Is Naltrexone-bupropion XL (naltrexone and bupropion) FDA approved for the treatment of Major Depressive Disorder (MDD) and marijuana use?

Naltrexone-Bupropion XL is NOT FDA Approved for MDD and Marijuana Use

Naltrexone-bupropion XL is not FDA approved for the treatment of major depressive disorder (MDD) or marijuana use disorder. 1 This combination medication is only FDA approved for chronic weight management in adults with obesity or overweight with weight-related comorbidities.

FDA-Approved Indications for Naltrexone-Bupropion XL

• Approved as an adjunct to reduced-calorie diet and increased physical activity for chronic weight management in adults with:
  • BMI ≥30 kg/m² (obesity) 1
  • BMI ≥27 kg/m² (overweight) with at least one weight-related comorbidity 1

FDA-Approved Indications for Individual Components

Bupropion (alone)

• FDA approved for major depressive disorder (MDD) 2, 3
• FDA approved for smoking cessation 2, 4
• Available formulations include immediate release (IR), sustained release (SR), and extended release (XL) 2, 5

Naltrexone (alone)

• FDA approved for alcohol dependence 1
• FDA approved for opioid dependence 1
• Not FDA approved for smoking cessation or marijuana use 4

Clinical Considerations for Off-Label Use

Potential for MDD Treatment

• While bupropion alone is FDA-approved for MDD, the naltrexone-bupropion combination has limited evidence for this indication 1
• A small open-label study in women with MDD showed improvement in depressive symptoms with naltrexone-bupropion XL, but this was not a primary outcome in large pivotal studies 1
• Most large clinical trials for naltrexone-bupropion excluded subjects with significant psychiatric disorders or those using antidepressants 1

Potential for Substance Use Disorders

• No FDA approval or strong evidence for marijuana use disorder treatment 4
• Limited data shows the combination may help with smoking cessation and mitigate associated weight gain 1, 4
• One study showed superior efficacy for smoking cessation at 7 weeks with naltrexone-bupropion combination compared to bupropion alone, but equivalent relapse rates at 6 months 1

Important Safety Considerations

• Contraindicated in patients requiring opioid therapy due to naltrexone's opioid antagonism 1
• Should be discontinued before procedures requiring opioid analgesia 1
• Should be avoided in patients with:
  • Uncontrolled hypertension 1
  • Seizure disorders (bupropion may lower seizure threshold) 1, 2
  • End-stage renal disease 1
  • Moderate to severe hepatic impairment (dose reduction required) 1, 2

Dosing Considerations

• Standard titration schedule for naltrexone-bupropion XL for obesity:
  • Start with 1 tablet daily (8 mg naltrexone/90 mg bupropion)
  • Weekly escalation to maintenance dose of 2 tablets twice daily
  • Second dose should not be taken late in day (risk of insomnia) 1
• Dose adjustments required for:
  • Moderate to severe renal impairment: reduce to half the daily dose 1, 2
  • Moderate to severe hepatic impairment: maximum 1 tablet daily 1, 2

Clinical Decision-Making

• For MDD treatment, bupropion alone is the FDA-approved option with established efficacy 3, 6, 5
• For marijuana use disorder, neither naltrexone, bupropion, nor their combination has FDA approval 4
• For patients with both obesity and MDD, naltrexone-bupropion XL might be considered off-label, but with careful monitoring 1, 7

In conclusion, clinicians should be aware that prescribing naltrexone-bupropion XL for MDD and/or marijuana use would constitute off-label use with limited supporting evidence.