Does naltrexone reduce cravings in adults with methamphetamine use disorder?

Naltrexone for Methamphetamine Cravings

Naltrexone shows modest benefit for methamphetamine cravings and use reduction, but the evidence is limited and effects are small—it should be considered only as an adjunct to comprehensive behavioral therapy in highly motivated patients, with the combination of extended-release naltrexone plus bupropion showing the strongest (though still modest) evidence.

Evidence Quality and Treatment Effect

The evidence for naltrexone in methamphetamine use disorder is substantially weaker than for alcohol or opioid use disorders, where it has FDA approval 1, 2. A 2019 systematic review found insufficient evidence to support naltrexone monotherapy for amphetamine/methamphetamine use disorders, with inconsistent results across the limited number of randomized controlled trials 3.

The most robust evidence comes from the 2021 ADAPT-2 trial published in the New England Journal of Medicine, which tested extended-release injectable naltrexone (380 mg every 3 weeks) combined with oral extended-release bupropion (450 mg daily) 4. This combination produced:

• 13.6% response rate versus 2.5% with placebo (treatment effect of 11.1 percentage points, P<0.001) 4
• Response was defined as at least 3 out of 4 methamphetamine-negative urine samples at study endpoint 4
• While statistically significant, the absolute response rate of 13.6% is notably low, meaning 86% of treated patients did not achieve the primary outcome 4

Mechanism and Neurobiological Effects

Naltrexone blocks mu-opioid receptors, which indirectly modulates dopamine neuron activity in the reward system 1, 5. In methamphetamine users, naltrexone:

• Reduces resting-state functional connectivity between ventral striatum, amygdala, hippocampus, and midbrain regions involved in reward processing 5
• Decreases coupling between executive control and default mode networks, potentially enhancing attentional resources while suppressing emotional/self-referential processing 6
• These connectivity changes correlate with reductions in methamphetamine use 5

However, a 2015 human laboratory study found that neither naltrexone (50 mg) nor bupropion (300 mg/day) alone or in combination altered methamphetamine self-administration or subjective effects, demonstrating the "robust behavioral effects of methamphetamine that could make it resistant to pharmacological manipulation" 7.

Clinical Algorithm for Use

Patient Selection Criteria

Only consider naltrexone for methamphetamine use disorder in patients who meet ALL of the following 1, 2, 4:

• Moderate or severe methamphetamine use disorder by DSM-5 criteria 4
• High motivation for treatment and abstinence 1, 2
• Enrolled in comprehensive behavioral therapy (individual, group, or family therapy) 8, 1
• No current opioid use and completely opioid-free for 7-10 days minimum 2
• No requirement for opioid pain medications 1, 2
• Normal or mildly elevated liver function tests without cirrhosis 1, 2

Dosing Protocol

Use the combination regimen that showed efficacy in the ADAPT-2 trial 4:

• Extended-release injectable naltrexone 380 mg intramuscularly every 3 weeks 4
• PLUS oral extended-release bupropion 450 mg daily 4
• Continue for at least 12 weeks to assess response 4

Alternatively, if injectable formulation is unavailable, oral naltrexone 50 mg daily can be used, though adherence may be problematic 1, 2.

Monitoring Requirements

• Baseline liver function tests and repeat every 3-6 months due to hepatotoxicity risk at supratherapeutic doses 1, 2
• Twice-weekly urine drug screens to objectively monitor methamphetamine use 4
• Screen for and monitor depression, anxiety, and insomnia before and during treatment, as naltrexone may worsen these conditions 1
• Assess craving levels at each visit using standardized measures 8

Expected Adverse Events

Common side effects with the naltrexone-bupropion combination include 4:

• Gastrointestinal disorders (nausea, constipation)
• Tremor
• Malaise and hyperhidrosis
• Anorexia
• Serious adverse events occurred in 3.6% of treated participants 4

Critical Safety Considerations

Precipitated withdrawal is the most dangerous risk: Patients must be completely opioid-free before starting naltrexone to avoid severe, potentially life-threatening withdrawal 2. Verify opioid-free status with urine drug screen and clinical assessment 2.

Increased overdose risk after discontinuation: Patients who stop naltrexone have decreased opioid tolerance and face increased risk of overdose and death if they return to opioid use 1, 2. Provide opioid overdose education and naloxone to all patients 2.

Contraindications 1, 2:

• Active opioid use or dependence
• Need for opioid analgesics
• Decompensated cirrhosis or acute hepatitis
• Pregnancy (offer alternative treatments)

Perioperative management: Hold oral naltrexone 2-3 days before elective surgery; hold extended-release formulation 24-30 days after last injection if opioids will be needed 1, 2.

Comparison to Other Treatment Options

Behavioral therapies remain first-line treatment for methamphetamine use disorder, as there are no FDA-approved pharmacotherapies specifically for this indication 8. Cognitive behavioral therapy combined with contingency management shows stronger evidence than pharmacotherapy alone 8.

The combination of naltrexone-bupropion represents the best available pharmacological option based on current evidence, but should always be integrated with comprehensive psychosocial treatment 8, 4. The medication alone is insufficient 8, 1.

Common Pitfalls to Avoid

• Do not use naltrexone monotherapy—the combination with bupropion showed superior results 4
• Do not prescribe without concurrent behavioral therapy—medication alone has minimal efficacy 8, 1
• Do not start naltrexone without verifying opioid-free status—this causes precipitated withdrawal 2
• Do not expect high response rates—even with optimal treatment, only 13.6% of patients achieved the primary outcome in the best available trial 4
• Do not continue indefinitely without response—assess treatment response after 12 weeks and discontinue if no benefit 4