Phenobarbital 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
Phenobarbital
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.
Taking amitriptyline (Elavil) together with phenobarbital creates two things to watch for. First, phenobarbital speeds up how fast your body breaks down amitriptyline, so the antidepressant level in your blood can drop and it may not work as well for you. Second, both medicines can make you very drowsy and can slow your breathing, so those effects can stack up. Amitriptyline can also make seizures a bit easier to trigger, which matters if you take phenobarbital for seizures.
Please don't change or stop either medicine on your own. This is very manageable. Your care team can adjust your doses and keep a closer eye on how you're doing so both medicines work safely.
Effect: Phenobarbital induces hepatic microsomal enzymes (CYP450), increasing amitriptyline metabolism and reducing TCA serum concentrations/exposure, potentially causing loss of antidepressant efficacy.
- Direction: Reduced TCA effect (enzyme induction); onset delayed as induction develops.
- Additive PD risk: Combined CNS and respiratory depression; TCAs also lower the seizure threshold, which may worsen seizure control.
- Evidence: Probable; scattered case reports of decreased TCA levels.
- Management: Monitor for reduced antidepressant response and for excess sedation/respiratory depression. TCA dose may need to be adjusted and individualized. Watch seizure control.
What happens
Reduced tricyclic antidepressant exposure and possible additive adverse effects
Interaction Deep Dive
Taking barbiturates together with a tricyclic antidepressant (TCA) can lead to enhanced metabolism of the TCA. Isolated cases have described patients whose TCA serum concentrations fell when a barbiturate was also present123. TCAs may additionally compromise seizure control by lowering the seizure threshold. Beyond this, the two drug classes produce additive depressant effects on both the CNS and respiration4.
Why it happens (mechanism)
Increased tricyclic antidepressant metabolism
How to manage this interaction
This combination can be managed well by your care team. Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise.
- Your amitriptyline dose may need to be adjusted and individualized because phenobarbital can lower its blood level and effect.
- Your team may monitor you more closely for signs the antidepressant isn't working, and for excess drowsiness or slowed breathing.
- If you take phenobarbital for seizures, tell your prescriber about any change in seizure control.
- Report heavy sedation, confusion, or breathing trouble promptly.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
1 report — tap to read
a) Investigators examined the pharmacokinetics of a single oral 100 mg dose of desipramine in eight patients with epilepsy who were receiving long-term PHENobarbital therapy and in eight healthy controls who were not taking any drugs. Every participant was classified as an extensive metabolizer according to the genetically determined CYP2D6-related metabolic polymorphism. In comparison with the controls, the epilepsy patients showed lower peak plasma desipramine concentrations (74 nmol/L vs. 107 nmol/L), reduced 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). It is thought that all barbiturates 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 should be anticipated with any pairing of a TCA and a barbiturate 5.
Common questions
Can I take Phenobarbital and Amitriptyline together?
Phenobarbital can lower amitriptyline's blood level so it works less well, and both drugs add to drowsiness and slowed breathing. Keep taking both as prescribed and let your care team adjust doses and monitor you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Phenobarbital and Amitriptyline 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 Phenobarbital and Amitriptyline interaction managed?
This combination can be managed well by your care team. Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise. Your amitriptyline dose may need to be adjusted and individualized because phenobarbital can lower its blood level and effect. Your team may monitor you more closely for signs the antidepressant isn't working, and for excess drowsiness or slowed breat… 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 Phenobarbital 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 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 Phenobarbital
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