Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review

This systematic review (2018) examines the efficacy of ketamine treatment for substance use disorder and summarizes evidence which suggests that ketamine may improve the ability to establish and maintain abstinence.

Abstract

Background: Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs.

Methods: A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018.

Results: Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials.

Conclusion: These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research.”

Authors: Jennifer L. Jones, Camilo F. Mateus, Robert J. Malcolm, Kathleen T. Brady & Sudie E. Back

Summary

INTRODUCTION

Alcohol and illicit drug use disorders are an escalating and complex global public health burden. Mortality rates have risen to epidemic proportions in some countries due to increasing prevalence of opioid use, and withdrawal symptoms can be severe.

Despite the high prevalence and substantial societal burden of substance use disorders, effective pharmacotherapy options are limited. Non-FDA approved medications are tried as standalone pharmacotherapies and in conjunction with behavioral interventions.

Ketamine is a potent, non-competitive NMDA receptor antagonist that has been shown to induce ultra-rapid remission of severe depression and suicidal ideation using sub-anesthetic dosages. These effects may improve ability to learn new behaviors and may be beneficial in the treatment of SUDs.

METHODS

A comprehensive search was conducted in the PubMed/MEDLINE, Scopus and clinicaltrials.gov databases from 1996 to 2018 for studies evaluating the efficacy of ketamine in humans for the treatment of substance use disorders or the treatment of withdrawal symptoms from a substance of abuse.

RESULTS

We identified seven completed relevant clinical studies and six ongoing relevant clinical trials evaluating the efficacy of ketamine in the treatment of cocaine use disorders.

Effects on Cocaine Use

Two published studies have evaluated the efficacy of ketamine for cocaine use disorder. The studies used a three-arm crossover design and evaluated the effects of low and high doses of ketamine on motivation to quit cocaine and on cravings. Ketamine increased motivation to quit cocaine over lorazepam and reduced cocaine craving on the VAS by 168 mm (a 60% change, p = 0.012). Ketamine also improved URICA scores and reduced frequency and amount of cocaine use in the follow-up period.

In a related follow-up study, 20 non-treatment seeking cocaine dependent participants received a single infusion of 0.71 mg/kg ketamine with 0.025 mg/kg midazolam as the active control. The rates of cocaine self-administration were reduced by 66%.

Effects on Opioid Use Disorder and Opioid Withdrawal

Two studies have evaluated the efficacy of ketamine for opioid use disorder. The high dose ketamine group achieved greater abstinence rates and had a more enduring decline in craving than the low dose ketamine group. In a follow-up study, Krupitsky et al. (22) found that repeated sessions of ketamine-assisted psychotherapy were more effective than single sessions in increasing abstinence from heroin.

A randomized controlled trial showed that ketamine could suppress physiologic response to opiate withdrawal. There were no significant group differences at 4 months on secondary outcome measures.

Effects on Alcohol Use Disorder and Alcohol Withdrawal Symptoms

Krupitsky et al. (24) found that ketamine-assisted psychotherapy reduced benzodiazepine requirements in patients with alcohol use disorder who underwent inpatient detoxification and residential treatment.

Ongoing Studies

A randomized controlled trial evaluating the efficacy of ketamine in alcohol use disorder is in progress. The study will compare ketamine with saline placebo and manualized relapse prevention psychotherapy with simple education about alcohol effects.

A randomized controlled trial of 40 subjects will evaluate the efficacy of ketamine in conjunction with motivational enhancement psychotherapy in reducing alcohol use.

A third study will evaluate the effects of ketamine on 65 subjects with alcohol use disorder and major depressive disorder. The study will use IV ketamine and 2 injections of naltrexone or saline placebo spaced 1 month apart.

Elias Dakwar, MD is leading a randomized, placebo-controlled trial of 150 subjects to evaluate the efficacy of ketamine in increasing ability to achieve and maintain abstinence from cocaine.

100 opioid users will be hospitalized for up to 5 days for detoxification followed by naltrexone initiation and 12 weeks of motivational enhancement therapy and mindfulness based relapse prevention psychotherapy.

A proof-of-concept study will use 0.71 mg/kg ketamine to treat cannabis use disorder and will assess abstinence rates at baseline and 6 week follow-up.

DISCUSSION AND FUTURE DIRECTIONS

Ketamine may improve the ability to establish and maintain abstinence in substance use disorders. However, these preliminary studies have several important limitations, including small sample sizes, narrow demographic sectors, and limited follow-up windows.

A number of important questions remain, including whether baseline motivation, desire to quit, or duration of prior abstinence influences the effectiveness of ketamine in achieving and maintaining abstinence.

Ketamine’s effects on withdrawal states are particularly important to further investigate. It has been shown to improve symptoms of opiate withdrawal, but more research is needed to determine whether it improves symptoms independent of rapid opioid induction under general anesthesia.

The addition of behavioral interventions to ketamine pharmacotherapy is understudied, but may help enhance long-term treatment outcomes.

Ketamine produces mild dissociative psychoactive effects at sub-anesthetic dosing, but recent studies suggest that therapeutic benefit may be mediated by participant perception of these psychoactive effects. Further studies are urgently needed to evaluate the therapeutic effects of ketamine in the treatment of substance use disorders.

AUTHOR CONTRIBUTIONS

JJ designed the strategy for the review, CM drafted the manuscript, RM, KB, and SB provided content and editorial oversight.