Diphenhydramine (DPH) is a commonly reported overdose that shares similar toxicities with other agents. such as tricyclic antidepressants, that interact with the fast sodium channels. Although physostigmine is considered an acceptable antidote for severe DPH toxicity, adverse effects such as seizures and cholinergic crisis may occur. We hypothesized that hypertonic saline or bicarbonate is equivalent or are better antidotes in an animal model of DPH toxicity. In a preliminary study. Sprague-Dawley rats were given toxic doses of DPH while continuous ECG, EEG, and blood pressure monitoring was performed. Seizures were the common toxic effect observed and was chosen. Four groups of 10 rats each were established as control physostigmine, hypertonic sodium bicarbonate, and hypertonic saline(3%) treatment. Control had initial "drop-off" seizure burst rates over time; seizure bursts in the treatment groups were compared to these rates. Hypertonic sodium bicarbonate was the most effective treatment, followed closely by hypertonic saline. Hypertonic sodium bicarbonate may interact with DPH neuronal sodium channels and may be considered adjuvant therapy in humans with DPH-induced seizures.