Evaluating Reduced Use and Abstinence as Outcomes in Pharmacotherapy Trials for Stimulant Use Disorder: A Meta-Analysis of 12 Randomized Controlled Trials.

Abstract

Importance: Cocaine and methamphetamine use disorders are major public health challenges with no approved pharmacological treatments. Reliance on complete abstinence as the sole end point in randomized controlled trials (RCTs) may hinder identification of effective therapies, as it is often overly stringent, whereas reduced stimulant use is a promising alternative given its association with improved health outcomes.

Objectives: To evaluate the treatment effect of pharmacological interventions tested in RCTs for stimulant use disorder, comparing reduced use to total abstinence.

Design, setting, and participants: A meta-analysis was conducted of 12 US National Institute on Drug Abuse-sponsored multisite RCTs conducted between 2001 and 2011 evaluating pharmacological interventions among people seeking treatment for cocaine or methamphetamine dependence. One-stage individual participant meta-analysis was used, and analyses were performed between August 2024 and November 2025.

Exposure: Tested pharmacotherapies included topiramate, bupropion, modafinil, ondansetron, tiagabine, cabergoline, reserpine, selegiline, and baclofen, each compared to placebo in double-blind trials. All participants received cognitive behavioral therapy regardless of treatment assignment.

Main outcomes and measures: The primary outcome was reduced drug use based on self-report, defined as a transition from high frequency (≥5 days/month) to low frequency (1-4 days/month) of stimulant use or transition to abstinence. Abstinence, verified by urine toxicology, served as the secondary outcome. Mixed-effects logistic regression models with random study effects and inverse probability weighting were used to estimate pooled treatment effects.

Results: A total of 2000 participants were included (1134 in cocaine RCTs and 866 in methamphetamine RCTs), of whom 587 (29.4%) were women, with a mean (SD) age of 39.7 (8.6) years. Overall, 446 participants (31.2%, weighted) achieved reduced use, whereas 184 (13.3%, weighted) achieved abstinence at the trial end point. No significant differences were observed between the pooled active treatment and placebo groups for either outcome, overall or when stratified by stimulant type. In analyses of individual medications, cabergoline showed positive effect sizes (Cohen h, 0.352; 95% CI, 0.115-0.590), indicating significantly higher rates of reduced cocaine use with cabergoline than pooled placebo.

Conclusions and relevance: The present findings of this meta-analysis underscore the importance of evaluating a continuum of outcomes rather than focusing solely on abstinence in RCTs. The results suggest that reductions in stimulant use may serve as meaningful efficacy signals that could be underestimated when relying solely on stringent outcomes, such as abstinence.