Could antihistamines typically used for treating allergies help people with long COVID? Growing evidence indicates that it may.

Between mid-March of 2020 and mid-July of 2021, more than 900 postings described apparent relief of long-COVID symptoms from taking antihistamines within the Facebook group Survivor Corps, a virtual COVID-19 research and advocacy organization. Among them were two middle-aged women contacted for investigation by Natalie Lambert, a biostatistics and health data sciences research professor at Indiana University School of Medicine.

In a February 7, 2022 case study published in The Journal for Nurse Practitioners by Lambert and a team of other clinicians, the two women are described as contracting COVID-19 in 2020 and then living with a host of long-COVID symptoms after their infections had resolved. Symptoms included cognitive dysfunction, skin rashes and bruises, chest pain, and extreme fatigue. Far into their course of long COVID, the women began using antihistamines to treat unrelated allergies. To their surprise, they also began experiencing relief from their long-COVID symptoms. Today, both women take a daily regimen of antihistamines and say they’ve almost returned to normal functioning.

Their experiences support the results of an October 5, 2021 study in The Journal of Investigative Medicine (JIM), in which 26 of 49 long-COVID patients were treated with antihistamines. Of these 26 patients, 19 experienced complete or partial relief of their symptoms versus just six of the remaining 23 patients who felt improvement. 

Mast Cells Run Amuck?

When a foreign body such as a virus or allergen is sensed, the body’s immune cells release histamine that promotes inflammation and swelling. Besides allergic reactions, histamine also affects brain messaging, raises the heart rate, and can increase stomach acid.

Experts theorize that uncontrolled mast cells (a type of immune cell) may be the culprit in some long-COVID cases, releasing a torrent of histamine in the body following coronavirus infection, similar to what is seen in people with mast cell activation syndrome (MCAS). There’s evidence that antihistamines dial down mast cell activity, in addition to blocking histamine compounds from attaching to cell receptors. 

Dr. Lawrence Afrin, a senior hematology/oncology consultant at the AIM Center for Personalized Medicine, says there’s mounting evidence that antihistamines could be effective in treating long COVID. The only question is “the mechanism by which those drugs help.”

A Closer Look at the Case Studies

The first female case study patient likely became sick with COVID-19 in January 2020 and presented with symptoms including extreme fatigue, fever, dry cough, chest discomfort, mouth ulcers, and skin rash. Most of the symptoms resolved within 24 days, but the rashes, chest pain, and other symptoms persisted. After that, new symptoms, including cognitive impairment and bruising emerged, while older symptoms returned in waves. 

During this time of long COVID, about six months after her initial infection, the patient ate cheese to which she knows she is allergic and took the over-the-counter antihistamine Benadryl® as a precaution. Thus, the patient had no expectations of relieving her long-COVID symptoms, explains Melissa Pinto, first author of the case study and an associate nursing professor at the University of California, Irvine. 

The following day, she awoke with significantly less fatigue and better mental focus. When the effects began to wane after several days, she again took Benadryl, and her symptoms improved. She continued the drug daily for the next six months.

Noticing her results, one of her clinicians prescribed the stronger antihistamine Vistaril® (hydroxyzine pamoate). Taken daily, she experienced the following results after nine months:

• A near-complete resumption of exercise tolerance and resolution of chest pain, fatigue, and brain fog
• Steady improvement in bruises, headaches, and rashes
• A 90% return of pre-COVID functioning, allowing her to resume work and regular exercise

The second female patient had a similar experience using Benadryl and Allegra®.

Promising Treatment

Antihistamine treatment for long-COVID patients seems promising, though Pinto emphasizes that the drugs may not help everyone and hopes for continued research. Dr. Paul Glynne, medical director of London’s Physician’s Clinic and first author of the JIM study, believes antihistamines should be started for most long-COVID patients and sees “very little downside” to the medicines.

Since the JIM study, Glynne’s clinic has treated all their long-COVID patients (now in the hundreds) with an antihistamine combination of H1 blockers for inflammation and allergy symptoms, and H2 blockers for reducing stomach acid. Their results have been promising, with about 65%-70% of patients seeing improvement. Typically, rashes and gastrointestinal symptoms resolve first, while symptoms like brain fog and fatigue can take weeks to improve.

Glynne notes that about 10%-20% of his long-COVID patients see no results with antihistamines. And of those who respond well, not all symptoms may improve—particularly autonomic nervous system dysfunction that controls activity such as heart rate. He also doesn’t believe there will be “one single pathway that you block or target that’s going to simply treat what is obviously a complex problem.”

Nevertheless, while much more research is needed on antihistamines and long COVID, Pinto said the easily accessible drugs could provide immediate relief for some patients. She stressed that patients should consult their doctor about possible risks and drug interactions before using over-the-counter antihistamines.

*Lanese, N. (2022, February 16). Antihistamines to treat long COVID: What you need to know. Live Science. https://www.livescience.com/antihistamines-to-treat-long-covid-pasc

Much about the novel coronavirus, i.e., COVID-19, is still not fully understood. As research progresses and our knowledge of the virus increases, information can change rapidly. We strive to update all of our articles as quickly as possible, but there may occasionally be some lag between scientific developments and our revisions.