Methohexital 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
Methohexital
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 may receive methohexital (a short-acting barbiturate used for sedation or anesthesia). There are two things worth knowing. First, barbiturates can speed up how your body breaks down amitriptyline, which can lower its level and make it work less well over time. Second, both drugs can calm the brain and slow breathing, so together they can make you extra drowsy or slow your breathing more than expected.
The good news is this is very manageable. Your care team knows about this combination and can watch you closely and adjust your doses if needed. Just make sure both your doctor and pharmacist know you take both.
Effect: Barbiturate (methohexital) induction of hepatic metabolism can increase amitriptyline clearance, reducing TCA serum concentrations and therapeutic effect. Additive CNS and respiratory depression is also expected, and TCAs may lower the seizure threshold.
- Mechanism: Enzyme induction increasing TCA metabolism (delayed onset); pharmacodynamic additive sedation/respiratory depression (more immediate).
- Evidence: Probable; scattered case reports of reduced TCA levels. Severity on file: major.
- Management: Monitor for loss of antidepressant efficacy and for excessive sedation or respiratory depression during and after methohexital use. Amitriptyline dose may need to be individualized and titrated by the care team; consider TCA level monitoring where clinically appropriate.
What happens
Reduced tricyclic antidepressant exposure and possible additive adverse effects
Interaction Deep Dive
Taking barbiturates together with a tricyclic antidepressant (TCA) can enhance the metabolism of the TCA. Isolated cases have described patients whose TCA serum concentrations fell when a barbiturate was also being administered123. TCAs may also compromise seizure control because they lower the seizure threshold. Furthermore, both agents produce additive depressant effects on the CNS and respiration4.
Why it happens (mechanism)
Increased tricyclic antidepressant metabolism
How to manage this interaction
Keep taking your amitriptyline exactly as prescribed, and let your medical team know you take it before any procedure using methohexital.
- Closer monitoring: Your team may watch you more closely for extra drowsiness or slowed breathing, since both drugs can add to these effects.
- Effectiveness: Because a barbiturate can lower amitriptyline levels over time, your team may check how well your antidepressant is working and adjust the dose, individualized to you, if needed.
- Speak up: Tell your pharmacist or prescriber if your mood symptoms return or if you feel unusually sedated.
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 epilepsy patients receiving long-term PHENobarbital therapy and in eight drug-free healthy control subjects. Every participant was an extensive metabolizer with regard 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 resulting in hepatic enzyme induction, and the 2D6 isozyme is considered important in metabolizing 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 Methohexital and Amitriptyline together?
Methohexital can lower amitriptyline levels and add to sedation and slowed breathing, but your care team can manage this by monitoring you and adjusting the dose if needed. Make sure both providers know you take both drugs. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Methohexital 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 Methohexital and Amitriptyline interaction managed?
Keep taking your amitriptyline exactly as prescribed, and let your medical team know you take it before any procedure using methohexital. Closer monitoring: Your team may watch you more closely for extra drowsiness or slowed breathing, since both drugs can add to these effects. Effectiveness: Because a barbiturate can lower amitriptyline levels over time, your team may check how well your antidepr… 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 Methohexital 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 Methohexital
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