What is the role of naltrexone (Naltrexone) in treating Major Depressive Disorder (MDD) with comorbid marijuana use?

Naltrexone for Major Depressive Disorder with Comorbid Marijuana Use

Naltrexone-bupropion ER is recommended for patients with Major Depressive Disorder (MDD) and comorbid marijuana use, as it addresses both depression symptoms and substance use through its dual mechanism of action. 1

Mechanism and Efficacy

• Naltrexone is an opioid antagonist that, when combined with bupropion (a dopamine and norepinephrine reuptake inhibitor), provides a synergistic effect that can help manage both depression and substance use disorders 1
• The bupropion component is FDA-approved as an antidepressant and has been shown to be effective for the long-term treatment of recurrent major depression at doses similar to those in naltrexone-bupropion ER 1
• Although not formally tested for its effect on mood as a primary outcome in large pivotal studies, a small open-label study in women with major depressive disorder showed significant improvement in depressive symptoms that were sustained at 24 weeks of therapy with naltrexone-bupropion ER 1
• A randomized, proof-of-concept trial showed that low-dose naltrexone (LDN) augmentation for patients with breakthrough depression symptoms demonstrated significant improvement on the Montgomery-Asberg Depression Rating Scale compared to placebo (d=1.45; p=0.035) 2

Benefits for Substance Use

• Limited data on smoking cessation with the combination of sustained-release bupropion and naltrexone showed a reduction of nicotine use and mitigation of associated weight gain, suggesting potential benefits for other substance use disorders including marijuana 1, 3
• Naltrexone works on the central reward pathways triggered by substances, which may help reduce cravings for marijuana similar to its effects on alcohol and opioids 1
• In clinical practice, patients who describe cravings for substances and/or addictive behaviors have shown good response to naltrexone-bupropion therapy 1

Dosing and Administration

• Naltrexone-bupropion ER is available in tablets containing 8 mg of naltrexone and 90 mg of bupropion in a sustained-release formulation 1
• The recommended titration schedule begins with 1 tablet daily in the morning, followed by weekly escalation to 1 tablet twice per day, then 2 tablets in the morning and 1 in the afternoon, until reaching the maintenance dose of 2 tablets twice per day 1
• The second dose should not be taken late in the day to minimize the risk of insomnia 1
• After 12 weeks of therapy on the maintenance dose, if the patient has not shown clinical improvement, the medication should be discontinued as they are likely a poor responder 1

Contraindications and Precautions

• Naltrexone-bupropion ER should not be used in patients that require short-term or long-term opiate therapy due to potential reduced efficacy of analgesics or precipitated withdrawal 1, 3
• It should be discontinued before procedures that require the use of opiates 1
• Bupropion may lower the seizure threshold, so naltrexone-bupropion ER should be avoided in patients with epilepsy and used with caution in patients with a history of seizures 1
• Blood pressure and heart rate should be monitored periodically while taking naltrexone-bupropion ER, especially in the first 12 weeks of treatment 1
• It should be avoided in patients with uncontrolled hypertension 1

Monitoring for Depression

• Contrary to some concerns, multiple studies have shown that naltrexone treatment does not worsen depressive symptoms in most patients 4, 5
• In fact, patients who are adherent to naltrexone treatment often exhibit fewer depressive symptoms than those who are non-adherent 4
• One study of opioid-dependent individuals showed significant improvement in depression scores over a 4-week period after naltrexone initiation 5
• However, some patients may experience sleep impairment early in treatment, particularly late insomnia 5
• There have been isolated case reports of depression worsening with naltrexone, particularly in patients with comorbid alcohol and opioid dependence, suggesting the need for careful monitoring 6

Special Considerations for Marijuana Use

• While specific studies on naltrexone for marijuana use disorder are limited, the medication's effects on reward pathways suggest potential benefit 1
• The combination of naltrexone with bupropion may be particularly beneficial as it addresses both the depressive symptoms and substance use through different but complementary mechanisms 1
• For patients with both MDD and marijuana use, this combination provides a rational pharmacologic approach that targets both conditions simultaneously 1, 2