Understanding Drug Interactions: What Not to Take with Benadryl?

October 8, 2025 •

4 min read

Between 2019 and 2020, antihistamines were involved in 3.6% of all drug overdose deaths in the United States, with diphenhydramine (the active ingredient in Benadryl) being the most common [1.10.2]. Knowing what not to take with Benadryl is crucial for your safety.

Quick Summary

Benadryl (diphenhydramine) can cause dangerous interactions when mixed with alcohol, CNS depressants, certain antidepressants (like MAOIs), and other anticholinergic drugs. Combining them can lead to excessive drowsiness, impaired coordination, and slowed breathing.

Key Points

Alcohol: Do not mix Benadryl with alcohol, as both are CNS depressants that amplify drowsiness and impairment [1.4.3].
CNS Depressants: Avoid taking Benadryl with benzodiazepines, opioids, or prescription sleep aids to prevent dangerous levels of sedation [1.5.1].
MAOIs: A dangerous interaction can occur if Benadryl is taken with or within 14 days of using an MAOI antidepressant [1.6.4].
Anticholinergic Drugs: Combining Benadryl with other anticholinergics (like certain antidepressants or bladder medications) increases side effects like confusion and dry mouth [1.7.1].
Other Antihistamines: Never take Benadryl with other antihistamines (like Zyrtec or Claritin) to avoid an increased risk of side effects and overdose [1.9.1].
Check Labels: Always check the active ingredients in cold, flu, and sleep medications, as many contain diphenhydramine [1.2.4].
Consult a Professional: Always inform your doctor or pharmacist of all medications you are taking before starting Benadryl [1.2.2].

Benadryl, the brand name for the drug diphenhydramine, is a first-generation antihistamine commonly used to treat allergy symptoms, hives, motion sickness, and insomnia [1.11.1, 1.11.3]. Because it's available over-the-counter (OTC), many people assume it's safe to use in any situation. However, Benadryl is a powerful medication that can interact negatively with many other substances, leading to potentially dangerous side effects. Understanding these interactions is key to using it safely.

The Pharmacology of Benadryl (Diphenhydramine)

Diphenhydramine works by blocking histamine, a chemical your body releases during an allergic reaction [1.11.1]. As a first-generation antihistamine, it readily crosses the blood-brain barrier [1.5.1]. This action is what causes its well-known side effect of drowsiness. It also has anticholinergic properties, meaning it blocks the neurotransmitter acetylcholine, which can lead to side effects like dry mouth, blurred vision, constipation, and difficulty urinating [1.2.2]. These two mechanisms—central nervous system (CNS) depression and anticholinergic effects—are the primary reasons for its many drug interactions.

Major Interactions: What to Avoid with Benadryl

Combining Benadryl with other substances that have similar effects can amplify the risks. It is critical to avoid certain medications and substances to prevent excessive sedation, cognitive impairment, and other serious complications.

Central Nervous System (CNS) Depressants

CNS depressants are substances that slow down brain activity. When combined with Benadryl, the sedative effects are compounded, leading to a dangerous level of CNS depression. This can cause extreme drowsiness, impaired coordination and judgment, slowed breathing, and even loss of consciousness [1.4.2, 1.4.3].

Alcohol: This is one of the most critical interactions. Both Benadryl and alcohol are CNS depressants. Mixing them can severely impair your ability to drive or operate machinery and increases the risk of falls and accidents [1.4.3]. The combination can cause profound drowsiness, dizziness, and confusion [1.2.2].
Benzodiazepines: Medications prescribed for anxiety, seizures, or insomnia, such as alprazolam (Xanax), diazepam (Valium), and lorazepam (Ativan), should not be taken with Benadryl. The additive sedative effects can be dangerously potent [1.5.1].
Opioids: Prescription pain medications like oxycodone, hydrocodone, and morphine are also CNS depressants. Taking them with Benadryl significantly increases the risk of extreme sleepiness and respiratory depression [1.2.2].
Sleep Aids: Both prescription sleep medications (like zolpidem/Ambien) and other OTC sleep aids can have additive effects with Benadryl. Many OTC sleep products actually contain diphenhydramine as their active ingredient, increasing the risk of an accidental overdose if taken with Benadryl [1.2.2, 1.2.4].

Monoamine Oxidase Inhibitors (MAOIs)

MAOIs are a class of antidepressants that have a particularly dangerous interaction with Benadryl. Medications like phenelzine (Nardil) and tranylcypromine (Parnate) can prolong and intensify the anticholinergic effects of Benadryl [1.6.5]. Taking Benadryl within 14 days of using an MAOI is contraindicated and can lead to serious side effects [1.6.4].

Other Anticholinergic Drugs

Since Benadryl has strong anticholinergic properties, taking it with other medications that have similar effects can lead to an accumulation of side effects. This is often referred to as anticholinergic burden, which can be especially problematic for older adults [1.7.1].

Tricyclic Antidepressants (TCAs): Drugs like amitriptyline and nortriptyline have both sedative and anticholinergic effects, which are amplified when taken with Benadryl [1.6.2].
Certain Antipsychotics: Medications such as quetiapine (Seroquel) and olanzapine (Zyprexa) can increase drowsiness, confusion, and constipation when combined with Benadryl [1.2.2].
Overactive Bladder Medications: Drugs like oxybutynin and tolterodine work by blocking acetylcholine. Combining them with Benadryl increases the risk of dry mouth, constipation, urinary retention, and blurred vision [1.2.3, 1.2.5].
Parkinson's Disease Medications: Some drugs for Parkinson's, like benztropine, also have anticholinergic effects [1.2.2].

Other Antihistamines

You should never take Benadryl with other antihistamines, including newer-generation ones like cetirizine (Zyrtec) or loratadine (Claritin), unless directed by a doctor [1.9.1]. Doing so increases the risk of side effects and potential antihistamine overdose. Always check the labels of multi-symptom cold and flu products, as many contain diphenhydramine or another antihistamine [1.2.4].


Drug/Substance Class	Examples	Primary Risk of Interaction with Benadryl
CNS Depressants	Alcohol, Benzodiazepines (Xanax, Valium), Opioids (Oxycodone)	Increased sedation, drowsiness, impaired coordination, slowed breathing [1.2.2, 1.5.1]
MAOIs	Phenelzine (Nardil), Isocarboxazid (Marplan)	Intensifies and prolongs anticholinergic effects; considered a dangerous interaction [1.6.4, 1.6.5]
Anticholinergic Drugs	Tricyclic Antidepressants, Oxybutynin, some Antipsychotics	Additive effects like dry mouth, blurred vision, urinary retention, confusion [1.7.1]
Other Antihistamines	Cetirizine (Zyrtec), Loratadine (Claritin), Hydroxyzine	Increased risk of side effects and antihistamine overdose [1.9.1, 1.9.2]
Certain Antidepressants	SSRIs (Zoloft, Prozac), SNRIs (Cymbalta), Trazodone	May increase drowsiness, confusion, and risk of serotonin syndrome [1.8.1, 1.8.2]

Conclusion: Prioritize Safety

While Benadryl is an effective and accessible medication, it is not without risks. Its sedative and anticholinergic properties create a high potential for interactions with a wide range of substances, most notably alcohol and other CNS depressants. Always read medication labels carefully, especially for multi-symptom products, to avoid accidentally doubling up on diphenhydramine or other antihistamines. Before taking Benadryl, inform your doctor or pharmacist about all other prescription medications, OTC drugs, and supplements you are using to prevent potentially harmful interactions. When in doubt, seek professional medical advice.

Authoritative Link: For more detailed information on diphenhydramine, you can visit the National Library of Medicine's resource page: https://www.ncbi.nlm.nih.gov/books/NBK526010/

Frequently Asked Questions

Yes, it is generally safe to take Benadryl with standard pain relievers like acetaminophen (Tylenol) or ibuprofen (Advil) [1.9.1]. However, be aware of combination products like Advil PM or Tylenol PM, which already contain diphenhydramine [1.2.2].

No, it is not recommended. Benadryl's effects can last for 4-6 hours, and its half-life is even longer [1.4.2, 1.11.3]. It's best to wait until the medication has completely cleared your system, which can take up to two days [1.4.5].

Combining Benadryl with SSRI antidepressants like Zoloft can increase side effects such as drowsiness, dizziness, confusion, and difficulty concentrating [1.8.2]. In rare cases, it could contribute to serotonin syndrome [1.8.1].

No, you should not take Benadryl and another antihistamine like Zyrtec or Claritin together unless specifically instructed by a doctor. Doing so increases the risk of side effects and potential overdose [1.9.1, 1.9.2].

Both Benadryl and prescription sleeping pills (like Ambien) are sedatives. Taking them together can cause excessive central nervous system depression, leading to extreme drowsiness, impaired coordination, and slowed breathing [1.2.2, 1.5.1].

Benadryl can increase the side effects of certain blood pressure medications like metoprolol, leading to dizziness or a slowed heart rate [1.2.2]. While Benadryl itself doesn't raise blood pressure, many combination cold medicines it's found in also contain decongestants that can [1.2.2].

Older adults are more sensitive to Benadryl's side effects, including confusion, drowsiness, memory problems, and an increased risk of falls [1.2.2]. The American Geriatrics Society generally recommends that older adults avoid diphenhydramine [1.11.4].