Benadryl Drug Interactions: What to Avoid and What to Tell Your Doctor

Benadryl (diphenhydramine) may be available over the counter, but that doesn't mean it's without risk. Diphenhydramine has significant interactions with a number of common medications — some of which can be dangerous. Before taking Benadryl, it's important to review your current medications with your pharmacist or doctor.

Why Does Benadryl Have So Many Drug Interactions?

Diphenhydramine interacts with other drugs through two main pathways:

Pharmacodynamic interactions: Diphenhydramine has CNS depressant and anticholinergic effects. Any other drug with these properties will have additive effects when combined with diphenhydramine — making both effects stronger.

Pharmacokinetic interactions (CYP2D6): Diphenhydramine is metabolized by and inhibits the CYP2D6 enzyme in the liver. This can increase blood levels of other drugs metabolized by CYP2D6.

Dangerous Combinations: Avoid These with Benadryl

1. Alcohol

Alcohol and diphenhydramine both depress the central nervous system. Combining them significantly increases sedation, impaired coordination, slowed reaction time, and judgment impairment. This combination can be dangerous when driving or operating machinery. Even moderate alcohol consumption (1–2 drinks) substantially increases the risk.

2. Opioid Pain Medications

Combining diphenhydramine with opioids (oxycodone, hydrocodone, codeine, morphine, tramadol, fentanyl) creates additive CNS and respiratory depression. This combination increases the risk of dangerous respiratory depression, overdose, and death. The FDA has issued warnings about combining antihistamines with opioids. If you are prescribed opioids for any reason, talk to your doctor before taking Benadryl.

3. MAO Inhibitors (MAOIs)

MAO inhibitors including phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), and selegiline (Emsam) prolong and intensify the anticholinergic effects of diphenhydramine. This combination can cause severe anticholinergic toxicity — extreme dry mouth, urinary retention, confusion, rapid heart rate, hyperthermia, and seizures. Do not take Benadryl if you are on a MAOI or within 14 days of stopping one.

4. Benzodiazepines and Sleep Medications

Benzodiazepines (Xanax, Ativan, Klonopin, Valium), Z-drugs (Ambien, Lunesta), and prescription sleep medications all have CNS depressant effects. Combining them with diphenhydramine adds to sedation and respiratory depression risk. Do not take Benadryl as a sleep aid if you are already taking a prescription sleep or anxiety medication without physician guidance.

5. Thioridazine (Mellaril)

Diphenhydramine inhibits CYP2D6, the liver enzyme that metabolizes thioridazine (an antipsychotic). This inhibition can significantly increase thioridazine blood levels, raising the risk of dangerous cardiac arrhythmias including QT prolongation and torsade de pointes. This combination should be avoided.

Important Caution: Gabapentinoids

Gabapentin (Neurontin) and pregabalin (Lyrica) are increasingly prescribed for pain, nerve damage, and anxiety. Both increase CNS sedation and can combine with diphenhydramine to cause dangerous respiratory depression. With millions of prescriptions for these drugs written annually, this is a particularly common and underappreciated interaction. Alert your doctor or pharmacist if you are taking either of these and need to use Benadryl.

Additive Anticholinergic Medications

Any medication with anticholinergic properties will add to diphenhydramine's anticholinergic effects. This can produce anticholinergic syndrome at doses that would be individually tolerable. Common medications with anticholinergic properties include:

Tricyclic antidepressants: amitriptyline (Elavil), nortriptyline, imipramine

Bladder medications: oxybutynin (Ditropan), tolterodine (Detrol), solifenacin (VESIcare)

First-generation antipsychotics: chlorpromazine, haloperidol

Some antidiarrheal medications: scopolamine

Other antihistamines: hydroxyzine (Vistaril), promethazine

Doubling Up on Diphenhydramine Products

Many OTC medications contain diphenhydramine as a hidden ingredient. If you take Benadryl for allergies and also take one of the following for another reason, you could be accidentally taking double the intended dose:

ZzzQuil (sleep) — contains diphenhydramine 50 mg

Unisom SleepGels (sleep) — contains diphenhydramine 50 mg

Tylenol PM, Advil PM, Aleve PM (pain + sleep) — contain diphenhydramine 25 mg

Benadryl Plus Congestion (allergy + decongestant) — contains diphenhydramine

Some nighttime cold formulas (NyQuil, etc.) — some versions contain diphenhydramine; check the label

What to Tell Your Doctor or Pharmacist

Before taking Benadryl, tell your healthcare provider or pharmacist if you are taking:

Any prescription sedatives, sleep aids, or anti-anxiety medications

Any opioid pain medications

Any MAO inhibitors or antidepressants

Any antipsychotic medications

Any bladder or incontinence medications

Any other OTC products that may contain diphenhydramine

For more on Benadryl's side effects and safety, see our Benadryl side effects guide. If you need to find Benadryl or a safer alternative at a pharmacy near you, medfinder can help.