What medications cannot be taken with Unisom? A Comprehensive Guide to Safe Use

October 10, 2025 •

4 min read

Doxylamine (Unisom SleepTabs) and diphenhydramine (Unisom SleepGels) are common over-the-counter sleep aids, but combining them with certain substances can be extremely dangerous. It's critical to know what medications cannot be taken with Unisom to avoid severe side effects, like excessive drowsiness or respiratory depression.

Quick Summary

Several drug classes interact with Unisom, potentially causing excessive sedation, impaired coordination, and other severe side effects. Avoid combining Unisom with other CNS depressants, antihistamines, and certain antidepressants. Always consult a healthcare provider or pharmacist regarding potential interactions.

Key Points

Avoid All CNS Depressants: Never combine Unisom with alcohol, opioids, or benzodiazepines, as this can lead to severe sedation, respiratory depression, and potentially fatal outcomes.
Do Not Double Up on Antihistamines: Taking Unisom with other oral or topical antihistamines can result in an overdose of the same class of medication, increasing the risk of severe side effects.
Check Nighttime Cold/Allergy Meds: Many nighttime cold and allergy medications contain the same active ingredients as Unisom, making combination use dangerous.
Avoid Certain Antidepressants: Specifically, combining Unisom with Monoamine Oxidase Inhibitors (MAOIs) is contraindicated and should be strictly avoided due to severe anticholinergic risks.
Be Wary of Other Sleep Aids: Combining Unisom with prescription sleep aids like Ambien or supplements like melatonin can cause excessive drowsiness and impair daily activities.
Talk to Your Doctor: The most critical step is to consult a healthcare provider or pharmacist about your full medication list to safely manage potential interactions.

Understanding Unisom's Active Ingredients

Before delving into specific interactions, it's important to know that Unisom is available in different formulations with different active ingredients. Unisom SleepTabs contain doxylamine succinate, while Unisom SleepGels and SleepMinis contain diphenhydramine. Both are first-generation antihistamines that cause sedation as a side effect by blocking histamine receptors in the brain. The primary risk with drug interactions is the compounding effect of combining Unisom with other medications that cause drowsiness or have anticholinergic effects. This can lead to intensified central nervous system (CNS) depression, impaired coordination, and other dangerous health issues.

Central Nervous System (CNS) Depressants

One of the most dangerous interactions involves combining Unisom with other CNS depressants. These medications and substances slow down brain activity, and their combined effect with Unisom's sedative properties can be life-threatening.

Alcohol

Alcohol is a potent CNS depressant that should be avoided completely when taking Unisom. The combination can cause excessive drowsiness, dizziness, and confusion. It also increases the risk of respiratory depression, which is a potentially fatal slowing of breathing.

Opioids

Prescription pain relievers like oxycodone (OxyContin, Percocet), hydrocodone, fentanyl, and tramadol are powerful CNS depressants. Taking these with Unisom can lead to extreme sedation, respiratory depression, coma, and even death. Many opioids also have anticholinergic effects, worsening side effects like constipation.

Benzodiazepines

Used to treat anxiety, seizures, and sleep disorders, benzodiazepines like alprazolam (Xanax), clonazepam (Klonopin), and diazepam (Valium) should not be combined with Unisom. This combination significantly increases the risk of profound sedation and slowed breathing.

Muscle Relaxers

Medications used for muscle pain and spasms, such as cyclobenzaprine (Amrix) and tizanidine (Zanaflex), also cause drowsiness. Taking them with Unisom can worsen these side effects and cause impaired motor function.

Other Antihistamines

Unisom's active ingredients are antihistamines, so combining it with other antihistamines, whether oral or topical, can lead to an overdose of the same medication class.

OTC Cold and Allergy Medications: Many nighttime cold and allergy remedies contain antihistamines like doxylamine or diphenhydramine. Taking a Unisom product with NyQuil, for example, could result in dangerously high doses of the same ingredient.
Other Oral Antihistamines: Prescription and other OTC antihistamines like cetirizine (Zyrtec), loratadine (Claritin), and hydroxyzine (Vistaril) should be avoided to prevent excessive side effects such as drowsiness, balance problems, and racing heart.
Topical Antihistamines: Even topical creams or sprays containing diphenhydramine should not be used with Unisom, as they can contribute to overall systemic exposure.

Antidepressants

While many people can take Unisom with some antidepressants under medical supervision, certain types pose significant risks.

Monoamine Oxidase Inhibitors (MAOIs): The combination of Unisom and MAOIs, such as selegiline or phenelzine, is considered contraindicated. This can lead to severe and persistent anticholinergic side effects.
Tricyclic Antidepressants (TCAs): TCAs like amitriptyline and nortriptyline have antihistamine and anticholinergic effects. Combining them with Unisom can greatly amplify side effects like dry mouth, drowsiness, and confusion.
SSRIs and SNRIs: Some modern antidepressants, like fluoxetine (Prozac) and venlafaxine (Effexor XR), can cause drowsiness. Adding Unisom may intensify this effect.

Other Interacting Medications

Several other classes of drugs can interact with Unisom, heightening the risk of adverse effects.

Other Sleep Medications: Combining Unisom with other sleep aids, such as prescription hypnotics like zolpidem (Ambien) or supplements like melatonin, can cause excessive and dangerous levels of sedation. This can lead to next-day impairment affecting driving and operating machinery.
Anticholinergic Drugs: Many medications have anticholinergic effects, which can be amplified by Unisom. These include certain medications for overactive bladder (e.g., oxybutynin), COPD, and motion sickness. This can worsen side effects like dry mouth, constipation, and trouble urinating.

Comparison Table: Unisom Interactions at a Glance


Drug Class	Examples	Potential Interaction Risk	Primary Danger	Avoid/Consult Doctor
Alcohol	Beer, wine, liquor	Increased CNS depression	Severe sedation, respiratory depression	Avoid
Opioids	Oxycodone, Fentanyl, Tramadol	Additive CNS depression	Profound sedation, respiratory failure	Avoid
Benzodiazepines	Xanax, Klonopin, Valium	Additive CNS depression	Extreme drowsiness, slowed breathing	Avoid
Other Antihistamines	Zyrtec, Benadryl (Diphenhydramine)	Overdose of antihistamine	Excessive sedation, cardiac issues	Avoid
MAOI Antidepressants	Selegiline, Phenelzine	Severe anticholinergic effects	Confusion, persistent sedation	Avoid
TCAs	Amitriptyline, Nortriptyline	Additive anticholinergic effects	Dry mouth, blurred vision, confusion	Consult Doctor
Muscle Relaxers	Cyclobenzaprine, Tizanidine	Additive CNS depression	Exacerbated drowsiness, impaired coordination	Avoid/Consult Doctor
Other Sleep Aids	Ambien, Melatonin	Exaggerated sedative effects	Excessive next-day drowsiness	Avoid

Conclusion

While Unisom offers temporary relief for occasional sleeplessness, it's not without serious risks when combined with other medications. The potential for additive CNS depression is the most significant concern and can lead to life-threatening respiratory problems. Before taking any Unisom product, it is essential to review all prescription and over-the-counter drugs, as well as supplements and alcohol, that you may be consuming. Always consult a healthcare professional or pharmacist to get personalized advice on potential drug interactions and ensure your safety. Taking the time to understand these risks can prevent serious harm and ensure you use Unisom responsibly. For more authoritative guidance on drug interactions, please consult resources like Drugs.com(https://www.drugs.com/drug-interactions/).

Frequently Asked Questions

No, you should never take Unisom with alcohol. Both are CNS depressants, and combining them can cause severe drowsiness, dizziness, and dangerously suppress your breathing.

You should not take Unisom with most nighttime cold or allergy medications, as they often contain antihistamines similar to Unisom's active ingredients. Combining them can lead to an overdose of antihistamines and excessive side effects.

Combining Unisom with opioids like oxycodone or fentanyl can lead to life-threatening side effects, including extreme sedation, severely slowed breathing, coma, and even death. This combination should be strictly avoided.

It depends on the type of antidepressant. You should avoid combining Unisom with MAOIs completely. For other antidepressants, especially TCAs, consult a healthcare provider, as there is a risk of increased drowsiness and other side effects.

Anticholinergic medications block acetylcholine, a chemical messenger in the body, causing side effects like dry mouth and constipation. Unisom also has anticholinergic effects, so combining them can amplify these side effects and increase drowsiness.

Yes, combining Unisom with other sleep aids, including supplements like melatonin or valerian root, is not recommended. These combinations can result in excessive drowsiness and next-day impairment.

Unisom itself does not typically interact directly with blood pressure medications, but it's important to be cautious. Some combination Unisom products may contain decongestants that can increase blood pressure, so always check the label. Consult your doctor if you have concerns.