Abuse liability and safety of oral lisdexamfetamine dimesylate in individuals with a history of stimulant abuse

Abstract

Lisdexamfetamine dimesylate (LDX) is the first prodrug stimulant and is indicated for the treatment of attention-deficit/hyperactivity disorder. A single-centre, double-blind, randomised, placebo-controlled, 6-period crossover study evaluated the abuse potential of single oral doses of 50, 100 (equivalent to 40 mg d-amphetamine), and 150 mg LDX, 40 mg d-amphetamine and 200 mg diethylpropion in 36 individuals with a history of stimulant abuse. On the primary abuse liability measure, maximum change of the Drug Rating Questionnaire-Subject Liking Scale compared with placebo, d-amphetamine and diethylpropion showed significant differences of 4.5 and 4.0 units, respectively (P < 0.001 for both vs placebo). LDX, administered at 50, 100 and 150 mg, showed nonsignificant differences of 2.0 and 2.1 units, respectively, at the two lower doses but a significant (P < 0.001 vs placebo) difference of 6.1 units at the highest dose. Subjects significantly favoured d-amphetamine 40 mg versus LDX 100 mg (2.4 units difference; P < 0.05). There was no significant difference in liking scores between d-amphetamine 40 mg and LDX 150 mg. Drug Rating Questionnaire-Subject Feel-Drug-Effect score was significantly lower for 100 mg LDX than for 40 mg d-amphetamine. There were no statistically significant differences between LDX and diethylpropion hydrochloride, a Schedule IV amphetamine-like stimulant, on abuse-related liking scores. Cardiovascular responses of LDX and d-amphetamine were similar at equivalent doses. In conclusion, at an equivalent amount of amphetamine base taken orally, LDX 100 mg had attenuated responses on measures of abuse liability compared with immediate-release d-amphetamine 40 mg. Abuse-related liking scores of LDX at a dose corresponding to a 50% higher amphetamine base (LDX 150 mg) were similar to d-amphetamine 40 mg.

Lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder: pharmacokinetics, efficacy and safety in children and adolescents

“…Of the doses tested, only d-amphetamine and LDX at the highest dose (150 mg) differed significantly from placebo in craving scores on the Drug Rating Questionnaire-Subject (DRQS) scale. In a pair-wise comparison of equivalent doses, d-amphetamine (40 mg) was associated with significantly higher craving scores compared with LDX (50 or 100 mg), indicating that abuse liability ("drug craving") is attenuated with LDX 22 . There are no studies available on the abuse potential of LDX compared with other controlled-release stimulants used in the treatment of ADHD, and there are as yet no data available for populations other than adults.…”

“…The hydrolysis of the inactive component to the active drug is a relatively slow process that occurs mainly in the blood [19][20][21] . It has been suggested that this relatively slow stage contributes to the long-lasting effect and possibly also to reduced "drug craving", an aspect considered critical in the development of abuse after both oral and intravenous administration 19,22 .…”

“…The results indicated that after 50 mg doses of LDX and 20 mg doses of d-amphetamine administered intravenously, only d-amphetamine differed significantly from the placebo in drug-craving ratings 19 . In a placebo-controlled study, orally-administered LDX (50, 100 and 150 mg) was compared with d-amphetamine 40 mg (equivalent to 100 mg of LDX) in adults (18-55 years of age) with a history of stimulant abuse 22 . Of the doses tested, only d-amphetamine and LDX at the highest dose (150 mg) differed significantly from placebo in craving scores on the Drug Rating Questionnaire-Subject (DRQS) scale.…”

Attention-Deficit/Hyperactivity Disorder and Substance Abuse

“…79 The prodrug formulation of dextroamphetamine, lisdexamfetamine, has a lower abuse potential than other stimulants and thus may be considered. 80,81 However, physicians should be aware that any psychoactive medication can be misused. As for all patients, it is important to carefully monitor medication adherence.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…LDX also produces similar feelings of subjective drug-liking on questionnaires in human volunteers as the 50% lower doses of AMPH base (Jasinski and Krishnan, 2009). The higher dose need likely represents the amount needed to achieve similar peak plasma AMPH concentrations and increases in the NAc DA levels, which at an equimolar ratio emerge slower and remain lower due to its extended absorption time of LDX.…”