What is the effectiveness of naltrexone (opioid receptor antagonist) in treating cannabis use disorder in adult patients?

Naltrexone for Cannabis Use Disorder: Limited Evidence of Effectiveness

Naltrexone is not currently recommended as a standard treatment for cannabis use disorder, as no medication-assisted therapy has been determined to be effective for cannabis-related substance use disorders according to established guidelines. 1

Current Guideline Position

• The American College of Physicians explicitly states that evidence-based medication-assisted therapy approaches exist for opioid use disorder, tobacco, and alcohol, but no medication-assisted therapy has yet been determined to be effective for the treatment of substance use disorders related to cocaine or stimulant use—and notably, cannabis is not mentioned as having any approved pharmacotherapy. 1

• Behavioral therapy remains the primary evidence-based approach for all cannabis use disorders, including cognitive-behavioral therapy, contingency management, relapse prevention, and motivational enhancement therapy. 1

Emerging Research Evidence

Despite the lack of guideline support, recent research studies suggest naltrexone may have some potential benefit:

Laboratory Studies Show Promise

• A 2015 controlled human laboratory study demonstrated that naltrexone maintenance (50 mg daily for 16 days) significantly reduced both active cannabis self-administration and positive subjective effects in daily cannabis smokers. 2

• Participants receiving naltrexone had 7.6 times lower odds of self-administering active cannabis compared to placebo, and this effect extended to reduced cannabis use in their natural environment. 2

• The mechanism appears to involve opioid antagonists modulating cannabinoid effects through the endogenous opioid system. 2

Clinical Trial Data

• A 2011 randomized comparison study of 59 patients found naltrexone to be the most efficacious of four pharmacological agents tested (naltrexone, bupropion, escitalopram, and bromazepam) for treating cannabis addiction over 120 days. 3

• Naltrexone showed the lowest dropout rate (4 patients) compared to other agents (6-8 dropouts) and was most effective in reducing anxiety and depression while increasing functioning. 3

Interesting Paradox in Opioid Treatment Populations

• An unexpected finding from opioid use disorder treatment shows that intermittent cannabis use (not abstinence or consistent use) was associated with improved retention in naltrexone treatment for opioid dependence. 4

• Intermittent cannabis users showed superior retention (median 133 days) compared to abstinent users (median 35 days) or consistent users (median 35 days) when treated with naltrexone for opioid dependence. 4

Critical Limitations and Caveats

Why Guidelines Don't Recommend It

• The research evidence consists primarily of small, short-term studies that have not been replicated in large-scale clinical trials. 2, 3

• The 2015 laboratory study specifically enrolled non-treatment-seeking daily cannabis smokers, which limits generalizability to patients motivated for treatment. 2

• No long-term outcome data exist on morbidity, mortality, or quality of life improvements with naltrexone for cannabis use disorder.

Safety Considerations If Used Off-Label

• Naltrexone cannot be used in patients requiring short-term or long-term opioid therapy, as it blocks pain relief from opioid agonists and can precipitate withdrawal. 1, 5, 6

• Liver function tests must be monitored at baseline and every 3-6 months due to potential hepatotoxicity at supratherapeutic doses. 1, 5

• Common intrinsic side effects include decreased appetite, stomach upset, headache, and decreased blood pressure. 2

• Patients must be counseled that discontinuing naltrexone increases overdose risk if they have concurrent opioid use due to decreased tolerance. 5

Clinical Algorithm for Real-World Practice

Given the absence of guideline support and limited evidence, the following approach is recommended:

1. First-line treatment: Behavioral interventions only - Use cognitive-behavioral therapy, contingency management, or motivational enhancement therapy as these have established evidence for cannabis use disorder. 1

2. Consider naltrexone only in specific circumstances:

   • Patient has failed multiple behavioral interventions
   • Patient has severe cannabis use disorder with significant functional impairment
   • Patient has no contraindications (no need for opioid analgesics, no acute hepatitis or decompensated cirrhosis)
   • Patient provides informed consent understanding this is off-label use with limited evidence 2, 3

3. If prescribing naltrexone off-label:

   • Start with 50 mg daily (oral formulation) 2
   • Check baseline liver function tests and repeat every 3-6 months 1, 5
   • Combine with intensive behavioral therapy (medication alone is insufficient) 1
   • Monitor for side effects: gastrointestinal upset, headache, decreased appetite 2
   • Reassess efficacy at 4-6 weeks; discontinue if no benefit 2

4. Extended-release injectable naltrexone (Vivitrol) is not recommended for cannabis use disorder as it has only been studied for opioid and alcohol use disorders, and the monthly injection format makes dose adjustment impossible. 5, 7

Bottom Line for Clinical Practice

Behavioral therapy remains the only evidence-based treatment for cannabis use disorder. 1 While emerging research suggests naltrexone may reduce cannabis self-administration and subjective effects, this has not translated into guideline recommendations or FDA approval. 2, 3 The decision to use naltrexone off-label should be reserved for treatment-refractory cases where behavioral interventions have failed, and only after careful consideration of contraindications and informed patient consent about the limited evidence base.