Is naltrexone used to treat methamphetamine use disorder?

Naltrexone for Methamphetamine Use Disorder

Naltrexone combined with bupropion shows modest efficacy for methamphetamine use disorder, but naltrexone monotherapy is not currently recommended as there is insufficient evidence to support its use alone.

Current Evidence for Combination Therapy

The strongest and most recent evidence comes from the ADAPT-2 trial, which demonstrated that extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg daily) produced a statistically significant but modest treatment effect in adults with moderate or severe methamphetamine use disorder 1. The weighted average response rate was 13.6% with naltrexone-bupropion versus 2.5% with placebo, yielding an 11.1 percentage point treatment effect (P<0.001) 1.

• The response was defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of treatment 1
• While statistically significant, the absolute response rate remained low at 13.6%, indicating that most patients did not achieve the primary outcome 1
• Common adverse events included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia, with serious adverse events occurring in 3.6% of participants 1

Evidence Against Naltrexone Monotherapy

A systematic review of randomized controlled trials concluded there is presently insufficient evidence to support the use of naltrexone alone for methamphetamine use disorder 2. Among four randomized controlled trials examining naltrexone for amphetamine or methamphetamine use:

• Only one of two studies showed significantly increased abstinence rates with naltrexone versus placebo for amphetamine use disorder 2
• For methamphetamine specifically, there was no statistical difference in abstinence rates between naltrexone and placebo in the only study reporting this outcome 2
• Naltrexone did attenuate some subjective effects and craving in laboratory settings, but this did not consistently translate to clinical abstinence 2

Mechanism of Action and Laboratory Findings

Naltrexone's potential utility is supported by controlled laboratory studies showing it can blunt cue-induced craving and attenuate hedonic subjective effects of methamphetamine 3. In a double-blind, placebo-controlled study:

• Naltrexone (50 mg oral) significantly reduced cue-induced craving for methamphetamine 3
• It decreased subjective ratings of "crave drug," "stimulated," and "would like drug access" after controlled methamphetamine administration 3
• These findings suggest a potential mechanism of action, though they do not guarantee clinical efficacy 3

Preclinical studies in mice demonstrate that naltrexone can reduce methamphetamine-induced behavioral sensitization and conditioned place preference, suggesting effects on incentive salience and reward-related memory 4.

Clinical Algorithm for Treatment Decisions

For patients with methamphetamine use disorder seeking pharmacotherapy:

1. First-line approach: Consider extended-release injectable naltrexone (380 mg every 3 weeks) combined with oral extended-release bupropion (450 mg daily), recognizing the modest response rate of approximately 14% 1

2. Patient counseling: Inform patients that while this combination shows statistically significant benefit over placebo, the absolute response rate is low and most patients will require additional interventions 1

3. Contraindications to assess:

   • Patients must be completely opioid-free before starting naltrexone to avoid precipitating withdrawal 5
   • Naltrexone cannot be used in patients requiring opioids for pain control 5
   • Obtain baseline liver function tests and monitor every 3-6 months due to potential hepatotoxicity 5
   • Screen for seizure history, as bupropion increases seizure risk 5

4. Monitoring protocol:

   • Obtain urine drug screens twice weekly to assess methamphetamine use 1
   • Assess for adverse events including gastrointestinal symptoms, tremor, and anorexia 1
   • Continue comprehensive psychosocial treatment, as medication alone is insufficient 5

5. Do not use naltrexone monotherapy for methamphetamine use disorder given insufficient evidence of efficacy 2

Critical Safety Considerations

Patients who discontinue naltrexone have decreased opioid tolerance and increased risk of overdose and death if they return to opioid use 5. This is particularly important given the high rates of polysubstance use among individuals with methamphetamine use disorder.

• For surgical patients on naltrexone, oral naltrexone should be held 2-3 days prior to elective procedures if opioids are expected 5
• Extended-release naltrexone should be held 24-30 days after the last injection before elective procedures 5

Common Pitfalls to Avoid

• Do not prescribe naltrexone monotherapy for methamphetamine use disorder based on its FDA approval for alcohol and opioid use disorder; the evidence does not support extrapolation to stimulant use disorders 2
• Do not initiate naltrexone without confirming complete opioid abstinence, as precipitated withdrawal can be severe 5
• Do not use naltrexone as standalone treatment; it must be combined with bupropion and comprehensive psychosocial interventions to achieve even modest efficacy 1
• Do not overpromise treatment outcomes; even with combination therapy, the majority of patients will not achieve sustained abstinence based on current evidence 1