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

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.

This was a randomised, double‑blind, counterbalanced crossover inpatient trial in cocaine‑dependent, non‑depressed adults who were not seeking treatment. Participants underwent up to three separate 6‑day hospitalisations, each separated by 2 weeks. The first inpatient phase always began with a single‑blind saline sham infusion to identify and exclude individuals who did not robustly choose cocaine at baseline. In the second and third hospitalisations participants were randomised 1:1 to receive either a ketamine infusion or an active control infusion (midazolam) in counterbalanced order. Eligibility required age 21–55 years, medical fitness and DSM‑IV cocaine dependence with minimum use criteria (at least two occasions of free‑base cocaine use per week at >$40 each). Exclusion criteria included physiological dependence on certain other substances (opioids, alcohol, benzodiazepines), history of psychosis or dissociative symptoms, current depressive or anxiety disorders, first‑degree family history of psychosis, marked obesity (BMI >35), and cardiovascular or pulmonary disease. Screening included toxicology, structured diagnostic interview (SCID), psychiatric and medical evaluation and standard laboratory tests. Each 6‑day hospitalisation followed the same schedule: a 2‑day washout, a sample session on day 3 (two obligatory smoked doses of free‑base cocaine, 25 mg each, to establish value and heighten craving), the infusion on day 4, a choice session on day 5 (five repeated choices between 25 mg cocaine and $11 starting ~28 h after infusion), and discharge on day 6. Cocaine choices occurred 14 min apart, with the choice recorded at the start and 7 min into each interval. Active infusions were prepared as a 2‑min bolus followed by a 50‑min slow drip: ketamine hydrochloride total dose 0.71 mg kg‑1 (0.11 mg kg‑1 bolus + 0.60 mg kg‑1 infusion) and midazolam 0.025 mg kg‑1 (preceded by a 2‑min saline bolus). The initial saline sham also served as baseline for percent reduction calculations. Safety monitoring included continuous ECG, automated blood pressure, oxygen saturation and medical coverage during and for 2 h after cocaine and study drug administrations. Psychological preparation and relaxation exercises were used around infusions. Follow‑up entailed thrice weekly visits for 2 weeks after each hospitalisation with urine toxicology and assessments of drug use, craving and side effects. The primary outcome was the number of cocaine choices at ~28 h post‑infusion; normality of dependent variables was assessed with Shapiro–Wilk tests. Primary and selected secondary comparisons used paired t‑tests and repeated‑measures ANOVA as appropriate, with two‑tailed α = 0.05; SAS 9.3 (reported as SAS 27 in the extraction) was used for analyses. The study was powered to detect a difference of at least one cocaine choice between active conditions.

Twenty of 26 enrolled participants completed the protocol and formed the final sample after exclusions (four excluded for insufficient baseline cocaine choices following saline, one for non‑compliance, one for seeking treatment). The final sample was predominantly African American, largely unemployed and showed high baseline cocaine use. All participants tolerated procedures without notable adverse medical events. Acute subjective effects: ketamine produced significantly greater acute dissociation during the infusion (measured by the Clinician‑Administered Dissociative States Scale) than midazolam and saline (P < 0.001), and midazolam produced greater acute dissociation than saline (P < 0.01). There were no significant differences between conditions on persistent dissociative effects assessed at least 24 h post‑infusion (Dissociative Experiences Scale). Ratings of the sample cocaine doses (potency and quality) did not differ across infusion conditions, indicating consistent subjective effects of the sample doses across hospitalisations. Primary outcome — cocaine self‑administration: for the primary analysis, 18 participants were included (two participants who maintained abstinence after ketamine and were ineligible for a third hospitalisation were retained in abstinence comparisons but excluded from the choice analysis). Ketamine reduced cocaine choices at ~28 h post‑infusion to an average of 1.61 choices, compared with 4.33 choices after midazolam. This difference was highly significant (t(17) = 5.43, P < 0.0001) and represented a 67% reduction relative to post‑saline baseline. Naturalistic cocaine use and craving: during the 2‑week follow‑up after each active condition, ketamine produced an initial reduction in cocaine use relative to baseline, but this advantage did not persist beyond several days and did not remain significantly different from midazolam over the monitoring period. Craving, assessed by a 100‑mm visual analogue scale beginning 24 h post‑infusion, showed a similar pattern: a significant early reduction following ketamine that was not sustained throughout follow‑up. Non‑reactivity: ketamine increased scores on the non‑reactivity subscale of the Five Facet Mindfulness Questionnaire, which assesses tolerance of distress without engaging in problematic behaviour. Mean non‑reactivity was 3.46 after ketamine versus 2.92 after midazolam (out of 5), a statistically significant difference (t(17) = -2.39, P < 0.05) that lasted at least 48 h. Abstinence: two participants who received ketamine during the second hospitalisation maintained abstinence during follow‑up for at least 2 weeks; no participant maintained abstinence after midazolam in the corresponding comparison (2/10 post‑ketamine vs 0/10 post‑midazolam). No persistent adverse effects were reported; acute dissociation resolved within about 30 min post‑infusion.

Dakwar and colleagues interpret these findings as the first demonstration in humans that a single sub‑anaesthetic ketamine infusion can substantially reduce cocaine self‑administration under controlled laboratory conditions, producing the largest such reduction reported to date. They emphasise that this effect is distinct from the modest effects previously observed with stimulant agonists, and suggest ketamine’s benefits may derive from rapid promotion of prefrontal plasticity and downstream processes (for example, brain‑derived neurotrophic factor and mTOR pathways) that correct dependence‑related neuroadaptations. The authors link the persistence of behavioural effects beyond the pharmacokinetic presence of ketamine and its metabolites to mechanisms similar to those proposed for ketamine’s antidepressant actions, noting convergent preclinical evidence that the drug can normalise reward‑related neurotransmission and reduce drug‑related behaviour via pro‑plasticity signalling. Improvements in non‑reactivity and early reductions in craving are highlighted as candidate mediators of reduced cocaine choice, and the brief abstinence observed in two participants is presented as consistent with a role for ketamine in initiating abstinence in disinterested individuals. Limitations acknowledged by the investigators include the highly controlled laboratory setting and a diagnostically and demographically relatively homogeneous sample, which may limit generalisability. They also note that the trial was not designed to establish neuronal mechanisms and that the sustained effects require further characterisation. Practical issues for clinical translation are discussed: ketamine’s psychoactive and abuse liability emphasise the need for medical administration (slow‑drip intravenous), possible frameworks to manage acute effects, and consideration of maintenance strategies such as serial infusions or adjunctive medications. The authors also propose that combining ketamine with behavioural interventions that train non‑reactivity (for example, relapse prevention strategies) could help translate short‑term neurobiological effects into longer‑term behavioural change. In conclusion, the study team calls for replication, mechanistic research and investigation of how ketamine might be integrated into treatment platforms for substance use disorders, arguing that these results open new directions for medication development aimed at shared neuroadaptations across affective and addictive disorders.