Bupropion and Naltrexone in Methamphetamine Use Disorder

N Engl J Med. 2021 Jan 14;384(2):140-153. doi: 10.1056/NEJMoa2020214.

Abstract

Background: The use of naltrexone plus bupropion to treat methamphetamine use disorder has not been well studied.

Methods: We conducted this multisite, double-blind, two-stage, placebo-controlled trial with the use of a sequential parallel comparison design to evaluate the efficacy and safety of extended-release injectable naltrexone (380 mg every 3 weeks) plus oral extended-release bupropion (450 mg per day) in adults with moderate or severe methamphetamine use disorder. In the first stage of the trial, participants were randomly assigned in a 0.26:0.74 ratio to receive naltrexone-bupropion or matching injectable and oral placebo for 6 weeks. Those in the placebo group who did not have a response in stage 1 underwent rerandomization in stage 2 and were assigned in a 1:1 ratio to receive naltrexone-bupropion or placebo for an additional 6 weeks. Urine samples were obtained from participants twice weekly. The primary outcome was a response, defined as at least three methamphetamine-negative urine samples out of four samples obtained at the end of stage 1 or stage 2, and the weighted average of the responses in the two stages is reported. The treatment effect was defined as the between-group difference in the overall weighted responses.

Results: A total of 403 participants were enrolled in stage 1, and 225 in stage 2. In the first stage, 18 of 109 participants (16.5%) in the naltrexone-bupropion group and 10 of 294 (3.4%) in the placebo group had a response. In the second stage, 13 of 114 (11.4%) in the naltrexone-bupropion group and 2 of 111 (1.8%) in the placebo group had a response. The weighted average response across the two stages was 13.6% with naltrexone-bupropion and 2.5% with placebo, for an overall treatment effect of 11.1 percentage points (Wald z-test statistic, 4.53; P<0.001). Adverse events with naltrexone-bupropion included gastrointestinal disorders, tremor, malaise, hyperhidrosis, and anorexia. Serious adverse events occurred in 8 of 223 participants (3.6%) who received naltrexone-bupropion during the trial.

Conclusions: Among adults with methamphetamine use disorder, the response over a period of 12 weeks among participants who received extended-release injectable naltrexone plus oral extended-release bupropion was low but was higher than that among participants who received placebo. (Funded by the National Institute on Drug Abuse and others; ADAPT-2 ClinicalTrials.gov number, NCT03078075.).

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Amphetamine-Related Disorders / drug therapy*
  • Bupropion / administration & dosage*
  • Bupropion / adverse effects
  • Delayed-Action Preparations
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Humans
  • Injections
  • Male
  • Medication Adherence
  • Methamphetamine* / urine
  • Middle Aged
  • Naltrexone / administration & dosage*
  • Naltrexone / adverse effects
  • Narcotic Antagonists
  • Young Adult

Substances

  • Delayed-Action Preparations
  • Narcotic Antagonists
  • Bupropion
  • Methamphetamine
  • Naltrexone

Associated data

  • ClinicalTrials.gov/NCT03078075