Does lisdexamfetamine maintenance help or hinder cognitive function in people with current methamphetamine dependence?

Background: Meta-analyses have identified impairments of moderate magnitude in cognitive function in people with methamphetamine dependence across multiple domains (verbal learning, attention, working memory and inhibitory control). Such cognitive impairments are associated with poorer treatment outcomes. Acute doses of stimulant medications can improve cognition in both drug-naïve control participants and those with stimulant dependence. It is possible that maintenance treatment with stimulant medications may increase tonic dopaminergic activity and stabilise cognitive function among people with methamphetamine dependence.

Methods: Secondary analysis of cognitive functioning during a double-blind, randomised placebo-controlled outpatient trial of lisdexamfetamine for participants with current methamphetamine dependence (ACTRN12617000657325). The active condition was 250mg lisdexamfetamine with a one-week induction and 12 week maintenance phase; assessments were conducted at weeks 1, 5, 9, 13 and 19. Outcomes included pencil and paper-based assessments of switching (Trails) and verbal learning (RAVLT), and computer-based assessments of processing speed (Digit Symbol), sustained attention (Rapid Visual Information Processing), working memory (N-Back), inhibitory control (Flankers). Covariates included general cognitive function (WTAR), days methamphetamine use and ADHD symptoms (WURS). 

Results: 116 participants (n=60 placebo; n=56 active) were included in this secondary analysis (of 155 enrolled) due to COVID restrictions during the trial limiting cognitive assessments. Analyses were conducted using mixed models using all available data. Most participants in both groups continued regular methamphetamine use during the trial (88% of active condition participants retained at week 13 had used in the past month; 50% using 14/28 days or more). Analyses of Trails and RAVLT data did not identify any significant advantage in processing speed, switching or verbal learning in participants while maintained on lisdexamfetamine over placebo participants. These effects were robust even when controlling for general cognition, days of methamphetamine use and ADHD symptoms. 

Conclusions: Analysis of pencil and paper measures of cognition (Trails and RAVLT) suggest that maintenance treatment with lisdexamfetamine did not improve these aspects of cognitive function in this trial. Given the modest reduction in methamphetamine use over the course of the trial it is possible that the continued phasic stimulant use in addition to the tonic maintenance dose may have undermined any potential ameliorative effects of lisdexamfetamine.