Two Pills Shaped Like Arrows


There is minor interaction between Zoloft (sertraline) and Benadryl (diphenhydramine) in that you may experience additive side effects like drowsiness and dizziness.[1]

However, an increased risk of major side effects, like internal bleeding, is unlikely and has never been reported on the combination.

Increased Side Effects

There is a risk of additive sedative effects when taking Benadryl with Zoloft.

Sedation, dizziness, difficulty concentrating and an overall feeling of somnolence (tiredness) are some of the most reported side effects of both drugs.[2][3]

Therefore, taking them together increases the risk of them occurring, and potentially in a more severe manner than taking either alone.

Zoloft and Benadryl are, however, in completely separate classes of medication and are not known to have additive pharmacologic effects aside from the side effects mentioned above. There should be no additional increase in risk in major side effects, like internal bleeding (as you mention in your question).

If you do take Zoloft and Benadryl together, just simply watch out for being more tired than usual.

You certainly should not partake in any activity that requires mental alertness (e.g. driving a car) until you know how the medications affect you too.


Taking Benadryl With Zoloft can result in additive sedative effects.

  1. ^ Elsevier ClinicalKey: Sertraline Monograph. ClinicalKey
  2. ^ Elsevier ClinicalKey: Diphenhydramine Monograph. ClinicalKey
  3. ^ Zoloft Prescribing Information. AccessFDA