What should you not mix with cold medicine? A Guide to Safe Usage

October 12, 2025 •

4 min read

In the U.S., nearly 70% of adults use over-the-counter (OTC) medications as a first response to cold and flu symptoms [1.4.1]. Understanding what you should not mix with cold medicine is crucial to prevent dangerous, and sometimes fatal, interactions.

Quick Summary

Avoid harmful interactions by knowing which substances and medications to not mix with cold medicine. This includes alcohol, certain antidepressants, blood pressure medication, and other OTC drugs with overlapping ingredients.

Key Points

Alcohol: Do not mix alcohol with cold medicine, as it can cause extreme drowsiness and increase the risk of liver damage when combined with acetaminophen [1.3.5, 1.3.3].
Prescription Antidepressants: Avoid cold meds with dextromethorphan if taking SSRIs/SNRIs, and avoid decongestants if taking MAOIs, to prevent serotonin syndrome or a hypertensive crisis [1.4.2].
Blood Pressure Medication: Decongestants like pseudoephedrine can raise blood pressure and interfere with the effectiveness of antihypertensive drugs [1.4.6].
Multiple OTC Cold Meds: Never take two multi-symptom cold medicines at once, as you risk overdosing on shared ingredients like acetaminophen [1.6.2, 1.6.4].
Sedatives: Combining cold medicines containing antihistamines (like diphenhydramine) with prescription sedatives can lead to dangerous levels of drowsiness [1.4.5].
NSAIDs: Do not combine different NSAIDs, such as ibuprofen and naproxen, to avoid increasing the risk of stomach bleeding [1.2.1].
Always Read the Label: The most critical safety step is to check the 'Active Ingredients' on the label to avoid accidentally doubling up on a drug [1.2.2, 1.6.2].

The Hidden Dangers in Your Medicine Cabinet

Over-the-counter (OTC) cold and flu medications are a staple in most households, offering relief from symptoms like coughing, congestion, and fever. While generally safe when used as directed, the risk of adverse effects skyrockets when these medications are mixed with other substances [1.6.1]. Many multi-symptom cold remedies contain several active ingredients, making it easy to accidentally double-dose or create a harmful combination with other medications you're taking [1.6.2, 1.6.4]. The key to safety is always reading the 'Active Ingredients' label on any OTC product before taking it.

Alcohol: A Common but Dangerous Combination

Mixing alcohol with any cold medicine is strongly discouraged [1.2.2]. Alcohol can intensify the side effects of many common cold medicine ingredients, particularly those that cause drowsiness, such as antihistamines (like diphenhydramine or doxylamine) and the cough suppressant dextromethorphan [1.2.3, 1.3.4]. This combination can lead to severe drowsiness, dizziness, and impaired motor control, making activities like driving extremely dangerous [1.3.5].

Furthermore, many cold medications contain acetaminophen for pain and fever relief [1.5.6]. Both alcohol and acetaminophen are processed by the liver. When taken together, especially with chronic alcohol use, the risk of severe, potentially fatal liver damage increases significantly [1.3.3, 1.3.7].

Prescription Medication Interactions

Certain prescription drugs can have dangerous interactions with the active ingredients in OTC cold medicines. It is vital to consult a doctor or pharmacist about your specific prescriptions.

Key interactions to be aware of:

MAOIs and Decongestants: Monoamine oxidase inhibitors (MAOIs), an older class of antidepressants, should not be mixed with decongestants like pseudoephedrine or phenylephrine. This combination can lead to a hypertensive crisis, a severe and rapid increase in blood pressure [1.4.2, 1.4.1].
SSRIs/SNRIs and Dextromethorphan: Antidepressants like SSRIs and SNRIs can interact with the cough suppressant dextromethorphan (DM). This mix can increase the risk of a rare but life-threatening condition called serotonin syndrome, caused by excessive serotonin in the brain [1.4.2, 1.4.3]. Symptoms include confusion, rapid heart rate, muscle stiffness, and high fever [1.4.3].
Blood Pressure Medications and Decongestants: Decongestants like pseudoephedrine and phenylephrine work by constricting blood vessels, which can raise blood pressure [1.4.6]. This effect can counteract the effectiveness of prescribed antihypertensive medications and is risky for anyone with hypertension or heart disease [1.4.1, 1.4.6].
Sedatives and Antihistamines: Prescription drugs for anxiety or sleep (like alprazolam, lorazepam, zolpidem) and other sedatives can have their effects dangerously amplified when taken with cold medicines containing antihistamines (e.g., diphenhydramine, doxylamine), leading to extreme drowsiness and increased risk of falls or accidents [1.2.3, 1.4.5].

The Risk of Doubling Up on OTC Medications

One of the most common mistakes is taking multiple OTC products without realizing they share the same active ingredients [1.6.2]. For example, taking a multi-symptom cold medicine like DayQuil and also taking Tylenol can lead to an acetaminophen overdose [1.6.4, 1.6.9]. An overdose of acetaminophen is the most common cause of acute liver failure in the United States [1.6.1].

Similarly, you should not mix different nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen [1.2.1]. Combining them increases the risk of side effects such as stomach bleeding and kidney problems [1.6.2]. Always check the labels to ensure you are not taking more than one product containing the same class of drug (e.g., NSAID, decongestant, antihistamine) at the same time [1.2.7].

Cold Medicine Ingredient Interaction Chart


Active Ingredient	Class	Commonly Found In	What NOT to Mix It With	Potential Risk
Acetaminophen	Analgesic / Antipyretic	Tylenol, DayQuil, NyQuil, Excedrin, many multi-symptom formulas [1.6.6]	Other acetaminophen products, Alcohol (especially >3 drinks/day) [1.3.7, 1.6.9]	Severe liver damage, overdose [1.6.1, 1.6.6]
Pseudoephedrine / Phenylephrine	Decongestant	Sudafed, Sudafed PE, Claritin-D, many multi-symptom formulas [1.5.3]	MAOIs, some antidepressants (TCAs), other decongestants, blood pressure medication [1.4.2, 1.4.6, 1.4.7]	Hypertensive crisis (severely high blood pressure), increased heart rate, reduced efficacy of blood pressure meds [1.4.2, 1.4.6]
Dextromethorphan (DM)	Cough Suppressant	Robitussin DM, Delsym, Mucinex DM, many multi-symptom formulas [1.5.3]	MAOIs, SSRIs, SNRIs (antidepressants), Alcohol [1.2.2, 1.4.2]	Serotonin syndrome, extreme drowsiness, increased risk of side effects [1.4.2, 1.2.2]
Diphenhydramine / Doxylamine	Antihistamine	Benadryl, NyQuil, ZzzQuil, Unisom, many "Nighttime" or "PM" formulas [1.2.7, 1.5.7]	Alcohol, sedatives, tranquilizers, other antihistamines, opioid pain relievers [1.2.3, 1.4.5]	Extreme drowsiness, dizziness, impaired coordination, increased risk of falls and accidents [1.2.3, 1.3.5]
Ibuprofen / Naproxen	NSAID	Advil, Motrin, Aleve [1.6.1]	Other NSAIDs (including Aspirin), Blood thinners [1.2.1, 1.2.4]	Increased risk of stomach bleeding, kidney problems [1.2.4, 1.6.2]

Conclusion: Prioritize Safety Above All

While cold medicines can provide necessary relief, their misuse and improper combinations pose significant health risks. The most crucial steps for safe use are to always read the active ingredients on the drug facts label, take only one medication containing the same type of active ingredient at a time, and avoid alcohol completely. If you are taking any prescription medications or have underlying health conditions like high blood pressure, heart disease, or liver problems, it is essential to speak with a healthcare provider or pharmacist before taking any OTC cold remedy. When in doubt, it is always safer to ask a professional.

For more authoritative information, you can visit the U.S. Food and Drug Administration's page on medication safety.

Frequently Asked Questions

No, you should not. Many multi-symptom cold medicines, like DayQuil or NyQuil, already contain acetaminophen, the active ingredient in Tylenol. Taking both can lead to an accidental overdose and cause serious liver damage [1.6.4, 1.6.9].

No, it is not safe. NyQuil contains an antihistamine (doxylamine), a cough suppressant (dextromethorphan), and acetaminophen. Alcohol intensifies the drowsiness caused by the first two ingredients and, when combined with acetaminophen, significantly increases the risk of liver damage [1.3.2, 1.3.6].

You should avoid cold medicines containing decongestants like pseudoephedrine or phenylephrine, as they can raise blood pressure [1.4.6]. Look for products specifically formulated for people with high blood pressure, or consult your doctor or pharmacist for safe alternatives like certain nasal sprays or saline rinses [1.4.1, 1.4.6].

No. Both ibuprofen and naproxen are nonsteroidal anti-inflammatory drugs (NSAIDs). Mixing them does not provide extra benefit and increases the risk of side effects like stomach upset and gastrointestinal bleeding [1.2.1].

Serotonin syndrome is a potentially life-threatening condition caused by too much serotonin in the brain. It can occur if you mix the cough suppressant dextromethorphan (DM), found in many cold remedies, with certain antidepressants like SSRIs or MAOIs [1.4.2, 1.4.3].

Many nighttime cold medicines contain antihistamines like diphenhydramine or doxylamine, which cause drowsiness. Combining these with a prescription sleep aid like zolpidem can result in excessive sedation, dizziness, confusion, and an increased risk of falls and other accidents [1.2.3, 1.4.5].

You must be very careful. Some allergy medications are antihistamines (like diphenhydramine), which are also common ingredients in 'nighttime' or 'multi-symptom' cold formulas. Doubling up on antihistamines can cause extreme drowsiness and other side effects. Always check the active ingredients on both products before combining them [1.2.7].