Anticholinergic Co-Medication Burden Does Not Predict Cardiac Toxicity in Adolescent Diphenhydramine Exposure: A Pharmacovigilance Study of the FDA Adverse Event Monitoring System

Abstract Objectives Social media trends such as the "Benadryl Challenge" have increased adolescent misuse of diphenhydramine (DPH), an over-the-counter antihistamine with anticholinergic activity. Whether co-ingested anticholinergic medications compound cardiac risk is untested. Using the Anticholinergic Cognitive Burden (ACB) scale, this study examined whether co-medication ACB burden is associated with outcome severity and cardiac toxicity in adolescent DPH cases reported to the FDA Adverse Event Monitoring System (AEMS). Methods This study extracted all adolescent reports (age 13–19) mentioning DPH in any drug role from AEMS, yielding 3,168 cases from 217,507 deduplicated records. Given non-normality (Shapiro–Wilk, all p Results Co-medication ACB burden correlated positively with case severity (ρ = 0.142, p Conclusion Anticholinergic co-medication burden and cardiac risk dissociate: burden tracks overall severity, but cardiac events concentrate in the youngest, least co-medicated adolescents, a profile consistent with deliberate single-agent overdose rather than polypharmacy. A low co-medication burden should not reassure clinicians triaging young adolescents.