Diazepam and Amitriptyline: Interaction Details
AI-assisted, pharmacist-reviewed · AI content regenerated Jul 11, 2026 · Source data updated Jul 2, 2026 · Sources: FDA labeling, DDInter 2.0, cited literature
Amitriptyline
Diazepam
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.
Both amitriptyline (an antidepressant) and diazepam (a medicine for anxiety or seizures) can make you feel drowsy, slow, and less alert on their own. When you take them together, those effects can add up. In a small study, people taking both did worse on tests of reaction time and staying alert. The good news is the diazepam didn't change the amount of amitriptyline in the blood, so this is really about feeling more sleepy or foggy than usual.
Be extra careful with driving or anything that needs sharp focus until you know how the combination affects you. Your care team can manage this, so talk with your pharmacist or doctor if you feel too drowsy.
Effect: Additive CNS/psychomotor impairment (reduced reaction time and vigilance) when diazepam is combined with amitriptyline.
- Mechanism: Pharmacodynamic (additive CNS depression), not pharmacokinetic. A controlled study found no change in amitriptyline or nortriptyline blood levels.
- Direction: Additive PD effect; neither agent is a prodrug requiring activation, so no directional flip.
- Onset: Rapid. Evidence: Probable, from a small (n=4) controlled study; magnitude not well quantified.
- Management: Counsel on additive sedation and impaired driving/complex motor tasks. Consider lowest effective doses and reassess if excessive sedation occurs.
What happens
Psychomotor deficits (decreased reaction time, decreased vigilance)
Interaction Deep Dive
In a controlled trial, giving diazepam together with amitriptyline produced additive impairments across several psychomotor tests1. A possible interaction between the two drugs was examined in four depressed patients who were taking 75 to 150 mg of amitriptyline per day along with 10 to 15 mg of diazepam per day2. The investigators found no alteration in the blood concentrations of either amitriptyline or nortriptyline. Further controlled trials or case reports will be required to establish how much impairment arises when these two agents are used together.
Why it happens (mechanism)
Additive psychomotor deficits
How to manage this interaction
Keep taking both medications exactly as prescribed unless your prescriber tells you otherwise. This interaction is about added drowsiness and slower reactions, not a change in drug levels.
- Notice how you feel, especially in the first days, before you drive or operate machinery.
- Avoid alcohol and other sedating medicines that could add to the effect.
- Your care team may adjust and individualize your doses, or monitor you more closely, if you feel too sedated.
- Tell your pharmacist or doctor if drowsiness, dizziness, or fogginess affects daily tasks.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) A controlled study assessing the performance of 90 healthy volunteers examined how fluoxetine, amitriptyline, or placebo affected diazepam. Each volunteer received one of six treatment combinations and completed performance assessments, including a critical tracking test, a divided attention test, a visual search task, a memory test, and a vigilance test. Fluoxetine by itself had no effect on performance, but when fluoxetine was combined with diazepam, there was a significant rise in the divided attention tracking error along with significant impairment on the vigilance test. Significant impairment was seen with amitriptyline alone and when it was given together with diazepam. Across most of the tests, combining amitriptyline with diazepam produced additive effects. The authors concluded that combining diazepam with an antidepressant may raise an individual's risk while driving and while carrying out other complex tasks 1.
Common questions
Can I take Diazepam and Amitriptyline together?
Taking amitriptyline and diazepam together can add up to more drowsiness and slower reaction times, so be cautious with driving until you know how you feel and let your care team know if it's too much. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diazepam and Amitriptyline interaction?
It is rated moderate. Can be significant — usually manageable with monitoring.
How quickly could this interaction happen?
The documented onset is "rapid". Effects can appear quickly, often within about 24 hours of combining the drugs.
How is the Diazepam and Amitriptyline interaction managed?
Keep taking both medications exactly as prescribed unless your prescriber tells you otherwise. This interaction is about added drowsiness and slower reactions, not a change in drug levels. Notice how you feel, especially in the first days, before you drive or operate machinery. Avoid alcohol and other sedating medicines that could add to the effect. Your care team may adjust and individualize your… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "probable". Good supporting evidence, though not definitively proven.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Diazepam or Amitriptyline 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 (2)
- Moskowitz H & Burns M: The effects on performance of two antidepressants, alone and in combination with diazepam. Prog Neuropsychopharmacol Biol Psychiatry 1988; 12:783-792. PubMed
- Otani K, Norton C, & Bertilsson L: No interaction of diazepam on amitriptyline disposition in depressed patients. Ther Drug Monit 1987; 9:120-122. PubMed
Keep reading about Amitriptyline
Keep reading about Diazepam
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