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

Abstract

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.

Conflict of interest statement

Conflict of Interest

No conflict declared.

Copyright © 2018. Published by Elsevier B.V.

Figures

Figure 1.. Study design.

Research assistants pre-screened 220 individuals, 104 of whom were eligible for participation. The most common reasons for exclusion at pre-screening were polysubstance use, clean from methamphetamine for too long, and MRI contraindications. Of the 104 eligible participants, 52 were randomized. Three eligible participants declined randomization. Of those randomized, 37 completed baseline and follow-up assessments that were available for analysis. Reasons for exclusion from analysis of those randomized included scheduling conflicts/no-shows and MRI confounds (artifacts, motion, did not complete task, etc.).

Figure 2.. Group by time interaction on methamphetamine use.

A two-way repeated measures ANOVA was conducted to examine whether any change in MA use is the result of an interaction between two factors: Treatment Group (placebo group or naltrexone group) and Time (Visit 1 or Visit 2). MA use was the dependent variable and the main effect of Group (Placebo group, XTR-NTX group) and Time (visit 1, visit 2) and the interaction of Group and Time was tested. The Group x Time interaction shows that these two factors interact to produce changes in MA use, where the XTR-NTX group shows reductions in MA use from Visit 1 to Visit 2 (F(2,35)=4.80, p =0.04.

Figure 3.. Treatment by time interaction on ventral striatal RSFC.

The naltrexone group exhibited reduced connectivity between ventral striatum, amygdala, hippocampus and midbrain between scan 1 and scan 2 (p

Figure 4.. Relationship between change in ventral striatal RSFC and change in MA use.

Scatter plot shows the relationship between changes in RSFC between ventral striatum and amygdala/hippocampus and changes in days of MA use across all subjects. An increase in RSFC was associated with an increase in the number of days of MA use.