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A combination of naltrexone and bupropion was helpful in slightly reducing drug use for those struggling with methamphetamine use disorder, according to a double-blind, placebo-controlled study.

During the 12-week trial, 13.6% of participants treated with 380-mg extended-release injectable naltrexone (Vivitrol) every 3 weeks plus 450 mg/day of oral extended-release bupropion (Wellbutrin) had at least three methamphetamine-negative urine samples versus only 2.5% of those who were on placebo (11.1% weighted difference, P<0.001), reported Madhukar Trivedi, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues.

Those on combination naltrexone and bupropion also had a nearly 10% lower weekly methamphetamine craving score on the visual analog scale, the group wrote in the .

Additionally, the treatment group had a modest 1% lower depression score on the Patient Health Questionnaire 9 scale and a 4% higher score on the Treatment Effectiveness Assessment, which specifically measures reduced substance use and improvements in lifestyle, health, and community and interpersonal interactions.

"The participants in our trial were severely affected by methamphetamine use disorder, with almost daily use before entry into the trial," the researchers noted, adding that there is currently no FDA-approved medication indicated for the treatment of this disorder.

Naltrexone, an opioid-receptor antagonist, has already been established as an effective treatment for opioid use disorder. The atypical antidepressant bupropion, a norepinephrine-dopamine reuptake inhibitor, is currently indicated for major depression and smoking cessation and is thought to reduce feelings of dysphoria associated with methamphetamine withdrawal.

In the first stage of the trial, a total of 403 individuals with moderate or severe methamphetamine use disorder were randomly assigned in a 0.26:0.74 ratio to receive combination naltrexone and bupropion or a placebo injectable-oral combination for 6 weeks. The majority of the study participants were white men.

In this stage, 16.5% (18 of 109) of participants in the active treatment group had a treatment response, defined as at least three methamphetamine-negative urine samples out of four samples at the end of 6 weeks. In contrast, only 3.4% (10 of 294) of those on placebo had achieved this same treatment response.

From there, the researchers re-randomized participants from the placebo group who didn't have this treatment response in a 1:1 ratio to receive naltrexone plus bupropion or placebo for another 6 weeks. In this second stage, which included 225 participants, 11.4% (13 of 114) of the participants in the treatment group achieved a response -- at least three methamphetamine-negative urine samples -- while only 1.8% (2 of 111) of those on placebo achieved this response.

During both trial stages, the participants came into the clinic twice a week to provide urine samples. Samples were vetted for validity based on temperature (between 90° to 100°F).

Overall, the rate of serious adverse events was low with the treatment, occurring in only 3.6% of those who received naltrexone-bupropion. The most common adverse events reported were gastrointestinal disorders (nausea, vomiting, and constipation), nervous system-related symptoms like tremor and headache, and psychiatric symptoms like anxiety and anorexia, as well as malaise and hyperhidrosis.

"Replication of our trial results in a more naturalistic effectiveness design could be a next step," Trivedi's group suggested.

A low inclusion of women and participant self-reporting of the oral bupropion half of the treatment regimen were acknowledged as study limitations.

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