What Cannot Be Mixed with Diphenhydramine?: A Guide to Dangerous Drug Interactions

October 11, 2025 •

3 min read

Over 60 million Americans use antihistamines like diphenhydramine (commonly known as Benadryl) to treat allergies or sleeplessness every year. While widely available over the counter, it is critical to know what cannot be mixed with diphenhydramine due to its potential for severe drug interactions and amplified side effects.

Quick Summary

This guide details the substances and medications that should not be combined with diphenhydramine, outlining specific drug-drug interactions and explaining why these combinations pose a serious health risk.

Key Points

Avoid Alcohol and Other CNS Depressants: Never combine diphenhydramine with alcohol, opioids, or benzodiazepines, as this can cause dangerous levels of sedation, respiratory depression, and increase overdose risk.
Prevent Antihistamine Overdose: Do not take diphenhydramine with other antihistamines, including non-drowsy allergy medicines, or combination cold and flu products, to avoid an overdose.
Be Cautious with Antidepressants: Certain antidepressants, especially older ones like TCAs and MAOIs, can cause severe side effects like extreme drowsiness and confusion when mixed with diphenhydramine.
Consult a Doctor for Pre-existing Conditions: If you have conditions like glaucoma, an enlarged prostate, breathing issues, or heart problems, consult a healthcare provider before using diphenhydramine, as it can worsen these conditions.
Read All Labels Carefully: Always check the active ingredients of any medication, including OTC cold remedies and sleep aids, to ensure you don't accidentally double-dose or combine with a similar substance.
Avoid Certain Herbal Supplements: Natural remedies such as Valerian root and St. John's Wort can increase diphenhydramine's sedative effects and should be avoided.
Mind Impaired Driving and Activities: Recognize that diphenhydramine, especially when combined with other substances, can significantly impair judgment, coordination, and reaction times. Avoid driving or operating heavy machinery.

Diphenhydramine is a first-generation antihistamine that acts as a central nervous system (CNS) depressant, meaning it slows brain activity. This sedative effect is responsible for both its ability to relieve allergy symptoms and its potential for dangerous interactions. Mixing it with other substances that also depress the CNS, or with medications that can compound its side effects, can lead to serious consequences, including extreme drowsiness, impaired coordination, and slowed breathing.

Combining with Central Nervous System (CNS) Depressants

Mixing diphenhydramine with other substances that also slow down the CNS is one of the most critical and common mistakes, amplifying sedative and depressant effects.

Alcohol

Combining diphenhydramine with alcohol is dangerous and should be avoided due to the risk of dangerously high sedation. This can lead to intensified drowsiness, impaired coordination, life-threatening respiratory depression, and increased overdose risk.

Prescription Sedatives, Opioids, and Muscle Relaxers

Prescription medications with CNS-depressing effects can be dangerously amplified by diphenhydramine. Combining diphenhydramine with sleep aids like zolpidem or eszopiclone, opioids such as morphine or oxycodone, or benzodiazepines like diazepam or alprazolam increases the risk of excessive sedation, confusion, slowed breathing, and impaired motor skills. Many over-the-counter sleep aids also contain diphenhydramine, increasing the risk of overdose.

Mixing with Other Anticholinergic Medications

Diphenhydramine has anticholinergic effects, causing side effects like dry mouth and blurred vision. Combining it with other anticholinergic drugs can intensify these effects and increase the risk of confusion, especially in older adults.

Antidepressants

Certain antidepressants, particularly tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), can interact with diphenhydramine. Combining diphenhydramine with TCAs can cause excessive sedation and confusion, while MAOIs can significantly increase diphenhydramine's side effects and should be avoided.

Potential Interactions with Common Medications and Supplements

Other Antihistamines and Allergy Medicines

Many cold and flu remedies contain antihistamines or diphenhydramine. Combining diphenhydramine with other antihistamines, even non-drowsy ones, can lead to an overdose and amplified side effects. Always read labels to avoid double-dosing.

Herbal Supplements

Certain herbal products with sedative properties can interact with diphenhydramine. Combining diphenhydramine with Valerian root or St. John's Wort can lead to dangerous levels of drowsiness. Melatonin can also cause excessive sleepiness when mixed with diphenhydramine.

Specific Health Conditions

Diphenhydramine can exacerbate certain medical conditions. Individuals with glaucoma, enlarged prostate, breathing problems like asthma or COPD, or heart disease should consult a doctor before use. The American Geriatrics Society advises against using first-generation antihistamines in older adults due to increased fall risk and memory issues.

Comparison of Common Diphenhydramine Interactions


Interaction Type	Examples	Primary Effect	Associated Risk Level
Alcohol	Beer, Wine, Spirits	Severe CNS depression, sedation	High: Potential for respiratory depression, overdose, and fatal accidents
Opioids	Oxycodone, Fentanyl	Exaggerated sedation, impaired breathing	High: Life-threatening respiratory depression and overdose risk
Other Antihistamines	Zyrtec, Claritin, Promethazine	Antihistamine overload, amplified side effects	Moderate to High: Increased drowsiness, confusion, and risk of overdose
Benzodiazepines	Xanax, Valium	Dangerous CNS depression, coordination loss	High: Significant impairment of motor skills and judgment
Tricyclic Antidepressants	Amitriptyline, Nortriptyline	Extreme drowsiness, dry mouth, confusion	High: Potentiated anticholinergic and sedative effects

Conclusion

While diphenhydramine effectively relieves allergies and sleep issues, combining it with other substances, particularly CNS depressants, poses significant risks. Dangerous interactions can occur with alcohol, opioids, benzodiazepines, certain antidepressants, other antihistamines, and some herbal supplements. Always read medication labels, check for potential interactions, and consult a healthcare professional before combining diphenhydramine with any other substance to ensure your safety.

Frequently Asked Questions

No, it is medically advisable to abstain from alcohol completely when taking diphenhydramine. Both substances are CNS depressants, and combining them significantly intensifies side effects like drowsiness, impaired coordination, and slowed breathing, even in small amounts.

No, you should not take diphenhydramine with other allergy medications like loratadine (Claritin) or cetirizine (Zyrtec), as this can lead to an overdose of antihistamines. Many cold and flu products also contain diphenhydramine, so always check the label.

It depends on the antidepressant, but extreme caution is required. Combining diphenhydramine with certain antidepressants, such as TCAs or MAOIs, can lead to severe sedation and other side effects. Always consult your doctor or pharmacist about potential interactions.

If you experience severe symptoms such as extreme drowsiness, confusion, breathing difficulties, or loss of consciousness, seek emergency medical attention immediately. For less severe effects, stop taking the medication and rest in a safe environment, then contact a healthcare professional for guidance.

No, diphenhydramine should only be used for short-term sleep issues. Long-term use is not recommended and has been associated with progressive memory impairment and an increased risk of dementia, particularly in older adults.

Yes, several herbal supplements can interact negatively. You should avoid supplements with sedative effects like valerian root and St. John's Wort, as they can increase drowsiness when combined with diphenhydramine.

Older adults are at a higher risk of severe sedation, confusion, impaired motor skills, and falls when taking diphenhydramine. They may also experience worsening symptoms of pre-existing conditions like glaucoma or an enlarged prostate.