Bupropion and Naltrexone in Methamphetamine Use Disorder

Methamphetamine use disorder is a pervasive public health issue in the United States, yet there are currently no FDA-approved medications for its treatment. This trial (ADAPT-2) aimed to evaluate the efficacy and safety of a combination regimen using extended-release injectable naltrexone and oral extended-release bupropion in adults diagnosed with moderate or severe methamphetamine use disorder.

The researchers conducted a multisite, double-blind, randomized controlled trial employing a sequential parallel comparison design. The 12-week study was divided into two 6-week stages. In the first stage, participants were randomized to receive either the naltrexone-bupropion combination or a placebo. Participants in the placebo group who failed to show a response—defined as having at least three methamphetamine-negative urine samples out of four collected in the final two weeks of the stage—were re-randomized for the second 6-week stage. This design was specifically chosen to enrich the study sample and minimize the impact of a high placebo response rate commonly observed in psychiatric clinical trials.

The combination therapy demonstrated superior outcomes compared to the placebo. Across the two stages of the trial, participants receiving the naltrexone-bupropion regimen showed a weighted average response rate of 13.6%, compared to 2.5% in the placebo group. This resulted in an overall treatment effect of 11.1 percentage points. While the absolute response rates were low, the difference between the two study arms was statistically significant. Regarding safety, while the treatment group reported higher incidences of adverse effects such as nausea, vomiting, and dizziness, the regimen was generally tolerated, and the occurrence of serious adverse events did not differ significantly between the treatment and placebo groups.