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

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 < 0.001), non-parametric tests were used. A multivariable logistic regression predicted cardiac toxicity; logistic and random-forest models were compared by cross-validated AUC. Results: Co-medication ACB burden correlated positively with case severity ({rho} = 0.142, p < 0.001) and differed by age group (H = 19.52, p < 0.001). However, burden and cardiac risk diverged: cardiac cases carried a lower burden (mean 0.55 vs 1.27) and were younger, and burden did not independently predict cardiac toxicity (OR = 0.927, 95% CI [0.841, 1.022], p = 0.128). Younger age was the strongest predictor (OR = 0.865 per year, p < 0.001); cardiac events occurred in 10.2% of 13-15-year-olds versus 4.9% of older adolescents. 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.