Amitriptyline and Pentobarbital: 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
Pentobarbital
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.
You've been prescribed amitriptyline (an antidepressant) and pentobarbital (a barbiturate). There are two things to know here. First, pentobarbital can speed up how your body breaks down amitriptyline, so the antidepressant may not work as well over time. Second, both medicines can make you very drowsy and can slow your breathing, and those effects can add up.
This is manageable. Please don't stop or change either medicine on your own. Your care team can watch how well your mood is controlled, adjust your dose if needed, and keep an eye on drowsiness and breathing. Let them know right away if you feel unusually sleepy, confused, or short of breath.
Effect: Barbiturate-induced enzyme induction increases hepatic metabolism of amitriptyline, lowering TCA serum levels and potentially reducing antidepressant efficacy. Onset is delayed (induction develops over days to weeks); evidence is probable, based on scattered case reports.
Additional concerns:
- Additive CNS and respiratory depression (sedation, hypoventilation).
- TCAs lower seizure threshold, potentially undermining barbiturate seizure control.
Management:
- Monitor for loss of antidepressant response; TCA dose may need to be adjusted and individualized.
- Monitor sedation and respiratory status, especially with pentobarbital.
- Watch seizure control if used for that indication.
What happens
Reduced tricyclic antidepressant exposure and possible additive adverse effects
Interaction Deep Dive
Taking a barbiturate together with a tricyclic antidepressant (TCA) can enhance the breakdown of the TCA. Isolated cases have described patients whose TCA serum concentrations dropped when a barbiturate was also being used123. TCAs may also compromise seizure management by lowering the seizure threshold. Beyond this, the two drug classes produce additive depression of the CNS and respiratory function4.
Why it happens (mechanism)
Increased tricyclic antidepressant metabolism
How to manage this interaction
Both medicines can be used together with appropriate oversight. Here is what typically happens:
- Your team may monitor how well your antidepressant is working, since the barbiturate can lower amitriptyline levels over time. Your amitriptyline dose may need to be adjusted and individualized by your care team.
- They may watch you more closely for drowsiness and breathing changes, because these drugs together increase sedation.
What to do: Keep taking both exactly as prescribed. Tell your pharmacist or prescriber if you feel unusually sleepy, confused, short of breath, or if your mood symptoms return. Do not stop either medicine on your own.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) The pharmacokinetics of a single oral 100 mg dose of desipramine were investigated in eight patients with epilepsy receiving long-term PHENobarbital therapy and in eight drug-free healthy controls. Every participant was an extensive metabolizer according to the genetically determined CYP2D6-related metabolic polymorphism. Relative to controls, the epilepsy patients showed lower peak plasma desipramine levels (74 nmol/L vs. 107 nmol/L), smaller desipramine area under the concentration-time curve values (1943 nmol/L/h vs. 3234 nmol/L/h), and shorter desipramine elimination half-lives (15.1 h vs. 20.6 h). All barbiturates are thought to produce comparable effects that induce hepatic enzymes, and the 2D6 isozyme is considered important in the metabolism of most or all TCAs. Consequently, comparable effects would be anticipated with any pairing of a TCA and a barbiturate 5.
Common questions
Can I take Amitriptyline and Pentobarbital together?
Pentobarbital can lower amitriptyline levels (possibly weakening its effect) and both drugs add to drowsiness and slowed breathing; keep taking both as prescribed and let your care team monitor your response and adjust the dose as needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Pentobarbital interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Amitriptyline and Pentobarbital interaction managed?
Both medicines can be used together with appropriate oversight. Here is what typically happens: Your team may monitor how well your antidepressant is working, since the barbiturate can lower amitriptyline levels over time. Your amitriptyline dose may need to be adjusted and individualized by your care team. They may watch you more closely for drowsiness and breathing changes, because these drugs t… 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 Amitriptyline or Pentobarbital 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 a safer alternative to one of these medications for me?
References (5)
- Moody JP, Whyte SF, MacDonald AJ, et al: Pharmacokinetic aspects of protriptyline plasma levels. Eur J Clin Pharmacol 1977; 11:51-56. PubMed
- Silverman G & Braithwaite R: Interaction of benzodiazepines with tricyclic antidepressants (letter). Br Med J 1972; 4:111. PubMed
- Burrows GD & Davies B: Antidepressants and barbiturates. Br Med J 1971; 4:113. PubMed
- Brodie MJ: Drug interactions in epilepsy. Epilepsia 1992; 33(suppl 1):S13-S22. PubMed
- Spina E, Avenoso A, Campo GM, et al: Phenobarbital induces the 2-hydroxylation of desipramine. Ther Drug Monit 1996; 18:60-64. DOI
Keep reading about Amitriptyline
Keep reading about Pentobarbital
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