Executive function moderates naltrexone effects on methamphetamine-induced craving and subjective responses

ABSTRACT

Background: Emerging evidence suggests that opioid receptor antagonists, such as naltrexone, are effective pharmacotherapies for alcohol, opioid, and possibly stimulant use disorders. It is posited that naltrexone exerts its effects, in part, by increasing functional connectivity between neural reward circuitry and frontal systems implicated in executive function. Yet no studies had examined whether executive function moderates these effects.

Objectives: This study examined whether a composite measure of executive function (EF) moderates the effect of naltrexone on craving for methamphetamine and subjective responses following infusion of the drug.

Methods: Individuals with methamphetamine use disorder (N = 30; 27% female) completed baseline neurocognitive assessments of premorbid and executive function, and an executive function factor was computed. Participants then underwent a randomized, double-blind, cross-over study of titration with naltrexone and placebo. Participants then received a 30-mg intravenous methamphetamine infusion and completed subjective response questionnaires at 8 times in the 120 minutes post-infusion.

Results: Multilevel mixed models indicated a significant EF × medication interaction, reflecting greater effects of naltrexone to decrease “desire to access the drug”, “want more of the drug”, “crave the drug”, “feel drug effects” and “feel high” in participants with low EF compared to those with high EF (Bs = .36–1.29, SEs = .14–.17, ps<0.01). These effects remained significant after controlling for premorbid cognitive functioning, baseline responses to methamphetamine, severity of methamphetamine use, and methamphetamine-related functional problems.

Conclusion: Naltrexone may be especially effective in methamphetamine-dependent individuals with low EF. Neuropsychological assessments may also provide predictive clinical utility not captured by traditional measures of substance use severity.

KEYWORDS:

• Methamphetamine
• executive function
• naltrexone
• craving
• substance use disorder

Authors contributions

LAR, KEC, and NAR were responsible for study concept, design, and data acquisition. ACL, ENG, RG, AV, and LM contributed to data cleaning, analysis, and interpretation of findings. ACL, ENG, and AV drafted the manuscript. PS and EDL provided critical revision of the manuscript. All authors critically reviewed content and approved final version for publication.

Disclosure of interest

LAR has received study medication from Pfizer and Medicinova and consulted for GSK. The authors report no other conflict of interest.

Additional information

Funding

This work was supported bythe National Institute on Drug Abuse under Grant [R21DA029831] and UCLA’s training Grants [5T32DA024635 & 4T32DA007272]; the National Institutes of Health NCATS: UCLA’s CTSI Grant [UL1TR001881]; the Tobacco Related Disease Research Program Grants [T29DT0371 &T30DT0950]; the National Institute on Alcohol Abuse and Alcoholism Grants [F32AA027699, 3R01AA026190-02S1 & K24AA025704]; UCLA’s Thomas P. and Katherine K. Pike Chair in Addiction Studies; UCLA’s Greene Family Trust.