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

This active placebo-controlled, double-blind, randomized, crossover, within-subjects study (n=20) investigated the effects of ketamine (49.7mg/70kg) on cocaine self-administration amongst medically healthy, non-treatment-seeking cocaine-dependent individuals. Faced with the choice to using cocaine (25mg) or receiving money ($11) after a single ketamine infusion, participants decreased cocaine self-administration by 67% and some of them maintained abstinence for at least 2 weeks after.

Abstract

Introduction: Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Converging evidence suggests a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine may work to correct these neuroadaptations and restore motivation for non-drug rewards.

Methods: Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs money later,

Results: we found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 h post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. #

Discussion: These findings signal new directions in medication development for substance use disorders.”

Authors: Elias Dakwar, Carl L. Hart, Frances R. Levin, Edward V. Nunes & Richard W. Foltin 

Summary

INTRODUCTION

Substance use disorders are characterized by progressively uncontrollable drug use despite negative consequences, and may be precipitated by neuroplastic alterations in striatal and prefrontal glutamate neurotransmission. These alterations may be implicated in several functional alterations in individuals with substance use disorders.

Though the reinforcing effects of cocaine have been studied extensively in laboratory animals, they have proven resistant to pharmacotherapy in human research. The only agents found to reduce cocaine self-administration are stimulants such as modafinil and amphetamine.

Recent clinical research indicates that ketamine, a widely used dissociative anesthetic, can improve depressive and anxiety disorders, as well as drug dependence. However, it is not clear whether these effects are new evidence of ketamine targeting dependence-related deficits or if they are simply extensions of its recognized impact on comparable subjective states.

We modified an established laboratory model of drug self-administration to assess the effect of ketamine on cocaine use. We predicted that ketamine would significantly decrease the number of cocaine choices, ranging from 0 to 5, ascertained at around 28 h post infusion.

Overview

Twenty non-depressed, cocaine-dependent individuals were hospitalized up to three times for 6 days at a time. They received 52-min sub-anesthetic infusions of ketamine or midazolam under double-blind conditions, and no psychotherapy or behavioral treatment was provided.

Participants

We recruited participants by word of mouth, advertising and referral. Eligible patients underwent a standardized diagnostic evaluation (SCID), a comprehensive blood cell assessment with differential, electrolyte panel including liver function tests, pseudocholinesterase levels to assess for appropriate metabolism of cocaine, and pregnancy tests for females.

Cocaine self-administration

Various protections were in place to reduce the risks associated with cocaine administration. A dose of 25 mg of free-base cocaine was used in this study, which was safely administered in prior studies with minimal adverse effects.

Two cocaine doses were administered starting at 1 pm on day 3 of each hospitalization, following a 2-day washout period. On day 5, participants received 11 dollars or 25 mg of free-base cocaine.

All cocaine administrations occurred 14 min apart, and participants received ratings after each dose was administered. There were no drug interactions between cocaine and ketamine or midazolam.

Infusion procedures

Inpatient Phase 1 participants received a sham infusion, and inpatient Phases 2 and 3 participants received two counter-balanced active infusions. All infusions were given in a highly controlled inpatient setting, and participants were informed throughout the study that they may possibly receive any of various substances.

Active control (saline bolus followed by midazolam 0.025 mg kg 1/min infused over 50 min) or ketamine hydrochloride (0.11 mg kg 1/min infused over 50 min) were administered at around 11 am on day 4 to ensure blinding.

Psychological preparation and relaxation exercises reduce anxiety during sub-anesthetic ketamine administration, and a Clinician Administered Dissociative States Scale is helpful in assessing subjective effects.

Compensation

Participants were given $5 for each screening visit, $20 for screening itself, $30 a day for the inpatient phase, and $60 a day for the final completion bonus. They were also provided $25 for each follow-up visit.

Statistical analyses

The distribution of values in dependent variables was normal using Shapiro-Wilk tests for all conditions. SAS27 was used to perform all tests, and paired t-tests were conducted for primary outcomes and non-reactivity scores.

Participants

26 participants were enrolled, 4 were removed for not choosing cocaine sufficiently at baseline, 1 was removed for seeking treatment.

All participants tolerated study procedures without notable adverse effects. There were no persistent dissociative or other adverse effects, and participants did not report significant changes in their pre-infusion responses to cocaine administration.

Two participants maintained abstinence in follow-up after receiving ketamine during the second hospitalization, which is consistent with prior data suggesting that ketamine promotes abstinence in previously disinterested individuals.4

Subjective effects of ketamine and midazolam infusions and cocaine administration were similar. Ketamine led to significantly greater acute dissociation than midazolam and saline, while midazolam led to greater acute dissociation than saline.

Non-reactivity

Ketamine significantly increased the non-reactivity subscale of the Five Facet Mindfulness Questionnaire, lasting at least 48 h post infusion.

DISCUSSION

This investigation of the N-methyl-D-aspartate receptor antagonist ketamine suggests that it may have enduring effects on problematic behavior and decision-making, alongside the previously reported effects on subjective states, such as dysphoria.

Ketamine reduces cocaine self-administration by targeting two important adaptations: drug craving and the disproportionate valuation of immediate drug over delayed non-drug rewards. These findings have important implications for substance use disorders more generally.

This trial was different from previous investigations because the participants were not simply cocaine users exceeding minimum use criteria, but also met DSM-IV criteria for cocaine dependence. Additionally, a single-blind sham condition was introduced to ascertain baseline cocaine self-administration.

Ketamine’s anti-addiction effects resemble those of its anti-depressant effects, and suggest that similar downstream pro-plasticity and modulatory mechanisms may be involved in the effects of ketamine on affective, stress-related and substance use disorders.

Ketamine’s rapid and persistent effects suggest a role in initiating abstinence, but it has demonstrated abuse liability. It may be feasibly integrated into the treatment of substance use disorders by developing comparable compounds.

Ketamine may be an effective treatment for cocaine use disorders, but sustaining efficacy is a challenge. A behavioral treatment platform may be important for further targeting dependence-related deficits and facilitating behavioral modification.

Study details

Topics studied
Addiction

Study characteristics
Placebo-Controlled Active Placebo Double-Blind Within-Subject Randomized

Participants
20

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