One Med Stands Out in Re-Analysis of Cocaine Use Disorder

No medication beat placebo for abstinence, but one showed promise when the goalposts moved

STUDY: Amin-Esmaeili M et al, JAMA Psychiatry 2026

STUDY TYPE: Meta-analysis of randomized controlled trials

FUNDING: National Institutes of Health

Background

Recently, the FDA changed the bar for medication approvals in substance use disorders, requiring reduction in use rather than sobriety as the goal. This analysis suggests we’d see different results if that was applied to studies of cocaine and methamphetamine use disorder.

The Study

• 2,000 adults in 12 NIDA-sponsored trials for cocaine or methamphetamine use disorder.
• Nine medications tested (including bupropion, modafinil, topiramate, and cabergoline), each versus placebo; all participants received cognitive behavioral therapy.
• Primary outcome: reduced use, defined as dropping from 5+ days/month to 1–4 days/month. Secondary outcome: abstinence verified by urine drug screen.

No medication beat placebo when abstinence was the measure (13.6% vs. 12.7%).

When reduced use was the outcome, results were modestly larger across the board but still not statistically significant for most drugs (32.5% vs. 29.3%, effect size = 0.068).

One exception stood out: cabergoline, a dopamine agonist used mainly for hyperprolactinemia, beat placebo on reduced cocaine use (44.2% vs. 27.6%, effect size = 0.35). It showed no advantage on abstinence.

Limitations

The trials pooled data across medications and sites, and individual drug arms were small. Most trials were conducted 15–25 years ago. Reduced use was not a prespecified outcome in any of the original studies. Results are exploratory, not confirmatory.

Practice Implications

• Cabergoline deserves a second look in cocaine use disorder. It has a plausible mechanism: it acts on the mesolimbic dopamine system that cocaine hijacks.
• It is also one of the most effective agents for prolactinemia.
• Dose for cocaine is weekly: 0.5 mg PO once per week (start 0.25 mg weekly).
• Dosing for prolactinemia: Start 0.25 mg weekly, increase by 0.25 mg twice weekly every 4 weeks, guided by serum prolactin levels (typically measured every 8 weeks during titration). Typical dose is 0.5 mg twice/week, max 1.5 mg twice/week.
• TOLERABILITY: Nausea (27%), headache (26%), and dizziness (15%); hypotension, fatigue.
• RISKS: Psychosis and hedonic dysregulation (similar to pramipexole). Cardiac (valvulopathy and fibrosis); FDA recommends a baseline echocardiogram before initiation and surveillance echocardiograms every 6–12 months.
• Learn about a large trial of mirtazapine in methamphetamine use disorder, which was too new to make it into this analysis.