Benadryl: Allergy Relief for Millions
"Achoo!”
For many people, springtime means sneezing, coughing, and itchy, watery eyes. Seasonal sonal allergies, also known as hay fever or allergic rhinitis, affect about a quarter of the country’s adults and about 20% of children, according to the U.S. Centers for Disease Control and Prevention. Allergies can also wreak havoc at other times of the year—depending on what trigger is present. In addition to seasonal waves of pollen, dust mites, mold, animal dander, poisonous plants, and some foods can set off a chain reaction in the body leading to uncomfortable allergic reactions, including cold-like symptoms or itchy, swollen skin.
The antihistamine Benadryl has provided temporary relief from allergy symptoms for millions of people since it was developed by George Rieveschl at a University of Cincinnati laboratory in the early 1940s and later approved by the U.S. Food and Drug Administration (FDA). Rieveschl was originally studying muscle relaxants when he discovered the compound diphenhydramine hydrochloride. He sold it under the name ‘Benadryl,’ among others. The medication was sold by Parke-Davis, followed by Pfizer, Johnson & Johnson, and now Kenvue, the former consumer healthcare division of Johnson & Johnson.
Over the years, the compound has found many additional uses. It helps control muscle movements in Parkinsonian syndromes, is an ingredient to control nausea in Dramamine, and is a sleep aid in the medication Nytol. Adjusting the structure led to the discovery of the antidepressant Prozac. Benadryl also inspired the development of other medications such as Tagamet, which reduces stomach acid to treat ulcers and heartburn. As with many drugs, Benadryl can have side effects—most notably, drowsiness—and can be harmful if taken improperly.
To reduce or eliminate these effects, researchers have developed second- and third-generation antihistamines.
All of these different versions and formulations represent a decades-long legacy of a trailblazing drug.
Clearing the air
In the early 1900s, adrenaline was a common treatment for asthma and allergies because it dilates and opens airways. Today, adrenaline, also known as epinephrine, is reserved for use only in response to severe allergic reactions, called anaphylaxis. An extreme response to an allergen, anaphylaxis can quickly escalate from minor symptoms such as itchy skin to life-threatening symptoms such as swollen and closed-off airways in a matter of seconds or minutes. Other allergy remedies have included ephedrine, amphetamines, and derivatives of caffeine such as theophylline and aminophylline.
As researchers learned more about how allergies affect the body, more precise therapies began to take shape. In 1907, Adolf Windaus and W. Vogt made histamine at the University of Freiburg by heating the amino acid histidine. A few years later in 1910, Henry H. Dale and colleagues at the Wellcome Physiological Research Laboratories isolated histamine from mold and found that the effects of it were similar to those of allergies. As time went on, researchers realized that histamine was indeed the culprit behind allergy symptoms in people.
An allergy is an exaggerated response to something foreign, like a pollen granule from a tree, that gets into the body. An allergen is a substance that is harmless to most people. But when a person with an allergy is exposed to an allergen, their body overreacts and mounts an immune response as if the allergen were a harmful invader. Antibodies against the allergen bind to it and bring it to mast cells, which release histamine. To flush the invader, histamine binds to receptors in mucous membranes, causing nearby blood vessels to dilate and become more permeable. Fluids are released and build up in neighboring tissues, leading to swelling, a runny nose, and watery eyes.
First antihistamines
The 1930s and 1940s ushered in many advances in allergy treatments. Daniel Bovet identified the first antihistamine at the Pasteur Institute in 1937 as he tried to develop therapies for asthma. In laboratory studies, the drug protected guinea pigs against histamine’s effects. Antergan debuted in 1942, and it was tweaked two years later and sold as Neoantergan.
Although early antihistamines offered much relief to people with allergies, these medications had severe side effects, such as extreme drowsiness. That’s where Rieveschl enters the picture.
Born in 1916 in Lockland, Ohio, Rieveschl had dreams of becoming an artist—not a chemist. At the Ohio Mechanics Institute, he pursued his passion. But upon graduating in 1933, despite submitting about 200 applications, he could not find a commercial art job. Fortunately, chemistry was his next choice, so he enrolled in the University of Cincinnati (UC) and earned a bachelor’s, a master’s, and a doctoral degree there.
Rieveschl became an assistant professor in UC’s department of chemical engineering and started a research program intending to discover new muscle relaxants in 1940. Fate intervened, however, and one of the compounds he synthesized called A524—Benadryl—proved to be a histamine blocker. Three years later, Rieveschl moved on to Parke-Davis (now part of Pfizer), and the company bought the rights to Benadryl. Rieveschl patented the discovery in 1947.
The U.S. FDA approved the drug in 1946, and the drug became available with a prescription. In 1985, it was approved in the U.S. for over-the-counter use, and it is currently available in many countries around the world, either over the counter or by prescription. Today the drug can be purchased in tablet or liquid form for oral use, or as a cream, gel, stick, or spray for topical use.
Treating allergies — and other conditions
Histamine is found in almost all tissues in the human body, and its varied health effects depend on the protein, or receptor, it binds to and in what tissue this happens. This became apparent in the 1940s when experiments showed that antihistamines didn’t have an effect on some things that histamine does in the body.
There are four known histamine receptors in people. H1 receptors are involved in allergic reactions and are on smooth muscles of the respiratory and cardiac systems, blood vessels, gastrointestinal tract, and nerve cells in the central nervous system. Benadryl does its job by blocking H1 receptors so they can’t latch onto histamine. In this way, the medication stops the body from developing symptoms such as a runny nose or skin irritation, but it does not address the underlying cause of the allergic reaction. The immune system still overreacts to a trigger substance. But because they only treat symptoms, some antihistamines can also provide relief to people who have other root causes for their runny noses, such as the common cold virus.
Diphenhydramine, a component of Benadryl, can cross the blood-brain barrier, a membrane that protects the brain by acting like a filter, and keeps many potentially harmful substances out while it allows other molecules in. Because Benadryl can sneak past this barrier and travel into the brain, it can block the H1 receptors there, causing drowsiness and suppressing the part of the brain that controls coughing. That’s why it is sold as a cough medication in some countries, such as Australia and India, in combination with other cough-suppressing compounds.
Because Benadryl can make people sleepy, it is an ingredient in some sleep aids, such as Nytol. It is also sold in combination with acetaminophen and ibuprofen in the products Tylenol PM and Advil PM, respectively. Some people use the medication alone to help them sleep, but experts point out that Benadryl-induced sleep is typically not ideal or satisfying. People with long-term insomnia should contact a physician for an assessment.
Blocking H1 receptors also helps curb motion sickness. In fact, diphenhydramine is an ingredient in Dramamine. In 1947, the drug company G.D. Searle sent dimenhydrinate, a derivative of diphenhydramine, to Leslie Gay and Paul Carliner at the Johns Hopkins Hospital to test its antihistamine effects, and a woman with hives was treated by taking the new compound. In an interesting case of serendipity, the woman came down with motion sickness when she rode the trolley to her appointment, but those symptoms disappeared after taking the medication. After further experimentation, the researchers found that dimenhydrinate indeed could alleviate motion sickness on land and water, and the motion sickness drug became available in 1949.
Throughout the years, H2, H3, and H4 histamine receptors were also discovered. Movement disorders, such as Parkinson’s disease, Parkinsonian syndromes, and movement dysfunction as a result of medication side effects can be alleviated by blocking all four receptors. Diphenhydramine is known to help Parkinson’s patients via its action on H1 receptors and muscarinic acetylcholine receptors, which are similar to H1 receptors and are involved in nerve function and regulation of acetylcholine release.
Benadryl inspires other medications
In the stomach, parietal cells produce hydrochloric acid that digests food. Too much acid can cause ulcers, or holes in the lining of the stomach and small intestine, and heartburn. Scientists knew that histamine could stimulate gastric acid secretion, but typical antihistamines couldn’t reduce or block its production.
In an attempt to find completely new histamine blockers that would work against H2 receptors, James Black began a research program at Smith Kline & French (now GSK) in 1964. After many years, his team discovered cimetidine, also known as Tagamet. FDA approved cimetidine in 1977, and it became available in the U.S. in 1983. Although it doesn’t treat the cause of ulcers, which is typically the bacterium Helicobacter pylori, it relieves ulcer pain and speeds up the healing process. Because it reduces acid production by blocking H2 receptors, it also can be used to treat acid reflux. Tagamet became the first blockbuster drug ever in 1986 when its sales surpassed $1 billion, and it was designated a National Historic Chemical Landmark in 1997 by the American Chemical Society.
In the 1960s and 1970s, the main treatments for depression were monoamine oxidase inhibitors (MAOIs), which degrade MAOs, and tricyclic antidepressants, which act by preventing MAO uptake. Both increase the levels of monoamines — such as the neurotransmitters norepinephrine, serotonin, and dopamine — in the brain. But MAOIs are toxic, and tricyclics are not very selective because they also affect acetylcholine levels, leading to harmful side effects. These medications are often drugs of last resort for patients who don’t respond well to other therapies.
Research on the antihistamine promethazine had already led to the development of an antipsychotic, chlorpromazine. So, a team at Eli Lilly & Co. led by David Wong, Ray Fuller, and Bryan Molloy in the early 1970s tweaked diphenhydramine to see if they could obtain a more selective antidepressant compared to the tricyclics. The result of their efforts was fluoxetine (Prozac), which was approved by FDA in 1987. It is a selective serotonin reuptake inhibitor, or SSRI, which is a class of drugs often prescribed first for patients with depression.
Controversies
As with many medications, Benadryl has had its share of controversies, though many arise from misuse or abuse of the drug.
The makers of Benadryl explicitly advise not to give the medication to a child to make them sleepy. Users are also warned against taking the medication with alcohol or other sedatives, which could boost the drowsiness effects.
Drowsiness has brought Benadryl back behind the counter in some countries, such as Germany, the Netherlands, and Sweden. In these areas, Benadryl is only available by prescription.
Taking more than the recommended dose of Benadryl can be toxic and result in hallucinations, seizures, dry mucous membranes, a high body temperature, and blurry vision. In 2020, some teenagers discovered the effects the hard way as a result of a TikTok Benadryl challenge. Youths intentionally overmedicated themselves and filmed their reactions. As a result, at least two teens died, and several were hospitalized.
Surprisingly, one “controversy” surrounding Benadryl stems from a misunderstanding. In 2023, an FDA advisory committee determined the compound phenylephrine in pill form doesn’t have enough scientific evidence to be considered an effective nasal decongestant. Diphenhydramine is not phenylephrine, but a product called Benadryl Allergy Plus Congestion includes phenylephrine. That led to some confusion in media reports as to whether Benadryl was being deemed ineffective as an allergy remedy, but that was not the case.
Next-gen antihistamines
Scientists are constantly working to improve and advance medications, and antihistamines are no exception. Benadryl is known today as a first-generation antihistamine. Because it causes people to become sleepy, scientists developed new, second- and third-generation medications, in the 1980s that target H1 receptors and are less likely to make users tired.
Although the early second-generation antihistamines — terfenadine (Seldane) and stemizole (Hismanal) — did not induce sleepiness, they were taken off the market because they reportedly had severe interactions with other drugs. However, other second-generation antihistamines are safe and effective at treating allergy symptoms. These medications include loratadine (Claritin), cetirizine (Zyrtec), and levocetirizine (Xyzal), among others. So far, the only third-generation antihistamine on the market is fexofenadine (Allegra).
The newer drugs on the market do not pass through the blood-brain barrier, so they don’t make users as drowsy as diphenhydramine does, but some tiredness is still possible. In the U.K., products sold under the Benadryl name contain second-generation antihistamines, such as acrivastine or cetirizine, as the active ingredient instead of diphenhydramine because they are less likely to induce sleep. The effects of newer antihistamines often last longer than those of older medications, so they can be taken less frequently.
Room for all
Second- and third-generation antihistamines have helped many people continue to work, drive, and learn because they are less sedating than older medications. However, there’s still room for Benadryl, nearly 80 years after it was first approved by FDA. Because antihistamines developed more recently don’t cross the blood-brain-barrier, they do not relieve cold symptoms like Benadryl does. In addition, people sometimes need help falling asleep as they struggle with allergy symptoms. There’s room for many types of antihistamines, both past and present. And without Benadryl as inspiration, newer antihistamines, as well as many medications that treat non-allergy conditions, such as heartburn and depression, might not exist.
Landmark dedication and acknowledgments
Landmark dedication
The American Chemical Society (ACS) designated the discovery of the compound diphenhydramine hydrochloride, sold under the name Benadryl among others as a National Historic Chemical Landmark (NHCL) in a ceremony in Cincinnati, Ohio, on September 10, 2025. The commemorative plaque reads:
In a University of Cincinnati laboratory in the early 1940s, assistant professor George Rieveschl synthesized diphenhydramine hydrochloride to treat allergy symptoms. In 1946, the U.S. Food and Drug Administration approved the antihistamine, which was branded as Benadryl and sold by Parke-Davis, now part of Pfizer. Today, Benadryl is available from Kenvue. Without Rieveschl’s discovery of this allergy-symptom fighting drug, current motion sickness and antidepressant drugs may have never been discovered. Second- and third-generation antihistamines that don’t induce as much drowsiness are now commonplace as a result of the discovery of Benadryl.
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