Why Do Some Antihistamines Make You Sleepy?

The arrival of allergy season often means a trip to the pharmacy to find relief from sneezing, itching, and a runny nose. With dozens of options on the shelf, a primary decision often rises: “Do I buy the one that makes me sleepy, or the one that doesn’t?” This simple choice points to a fundamental and fascinating difference in how these common medications work. While both types of antihistamines combat the same symptoms, their side effects on the brain are a result of a decades-long evolution in pharmaceutical science.

This article will delve into the science behind antihistamine side effects, explaining what histamine is, how different generations of drugs interact with your body, and the one difference in their chemical structure that determines whether your allergy pill will make you want to go to bed or go about your day.

To understand how antihistamines work, we must first understand histamine. Histamine is a chemical produced by your immune system and stored in immune cells called mast cells and basophils. When your body encounters an allergen such as pollen, pet dander, or dust, these cells release histamine into the bloodstream.

Histamine then travels to various parts of the body and binds to specific receptors on the surface of cells, called histamine receptors. It is this binding that triggers the classic allergy symptoms:

• In the nose, histamine leads to itching, sneezing, and a runny nose.
• In the eyes, it causes redness, swelling, and itchiness.
• In the skin, it causes hives and rashes.

Antihistamines work by doing exactly what their name implies: they block these histamine receptors, preventing histamine from binding to them and, therefore, preventing the symptoms. ^[1] The type of antihistamine used for allergies targets the H1 histamine receptors.

The first antihistamines developed, starting in the 1930s, are known as first-generation H1 blockers. These medications are effective at treating allergy symptoms, but they come with a well-known and often unwanted side effect: drowsiness.

• Diphenhydramine (brand name: Benadryl)
• Chlorpheniramine (brand name: Chlor-Trimeton)
• Doxylamine (found in some over-the-counter sleep aids)

The science behind their sedative effect lies in their chemical structure. First-generation antihistamines are lipophilic, meaning they are fat-soluble. This allows them to easily cross the blood-brain barrier (BBB), a protective filter of tightly packed cells that prevents many substances from entering the brain. ^[2]

Once these drugs cross the BBB, they begin to block the H1 histamine receptors in the brain. In the brain, histamine is not a cause of allergy symptoms; instead, it is a key neurotransmitter that promotes wakefulness, alertness, and attention. By blocking these receptors, the drugs interfere with the brain’s natural wakefulness signals, causing a sedative effect that leads to drowsiness and a feeling of being “out of it”.

In addition to drowsiness, first-generation antihistamines can cause other side effects due to their interaction with other receptors in the body, particularly muscarinic acetylcholine receptors. This can lead to what are known as anticholinergic side effects, including:

• Dry mouth
• Blurred vision
• Dizziness
• Constipation

By the 1980s, pharmaceutical researchers had recognized the problem of drowsiness and set out to create more targeted drugs. The result was the development of second-generation H1 blockers, which are now the most recommended choice for daytime allergy relief.

• Cetirizine (brand name: Zyrtec)
• Loratadine (brand name: Claritin)
• Fexofenadine (brand name: Allegra)

The difference with these newer drugs is their chemical structure. Second-generation antihistamines are designed to be larger and more hydrophilic (water-soluble). This chemical profile makes it extremely difficult for them to pass through the protective blood-brain barrier.

Because they cannot enter the brain, they are unable to block the wakefulness-promoting histamine receptors there. Instead, they primarily act on the H1 receptors in the rest of the body, providing effective relief from sneezing, itching, and a runny nose without causing a sedative effect. This targeted action is what makes them “non-drowsy” for the vast majority of people. ^[4]

While second-generation antihistamines are generally considered non-drowsy, there are some important nuances. For example, some individuals may experience mild sedation from cetirizine (Zyrtec) at higher doses. This may be due to individual differences in metabolism or a slightly greater ability of this drug to penetrate the BBB compared to others in its class.

Choosing the right antihistamine depends on your specific needs and a careful consideration of the side effects.

• For Daytime Relief: If you need to be alert for work, driving, or school, opt for a second-generation, non-drowsy antihistamine like loratadine, cetirizine, or fexofenadine.
• For Nighttime Relief: If your allergy symptoms are interfering with your sleep, a first-generation antihistamine can be a viable option, as its sedative effect may help you get a full night’s rest. However, be aware of the other side effects.
• As a Sleep Aid: Many over-the-counter sleep aids contain diphenhydramine or doxylamine. While effective for short-term use, experts do not recommend long-term use due to the risk of tolerance and other side effects. ^[5]
• Consult a Professional: Always talk to a doctor or pharmacist to choose the right medication. This is especially important for children, seniors, or those with underlying health conditions, as some antihistamines can have dangerous interactions with other medications.