HARMONIZING ADVERSE EVENT CRITERIA TO IMPROVE CNS-RELATED SAFETY AND ABUSE SIGNAL DETECTION IN CLINICAL TRIALS

Accurate adverse event (AE) collection is central to evaluating the safety, abuse, and dependence potential of CNS-active drugs, including psychedelics, and to informing labeling and scheduling decisions. Yet current regulatory and operational frameworks create a number of challenges to capturing the full spectrum of CNS-related events. A recurring problem, highlighted by the FDA including by its 2024 advisory committee review of MDMA-assisted therapy (U.S. Food and Drug Administration, 2024), is the systematic under-capture of positive or pleasurable effects (eg, elevated mood, prosocial behavior, empathogenic responses) that are treated solely as therapeutic outcomes rather than AEs relevant to abuse liability and risk management. This issue is compounded by the ICH E6(R3), (International Council for Harmonisation, 2025) and FDA definition of an AE as “any unfavorable medical occurrence in a trial participant administered the investigational product,” which can implicitly discourage documentation of experiences perceived as beneficial but directly relevant to scheduling and risk communication. Additional complexity arises when highly subjective descriptions (eg, “feeling connected,” “more open,” “expanded”) are coded into broad MedDRA preferred terms such as “mood altered,” “dysphoria,” or “feeling abnormal” that away strip nuance, obscure mechanistically important patterns, and limit cross-study comparability. These challenges are further amplified in psychotherapy-augmented and psychedelic paradigms, where expectancy effects and functional unblinding influence both participant reporting and investigator interpretation of AEs. To harmonize AE criteria in CNS-active drug trials, we propose: (1) adoption of working definitions that explicitly encompass both positive and negative experiences across somatic, affective, cognitive, and perceptual domains; (2) key dimensions for characterizing CNS-related events (eg, valence, intensity, time course, phenomenology, context, and abuse relevance); (3) a draft taxonomy structure intended to support more consistent mapping from verbatim language to MedDRA terms; (4) a practical guidance for training study personnel to recognize and code positive-effect and mixed-valence experiences without inflating therapeutic endpoints; as well as (5) a practical guidance for training study participants to report experiences they perceive as therapeutic along with those they perceive as undesirable. Together, these harmonized criteria are intended to support the acquisition of more complete and consistent AE datasets, improve CNS-related safety and abuse signal detection, and better align CNS-active drug programs with evolving regulatory expectations and public health needs.