The Combination Drug for Methamphetamine Outperformed Placebo Again. The FDA Still Has Nothing Approved.

There is no FDA-approved medication for methamphetamine use disorder. Not one. The agency has approved medications for opioid use disorder (methadone, buprenorphine, naltrexone), for alcohol use disorder (naltrexone, acamprosate, disulfiram), for nicotine dependence (varenicline, bupropion, nicotine replacement). For methamphetamine — a drug used by an estimated six million Americans with stimulant use disorder, a drug contributing to overdose deaths that have been climbing as fentanyl-methamphetamine polysubstance use has grown — the FDA has approved nothing.

ADAPT-2 is the closest we have to a candidate, and secondary analyses published in June 2026 add to the case for taking it seriously.

What the trial tested

The Accelerated Development of Additive Pharmacotherapy Treatment-2 (ADAPT-2) trial, whose primary results were published in the New England Journal of Medicine in January 2021, tested a combination approach: extended-release injectable naltrexone (the same medication used for opioid use disorder, given monthly by injection) plus extended-release oral bupropion (better known as Wellbutrin, an antidepressant used off-label for smoking cessation). The combination — sometimes called NXTB — is based on a theory about how these two drugs work together: naltrexone blocks the reward pathway that methamphetamine activates; bupropion reduces craving by modulating dopamine and norepinephrine availability. Neither drug alone has produced robust results for meth. Together, in the primary trial, they outperformed placebo on the primary endpoint.

What the new analyses show

The June 2026 secondary analyses published in PMC examined questions the primary trial couldn’t fully answer: did the benefit persist beyond the 6-week primary endpoint? What was driving the effect — craving reduction, impulsivity reduction, something else?

Key findings: the 27 percent rate of methamphetamine-negative urine tests in the NXTB arm (versus 11 percent in the placebo arm) held through 12 weeks of follow-up. The benefit did not erode after the initial active treatment period. Analyses of craving and impulsivity scores suggest that bupropion’s effect on dopaminergic tone — essentially, how the brain responds to reward anticipation, translated: the mental experience of wanting the drug — may be a mediating mechanism. Participants who showed greater reductions in self-reported craving at week four showed greater reductions in methamphetamine use at weeks eight and twelve.

What the data doesn’t answer

Twenty-seven percent is better than eleven percent. It is not remission. Most NXTB participants in the trial were still using methamphetamine at the 12-week mark. The treatment reduced use; it did not produce widespread abstinence. The translation of a clinical trial endpoint — methamphetamine-negative urine tests at a defined time point — into real-world treatment benefit for a person with stimulant use disorder involves assumptions about what the right outcome measure should be, assumptions that treatment researchers debate.

There are also practical questions. Extended-release naltrexone requires monthly injections in a clinical setting. Sustained bupropion exposure carries cardiovascular and seizure risk in some populations. The combination requires motivated engagement from both patient and provider. The regulatory path to FDA approval for a combination drug in a new indication is not straightforward, and no sponsor has yet submitted an NDA for NXTB for methamphetamine use disorder.

The gap that the data illuminates

What the ADAPT-2 secondary analyses do, regardless of whether they move the regulatory needle, is put in writing — peer-reviewed, replicated at 12 weeks — the reality that methamphetamine use disorder is pharmacologically tractable. It responds to medication the way other use disorders respond to medication. The dopamine and norepinephrine systems that methamphetamine hijacks are the same systems targeted by drugs that work elsewhere in addiction medicine. The gap is not scientific. It is commercial and regulatory: the candidate drug is off-patent, the regulatory path is expensive, and no company has the incentive structure to fund a Phase 3 program for a combination of generics in an underinsured population.

The dopamine and norepinephrine systems that methamphetamine hijacks are the same systems targeted by drugs that work elsewhere in addiction medicine.

This is a pattern worth naming, because it is not specific to methamphetamine. The treatments most urgently needed by people in the highest-burden segments of the addiction epidemic are frequently those for which there is no commercial development pathway. The science does not have to solve this problem. Policy does.

For providers seeing patients with stimulant use disorder now: contingency management — a behavioral intervention where patients receive small financial rewards for submitting negative drug tests, building the brain’s natural reward response through a replacement track — remains the most evidence-supported intervention for meth use disorder and has SAMHSA endorsement. It is underused in clinical settings, partly due to a prior federal cap on reward amounts that has since been lifted in some programs. If your patient cannot access a clinical trial and will not respond to behavioral intervention alone, NXTB is available off-label; the evidence base is real enough to support a conversation about it.