Dopamine transporter and beyond: evolving targets and combination strategies in stimulant use disorder.

Abstract

Stimulant use disorder (StUD), including cocaine and methamphetamine use disorders, remains a major unmet clinical need with no approved pharmacotherapies. Despite strong mechanistic rationale, dopamine transporter (DAT)-directed strategies have largely failed to translate into consistent clinical benefit. This review evaluates the contemporary pharmacotherapy landscape for StUD, focusing on phase II/III clinical trials and systematic reviews published from January 2020- April 2026. Evidence was identified through PubMed/MEDLINE and ClinicalTrials.gov and synthesized narratively due to study heterogeneity. Therapeutic approaches are organized by mechanistic class, including DAT-targeting agents, non-DAT strategies (multi-monoaminergic, glutamatergic, serotonergic, and neuroimmune), and combination pharmacotherapy. Across studies, monotherapies generally demonstrate limited or inconsistent efficacy, although mirtazapine has shown the most consistent positive findings. Combination pharmacotherapy approaches, particularly naltrexone-bupropion, have generated some of the most encouraging clinical results to date. The role of DAT is reappraised within emerging biological frameworks and a systems-level model of addiction. Current evidence supports a reappraisal of DAT as one component of a broader neurobiology of stimulant addiction. Future therapeutic development may benefit from moving beyond DAT-centric strategies toward integrated, multi-target approaches. Combination pharmacotherapy represents a promising direction for investigation, although available evidence remains heterogeneous and requires substantial clinical validation.