Does Trazodone have diphenhydramine? (3 differences)

In this article, we will discuss whether Trazodone contains diphenhydramine. We will also discuss some basic differences between the two medications.

Does Trazodone have diphenhydramine?

No, Trazodone does not contain diphenhydramine (Benadryl). Both are different medications used for different purposes.

Trazodone is a serotonin antagonist and reuptake inhibitor (SARI) and an antidepressant. It is an FDA-approved medication for major depressive disorder (MDD) (1).

Diphenhydramine is a first-generation antihistamine available as an over-the-counter (OTC) medication for treating conditions like dystonia, insomnia, pruritis, urticaria, vertigo, and motion sickness (2).

Trazodone and diphenhydramine are entirely different medications. They differ in their mechanism of action, indications, side effects and contraindications.

How does Trazodone differ from diphenhydramine?

Trazodone and diphenhydramine differ in the following aspects:

Mechanism of action

Trazodone is a SARI and it works by blocking the reuptake of serotonin which increases serotonin levels in the body. It also acts as an antagonist of some serotonin receptors and histamine (H1) and alpha-1 adrenergic receptors (3).

Due to its effects on serotonin, Trazodone has antidepressant activity. As it blocks different receptors, it also has a sedative action in low doses.

Benadryl, on the other hand, is an antihistamine which shows its effects by attaching to H1-receptors and preventing histamine from binding to it. Histamine is a chemical substance seen in an allergic reaction and is known for causing symptoms of allergy such as runny nose, watery eyes etc (2).

Diphenhydramine also produces sedation and is sometimes used to induce sleep during allergic reactions.

Therapeutic indications

Trazodone is an FDA-approved drug for major depressive disorder (MDD). It is also used off-label for the following conditions (3):

  • Insomnia
  • Anxiety
  • Fibromyalgia
  • Bulimia
  • Substance abuse

Diphenhydramine, on the other hand, is used for the following therapeutic indications (2):

  • Insomnia
  • Allergy
  • Pruritis
  • Urticaria
  • Vertigo

Side effects

Commonly reported side effects of Trazodone include (4):

  • Headache
  • Dry mouth
  • Fatigue
  • Blurred vision
  • Dizziness
  • Constipation
  • Drowsiness
  • QT prolongation
  • Acid reflux
  • Decreased concentration
  • Suicidal thoughts
  • Visual hallucinations
  • Orthostatic hypotension

Side effects of diphenhydramine include (5):

  • Sedation
  • Dizziness/lightheadedness
  • Urinary retention
  • Increased heart rate
  • Constipation
  • Blurred vision

Can you use Trazodone and diphenhydramine together?

Trazodone and diphenhydramine combination should only be used under medical supervision. Although these two meds don’t chemically interfere with one another, they can cause some similar side effects, which is the main reason why their combination is usually avoided.

Both Trazodone and diphenhydramine are sedative medications, and taking them together can increase the risk of excessive sedation. This can lead to dizziness, confusion, and impaired motor coordination.

Their combination can also increase the risk of respiratory depression, which is a potentially life-threatening condition characterized by slow, shallow breathing.

Trazodone and diphenhydramine can also cause cognitive impairment, including drowsiness, confusion and difficulty concentrating when taken alone. Combining these medications can further increase the risk of impaired cognition, which can affect their daily life activities.

Combining these medications increases the risk of side effects including allergic reactions gastrointestinal upset and cardiac arrhythmias.

What are alternatives to diphenhydramine while taking Trazodone?

If you are taking Trazodone and need an alternative to diphenhydramine for allergy or cold relief, there are several options that are generally considered safe to use with Trazodone. These include:

Second generation antihistamines

Medications like loratadine, cetirizine and fexofenadine are considered safer options to manage allergy symptoms without causing significant drowsiness.

Nasal corticosteroids

Nasal sprays like Flonase and triamcinolone can be used for nasal allergy symptoms. These sprays do not get absorbed in systemic circulation as oral medications do. This reduces the chances of adverse events.


OTC decongestants like pseudoephedrine can help with nasal congestion, but it is essential to use them cautiously and consult your healthcare provider, as they may increase blood pressure.

Natural remedies

Natural remedies like honey water, steam inhalation, or herbal supplements like butterbur or quercetin may provide relief from allergy symptoms. However, talk to your healthcare provider before taking any herbal supplements to avoid potential interactions.

In my opinion, Trazodone and diphenhydramine are distinct medications with different mechanisms of action and purposes. While both medications can cause drowsiness and sedation, they are not the same drug, nor do they contain each other as active ingredients.

I suggest using them as prescribed and directed by a healthcare professional to achieve their intended therapeutic effects and avoid potential adverse reactions.




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