Amitriptyline and Diphenhydramine Injection: Interaction Details
AI-assisted, pharmacist-reviewed · Source data updated Aug 8, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Diphenhydramine Injection
How we grade severity & evidence
Severity levels
- Contraindicated: These should generally not be used together.
- Major: Potentially serious — often needs a change or close monitoring.
- Moderate: Can be significant — usually manageable with monitoring.
- Minor: Usually limited clinical impact.
Evidence grades
- Established: Well documented — supported by controlled studies or strong clinical data.
- Probable: Good supporting evidence, though not definitively proven.
- Suspected: Some evidence suggests this interaction, but it is not well established.
- Possible: Limited or conflicting evidence; the interaction may occur.
- Theoretical: Predicted from the drugs' pharmacology; not yet confirmed in people.
Ratings come from the documented interaction literature and are reviewed by a pharmacist. They describe the documented risk of the combination, not what will necessarily happen to you — your dose, timing, and health picture all matter.
What happens
Increased anticholinergic effects (dry mouth, urinary retention)
Interaction Deep Dive
Concomitant antidepressants with strong anticholinergic effects (eg, amitriptyline, trimipramine, amoxapine, doxepin, imipramine, nortriptyline, maprotiline) and antihistamines may increase the possibility of adynamic ileus, urinary retention, or chronic glaucoma. This interaction may be more prominent in elderly patients1.
Why it happens (mechanism)
Additive anticholinergic effects
Common questions
Can I take Amitriptyline and Diphenhydramine Injection together?
Increased anticholinergic effects (dry mouth, urinary retention) Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Diphenhydramine Injection interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Amitriptyline or Diphenhydramine Injection need adjusting while I take them together?
- What symptoms should prompt me to call you or my prescriber right away?
- Does the timing of my doses matter for this combination?
- Is there anything you'd monitor while I'm on both?
References (1)
- Blazer DG, Federspiel CF, Ray WA, et al: The risk of anticholinergic toxicity in the elderly: a study of prescribing practices in two populations. J Gerontol 1983; 38:31-35. DOI
Keep reading about Amitriptyline
Keep reading about Diphenhydramine Injection
These medications also interact with supplements
Prescription drugs aren't the whole picture — herbal and dietary supplements can interact with them too. From the evidence-graded Natural Medicines database:
major · moderate · minor — check everything you take with our drug–supplement interaction checker.
Check another combination
Our instant two-drug interaction checker is almost here.
Still have questions about this combination?
Every question gets a real answer from a licensed pharmacist — free, and usually within a day.
Ask the pharmacist