A REVIEW OF THE ABUSE LIABILITY OF ATOMOXETINE, A NONSTIMULANT PHARMACOTHERAPY FOR ADHD

A. J. Allen; F. Bymaster; D. Michelson; C. Thomason; M. Kallman; D. Jasinski; R. Dickson; D. Clarke

doi:10.1055/s-2006-945669

Neuropediatrics, Table of Contents

A REVIEW OF THE ABUSE LIABILITY OF ATOMOXETINE, A NONSTIMULANT PHARMACOTHERAPY FOR ADHD

AJ Allen ¹, F Bymaster ¹, D Michelson ¹, C Thomason ¹, M Kallman ¹, D Jasinski ², R Dickson ³, D Clarke ¹

¹Lilly Research Laboratorios, Indianápolis, IN, United States
²Johns Hopkins University School of Medicine, Baltimore, MD, United States
³Eli Lilly Canada, Toronto, ON, Canada

Abstract

Objectives: Psychostimulants have been the standard pharmacotherapies for the treatment of attention-deficit/hyperactivity disorder (ADHD), but are associated with abuse potential. Atomoxetine, a non-amphetamine, selective norepinephrine reuptake inhibitor, is approved as a treatment for ADHD. Receptor binding, preclinical behavioral, and human laboratory studies of the abuse liability of atomoxetine are summarized.

Methods: Binding affinities of atomoxetine were determined for monoamine transporters and other neurotransmitter-related receptors, ion channels, and transporter binding sites. The potential stimulant effects of atomoxetine were evaluated preclinically in a mouse locomotor activity study. Drug discrimination studies using rats, pigeons, and monkeys were reviewed, and self-administration studies using monkeys trained to discriminate cocaine or methamphetamine or self-administer cocaine were conducted. Additionally, a human laboratory study was conducted to examine the subjective, physiological, and psychomotor effects of atomoxetine, as compared to placebo, desipramine, phentermine, and methylphenidate.

Results: Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for dopamine transporters or actions at GABAA receptors. Atomoxetine did not stimulate locomotor activity in mice. In drug discrimination studies, atomoxetine produced a profile similar to that of drugs without abuse liability. Atomoxetine, like desipramine and in contrast to methylphenidate and amphetamine, did not maintain self-administration in monkeys and was not preferred over food delivery up to doses that decreased response rates, consistent with limited reinforcing strength. Results from human drug abusers indicated that atomoxetine has significantly less abuse liability than methylphenidate and phentermine, and no greater abuse liability than desipramine.

Conclusion: Data from receptor binding, preclinical behavioral, and human laboratory studies suggest that atomoxetine lacks abuse potential is not an amphetamine-like agent.