Death due to diphenhydramine toxicity: A 9‐year review from the Cook County Medical Examiner's Office and a review of the literature

Diphenhydramine (DPH) is a widely available first-generation antihistamine that, in supratherapeutic doses, can cause severe toxicity and even death. While commonly reported in cases of combined drug toxicity, fatalities attributed to DPH toxicity alone are rarely documented in forensic literature. A retrospective review was conducted of deaths attributed solely to DPH toxicity, investigated by the Cook County Medical Examiner's Office (CCMEO) between 2015 and 2024. Demographic information, postmortem findings, and circumstantial data were collected from autopsy, toxicology, and investigative reports. Twenty-five cases were included (13 males, 12 females; age range 14-55 years). Peripheral blood concentrations ranged from 3300 to 228,000 ng/ml. The most commonly observed autopsy findings included pulmonary edema and pill fragments in the gastrointestinal tract. Most cases (20 out of 25) were certified as suicides, with depression being the most frequently identified psychiatric risk factor. A comparative review of the literature (1998-2024) confirmed the wide variability of DPH peripheral blood concentration in cases of acute toxicity, ranging from 14,640 to 285,000 ng/ml. Demographic patterns and manner of death prevalence were similar to the CCMEO cases, with additional reports highlighting adolescent overdoses linked to social media challenges and intentional ingestions among socially vulnerable individuals. DPH-only toxicity should be carefully considered in postmortem investigations, especially due to the lack of specific autopsy findings and the wide range of postmortem concentrations in all matrices. Circumstantial evidence, scene findings, and reference to the available literature are essential for the accurate certification of the cause and manner of death in such cases.