A preliminary randomized clinical trial of naltrexone reduces striatal resting state functional connectivity in people with methamphetamine use disorder

Drug Alcohol Depend. 2018 Nov 1:192:186-192. doi: 10.1016/j.drugalcdep.2018.07.045. Epub 2018 Sep 21.


Objective: Naltrexone has been shown to attenuate craving and the subjective effects of methamphetamine. Although naltrexone has modulatory effects on neural activity at dopaminergic synapses, the effect on striatal connectivity is unclear. As methamphetamine use is associated with greater resting-state functional connectivity (RSFC) in the dopaminergic system, we examined whether extended-release naltrexone (XR-NTX) can normalize striatal connectivity and whether changes in RSFC are associated with changes in craving and methamphetamine use.

Methods: Thirty-seven participants in or seeking treatment for methamphetamine use disorder took part in this clinical trial at a university-based research clinic between May 2013 and March 2015 (Clinicaltrials.gov NCT01822132). Participants were randomized by a random number generator to a single four-week injection of XR-NTX or placebo. Functional magnetic resonance imaging (fMRI) and self-reported measures of craving and methamphetamine use were conducted before and after double-blinded randomization.

Findings: There was a significant reduction in methamphetamine use in the naltrexone group and a significant treatment-by-time interaction on RSFC between the ventral striatum, amygdala, hippocampus, and midbrain. Connectivity was significantly reduced over time in participants randomized to naltrexone but unchanged in those randomized to placebo (p < 0.05, whole-brain corrected). Interactions between treatment and changes in connectivity show that significant reductions in connectivity were associated with reductions in methamphetamine use.

Conclusions: Neurobiological deficits associated with methamphetamine use may undermine the efficacy of pharmacotherapies that directly target the dopamine reward system. Naltrexone, via antagonism of indirect mu-opioid effects on dopamine neurons, may attenuate reward system connectivity and aid in methamphetamine use treatment.

Keywords: Methamphetamine; Naltrexone; Resting-state fMRI; Striatum.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Amphetamine-Related Disorders / diagnostic imaging*
  • Amphetamine-Related Disorders / drug therapy
  • Amygdala / diagnostic imaging
  • Amygdala / drug effects
  • Amygdala / physiology
  • Delayed-Action Preparations
  • Female
  • Hippocampus / diagnostic imaging
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Humans
  • Magnetic Resonance Imaging* / methods
  • Male
  • Methamphetamine / adverse effects*
  • Middle Aged
  • Naltrexone / pharmacology
  • Naltrexone / therapeutic use*
  • Narcotic Antagonists / pharmacology
  • Narcotic Antagonists / therapeutic use*
  • Neural Pathways / diagnostic imaging
  • Neural Pathways / drug effects
  • Neural Pathways / physiology
  • Rest / physiology
  • Ventral Striatum / diagnostic imaging*
  • Ventral Striatum / drug effects
  • Ventral Striatum / physiology


  • Delayed-Action Preparations
  • Narcotic Antagonists
  • Methamphetamine
  • Naltrexone

Associated data

  • ClinicalTrials.gov/NCT01822132