Amitriptyline and Mephobarbital: 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
Mephobarbital
No brand names on record
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.
Here's what's going on. Mephobarbital is a barbiturate, and it can speed up how your body breaks down amitriptyline (Elavil). That means your amitriptyline levels can drop, so it may not work as well for your mood or pain.
At the same time, both drugs can make you drowsy and can slow your breathing, so together they may make you extra sleepy or foggy. Amitriptyline can also lower the seizure threshold, which matters since barbiturates are often used for seizures. The good news is your care team can manage this by checking how you're doing and adjusting your doses. Please don't stop either medicine on your own, just talk with your doctor or pharmacist.
Effect: Barbiturate (mephobarbital) induction of hepatic microsomal enzymes increases amitriptyline metabolism, lowering TCA serum concentrations and potentially reducing antidepressant efficacy. Onset is delayed (enzyme induction develops over days to weeks); evidence is probable.
- PK direction: reduced TCA exposure (lower AUC/Cmax) via increased clearance.
- PD concerns: additive CNS and respiratory depression (sedation, hypoventilation); amitriptyline lowers seizure threshold, potentially undermining seizure control.
- Management: monitor clinical response and sedation/respiratory status; TCA dose may need to be individualized and adjusted, with closer monitoring during initiation or discontinuation of the barbiturate. Consider TCA level monitoring where available.
What happens
Reduced tricyclic antidepressant exposure and possible additive adverse effects
Interaction Deep Dive
Using a barbiturate together with a tricyclic antidepressant (TCA) can enhance the metabolism of the TCA. Isolated cases have described patients whose serum TCA concentrations fell when a barbiturate was present123. TCAs may also compromise seizure control by lowering the seizure threshold. Furthermore, these agents produce additive depressant effects on the CNS and respiratory function4.
Why it happens (mechanism)
Increased tricyclic antidepressant metabolism
How to manage this interaction
The main point: this combination can lower how much amitriptyline is working while adding to drowsiness and slowed breathing. Your care team can handle this.
- Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise.
- Your amitriptyline dose may need to be adjusted and individualized, and your team may monitor you more closely, especially when the barbiturate is started or stopped.
- Tell your team if your depression or pain symptoms return or worsen, or if you feel unusually sleepy or have trouble breathing.
- Ask your pharmacist or doctor before making any changes.
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 epilepsy patients receiving long-term PHENobarbital therapy and in eight healthy controls who were not taking any medication. Every participant was an extensive metabolizer according to the genetically determined CYP2D6-related metabolic polymorphism. Relative to the controls, the epilepsy patients showed reduced peak plasma desipramine concentrations (74 nmol/L vs. 107 nmol/L), lower 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 would be anticipated with any pairing of a TCA and a barbiturate 5.
Common questions
Can I take Amitriptyline and Mephobarbital together?
Mephobarbital can lower amitriptyline levels (weaker effect) while both add to sedation and slowed breathing, so your care team may adjust the amitriptyline dose and monitor you more closely. Keep taking both as prescribed and report returning symptoms or excess drowsiness. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Mephobarbital 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 Mephobarbital interaction managed?
The main point: this combination can lower how much amitriptyline is working while adding to drowsiness and slowed breathing. Your care team can handle this. Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise. Your amitriptyline dose may need to be adjusted and individualized, and your team may monitor you more closely, especially when the barbiturate is st… 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 Mephobarbital 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 Mephobarbital
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