What Drugs Cannot Be Taken With Antihistamines?

October 12, 2025 •

4 min read

According to the Cleveland Clinic, first-generation antihistamines are a common cause of drug overdose, often happening when they are mistakenly combined with other medications. This makes understanding what drugs cannot be taken with antihistamines a critical safety measure for anyone using these common allergy and cold remedies.

Quick Summary

Combining antihistamines with certain medications can cause serious adverse effects. This guide details potentially dangerous interactions with CNS depressants like alcohol and opioids, other allergy products, anticholinergic drugs, and specific foods. The article distinguishes between first- and second-generation antihistamines, outlining safety precautions and when to seek medical advice.

Key Points

Avoid CNS Depressants: Do not combine sedating antihistamines with alcohol, opioids, or prescription sleep aids to prevent severe drowsiness, dizziness, and breathing problems.
Check Active Ingredients: Always read the labels of cold and flu products, as many contain hidden antihistamines; taking multiple products with the same active ingredient can lead to an overdose.
Beware of First-Gen Effects: Older, first-generation antihistamines like Benadryl have significant CNS and anticholinergic effects, increasing the risk of adverse interactions with medications like certain antidepressants.
Take Fexofenadine with Water Only: If you take fexofenadine (Allegra), avoid fruit juices like grapefruit, orange, and apple juice, as they can significantly reduce the medication's effectiveness.
Consult a Professional: Discuss all medications, including OTCs and supplements, with a healthcare provider or pharmacist before starting an antihistamine to check for potential and specific interactions.
Second-Gen are Safer for Sedation: Newer, non-sedating antihistamines like Claritin and Zyrtec are generally safer to combine with other medications because they do not readily cross the blood-brain barrier.
Separate from Antacids: Antacids containing magnesium or aluminum can hinder the absorption of fexofenadine; separate administration by a few hours to ensure proper efficacy.

Antihistamines are a diverse class of drugs used to treat allergic reactions, cold symptoms, and sometimes for sleep or motion sickness. These medications work by blocking histamine, a compound involved in allergic responses. However, their interaction with other substances can lead to amplified side effects, reduced effectiveness, or dangerous health complications. The key to safe usage lies in understanding which specific drugs and substances to avoid based on the type of antihistamine.

First-Generation vs. Second-Generation Antihistamines

Before exploring specific interactions, it is essential to distinguish between the two primary types of antihistamines:

First-Generation (Sedating): These older antihistamines, such as diphenhydramine (Benadryl) and doxylamine (Unisom), easily cross the blood-brain barrier. This allows them to act on the central nervous system (CNS), causing drowsiness and other side effects. Their CNS activity is the primary reason for many significant drug interactions.
Second-Generation (Non-Sedating): Newer antihistamines, like cetirizine (Zyrtec), loratadine (Claritin), and fexofenadine (Allegra), are less lipophilic and don't cross the blood-brain barrier as readily. This results in fewer CNS side effects and a lower risk of interactions with other sedating medications, though caution is still necessary.

Central Nervous System Depressants

Combining antihistamines, especially first-generation types, with other CNS depressants can lead to excessive sedation, impaired coordination, and slowed breathing, which can be life-threatening.

Alcohol

Alcohol enhances the sedative effects of antihistamines, even newer ones that are generally less drowsy. This combination can cause significant drowsiness, dizziness, impaired motor skills, and confusion, increasing the risk of accidents.

Opioid Pain Medications

Opioids (e.g., oxycodone, tramadol, morphine) and sedating antihistamines both suppress the CNS. The combined effect can cause dangerously low blood pressure, severe sleepiness, and life-threatening respiratory depression.

Sleep Aids

Many over-the-counter (OTC) sleep aids, including some Tylenol PM and Advil PM products, contain diphenhydramine. Taking a separate antihistamine alongside these products can lead to a dangerous overdose of the same active ingredient. Prescription sleep medications (e.g., zolpidem, eszopiclone) and sedating antihistamines should also not be mixed.

Benzodiazepines and Muscle Relaxers

Benzodiazepines (e.g., alprazolam, lorazepam) and muscle relaxers (e.g., cyclobenzaprine) are other powerful CNS depressants. Mixing them with sedating antihistamines intensifies effects like drowsiness and confusion.

Other Interacting Medications

Other Antihistamine Products

It's important to read all labels carefully, as many cold, flu, and combination products contain an antihistamine. Taking multiple products with antihistamines at once can increase side effects and the risk of overdose.

Anticholinergic Drugs

First-generation antihistamines possess anticholinergic properties, and combining them with other medications that block acetylcholine can produce severe side effects. This can worsen effects such as dry mouth, constipation, blurry vision, and difficulty urinating. Examples include some antidepressants and medications for overactive bladder or Parkinson's disease.

Antidepressants

Certain antidepressants, particularly older tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), can interact with antihistamines. TCAs have sedating and anticholinergic effects that are compounded by antihistamines. MAOIs also share sedating side effects.

Antacids

For the non-sedating antihistamine fexofenadine (Allegra), antacids containing aluminum or magnesium can reduce its absorption. To avoid this, it is recommended to take antacids and fexofenadine at different times, separated by at least two hours.

Antibiotics and Antifungals

Some antibiotics (e.g., erythromycin) and antifungals (e.g., ketoconazole) can significantly increase the concentration of certain antihistamines in the blood, leading to a higher risk of side effects. While older antihistamines were the main concern, interactions can still occur with some newer ones like fexofenadine.

Food and Lifestyle Interactions

Fruit Juice

Fruit juices like grapefruit, orange, and apple juice can interfere with the absorption of fexofenadine (Allegra). To ensure maximum effectiveness, avoid taking fexofenadine with these juices and instead use water.

Cannabis

Similar to alcohol and other CNS depressants, cannabis can amplify the sedative effects of antihistamines, leading to increased drowsiness, dizziness, and confusion.

Comparison Table: First-Generation vs. Second-Generation Antihistamine Interactions


Interaction Type	First-Generation (e.g., Benadryl)	Second-Generation (e.g., Claritin, Zyrtec)
Alcohol	Significant Risk. Intensified drowsiness, dizziness, and impaired coordination.	Low to Moderate Risk. Risk of sedation is lower but still possible; caution is advised.
Opioids	Significant Risk. Extreme sedation, breathing difficulties, and overdose risk.	Low to Moderate Risk. Lower risk of severe CNS depression compared to first-gen.
Sleep Aids	Significant Risk. Extreme drowsiness and potential overdose if product contains diphenhydramine.	Moderate Risk. Can increase drowsiness if other sleep aids are used.
Anticholinergics	Significant Risk. Worsened anticholinergic side effects like dry mouth and constipation.	Low Risk. Less pronounced anticholinergic activity and lower risk of these side effects.
Antidepressants	Significant Risk. Increased sedation and anticholinergic effects with certain classes (TCAs, MAOIs).	Moderate Risk. Some SSRIs/SNRIs can cause drowsiness, and this effect can be worsened.
Antacids (Magnesium/Aluminum)	Low Risk. No significant interaction reported.	Significant Risk. Can decrease absorption and efficacy of fexofenadine (Allegra).

Conclusion

Understanding potential drug interactions is vital for safe medication use. First-generation antihistamines, due to their effect on the central nervous system, have more significant interactions, particularly with other sedating substances like alcohol, opioids, and certain antidepressants. While second-generation antihistamines are generally safer in this regard, specific interactions with antacids or fruit juice can affect their efficacy, and they can still cause increased drowsiness when combined with other CNS depressants. Always read medication labels carefully and, when in doubt, consult a pharmacist or doctor. Keeping a current list of all medications, including OTC products, is the best way to prevent potentially dangerous interactions and ensure the best treatment outcome. For further reading on safe medication practices, the National Institutes of Health (NIH) offers detailed information on drug interactions.

Visit the NIH for more information

Frequently Asked Questions

No, you should not combine sedating antihistamines like Benadryl (diphenhydramine) with benzodiazepines such as Xanax (alprazolam). Both are central nervous system depressants, and taking them together can cause extreme drowsiness, confusion, and impaired coordination.

No, it is not safe to mix any antihistamine with alcohol. Both are CNS depressants, and the combination can lead to dangerous levels of sedation, dizziness, and poor motor skills, increasing the risk of accidents.

Unless directed by a healthcare professional, you should not take multiple antihistamines simultaneously. This can increase the risk of side effects like excessive drowsiness, dry mouth, and blurry vision.

No, but fruit juices like grapefruit, orange, and apple can significantly reduce the absorption and effectiveness of fexofenadine (Allegra). This interaction is specific to fexofenadine and generally does not affect other antihistamines.

Always check the labels of cold and flu products for active ingredients. Many multi-symptom products already contain an antihistamine. Taking an additional antihistamine, such as a separate allergy pill, would be a form of double-dosing and could lead to overdose.

Yes. Some older antihistamines had serious interactions with macrolide antibiotics like erythromycin and antifungals like ketoconazole, though these antihistamines are no longer common. However, some modern antihistamines like fexofenadine can still have increased side effects when combined with these drugs.

If you are taking a first-generation (sedating) antihistamine, you should not drive or operate heavy machinery. These drugs can cause drowsiness and impair judgment. Even non-sedating antihistamines can cause drowsiness in some individuals, so it is important to know how your body reacts before driving.