Mediators of Treatment Response in Clinical Trial of Naltrexone and Bupropion for Methamphetamine Use Disorder: A Longitudinal Mediation Analysis

BackgroundThe mechanisms underlying pharmacological treatments for stimulant use disorders are poorly understood. This study examined whether changes in craving, depressive symptoms, and/or impulsivity mediate treatment effect in pharmacotherapy with combined naltrexone and bupropion for methamphetamine use disorder. MethodsThe study was based on secondary analysis of data from the Accelerated Development of Additive Pharmacotherapy Treatment for methamphetamine disorder (ADAPT-2) trial which randomized adults with methamphetamine use disorder to combined treatment with injectable naltrexone (380 mg every three weeks) plus oral bupropion (450 mg daily) versus placebo. A total of 403 adults with methamphetamine use disorder participated in the first Stage; 225 of first Stage participants in the placebo arm who did not respond to treatment were re-randomized in the second Stage. Mediation effects were examined using longitudinal multi-level structural equation modeling. ResultsNaltrexone-bupropion treatment was associated with decreases in drug use, craving, depressive symptoms, and impulsivity. The indirect effect of treatment through change in craving was significant (self-reported use=-0.21, 95% Credible Interval [CrI]=-0.35, -0.09; drug screen-ascertained use=-0.36, 95% CrI=-0.63, -0.16). Change in craving mediated 56% of the treatment effect on self-reported use and 45% of the effect on drug screen-ascertained use. Estimates for mediated effects for depressive symptoms and impulsivity were smaller in magnitude and non-significant. ConclusionReduction in craving mediates the effect of naltrexone-bupropion pharmacotherapy in methamphetamine use disorder. Craving may serve as a surrogate measure of treatment efficacy in short-term trials and help identify promising candidate medications to be tested in larger and longer-term trials. Trial RegistrationClinicalTrials.gov number: NCT03078075.