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

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

Author information

1
Department of Psychiatry, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA; Department of Behavioral Neuroscience, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA; Research and Development Service, Veterans Affairs Portland Health Care System, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, USA; Methamphetamine Abuse Research Center, Oregon Health and Science University and Veterans Affairs Portland Health Care System, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA. Electronic address: kohno@ohsu.edu.
2
Department of Psychiatry, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA; Research and Development Service, Veterans Affairs Portland Health Care System, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, USA.
3
Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA; Advanced Imaging Research Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
4
Department of Psychiatry, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA; Department of Behavioral Neuroscience, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA; Research and Development Service, Veterans Affairs Portland Health Care System, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, USA; Mental Health Division, Veterans Affairs Portland Health Care System, 3710 SW US Veterans Hospital Rd., Portland, OR 97239, USA; Methamphetamine Abuse Research Center, Oregon Health and Science University and Veterans Affairs Portland Health Care System, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
5
Section of Addiction Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.

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

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