Are Benadryl-Associated Toxicities Enough to Pull It From Shelves?

In September 2020, the FDA issued a statement about the “Benadryl Challenge,” which included ingesting high doses of Benadryl to induce hallucination and posting a video to TikTok, due to adolescents overdosing and subsequently dying.¹ In the statement, the FDA warns “that taking higher than recommended doses of the common over-the-counter (OTC) allergy medicine diphenhydramine (Benadryl) can lead to serious heart problems, seizures, coma, or even death.”²

Experts call for the review of diphenhydramine and possibly replacing it with second-generation antihistamines that have similar efficacy with fewer adverse events. | Image Credit: Eric Hood - stock.adobe.com

This ongoing challenge prompted James Clark, MD, assistant professor in the School of Medicine at Johns Hopkins University, and co-authors Eli Meltzer, MD, and Robert Naclerio, MD, to release a review calling for the review of diphenhydramine and possibly replacing it with second-generation antihistamines that have similar efficacy with fewer adverse events (AEs).³

“This is a medication that's been around for nearly 80 years, and a lot of people use it and had very good effects,” Clark said. “The pharmacist is often the person who is one of the few people who meets and confronts a lot of patients, and I think it's just making sure that patients are aware of the risks associated with it.”

Diphenhydramine is commonly used to manage allergic disorders, insomnia, pruritus, urticaria, vertigo, motion sickness, and dystonias. The drug became the first antihistamine approved in the US in 1946 and now appears in over 300 formulations, including OTC medications for allergy, cough and cold, and sleep. Although there is not a ton of data on sales involving diphenhydramine, in 2022, there were over 1 million estimated prescriptions in the US.^3,4

The drug is an H1 agonist, with H1 receptors located on respiratory smooth muscles, vascular endothelial cells, cardiac tissue, the gastrointestinal tract, and more. The drug reverses histamine’s effects on capillaries, which reduces allergic reaction symptoms.⁵ However, as a first-generation antihistamine, diphenhydramine also crosses the blood-brain barrier.

“It actually has anticholinergic properties, so it can cause things like confusion, dizziness, urinary retention, dry mouth, constipation, [and] blurred vision,” Clark said. ”There's been links with long-term use to things like dementia.”

Clark said that the margin between the therapeutic and toxic dose of diphenhydramine is narrow. The potential for abuse of this medication is high, especially due to its highly accessible nature. Although there are many cases where overdose can be associated with self-harm or suicidal ideology, there are instances where diphenhydramine has been used for euphoric effects.⁶

Signs and symptoms of overdose include delirium, agitation, confusion, hallucinations, tremor, seizures, flushed skin, blurred vision, urinary retention, and tachycardia. Within 1 hour of ingestion, decontamination as treatment can be considered, such as a single dose of activated charcoal. However, there is currently no reverse to the effects of toxicity. Therapy mainly addresses symptoms of intoxication and overdoses, including benzodiazepine for seizures and sodium bicarbonate for ventricular arrhythmia.^5,6

However, in second-generation antihistamines, similar AEs have been reduced with cetirizine (Zyrtec) or loratadine (Claritin) or AEs are absent with fexofenadine (Allegra).¹

“Data seems to support that they have a comparable therapeutic effect,” Clark said. “[Make] sure that you talk to physicians, and even try alternatives, such as nasal steroid sprays, which can be a great solution for [allergy] symptoms.”

As for sleep, Clark added that diphenhydramine can actually disrupt a normal sleep schedule. Although it can help patients fall asleep, it does not necessarily mean the patient will get a restorative sleep. He suggests speaking to a health care professional who specializes in sleep management.

Pharmacists play a large role in offering guidance and education to patients on OTC allergy products. As part of the recommendations, patients can ensure there are no drug-drug interactions and even help patients mitigate and manage allergy triggers.⁷

“Community pharmacists are in a great location where they have a lot of trust from patients they often [see],” Clark said. “They are often the only person that a patient will see when they’re choosing over-the-counter medication.”

Pharmacists can also be involved in disease prevention, maintenance of health conditions, and assistance in health challenges, strengthening access to treatment. Furthermore, pharmacists can help educate patients on the negative outcomes of improper OTC use and provide clinical services for patients.

“Pharmacists have a lot of things placed on their table of things to do, and I'm not sure how much pharmacists are rewarded for doing education when they have so many other tasks and demands that are put on them,” Clark said. “I think it's probably a challenging situation for pharmacists to provide the amount of education that they would probably like to do. So, I think it's just finding ways that pharmacists can be rewarded and encouraged to do that.”

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REFERENCES

1. Miller SG. FDA issues warning on 'Benadryl Challenge,' a rumored viral trend. NBC News. September 24, 2020. Accessed July 28, 2025. https://www.nbcnews.com/health/health-news/fda-issues-warning-benadryl-challenge-rumored-viral-trend-n1240986

2. FDA. FDA warns about serious problems with high doses of the allergy medicine diphenhydramine (Benadryl). September 24, 2020. Accessed July 28, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-serious-problems-high-doses-allergy-medicine-diphenhydramine-benadryl

3. Clark JH, Meltzer EO, Naclerio RM. Diphenhydramine: It is time to say a final goodbye. World Allergy Organ J. 2025;18(2):101027. Published 2025 Jan 25. doi:10.1016/j.waojou.2025.101027

4. Diphenhydramine - Drug Usage Statistics. ClinCalc DrugStats database. 2024 https://clincalc.com/DrugStats/Drugs/Diphenhydramine. Accessed July 28, 2025.

5. Sicari V, Patel P, Zabbo CP. Diphenhydramine. [Updated 2025 Mar 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK526010/

6. Huynh DA, Abbas M, Dabaja A. Diphenhydramine Toxicity. [Updated 2023 Apr 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557578/

7. Biscaldi L. As Fall Allergy Season Approaches, Encourage Patients to Begin Medicating Today. Drug Topics. August 15, 2024. Accessed July 28, 2025. https://www.drugtopics.com/view/as-fall-allergy-season-approaches-encourage-patients-to-begin-medicating-today

8. Gallagher A. Pharmacists Help Educate Patients on Self-Care, OTC Interventions. Drug Topics. April 4, 2025. Accessed July 28, 2025. https://www.drugtopics.com/view/pharmacists-help-educate-patients-on-self-care-otc-interventions