The Only Drug Combo That's Worked Against Meth Is Still Waiting on the FDA

In January 2021, the New England Journal of Medicine published the first Phase 3 evidence that a drug combination could meaningfully reduce methamphetamine use. The trial was run through NIDA’s Clinical Trials Network across multiple sites. The combination: extended-release injectable naltrexone and oral bupropion XL — two drugs already FDA-approved for other indications. Among 403 adults with moderate or severe methamphetamine use disorder, 13.6 percent of participants on the combination significantly reduced or stopped use, versus 2.5 percent on placebo. By meth treatment standards, that effect size was historic.

More than five years later, there is still no FDA-approved pharmacotherapy for methamphetamine use disorder.

That gap is not inertia or oversight. It’s the regulatory reality: a combination of two off-label medications showing efficacy in a single Phase 3 trial doesn’t automatically produce an approval, particularly when neither manufacturer had a direct financial incentive to run the development process and file an NDA. The NEJM result was generated through public NIDA funding, not by Alkermes or Arbor Pharmaceuticals investing in a new commercial indication for their products. The path from “this works” to “this is approved” requires a sponsor with the resources and motivation to file — and for meth, no commercial sponsor has stepped forward to do that.

A confirmatory Phase 3 trial is currently recruiting through UCSD and other network sites, with estimated completion in 2027. The replication is designed to produce the kind of consistent evidence base the FDA would require for approval. If it replicates the NEJM findings, the path to approval becomes clearer, though still requires a filing.

In the meantime, clinicians can prescribe naltrexone and bupropion individually for their approved indications and, in practice, use them in combination off-label. The evidence base supports this. The infrastructure doesn’t make it easy: extended-release naltrexone (Vivitrol) requires injection in a clinical setting, bupropion requires a separate prescription, and treatment facilities that specialize in meth use disorder often lack the MAT infrastructure that opioid-focused programs have built up over two decades of buprenorphine expansion.

Methamphetamine use disorder killed roughly 32,500 people in 2022 — most of them in polysubstance combinations with opioids, but many from stimulant toxicity and cardiovascular effects alone. Contingency management — the behavioral intervention that has shown the most consistent evidence in stimulant treatment — has its own reimbursement battles in Medicaid. The 2021 NEJM result handed the field a pharmacological option. What the field still lacks is the regulatory and financial infrastructure to deliver it at scale.

The 2027 Phase 3 completion date means the FDA conversation is at least 18 months away, assuming the trial succeeds and a sponsor files. For the people in meth treatment today, the best available option is a combination of two off-label drugs that most treatment programs aren’t set up to prescribe.