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.

Pharmacological Treatment of Methamphetamine/Amphetamine Dependence: A Systematic Review

“…Nine of the 43 studies (21%) enrolled only males [24,29,30,34,46,52,55,57,58], however not all of these were by design. One study [45] did not report the sample by those randomised, only by completers (in a non-intention-to-treat analysis) and so the total randomised figure of men versus women was not able to be determined based on randomisation (authors did not respond to a request for further data).…”

“…Study completion rates were low, with studies reporting the proportion of the sample who did not complete the protocol as 38.4% of the total randomised. Eighty-three percent of studies analysed their results by intention-totreat, while five (12%) [33,46,53,57,61] were unclear in this regard and two (5%) [24,45] did not. Females were underrepresented in the data, being only 29.7% of the total participants.…”

“…The studies were overwhelmingly government or academic funded (65.1%, n = 28) [24-28, 30, 32, 33, 35-42, 44, 47, 50, 51, 54, 55, 57, 58, 60, 63, 64, 66]. Ten studies (23.3%) were funded by pharmaceutical companies, or the study drug(s) were provided by a pharmaceutical company, or a mix of funding and drugs were provided by a pharmaceutical company [29,31,45,46,48,49,56,59,61,65]. Four studies (9.3%) did not state their funding source [43,52,53,62], and one study (2.3%) received no funding [34].…”

“…There was no difference in MA use by UDS in the treatment arm compared with placebo in the extended-release studies [29,56]. One study of naltrexone (a single 4-week injection) reported on 37 of 52 randomised participants and found a reduction in past 30-day MA use, but relied entirely on self-report [45], and there was a crossover in primary outcome measures given the past 30-day questionnaires were administered within 3 weeks of each other. One outpatient study of AMPH-dependent participants in Sweden reported fewer AMPH-positive UDS in the naltrexone (50 mg po OD) arm compared with placebo [42], a result shared by the study examining naltrexone implants (1000 mg subcutaneously) administered to Russian participants with AMPH dependence [63].…”

Immunopharmacotherapeutic advancements in addressing methamphetamine abuse

“…7,20 Clinical trials examining dopaminergic agents, serotonergic agents, g-aminobutyric acid agents, glutamatergic agents, cholinesterase inhibitors, benzoquinolizine derivatives, opioid agents, and nicotinic agents have been observed with varying results in regards to their effects on METH users. 7,13,21 Dopamine agonists, modafinil [22][23][24][25][26] and bupropion, [27][28][29][30][31][32][33][34] have demonstrated beneficial responses in METH-dependent patients, while naltrexone, [35][36][37][38][39] an opioid antagonist, seemed to reduce amphetamine's reinforcement effects. Despite the promising start, naltrexone revealed conflicting results with some studies showing no differences in METH use between treatment and placebo groups.…”