R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder1

Pharmacol Biochem Behav. 2020 Jul:194:172927. doi: 10.1016/j.pbb.2020.172927. Epub 2020 Apr 22.


Substance abuse disorder continues to have devastating consequences for individuals and society and current therapies are not sufficient to provide the magnitude of medical impact required. Although some evidence suggests the use of ketamine in treating various substance use related- symptoms, its adverse event profile including dissociation, dysphoria, and abuse liability limit its potential as a therapy. Here, we outline experiments to test our hypothesis that (R)-ketamine can both alleviate withdrawal symptoms and produce effects that help sustain abstinence. In morphine-dependent rats, (R)-ketamine alleviated naloxone-precipitated withdrawal signs. (R)-ketamine also blocked morphine-induced place preference in mice without inducing place preference on its own. We also evaluated whether (R)-ketamine would induce anhedonia, a counter-indicated effect for a drug abuse treatment agent. S-(+)- but not R-(-)-ketamine produced anhedonia-like responses in rats that electrically self-stimulated the medial forebrain bundle (ICSS). However, time-course studies of ICSS are needed to fully appreciate these differences. These data begin to support the claim that (R)-ketamine will dampen withdrawal symptoms and drug liking, factors known to contribute to the cycle of drug addiction. In addition, these data suggest that (R)-ketamine would not produce negative mood or anhedonia that could interfere with treatment. It is suggested that continued investigation of (R)-ketamine as a novel therapeutic for substance abuse disorder be given consideration by the preclinical and clinical research communities. This suggestion is further encouraged by a recent report on the efficacy of (R)-ketamine in treatment-resistant depressed patients at a dose with little measurable dissociative side-effects.

MeSH terms

  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / pharmacology
  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Humans
  • Ketamine / administration & dosage
  • Ketamine / pharmacology*
  • Male
  • Medial Forebrain Bundle / drug effects
  • Mice
  • Morphine / administration & dosage
  • Morphine / pharmacology*
  • Morphine Dependence / drug therapy
  • Morphine Dependence / metabolism
  • Naloxone / pharmacology
  • Opioid-Related Disorders / drug therapy*
  • Opioid-Related Disorders / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Self Stimulation / drug effects
  • Substance Withdrawal Syndrome / drug therapy*
  • Substance Withdrawal Syndrome / metabolism


  • Analgesics, Opioid
  • Antidepressive Agents
  • Naloxone
  • Esketamine
  • Ketamine
  • Morphine