Preclinical Assessment of Lisdexamfetamine as an Agonist Medication Candidate for Cocaine Addiction: Effects in Rhesus Monkeys Trained to Discriminate Cocaine or to Self-Administer Cocaine in a Cocaine Versus Food Choice Procedure

Abstract

Background:Chronic amphetamine treatment decreases cocaine consumption in preclinical and human laboratory studies and in clinical trials. Lisdexamfetamine is an amphetamine prodrug in which L-lysine is conjugated to the terminal nitrogen of d-amphetamine. Prodrugs may be advantageous relative to their active metabolites due to slower onsets and longer durations of action; however, lisdexamfetamine treatment’s efficacy in decreasing cocaine consumption is unknown.Methods:This study compared lisdexamfetamine and d-amphetamine effects in rhesus monkeys using two behavioral procedures: (1) a cocaine discrimination procedure (training dose = 0.32mg/kg cocaine, i.m.); and (2) a cocaine-versus-food choice self-administration procedure.Results:In the cocaine-discrimination procedure, lisdexamfetamine (0.32–3.2mg/kg, i.m.) substituted for cocaine with lower potency, slower onset, and longer duration of action than d-amphetamine (0.032–0.32mg/kg, i.m.). Consistent with the function of lisdexamfetamine as an inactive prodrug for amphetamine, the time course of lisdexamfetamine effects was related to d-amphetamine plasma levels by a counter-clockwise hysteresis loop. In the choice procedure, cocaine (0–0.1mg/kg/injection, i.v.) and food (1g banana-flavored pellets) were concurrently available, and cocaine maintained a dose-dependent increase in cocaine choice under baseline conditions. Treatment for 7 consecutive days with lisdexamfetamine (0.32–3.2mg/kg/day, i.m.) or d-amphetamine (0.032–0.1mg/kg/h, i.v.) produced similar dose-dependent rightward shifts in cocaine dose-effect curves and decreases in preference for 0.032mg/kg/injection cocaine.Conclusions:Lisdexamfetamine has a slower onset and longer duration of action than amphetamine but retains amphetamine’s efficacy to reduce the choice of cocaine in rhesus monkeys. These results support further consideration of lisdexamfetamine as an agonist-based medication candidate for cocaine addiction.

Maintenance on naltrexone + amphetamine decreases cocaine-vs.-food choice in male rhesus monkeys

“…Additionally, for experiments with amphetamine ± naltrexone, a Tukey HSD test was performed to compare effects of saline treatment, amphetamine alone treatment, and amphetamine + naltrexone treatment within a unit cocaine dose of 0.032 mg/kg/injection cocaine. This unit dose was chosen for these comparisons because previous results from our laboratory have demonstrated that this unit cocaine dose is most sensitive to treatment with amphetamine and other monoamine transporter substrates [Banks, 2011; Banks, 2013b; Banks, 2015]. This statistical approach has also been utilized in other preclinical cocaine vs. food choice studies [Czoty, 2005].…”

Pilot study of the effects of lisdexamfetamine on cocaine use: A randomized, double-blind, placebo-controlled trial

“…Importantly, this relationship cannot be interpreted as causal since the full randomized sample was not analyzed. Yet, the possible efficacy of LDX is suggested and further supported by Banks et al (2015) preclinical results. Finally, as noted below, FDA dosing constraints existed for this preliminary proof of concept study.…”

“…Still, most recently, Levin et al (2015) reported dose related concurrent reduction in cocaine use and ADHD in a population with comorbid conditions. In sum, amphetamine analogues are the only agents for which significant benefits have been observed and the “prodrug” strategy represented by LDX may be the current optimal approach (e.g., Banks et al 2015) while pursuing development of medications with enhanced risk-benefit profiles for cocaine dependence.…”

“…Most recently, researchers have identified more specifically the hydrolysis pathways determining stability of dose exposure, longer duration of action, and lowered plasma concentrations, along with longer time to peak concentration compared to immediate release dextroamphetamine, notably when delivered by routes other than oral (e.g., IV; Ermer et al, 2010; Jasinski and Krishnan, 2009a, b; Wigal et al, 2010). Studies conducted in rhesus monkeys found that LDX had a slower onset and longer duration of action than amphetamine but retained amphetamine’s efficacy to reduce cocaine choice in a cocaine-vs.-food choice procedure (Banks et al, 2015). These results were interpreted to suggest that LDX may have lower abuse liability than amphetamine but similar therapeutic efficacy for treatment of cocaine abuse (Banks et al, 2015).…”

“…Studies conducted in rhesus monkeys found that LDX had a slower onset and longer duration of action than amphetamine but retained amphetamine’s efficacy to reduce cocaine choice in a cocaine-vs.-food choice procedure (Banks et al, 2015). These results were interpreted to suggest that LDX may have lower abuse liability than amphetamine but similar therapeutic efficacy for treatment of cocaine abuse (Banks et al, 2015). In combination, these factors are posited to limit abuse liability of LDX (Hutson et al, 2014).…”