Categorization of Abuse Potential-Related Adverse Events

All drugs with central nervous system activity must undergo an assessment of their abuse potential, and these data must be included in a New Drug Application. Part of this assessment is an analysis of treatment-emergent adverse events that occur during clinical development. Using an iterative consensus strategy, we evaluated and grouped an available list of 213 flag terms for abuse potential from the Food and Drug Administration, into categories and assessed the relevance of the terms to primary abuse behavior. Consequences of abuse (28%) were most common, followed by diagnoses (19%), altered thoughts (18%), cognitive effects (10%), stimulation/anxiety (9%), central nervous system depression (9%), and mood elevation (1%). The vast majority of abuse potential-related terms reflects treatment-emergent adverse events, not behaviorally motivating features to abuse a drug. Almost 30% of terms are related to altered perception or altered cognition. These are serious consequences in the context of abusable psychoactive drugs. Only 20% of terms were rated as definitely or probably reflecting intrinsic behavioral reinforcing potential, and 30% were assessed as having weak predictive utility. Sponsors need to have an explicit strategy for collecting, interpreting, and analyzing abuse-related adverse event information completely and accurately.