ToxCard: Diphenhydramine Toxicity

Authors: Rachael Hamm, MD Emergency Medicine Resident, Carolinas Medical Center, Atrium Health Kathryn Kopec, DO, Emergency Medicine Attending & Medical Toxicologist, Carolinas Medical Center, Atrium Health // Reviewed by: Tony Spadaro, MD, MPH (Assistant Professor of Emergency Medicine, Medical Toxicology, and Addiction Medicine at University of Pennsylvania); Alex Koyfman, MD (@EMHighAK); Brit Long, MD (@long_brit)

Case:

A 25-year-old female with a past medical history of depression presents to the ED via EMS after being found down at home next to an empty bottle (300 tablets) of 25 mg diphenhydramine. 

En route to the hospital the patient had a generalized tonic-clonic seizure and received 5 mg of IV midazolam. On arrival the patient is agitated and combative, with initial vital signs of temperature of 39.1 C, heart rate of 150 BPM, blood pressure 140/80 mmHg, respiratory rate of 24 breaths/min, and oxygen saturation of 100% on room air.

Exam demonstrates flushed cheeks, dry mucus membranes, reactive pupils 6 mm bilaterally, and suprapubic tenderness. She is actively hallucinating, picking at unseen objects on her gown. The patient has another generalized tonic-clonic seizure lasting 2 minutes and receives 10 mg of midazolam. Her ECG is shown below. 

Questions:

1. What are the clinical manifestations of a diphenhydramine overdose?
2. What EKG abnormalities and cardiac complications are associated with severe toxicity?
3. How are diphenhydramine overdoses managed?
4. Are there any antidotes/reversal agents that should be considered in anticholinergic overdose?

Background:

Diphenhydramine is most commonly used for seasonal allergies, mild to severe allergic reactions, and as a sleep aid. It is important to be aware that diphenhydramine can be found in many over the counter combination medications. Diphenhydramine was one of the most common drugs involved in suicide-related deaths in 2023.¹

Diphenhydramine overdose has also unfortunately become a recent public health issue as there was a popular Tik Tok “Benadryl challenge” where adolescents would intentionally take extra diphenhydramine to get high and post their behavior. There are at least two confirmed deaths of teenagers after participating in this challenge with multiple hospitalization and poison center cases reported.²

At therapeutic effects diphenhydramine acts primarily as an antihistamine, but at higher doses produces anticholinergic toxicity, CNS delirium, seizures, and cardiotoxicity.^3,4 Diphenhydramine is a first-generation antihistamine that binds to H1-histamine and muscarinic receptors.³ This results in sedation and anticholinergic effects respectively. Peripheral histamine antagonism is responsible for its ability to treat allergic symptoms.³ Due to its lipophilicity, diphenhydramine readily crosses the blood brain barrier, and its central histamine antagonism leads to CNS effects such a sedation, delirium, hallucinations, and confusion.

Diphenhydramine also acts as an sodium channel blocker, this can causes QRS widening and arrhythmias.^3,4 It also has the ability to act as a potassium channel blocker, which can cause prolongation of the QT, however, Torsade de Pointes can occur.⁴

Clinical Presentation:

The onset of symptoms is normally 1 – 2 hours as the peak plasma concentration is reached at 2 – 3 hours, although can be delayed in massive ingestions due to delayed GI transit and absorption.⁵ Ingestions of > 7.5 mg/kg (~ 500 mg) are likely to have clinically significant toxicity. Poison Control Centers’ often refer patients to the hospital for evaluation at this dose or greater.⁶  Ingestions > 20 mg/kg (~ 1.5g) are potentially lethal.⁷

Most common presenting symptoms are:

• Mild toxicity: sedation, nausea/vomiting, anticholinergic signs
• Moderate toxicity: confusion, hallucinations, EKG disturbances (QT prolongation, QRS widening, tachycardia)
• Severe toxicity (> 1.5g)⁷ : delirium, seizures, arrhythmias, coma

Anticholinergic findings⁴:

• Delirium/agitation, picking at the air or objects, hallucinations, flushed skin, dry mucus membranes, mydriasis, urinary retention, hyperthermia, tachycardia, seizures, coma

Sodium channel blocking features^3,8:

• Wide QRS >120 msec, hypotension, arrhythmias, seizures

*Acidemia, elevated anion gap and prolonged QRS (Na+ channel blockade) are the strongest risk factors for poor outcomes.⁹

Diagnosis:

• Diphenhydramine toxicity is a clinical diagnosis – primarily based on history and physical exam.
• There are no lab tests that can confirm diphenhydramine exposure.^4,10
  • Diphenhydramine has been reported to cause a false positive opiate assay.¹¹
• Vitals signs: can see hyperthermia, tachycardia, hypertension⁴
• Always obtain an EKG to assess for cardiotoxicity:^3,8,12
  • Prolonged QRS (Na⁺ channel blockade)
  • Prolonged QTc (K⁺ channel blockade)
• Laboratory testing should include BMP, LFTs, VBG and creatine kinase (CK)^3,4
• Always obtain co-ingestion labs including acetaminophen and salicylate level

Management:

• The treatment of diphenhydramine toxicity is largely supportive and aimed at management of symptoms that arise.
• Activated charcoal can be considered, if the ingestion was recent and the patient is able to protect their own airway.^4,8,10
• Airway, Breathing, and Circulation takes priority
• Standard treatment for hyperthermia as needed such as cold IV fluids, ice packs and cooling blankets.
• Hemodynamics:^4,8
  • Tachycardia: treating agitation may reduce tachycardia
  • Hypertension: normally does not require antihypertensives, treatment of agitation may help
  • Hypotension: Fluid resuscitation, use vasopressors as needed
• Agitation is very common^3,4
  • Benzodiazepines are first line therapy
    • May need larger or multiple doses.
  • Avoid antipsychotics
    • Can worsen anticholinergic effects and lower seizure threshold
  • Urinary retention is common in anticholinergic toxicity and can lead to agitation
    • Foley catheter placement is recommended if urinary retention is present on bladder scan
  • Seizures are due to multiple mechanisms (anticholinergic effects and Na⁺ channel blockage).^3,4,8
    • Benzodiazepines are first line therapy
    • Acidemia will worsen sodium channel effects, intubation, and sedation with propofol may be required for recurrent seizures.
  • Rhabdomyolysis is a rare side effect; the mechanism is not well understood. Possibly related to increased muscle activity and/or the antihistamine may cause direct injury to the muscle.¹³
    • Recommend isotonic crystalloids
    • Check CK
• QRS prolongation
  • Sodium bicarbonate boluses⁸
  • Dose: 1 – 2 mEq/kg
  • Can be repeated as needed to narrow QRS
  • Indications: ventricular arrythmia, QRS > 100 ms with hypotension
  • If QRS is unresponsive to sodium bicarbonate, continued dysrhythmias, pH > 7.55, or Na⁺ > 150 – can give lidocaine
  • Lidocaine rapidly binds the Na⁺ channel and can compete with diphenhydramine. Consider lidocaine bolus at 1-2 mg/kg.¹⁴
  • Avoid acidemia, lower pH will worsen sodium channel effects
• QTc prolongation
  • Optimize electrolytes with Mg²⁺ > 2 and K⁺ > 4
  • Tachycardia is often protective against torsade de pointes; TdP is uncommon in diphenhydramine ingestion.¹³

In certain cases, anticholinergic toxicity can be treated with a reversal agent. Classically, physostigmine is the antidote/reversal agent for this toxidrome. However, within the last 4 years physostigmine has been on shortage and is no longer being produced in the US.¹⁵ This has led to examining other reversal agent options, such as rivastigmine.¹⁵

Indications for the use of physostigmine or rivastigmine are patients in whom an anticholinergic toxidrome is known or strongly suspected or patients with severe agitation, delirium, and hallucinations.¹²

• Physostigmine⁸ –
  • Acetylcholinesterase inhibitor that crosses the blood brain barrier (BBB) and leads to increased acetylcholine levels.
  • This helps counteract the effects of anticholinergic drugs
  • Complications/concerns
    • Cardiac arrest has occurred after physostigmine administration with Tricyclic Antidepressants (TCA) overdoses.
    • Its use when there is concern for TCA co-ingestion (or other Na⁺ channel blocking agents) or if the patient is bradycardic is controversial.¹⁶
      • For further discussion on this topic, see ToxCard on Physostigmine here:
    • Highly effective at resolving agitated delirium (better than benzodiazepines).⁸
    • Dosing:
      • Adults – 1 mg IV slowly over 5 minutes, stop infusion if heart rate < 60. Expected duration of action is ~ 45 – 60 minutes. Will likely have to repeat the dose in 1-2 hours.

• Rivastigmine¹⁷ –
  • Long-acting acetylcholinesterase inhibitor that crosses the BBB
  • Available in oral and transdermal patch formulations.
  • Dosing:
    • Oral: Adults – 3 – 6 mg every 3-6 hours until symptoms resolve, with a max of 12mg/day^17,18
    • Patch: Adults – 9.5 mg, remove every 24 hours. Place on back or other location that patient cannot remove on their own.¹⁸

Disposition

• Unintentional ingestions can be discharged from the emergency department if they remain asymptomatic beyond 4 – 6 hours of oral exposure.⁴
• All intentional ingestions will likely need psychiatry evaluation once medically cleared.
• Patients that are displaying symptoms will require admission for further monitoring and potential treatment of their anticholinergic toxidrome.
• Call the regional poison control center, 1-800-222-1222, or local medical toxicologist if available

Case Follow-up:

The patient received 2 ampules (100 mEq) of IV sodium bicarbonate and subsequently had narrowing of her QRS. She was intubated for airway protection, sedated with propofol, and was admitted to the ICU. In the ICU, she was managed with a sodium bicarbonate infusion, IV fluids, and external cooling for hyperthermia. Physostigmine was avoided given her QRS widening and seizure activity. Continuous cardiac monitoring showed normalization of her QRS within hours and gradual improvement of QTc with electrolyte repletion. On hospital day 2, sedation was weaned with resolution of agitation and no further seizures, and she was extubated. On hospital day 3, her anticholinergic symptoms had resolved, and she was medically cleared for psychiatric evaluation.

Clinical Pearls: 

• Diphenhydramine is an over-the-counter antihistamine that results in sedation, anticholinergic effects, and in severe cases arrhythmias and seizures in overdose.
• QRS widening (> 100 msec) is a red flag for severe toxicity and predicts seizures/arrhythmias due to sodium channel blockade.
  • Treat early with IV sodium bicarbonate.
• Benzodiazepines are the first line for both agitation and seizures. Patients often require large, repeated doses.
• Avoid antipsychotics as they can worsen anticholinergic effects and lower seizure threshold.
• Physostigmine can reverse anticholinergic delirium but should be avoided in patients with QRS widening or seizures due to risk of cardiac instability.
• Most patients will improve in 24 – 48 hours.

References:

1. Garnett MF, Cisewski JA, Ahmad FB. Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2017–2023. In: National Vital Statistics Reports [Internet]. National Center for Health Statistics (US); 2026. doi:10.15620/cdc/174640
2. Elkhazeen A, Poulos C, Zhang X, Cavanaugh J, Cain M. A TikTok^TM “Benadryl Challenge” death-A case report and review of the literature. J Forensic Sci. 2023;68(1):339-342. doi:10.1111/1556-4029.15149
3. Sicari V, Patel P, Zabbo CP. Diphenhydramine. In: StatPearls. StatPearls Publishing; 2026. Accessed March 14, 2026. http://www.ncbi.nlm.nih.gov/books/NBK526010/
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12. Holger JS, Harris CR, Engebretsen KM. Physostigmine, sodium bicarbonate, or hypertonic saline to treat diphenhydramine toxicity. Vet Hum Toxicol. 2002;44(1):1-4.
13. Ali Z, Khan M, Ullah W, Kpehor AA, Cheema MA. QT interval prolongation and rhabdomyolysis associated with diphenhydramine toxicity: a case report. Journal of Community Hospital Internal Medicine Perspectives. 2020;10(2):151-153. doi:10.1080/20009666.2020.1749511
14. Makki KM, Mandil D, Hopson R, et al. Lidocaine for Sodium Channel Toxicity in Diphenhydramine Overdose: A Case Report. Clinical Practice and Cases in Emergency Medicine. 2025;9(2). doi:10.5811/cpcem.41491
15. Berg M, Strand A, Garrett ND, Keric A, Wilkinson J. Rivastigmine as an alternative treatment for anticholinergic toxidrome in light of the physostigmine shortage: A case series. The American Journal of Emergency Medicine. 2025;94:144-147. doi:10.1016/j.ajem.2025.04.047
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