vs. placebo) with high discontinuation rates, making this a second-line option after semaglutide or phentermine-topiramate when those agents are contraindicated or unavailable. 123