What are the potential interactions between naltrexone (opioid receptor antagonist) and marijuana?

Naltrexone and Marijuana Interaction

There is no direct pharmacological contraindication to concurrent use of naltrexone and marijuana, as naltrexone acts on opioid receptors while cannabis acts primarily on cannabinoid receptors—these are separate receptor systems with no direct interaction.

Mechanism and Pharmacology

• Naltrexone is a competitive opioid receptor antagonist (primarily mu, kappa, and delta receptors) with a plasma half-life of 4 hours and an active metabolite (6-β-naltrexol) with a 13-hour half-life 1.
• Cannabis acts on the endocannabinoid system through CB1 and CB2 receptors, which are distinct from opioid receptors 2.
• No direct pharmacokinetic or pharmacodynamic interaction exists between these two receptor systems 1.

Clinical Evidence on Combined Use

In Opioid Dependence Treatment

• Intermittent cannabis use (1-79% positive urine samples) was associated with superior retention in naltrexone treatment for opioid dependence, with median retention of 133 days compared to 35 days in cannabis-abstinent patients 3.
• Patients with intermittent cannabis use showed greater adherence to naltrexone pill-taking compared to those who were cannabis-abstinent or consistent heavy users 3.

In Cannabis Use Disorder

• Naltrexone 50mg daily significantly reduced cannabis self-administration and positive subjective effects ("good effect") in daily cannabis smokers 2.
• Participants on placebo had 7.6 times the odds of self-administering active cannabis compared to those on naltrexone (95% CI: 1.1-51.8) 2.
• This suggests naltrexone may have therapeutic potential for reducing cannabis use, though the mechanism is not fully understood 2.

Safety Considerations

Common Side Effects of Naltrexone (Unrelated to Cannabis)

• Nausea occurs in 4.6-9.6% of patients 4.
• Headache occurs in 0.9-1.8% of patients 4.
• Dizziness occurs in 0.7-1.4% of patients 4.
• Depression occurs in 0.1-1.3% of patients 4.

Critical Warnings

• Naltrexone blocks opioid receptors and will precipitate withdrawal in opioid-dependent patients 1.
• Oral naltrexone should be held 2-3 days before elective surgery if opioid analgesia is anticipated 1.
• Extended-release injectable naltrexone should be held 24-30 days before elective surgery if opioids are expected 1.
• Patients on naltrexone who require emergency opioid analgesia may need higher doses or alternative pain management strategies due to receptor blockade 1.

Clinical Bottom Line

Concurrent use of naltrexone and marijuana is not contraindicated from a pharmacological standpoint. The evidence suggests potential benefits in specific contexts (improved naltrexone adherence in opioid dependence treatment, or reduced cannabis use when naltrexone is used therapeutically for cannabis use disorder) 3, 2. The primary concerns with naltrexone relate to its opioid receptor blockade—not cannabis interaction—particularly the risk of precipitating opioid withdrawal and interfering with opioid analgesia 1.