What happens if you take antihistamines with antidepressants?

October 11, 2025 •

4 min read

An estimated 21 million U.S. adults have experienced at least one major depressive episode, many of whom take antidepressants. For these individuals, it is crucial to understand what happens if you take antihistamines with antidepressants due to potential drug interactions.

Quick Summary

Combining certain antihistamines with antidepressants can increase sedation, anticholinergic effects, and in some cases, lead to the potentially serious condition of serotonin syndrome. The severity of the interaction depends on the specific medications involved.

Key Points

Heightened Sedation: Combining first-generation (older) antihistamines like diphenhydramine with antidepressants can lead to dangerously increased drowsiness and impaired coordination.
Risk of Serotonin Syndrome: When taken with SSRI/SNRI antidepressants, some antihistamines (especially diphenhydramine and dextromethorphan) can contribute to a potentially life-threatening serotonin syndrome.
Exacerbated Side Effects with TCAs: Older tricyclic antidepressants (TCAs) have anticholinergic effects that are amplified by combining them with first-generation antihistamines, worsening side effects like dry mouth and confusion.
Safer Alternatives Exist: For individuals on antidepressants, second-generation (non-sedating) antihistamines like loratadine (Claritin) or cetirizine (Zyrtec) are generally considered safer options for allergy relief.
Consult a Professional: Always consult a doctor or pharmacist before combining any antihistamine with an antidepressant to ensure safety and avoid severe health complications.
Read All Labels: Many over-the-counter products for sleep, cold, or flu contain sedating antihistamines; it is crucial to read labels to avoid accidental combination.

For many people, antihistamines are a common over-the-counter remedy for allergies, while antidepressants are a cornerstone of treatment for mental health conditions. While both classes of drugs are widely used, they can interact in significant and sometimes dangerous ways. The type of interaction that occurs depends heavily on the specific antihistamine and antidepressant being taken.

The Mechanism of Interaction: Why Combination Can Be Risky

Drug interactions happen when a patient's body processes one medication differently because of the presence of another. The two main ways antihistamines and antidepressants can interfere with each other are through additive effects and by affecting neurotransmitters.

Additive Sedative Effects

One of the most common and noticeable interactions involves increased sedation. First-generation (older) antihistamines, such as diphenhydramine (Benadryl), are known for causing significant drowsiness because they can cross the blood-brain barrier. Many antidepressants, including SSRIs (like sertraline/Zoloft and fluoxetine/Prozac) and SNRIs (like duloxetine/Cymbalta), can also cause drowsiness, particularly when a patient first starts taking them. When combined, the sedative effects are intensified, which can lead to excessive sleepiness, dizziness, confusion, and impaired motor coordination.

Anticholinergic Overload

First-generation antihistamines and some older antidepressants, specifically tricyclic antidepressants (TCAs) like amitriptyline, have anticholinergic properties. This means they block a neurotransmitter called acetylcholine, which is involved in bodily functions like muscle control, digestion, and cognitive processes. Taking both a first-generation antihistamine and a TCA can dramatically increase anticholinergic side effects, which include:

Dry mouth and eyes
Blurred vision
Constipation
Difficulty urinating
Confusion

Risk of Serotonin Syndrome

Selective Serotonin Reuptake Inhibitors (SSRIs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) work by increasing serotonin levels in the brain. Some antihistamines, particularly diphenhydramine and cough suppressants containing dextromethorphan (found in many 'PM' or cold-and-flu products), can also affect serotonin. The combination can cause dangerously high levels of serotonin, a condition known as serotonin syndrome. This is a potentially life-threatening condition that requires immediate medical attention.

High-Risk Combinations to Avoid

First-Generation Antihistamines (Diphenhydramine) with SSRIs/SNRIs: This combination carries the highest risk of both excessive sedation and serotonin syndrome. This includes products like Benadryl and Tylenol PM.
First-Generation Antihistamines with Tricyclic Antidepressants (TCAs): The risk of profound sedation and amplified anticholinergic side effects is very high, especially with TCAs like amitriptyline and imipramine.
Cough/Cold Medicines containing Dextromethorphan and SSRIs: Dextromethorphan is a serotonin booster and can dangerously interact with antidepressants, increasing the risk of serotonin syndrome.

Lower-Risk Combinations (with Caution)

Second-generation antihistamines, such as loratadine (Claritin) and cetirizine (Zyrtec), are less likely to cause interactions because they are non-sedating and do not significantly cross the blood-brain barrier. However, some individuals, especially the elderly, may still experience mild drowsiness, and the risk can be amplified by a sedating antidepressant. It is still vital to consult a healthcare professional before combining any medication.

Comparison Table of Antihistamine-Antidepressant Interactions


Antihistamine Type	Common Examples	Antidepressant Type	Common Examples	Primary Interaction Risk	Severity	Recommendation
First-Gen (Sedating)	Diphenhydramine (Benadryl)	SSRIs, SNRIs	Sertraline (Zoloft), Duloxetine (Cymbalta)	Serotonin Syndrome, Extreme Sedation	High	Avoid unless medically necessary and with strict monitoring.
First-Gen (Sedating)	Diphenhydramine (Benadryl)	TCAs	Amitriptyline (Elavil), Imipramine (Tofranil)	Profound Sedation, Severe Anticholinergic Effects	High	Avoid due to amplified side effects.
First-Gen (Sedating)	Diphenhydramine (Benadryl)	MAOIs	Phenelzine (Nardil)	Increased Side Effects (Dry mouth, drowsiness)	Moderate	Avoid without medical consultation.
Second-Gen (Non-Sedating)	Cetirizine (Zyrtec)	SSRIs, SNRIs	Sertraline (Zoloft), Escitalopram (Lexapro)	Increased Drowsiness	Low to Moderate	Use with caution; monitor for increased sedation.
Second-Gen (Non-Sedating)	Loratadine (Claritin)	All Antidepressants	(Various)	Minimal	Low	Generally safer, but consult a doctor.

What to Do If You Need Allergy Relief on Antidepressants

Consult Your Healthcare Provider: Always speak to your doctor or pharmacist before taking any over-the-counter medication with your prescription antidepressant. They can provide personalized advice based on your specific health profile.
Opt for Second-Generation Antihistamines: Non-sedating antihistamines like cetirizine (Zyrtec), loratadine (Claritin), or fexofenadine (Allegra) are generally considered safer options for allergy relief while on antidepressants.
Read Labels Carefully: Many over-the-counter products, especially those for cold, flu, and sleep, contain sedating antihistamines like diphenhydramine. Always check the active ingredients.
Monitor for Side Effects: If you do take both medications, be vigilant for signs of increased drowsiness, confusion, or more severe symptoms of serotonin syndrome.

Conclusion

Combining antihistamines with antidepressants, especially first-generation antihistamines, poses significant risks, including excessive sedation and the potentially life-threatening condition of serotonin syndrome. The severity of the interaction depends on the specific drugs, with non-sedating, second-generation antihistamines representing a lower-risk option. However, no combination should be undertaken without consulting a healthcare professional. Always prioritize safety and open communication with your doctor about all medications you are taking, both prescription and over-the-counter. For more detailed clinical information on drug interactions, resources like the National Institutes of Health (NIH) can provide further guidance.

Note: This article is for informational purposes only and does not constitute medical advice. Always consult a healthcare professional before combining medications.

: People's Pharmacy. "Bad Mix? Diphenhydramine – Benadryl and SSRI Antidepressants". https://www.peoplespharmacy.com/articles/bad-mix-diphenhydramine-benadryl-and-ssri-antidepressants : MedShadow Foundation. "Can I Take Benadryl with Zoloft?". https://medshadow.org/can-i-take-benadryl-with-zoloft/ : Drugs.com. "Amitriptyline and Benadryl Interactions". https://www.drugs.com/drug-interactions/amitriptyline-with-benadryl-168-0-896-1617.html : SingleCare. "Don't take these medicines with Benadryl". https://www.singlecare.com/blog/diphenhydramine-interactions/

Frequently Asked Questions

Non-drowsy, second-generation antihistamines like loratadine (Claritin) or fexofenadine (Allegra) are generally considered safer to take with antidepressants than older, sedating versions. However, you should still consult your doctor or pharmacist to confirm the safety of your specific combination.

Taking Benadryl (diphenhydramine) with an SSRI antidepressant like sertraline (Zoloft) is not recommended without medical supervision due to the significant risk of excessive sedation and, in some cases, serotonin syndrome.

Signs of excessive sedation can include extreme drowsiness, dizziness, confusion, difficulty concentrating, impaired motor coordination, and blurred vision. If you experience these symptoms, you should contact a healthcare professional.

Certain antihistamines may interact with the metabolic pathways of antidepressants, potentially altering their plasma concentrations. While this effect is not universal, it is a possibility that your doctor will consider when advising you.

Serotonin syndrome symptoms include agitation, hallucinations, elevated heart rate and blood pressure, shivering, sweating, muscle twitches, and in severe cases, seizures and high fever. Seek immediate medical attention if you suspect serotonin syndrome.

Yes, some older medications, particularly tricyclic antidepressants (TCAs) like amitriptyline, were developed from antihistamines and have significant antihistamine properties that contribute to their sedating effects.

If you accidentally combine a sedating antihistamine with your antidepressant, monitor yourself for signs of extreme drowsiness, confusion, or other severe side effects. If you experience severe symptoms like rapid heartbeat, agitation, or fever, seek immediate medical care. If symptoms are mild, stop taking the antihistamine and consult your doctor for advice.