Targeting the Nicotinic Cholinergic System to Treat Attention-Deficit/Hyperactivity Disorder: Rationale and Progress to Date

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is a common chronic neurobehavioral disorder related to clinically significant levels of inattention, hyperactivity, and/or impulsivity. ADHD begins in childhood and symptoms persist into adulthood for the majority of those with the disorder. Associated features of ADHD include emotion dysregulation and cognitive impairments, which contribute to the considerable functional impairments in this disorder. Current approved treatments are reasonably effective; however, a significant need remains for new pharmacotherapies, both for individuals who do not achieve a full therapeutic response and for symptoms that are under-treated including cognition and emotion regulation. The striking relationship between ADHD and cigarette smoking and the known effects of nicotine on cognition has spurred research into the therapeutic potential of nicotinic agents for ADHD. Although there are no approved medications for ADHD that target nicotinic acetylcholine receptor (nAChR) function, results from many trials of nicotinic drugs are available and reviewed in this article. ADHD symptoms were reduced in the majority of published studies of nicotine and novel α4β2 nicotinic agonists in adult ADHD. The drugs were generally well tolerated, with mild to moderate side effects reported, which were largely consistent with cholinergic stimulation and included nausea, dizziness, and gastrointestinal distress. Within-subject crossover study designs were used in the majority of positive studies. This design may be particularly useful in ADHD trials because it minimizes variability in this notoriously heterogeneous diagnostic group. In addition, many studies found evidence for a beneficial effect of nicotinic stimulation on cognitive and emotional domains. Thus, targeting nAChRs in ADHD appears to have a modest clinical benefit in adult ADHD. Continued refinement of nAChR agonists with greater specificity and fewer side effects may lead to even more effective nAChR agonists for ADHD. Future clinical trials in ADHD should include direct measures of neuropsychological performance and emotion regulation.