The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers

Abstract

Background: Cocaine dependence involves problematic neuroadaptations that might be responsive to modulation of glutamatergic circuits. This investigation examined the effects of subanesthetic ketamine infusions on motivation for quitting cocaine and on cue-induced craving in cocaine-dependent participants, 24 hours postinfusion.

Methods: Eight volunteers with active DSM-IV cocaine dependence not seeking treatment or abstinence were entered into this crossover, double-blind trial. Three 52-min intravenous infusions were administered: ketamine (.41 mg/kg or .71 mg/kg) or lorazepam 2 mg, counterbalanced into three orderings in which ketamine .41 mg/kg always preceded the .71 mg/kg dose. Infusions were separated by 48 hours, and assessments occurred at baseline and at 24 hours postinfusion. Outcomes were change between postinfusion and preinfusion values for: 1) motivation to quit cocaine scores with the University of Rhode Island Change Assessment; and 2) sums of visual analogue scale craving ratings administered during cue exposure.

Results: Compared with the active control lorazepam, a single ketamine infusion (.41 mg/kg) led to a mean 3.9-point gain in University of Rhode Island Change Assessment (p = .012), which corresponds to an approximately 60% increase over preceding values. There was a reduction of comparable magnitude in cue-induced craving (p = .012). A subsequent ketamine infusion (.71 mg/kg) led to further reductions in cue-induced craving compared with the control. Infusions were well-tolerated.

Conclusions: Subanesthetic ketamine demonstrated promising effects on motivation to quit cocaine and on cue-induced craving, 24 hours postinfusion. Research is needed to expand on these preliminary results and to evaluate the efficacy of this intervention in clinical settings.

Trial registration: ClinicalTrials.gov NCT01790490.

Keywords: Addiction; cocaine; craving; glutamate; ketamine; motivation.

Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1. K1 Effects, 24 hours Post-Infusion

The difference across a condition between the post-infusion score and the immediately preceding score for LZP vs. K1 (change score). Bars represent mean difference; errors bars represent standard errors of the mean (SEMs). Median values are available in Findings. (a) paired comparison of URICA change scores, K1 vs. LZP, n=8, * p=0.012. (b) paired comparison of cue-induced craving (sum VAS score) change scores, K1 vs. LZP, n=8, **p=0.012. (c) independent comparison of URICA change scores following the first infusion, K1 (n=5) vs. LZP (n=3),*** p=0.051. (d) independent comparison of change scores for sum VAS scores following first infusion, p=0.1.

Figure 2

Persistent (>72 hr) K1 effects; K2 Effects, 24 hours Post-infusion: Figures (a) and (b) show baseline and post-infusion URICA and VAS scores by infusion order (1st or 2nd) for LZP (n=3) and K1 (n=3); Figures (c) and (d) show difference from preceding assessment, LZP vs K2, in subjects who received K1 in the 1st infusion (n=5) (mean values and SEMs shown; median values are provided in Findings).(a) URICA assessments for LZP were significantly different when LZP was administered 1st or 2nd, * p = 0.047, suggesting a post-K1 carry-over effect.(b) LZP order effects with sum VAS scores, ** p = 0.1.(c) paired within-subject comparison of URICA by condition, K2 vs. LZP, in those who received K1 in the first condition (n=5); non-significant, p=0.11. (d) paired within-subject comparison of sum VAS scores by condition in those who received K1 in the first infusion (n=5), K2 vs. LZP, $ p=0.046.

Figure 3. Acute Medication Effects

Acute medication effects for each condition, with bars demonstrating mean values and error bars SEMs. (a) level of dissociation assessed by the CADSS, with LZP (2±1.8) significantly different from K2 (22±7.2), *p=0.047. (b) drug liking scores, assessed by VAS, were comparable and low for all conditions.