Cocaine self-administration disrupted by the N-methyl-D-aspartate receptor antagonist ketamine: a randomized, crossover trial

Introduction

Repeated drug use is thought to drive sustained neural adaptations—principally in glutamatergic transmission in prefrontal and striatal circuits—that reduce sensitivity to non-drug rewards and increase craving, impulsivity and cue reactivity. Although animal studies have shown that modulation of the N-methyl-D-aspartate (NMDA) receptor can disrupt cocaine reinforcement, prior NMDA-targeting agents have not demonstrated clear benefit in humans. Recent clinical work has shown that a single sub‑anaesthetic intravenous infusion of ketamine produces rapid and sustained antidepressant and anxiolytic effects, effects that have been linked to promotion of prefrontal plasticity and downstream factors such as brain‑derived neurotrophic factor; preliminary self-report data also suggested ketamine might reduce craving and increase motivation for non‑drug rewards in people with substance dependence. This trial set out to test whether a single sub‑anaesthetic ketamine infusion, compared with an active control (midazolam), would reduce cocaine self‑administration and alter dependence‑related behaviours at a time when ketamine’s psychiatric effects typically peak (around 24–72 h). Using a randomised, double‑blind, counterbalanced crossover design and a laboratory choice paradigm that contrasts immediate cocaine (25 mg per choice) with delayed monetary reward ($11), the investigators hypothesised that ketamine would reduce the number of cocaine choices assessed at approximately 28 h post‑infusion and would produce persistent changes in craving, reactivity and naturalistic cocaine use.