Does Benadryl interact with Zoloft? 

Does Benadryl interact with Zoloft?

Yes, Benadryl does interact with Zoloft in terms of side effects. Benadryl is a first-generation antihistamine which is sedative in nature (1). Zoloft, on the other hand, is one of the most commonly prescribed antidepressants. (2)

Since both Zoloft and Benadryl can cause tiredness and drowsiness, concomitant use can increase the risk of these side effects. If we talk about the elderly population, the side effects are more prominent in them as their bodies eventually become slow in drug metabolism and excretion (1,2). 

Additionally, combining these medications may cause other side effects such as dry mouth, blurred vision, and difficulty concentrating. It’s crucial to avoid activities that require mental alertness, such as driving or operating heavy machinery while taking Benadryl and Zoloft together (1,2).

Benadryl may also cause nosebleeds in some people, which could be more pronounced if Zoloft is taken concomitantly, as this antidepressant can cause mild blood thinning.

Other sedative antihistamines, like Hydroxyzine, Chlorpheniramine, etc can also interact with Zoloft and other antidepressants, especially if these meds also make you drowsy.

If you are prescribed both medications, your healthcare provider should be aware of this potential interaction and will monitor your response to the medications closely. They may adjust the dosages or recommend alternative medications to avoid any adverse effects.

Alternatives to Benadryl while taking Zoloft

If you are taking Zoloft and need an alternative to Benadryl for allergy or cold relief, there are several options that are generally considered safe to use with Zoloft. 

It’s essential to discuss these alternatives with your healthcare provider before starting any new medication. Here are some alternatives to Benadryl while taking Zoloft:

Second-generation antihistamines

Medications like Claritin (loratadine), Zyrtec (cetirizine), and Allegra (fexofenadine) are considered safer options to manage allergy symptoms without causing significant drowsiness. (3)

Nasal corticosteroids

Nasal sprays like Flonase (Fluticasone) or Nasacort (Triamcinolone) can be used for nasal allergy symptoms without interacting with Zoloft. These sprays don’t get absorbed in systemic circulation as oral medications do. This reduces the chances of adverse events. 

Saline nasal rinses

Using the saline solution for nasal irrigation can help relieve congestion and nasal irritation without any drug interactions.


Over-the-counter decongestants like Sudafed (Pseudoephedrine) can help with nasal congestion, but it’s essential to use them cautiously and consult your healthcare provider, as they may increase blood pressure.

Natural remedies

Some people find relief from allergy symptoms with natural remedies like local honey, steam inhalation, or herbal supplements like butterbur or quercetin. However, it’s crucial to talk to your doctor before trying any herbal supplements to avoid potential interactions.

Remember, always talk to your healthcare provider before starting any new medication or supplement, even if it is available over the counter. 

They will consider your specific health needs and ensure that the chosen alternative is safe and effective for you, taking into account your current medications, including Zoloft.

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Singh HK, Saadabadi A. Sertraline. 2023 Feb 13. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 31613469.


Sicari V, Zabbo CP. Diphenhydramine. 2022 Jul 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30252266.


Slater JW, Zechnich AD, Haxby DG. Second-generation antihistamines: a comparative review. Drugs. 1999 Jan;57(1):31-47. doi: 10.2165/00003495-199957010-00004. PMID: 9951950.

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