The Effects of Naltrexone on Neural Responses to Methamphetamine Cues

Background: No medications are approved by the FDA for the treatment of methamphetamine use disorders; yet, preclinical and clinical evidence advances naltrexone as a promising candidate. This dissertation investigated the effects of naltrexone on functional magnetic resonance imaging (fMRI) measures of functional connectivity during methamphetamine cue processing and subjective craving for methamphetamine.Methods: A final sample of 23 non-treatment seeking individuals with methamphetamine use disorders (74% male, mean age=34.70 [SD=8.95]) were enrolled within a randomized, placebo controlled, within-subject design and underwent two blood-oxygen-level dependent (BOLD) methamphetamine cue-reactivity paradigms following three days of naltrexone treatment (50mg) and matched time for placebo. fMRI analyses tested naltrexone-induced differences in BOLD activation associated with methamphetamine and control cues, resting-state cerebral blood flow (CBF), and functional connectivity (using psychophysiological interaction analysis) during methamphetamine cue processing. Results: Analyses revealed that (1) the novel methamphetamine cues task employed was successful in eliciting cue-induced craving and relevant regional activation, (2) greater subjective methamphetamine craving is related to enhanced recruitment of prefrontal regions, (3) naltrexone moderates methamphetamine cue-reactivity in sensorimotor regions, (4) the BOLD results are not a reflection of CBF changes induced by naltrexone, (5) reduced activation of sensorimotor regions during methamphetamine cue processing by naltrexone is related to functional connectivity of dorsal striatum, ventral tegmental area (VTA), periaqueductal gray, and precuneus with visual, sensory, and motor-related regions, (6) naltrexone enhances dorsal striatum, VTA, and sensorimotor region functional connectivity with the frontal cortex during methamphetamine cues processing , and (7) naltrexone weakens the associations between subjective craving and precuneus functional connectivity with sensorimotor regions and strengthens the associations between subjective craving and dorsal striatum and precuneus connectivity with frontal regions during methamphetamine cue processing, as compared to placebo. Conclusions: The results of this study provide the first evidence of naltrexone-induced changes in BOLD measures of methamphetamine cue-induced craving. The results suggest that naltrexone may be functioning to reduce the salience of the methamphetamine cues by reducing sensorimotor processing and integration, and by engaging greater frontal regulation of salience attribution via pathways linking the dorsal striatum, midbrain, and precuneus to frontal, dorsal striatal, and sensorimotor regions during cue processing