Combination of Naltrexone and Bupropion May Help Treat Meth Use Disorder, Study Finds

A combination of two medications, injectable naltrexone and oral bupropion, reduces drug use among people with moderate or severe methamphetamine use disorder, according to a double-blind, placebo-controlled study reported in the New England Journal of Medicine.

Rates of meth use (and overuse) have been high in some segments of the gay male population and men who have sex with men (MSM), and there is anecdotal evidence that meth use has been increasing during the COVID-19 pandemic. Meth is also associated with a higher risk of HIV and other sexually transmitted infections among MSM.

A potent stimulant, methamphetamine increases the level of dopamine, a brain chemical associated with pleasure. Meth use disorder can result in devastating medical and mental health complications—including anxiety, confusion, paranoia, aggression, and delusions—and even fatal overdoses. Between 2015 and 2018, 1.6 million U.S. adults reported meth use over the past year, according to the Centers for Disease Control and Prevention, and more than half of them had a meth use disorder. There is currently no U.S. Food and Drug Administration (FDA)–approved treatment for meth use disorder—or for disorders involving use of other stimulants, such as cocaine.

Study Details: ADAPT-2 for Severe Meth Use Treatment

The study—known as the Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder study, or ADAPT-2—was conducted on 403 adult volunteers from 2017 to 2019 within clinics that run treatment programs affiliated with the National Institute on Drug Abuse Clinical Trials Network (NIDA CTN). All participants had moderate to severe methamphetamine use disorder. The average participant age was 41; the cohort was 69% male (no data were available on the number of transgender or nonbinary participants) and 71% white (14% Latinx, 12% Black). One out of four participants was living with HIV.

Over the course of two six-week stages, participants in the treatment group were given an injection of 380-mg extended-release naltrexone every three weeks, plus 450-mg daily extended-release tablets of bupropion. Those in the control group were given placebo. If at least three of four urine screens at the end of a six-week stage were negative for methamphetamine, researchers determined that the participant had responded to treatment during that stage.

After the first six weeks, 13.6% of participants treated with naltrexone and bupropion had at least three meth-negative urine samples, versus only 2.5% of those on placebo (11.1% weighted difference; P < .001). They also reported slightly less meth craving.

Questionnaire responses indicated that participants in the treatment arm reported slightly lower rates of depression and a somewhat higher score on the Treatment Effectiveness Assessment compared to participants in the placebo arm.

In the second six-week stage, thanks to adherence counseling and mobile app reminders, adherence remained at 77.4% and 82.0% in the treatment and placebo groups, respectively.

Why Did Naltrexone/Bupropion Work in Treating Heavy Meth Use?

“The result [of naltrexone/bupropion] is almost six times greater than the placebo,” lead study author Madhukar Trivedi, M.D., a professor at the University of Texas Southwestern Medical Center in Dallas, told TheBodyPro. He added that the medication combo was well tolerated, and the study team didn’t lose any study participants due to side effects. He also noted that the efficacy of the combination was similar across races, ages, and between men and women.

Trivedi said it’s not clear exactly how the combination works to reduce meth use and cravings, but that any positive findings were encouraging—and a six-fold difference was all the more so. “If I had a patient with meth use disorder, it wouldn’t matter how much they improve, as long as they do improve,” he said.

Injectable naltrexone (sold as Vivitrol in the U.S.) is an opioid receptor antagonist (similar to naloxone), meaning that it binds to opioid receptors to reverse and block the effects of opioids. It also might reduce the euphoria and cravings that come with meth use. It’s used in treating addiction to heroin and synthetic opioids, as well as alcohol.

Bupropion (available generically, as well as under brand names including Wellbutrin and Zyban) is an antidepressant and smoking-cessation aid; it is also used to prevent depression caused by seasonal affective disorder (SAD). It’s possible that it acts on the dopamine and norepinephrine systems to minimize dysphoria that accompanies meth withdrawal.

“The population we studied had one thing in common, which is they used meth 27 days out of 30. This is a serious form of the disorder,” Trivedi said. “The good news is that some of the structural and neurochemical brain changes are reversed in people who recover, underscoring the importance of identifying new and more effective treatment strategies.”

Trivedi said that he wants to conduct more research into why the combination appears to work as well as it does, and to explore whether it will be effective against other stimulant use disorders. He also said it could be helpful to better understand some of the nuances of using the combination, such as whether it is more or less effective in treating binge users of meth.

The Future for Naltrexone/Bupropion as a Meth Use Treatment Option

Trivedi noted that the study doesn’t suggest that naltrexone/bupropion should be considered as a substitute for behavioral therapy like contingency management, but he said that such therapies could be used concurrently.

There are no statistics on how many clinicians are already prescribing naltrexone/bupropion, off label, for meth use disorder. (The combination is not FDA-approved for this use.) That said, prescriptions written for off-label use are fairly common; a 2006 U.S. study determined that approximately one in five prescriptions of commonly prescribed medications were off-label. The American Medical Association recommends off-label use when it is “based on sound scientific evidence and sound medical opinion.”

One potential limiting factor in the provision of naltrexone/bupropion for meth use is cost, at least for naltrexone. Trivedi said that it may be a while before insurance covers such treatment, with or without FDA approval.

“Insurance companies tend to stigmatize addictions,” he said, “but if this [treatment] were for, say, arthritis, they would probably pay for it right away.”