Understanding Benadryl (Diphenhydramine)
Benadryl is the brand name for diphenhydramine, a first-generation antihistamine used to treat allergy symptoms, hives, insomnia, and motion sickness [1.2.1, 1.4.5]. It works by blocking histamine receptors in the body [1.4.2]. Because it crosses the blood-brain barrier, it also acts on the central nervous system (CNS), which causes its well-known side effect of drowsiness [1.4.2]. This CNS effect is central to why it interacts negatively with many other substances. The active ingredient, diphenhydramine, is also found in many combination over-the-counter (OTC) products like Advil PM, Aleve PM, and Tylenol PM [1.3.4, 1.4.2]. It is critical to read labels carefully to avoid accidentally taking a double dose of diphenhydramine [1.6.1].
The Most Dangerous Combination: Benadryl and Alcohol
Mixing alcohol and Benadryl is strongly advised against by health professionals [1.2.2]. Both are central nervous system (CNS) depressants, meaning they slow down brain activity [1.5.2, 1.6.2]. When taken together, their effects are amplified, leading to a range of dangerous symptoms [1.6.3].
Risks of mixing Benadryl and Alcohol include:
- Intensified Drowsiness and Sedation: The primary risk is a significant increase in sleepiness and sedation, which can impair your ability to perform tasks that require alertness, such as driving [1.5.2, 1.2.1].
- Impaired Motor Skills and Coordination: The combination can lead to dizziness, unsteadiness, and poor motor control, increasing the risk of falls and accidents, especially in older adults [1.5.2, 1.4.2].
- Cognitive Impairment: Users may experience confusion, brain fog, and difficulty concentrating [1.2.2, 1.6.3]. Benadryl is an anticholinergic drug, which blocks the neurotransmitter acetylcholine, essential for memory and learning. Alcohol also impairs these functions, and combining them can worsen these effects [1.5.5].
- Respiratory Depression: In severe cases, the combination can slow breathing to dangerous levels [1.2.2].
- Increased Risk of Overdose: Combining these substances can lead to an overdose, with symptoms like hallucinations, seizures, and loss of consciousness [1.2.1, 1.5.4].
It's important to be aware of hidden sources of alcohol in other medications, such as some cough syrups and laxatives, which can contain up to 10% alcohol [1.5.2, 1.5.5].
Major Drug Classes to Avoid with Benadryl
Beyond alcohol, numerous prescription and over-the-counter medications can interact negatively with Benadryl. The primary concern is additive CNS depression and anticholinergic effects.
Central Nervous System (CNS) Depressants
This is the broadest and most critical category of interacting medications. Since Benadryl is itself a CNS depressant, combining it with others amplifies sedative effects and risks [1.6.5].
- Opioids: Pain medications like oxycodone, hydrocodone, morphine, and fentanyl have sedative effects. Taking them with Benadryl can lead to extreme sleepiness, respiratory depression, low blood pressure, and even death [1.3.2, 1.6.2].
- Benzodiazepines: Prescribed for anxiety, seizures, or insomnia, drugs like alprazolam (Xanax), diazepam (Valium), and lorazepam (Ativan) should not be taken with Benadryl. Both cause sedation, and combining them can lead to amplified effects, confusion, and impaired coordination [1.6.1, 1.9.4].
- Sleep Aids (Sedative-Hypnotics): Prescription sleep medications like zolpidem (Ambien) and eszopiclone (Lunesta), as well as many OTC sleep aids, should not be mixed with Benadryl. Many OTC sleep aids actually contain diphenhydramine, increasing the risk of overdose [1.3.4, 1.9.4].
- Muscle Relaxers: Medications like cyclobenzaprine can cause drowsiness, an effect that is heightened when mixed with Benadryl [1.2.5].
Antidepressants
Several classes of antidepressants can interact with Benadryl, increasing side effects like drowsiness, dry mouth, and confusion [1.2.2].
- Monoamine Oxidase Inhibitors (MAOIs): This is a particularly dangerous interaction. MAOIs like phenelzine (Nardil) and isocarboxazid (Marplan) prolong and intensify the anticholinergic effects of Benadryl. Many manufacturers consider use within 14 days of an MAOI to be a contraindication [1.7.2, 1.7.3].
- Tricyclic Antidepressants (TCAs): Drugs like amitriptyline (Elavil) are closely related to antihistamines and also cause sedation. Combining them with Benadryl can lead to excessive sedation, blurred vision, and dry mouth [1.6.1, 1.3.5].
- SSRIs and SNRIs: Medications like sertraline (Zoloft), paroxetine (Paxil), and duloxetine (Cymbalta) can cause drowsiness, which is increased when taken with Benadryl [1.2.2, 1.6.1].
Other Antihistamines and Anticholinergic Drugs
- Other Antihistamines: You should never take Benadryl with other antihistamines like cetirizine (Zyrtec), loratadine (Claritin), or hydroxyzine (Vistaril) unless directed by a doctor. Doing so increases the risk of side effects and overdose [1.2.2, 1.3.1]. Also, avoid combination cold and cough remedies that already contain an antihistamine [1.2.4].
- Anticholinergic Drugs: Benadryl has anticholinergic properties. Combining it with other drugs that have similar effects—such as medications for overactive bladder (oxybutynin), Parkinson's disease (benztropine), or some antipsychotics—can increase the risk of dry mouth, constipation, urinary retention, blurred vision, and confusion [1.3.4, 1.8.4].
Comparison of Benadryl Alone vs. Mixed
| Feature | Benadryl (Alone) | Benadryl + CNS Depressant (e.g., Alcohol, Opioids) |
|---|---|---|
| Primary Effect | Allergy relief, sedation [1.2.1] | Profound Sedation & CNS Depression [1.5.2] |
| Cognitive Impact | Drowsiness, possible confusion, impaired coordination [1.4.1] | Severe confusion, dizziness, memory impairment, poor judgment [1.6.3, 1.5.5] |
| Physical Risks | Dry mouth, constipation, blurred vision [1.4.4] | Significantly increased risk of falls, accidents, slowed breathing, overdose, and death [1.5.2, 1.3.2] |
| Driving/Operating Machinery | Not recommended [1.4.4] | Extremely Dangerous and must be avoided [1.5.2] |
Other Notable Interactions
- Natural Supplements: Be cautious with supplements that cause drowsiness, such as melatonin, valerian root, kava, and ashwagandha, as they can lead to excessive sleepiness when combined with Benadryl [1.10.1, 1.10.3].
- Grapefruit Juice: Grapefruit juice can affect how the body absorbs certain medications. For some antihistamines, it can block transporters in the intestine, reducing the drug's effectiveness [1.11.3, 1.11.4].
- Cannabis: Combining cannabis with Benadryl can increase side effects like drowsiness, dizziness, and difficulty concentrating [1.3.4, 1.6.3].
Who Should Be Especially Cautious?
Certain individuals should avoid Benadryl or use it only after consulting a healthcare provider due to increased risks [1.4.2]. This includes people with:
- Narrow-angle glaucoma
- Breathing problems like asthma or chronic bronchitis
- Enlarged prostate or urinary retention issues
- Heart disease or high blood pressure
- Dementia, as long-term use of anticholinergics has been associated with increased dementia risk [1.8.2].
- Older adults (65+) are more sensitive to side effects like confusion, dizziness, and falls [1.4.2].
Conclusion: Prioritize Safety
While Benadryl is an effective and easily accessible medication, its potential for serious interactions cannot be overlooked. The most critical rule is to avoid mixing it with alcohol and other CNS depressants, including opioids and benzodiazepines. Always read medication labels to check for diphenhydramine in other products and consult with a doctor or pharmacist about what you should not mix with Benadryl, especially if you take other medications or have underlying health conditions [1.3.3]. If you accidentally mix Benadryl with an interacting substance, monitor for severe side effects and seek medical attention if you experience extreme drowsiness, confusion, hallucinations, or trouble breathing [1.5.3]. For immediate guidance, Poison Control is available 24/7 [1.2.1].
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult with a qualified healthcare professional before taking any medication or changing your treatment plan.
Authoritative Link: FDA - Grapefruit Juice and Some Drugs Don't Mix [1.11.3]
