By Karen Kier
Pharmacist on behalf of the ONU HealthWise team

In November of 1967, the Beatles released their song “Hello, Goodbye” as a single. Paul McCartney used a very unique writing style when developing the song. He asked Alistair Taylor, a Beatles aide, to say the opposite to anything he said and the song generated from there. The song was a major hit in the United States and the United Kingdom.  Eventually, the song was put on the Magical Mystery Tour soundtrack. McCartney often uses the song in his concerts. 

Is it time to say goodbye to the antihistamine diphenhydramine (Bendryl®)?

Diphenhydramine was first synthesized in 1943 at the University of Cincinnati as researchers George Rievesch and Fred Huber were trying to create a muscle relaxant. What they found was a drug that blocked histamine and was effective for allergies and allergic reactions. This was a pioneering advance in the treatment of allergies. The drug was first approved by the FDA in 1946 as a prescription product. In 1982, diphenhydramine was approved for over-the-counter (OTC) use to promote sleep. By 1984, diphenhydramine was approved for OTC use for all indications including allergies, cough, and colds. 

After seeing a commercial for ZzzQuilTM for sleep, I was reminded of the FDA petition to remove diphenhydramine from the OTC market for allergies, cough, and colds. ZzzQuilTM capsules and liquid only contain diphenhydramine for sleep. This is only one brand of many promoted for sleep using this as the active ingredient.  Sleep was a side effect of diphenhydramine when it was initially approved for allergies. This is a good example of using a side effect of a drug for therapeutic benefit of sleep. 

On January 25, 2025, a group of experts published an article in the World Allergy Organization Journal indicating it was time to say goodbye to oral diphenhydramine for allergies due to better antihistamines on the market with much fewer side effects. In September of 2025, the American College of Allergy, Asthma, and Immunology made the same recommendation to remove oral diphenhydramine from the market due to the side effect profile and better agents were available for patients. On December 11, 2025, a group of medical experts and researchers from Johns Hopkins University and the University of Florida filed a formal petition with the FDA to remove oral diphenhydramine from the market with similar concerns. 

These articles and petitions would not remove the topical creams for rashes and insect bites or the injectable forms used in hospitals, ambulances, or clinics to treat life-threatening allergic reactions.

Diphenhydramine products do have a significant side effect profile, which can be especially difficult for younger and older patients. Nationwide Children’s website has an excellent expert blog about the dangers of diphenhydramine for children with answers for better options. The website can be found here. 

The issue related to sedation or sleep with diphenhydramine is the drug crosses into the brain tissue. The peak sedation effect in the brain occurs within 1 to 3 hours of taking the medication, but it can take an extended period of time to flush from the body and the brain. This could be as short as 4 hours, but could extend up to 49 hours in some patients. The drug can cause confusion and grogginess. A study in the Annals of Internal Medicine indicated patients driving was more affected by diphenhydramine than driving impaired by alcohol. This impact is significant. 

Diphenhydramine is considered a first-generation antihistamine and this class has not only significant brain effects, but they possess anticholinergic effects. Anticholinergic side effects include dry mouth, dry eyes, sleepiness, blurred vision, constipation, overheating (heat stroke), delirium, hallucinations, fast heart rate, falls, and inability to empty the bladder. Men who have an enlarged prostate can suffer from a lack of urinary flow with diphenhydramine, which could result in a trip to the emergency room. Elderly individuals may be more prone to confusion and falls.

For allergies and colds, it is recommended to use oral second-generation antihistamines such as loratadine (Claritin®), fexofenadine (Allegra®), cetirizine (Zyrtec®, and levocetirizine (Xyzal®). The second-generation antihistamines do not cause as much drowsiness as the first-generation antihistamines such as diphenhydramine and have little to no anticholinergic effects. 

The experts are not wrong, it may be time to say goodbye to diphenhydramine and hello to safer alternative choices for allergies.  If you are having sleep issues, it is good to discuss this with a healthcare provider, because there are better prescription sleep aids than the OTC products. Ask your pharmacist or healthcare professional for better choices.