Amitriptyline and Estriol: 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
Estriol
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.
You're taking amitriptyline (an antidepressant) along with estriol (an estrogen). In some cases, estrogen can slow down how your liver breaks down amitriptyline, letting more of it build up. Oddly, people can notice two things at once: the antidepressant may seem to work less well, while side effects go up, like drowsiness, feeling lightheaded when you stand, or restlessness.
This is uncommon, tends to show up gradually, and seems to depend on the estrogen dose. The good news is your care team can handle it easily by adjusting doses if needed. Just let them know if you notice any of these changes.
Effect: Estrogen (estriol) may alter TCA response, with paradoxical loss of antidepressant efficacy alongside signs of tricyclic toxicity (sedation, orthostatic hypotension, akathisia).
Mechanism: Possible inhibition of hepatic metabolism of amitriptyline, increasing exposure; effect appears estrogen dose-related. Neither agent is a prodrug, so inhibition raises active TCA levels.
- Direction: increased TCA toxicity, possible reduced antidepressant effect
- Onset: delayed
- Evidence: established, though based on isolated cases; severity minor
- Management: monitor for altered TCA response, especially in patients stabilized on a TCA who start estrogen; downward dose adjustment of either agent, or withdrawal, may be needed.
What happens
Possible attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in a small number of documented instances, been shown to either enhance or diminish the pharmacologic activity of tricyclic antidepressants3, with reports describing a paradoxical scenario in which antidepressant efficacy is lost while signs of tricyclic toxicity emerge at the same time 1. This interaction seems to depend on the estrogen dose 2, and it is likely to carry clinical significance chiefly for patients who were already stabilized on tricyclic therapy and are then begun on estrogen treatment 6.
Why it happens (mechanism)
Possible inhibition of hepatic metabolism of the tricyclic antidepressant
How to manage this interaction
Keep taking both medications as prescribed unless your prescriber tells you otherwise. This interaction is usually mild and manageable.
- Watch for changes such as increased drowsiness, dizziness on standing, restlessness, or your depression symptoms returning.
- Report these to your pharmacist or prescriber if you notice them, especially if you were doing well on amitriptyline before starting estriol.
- If needed, your care team may adjust the dose of either drug, individualized to you, to restore benefit or ease side effects, or occasionally change a medication.
Your team can monitor you more closely to keep things on track.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) Several studies assessed the qualitative outcomes of giving estrogen together with TCAs. In one trial, 30 depressed female prisoners were randomized into four treatment groups. Ten patients received placebo, 10 received imipramine (150 mg daily) plus placebo, five received imipramine (150 mg daily) with ethinyl estradiol (50 mcg daily), and five received imipramine (150 mg daily) with ethinyl estradiol (25 mcg daily). The 10 patients on placebo showed no improvement across the six weeks of the study. The 10 patients receiving estrogen and imipramine showed significantly greater symptom improvement than the 10 patients on imipramine alone. Nevertheless, after two weeks the five patients on imipramine plus high-dose estrogen had improved less than those on imipramine plus low-dose estrogen. The sole reported side effect was drowsiness, which occurred only in patients taking imipramine. After ethinyl estradiol was stopped, a period of two weeks was needed for the high-dose estrogen group to reach the same level as the low-dose group. This finding was attributed to residual estrogen remaining in the high-dose group. In another group, five women taking imipramine 150 mg and ethinyl estradiol 50 mrg daily improved less than 10 patients receiving imipramine only. In addition, patients on the combination experienced severe side effects including lethargy, coarse tremor, and systolic hypotension 1.
b) A 32-year-old woman taking conjugated estrogens 2.5 mg and imipramine 100 mg developed lethargy, tremors, and features of depersonalization. After two years of therapy, she raised her estrogen dose to 5 mg and then to 7.5 mg daily. She became nauseated, had persistent headaches, and had low normal blood pressure. All laboratory tests were normal. When the estrogen was discontinued, the side effects subsided. Some investigators have suggested that the side effects arose from increased TCA effects secondary to estrogen inhibition of hepatic microsomal enzymes 32.
c) In a study, women received clomipramine with oral contraceptives or clomipramine alone. At the study's start there were 30 women on the combination, but 12 later withdrew. The 18 patients on the combination were matched with 18 patients on clomipramine alone. No significant difference was seen in the patients' responses to clomipramine. It was suggested that there was no significant difference in side effects between the groups; however, the groups were matched after patients had dropped out of the study. Had matching been done before the study, different conclusions might have been reached 4.
d) The effects of oral contraceptives on clomipramine were examined in 42 women aged 18 to 40. Twenty-three women took clomipramine 25 mg at bedtime, while 19 took clomipramine 25 mg at bedtime along with oral contraceptives. During the four-week study, three control patients (two because of side effects) and five in the experimental group (two because of side effects) withdrew. Venous blood samples were collected weekly to measure serum clomipramine concentrations. No difference in serum concentrations was found between the groups. However, this result may be partly attributable to the low dose of clomipramine administered 5.
e) The development of akathisia was reported in 3 patients receiving conjugated estrogens and tricyclic antidepressants concurrently. A 24-year-old patient on clomipramine 120 mg daily for anorexia nervosa and conjugated estrogens 1.25 mg daily for amenorrhea developed restless legs and a persistent urge to move constantly. Estrogen was stopped and benztropine 2 mg was given, producing marked reduction and resolution within 48 hours. Akathisia and disorientation developed in a 55-year-old patient on conjugated estrogen 1.25 mg daily who was prescribed amitriptyline 50 mg daily for depression. Within hours of amitriptyline, the patient was confused, restless, and had an inner urge to move continuously. The symptoms resolved after amitriptyline was discontinued. A third case of akathisia was reported in a 35-year-old patient who received conjugated estrogen 1.25 mg daily and amitriptyline 50 mg daily. Akathisia appeared within a few hours after the first amitriptyline dose and resolved within 48 hours after the antidepressant was discontinued 6.
f) The absolute bioavailability of imipramine rose in women receiving low-dose oral contraceptives (50 mcg or less of ethinyl estradiol) from 27% to 44% (p less than 0.05), as shown by an increase in the area under the plasma concentration time curve 7.
g) Estrogens may inhibit the oxidation of TCAs by affecting hepatic microsomal enzymes 8. Many TCAs are metabolized through oxidation and conjugation pathways. Inhibition of TCA oxidation could lead to accumulation and toxicity resulting from decreased clearance. Estrogens are suspected of having additional effects on the central nervous system that produce an antidepressant effect 9.
Common questions
Can I take Amitriptyline and Estriol together?
Estriol may raise amitriptyline levels, sometimes causing more side effects while reducing its antidepressant benefit, but this is uncommon and mild. Tell your care team about any drowsiness, dizziness, restlessness, or return of depression so they can adjust doses if needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Estriol interaction?
It is rated minor. Usually limited clinical impact.
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 Estriol interaction managed?
Keep taking both medications as prescribed unless your prescriber tells you otherwise. This interaction is usually mild and manageable. Watch for changes such as increased drowsiness, dizziness on standing, restlessness, or your depression symptoms returning. Report these to your pharmacist or prescriber if you notice them, especially if you were doing well on amitriptyline before starting estriol… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "established". Well documented — supported by controlled studies or strong clinical data.
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 Estriol 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 (9)
- Prange AJ Jr: Estrogens may well affect response to antidepressants. JAMA 1972; 219:143-144.
- Khurana RC: Estrogen-imipramine interaction (letter). JAMA 1972; 222:702-703. PubMed
- Somani SM & Khurana RC: Mechanism of estrogen-imipramine interaction (letter). JAMA 1973; 223:560. DOI
- Beaumont G: Drug interactions with clomipramine. J Int Med Res 1973; 1:480-484.
- Luscombe DK & John V: Influences of age, cigarette smoking and the oral contraceptive on plasma concentrations of clomipramine. Postgrad Med J 1980; 56(suppl 1):99-102.
- Krishnan KR, France RD, & Ellinwood EH: Tricyclic-induced akathisia in patients taking conjugated estrogens. Am J Psychiatry 1984; 141:696-697. PubMed
- Abernethy DR, Greenblatt DJ, & Shader RI: Imipramine disposition in users of oral contraceptive steroids. Clin Pharmacol Ther 1984; 35:792-797. PubMed
- John VA, Luscombe DK, & Kemp H: Effects of age, cigarette smoking and the oral contraceptive on the pharmacokinetics of clomipramine and its desmethyl metabolite during chronic dosing. J Int Med Res 1980; 8(suppl 3):88-95.
- Oppenheim G: Estrogens in the treatment of depression: neuropharmacological mechanisms. Biol Psychiatry 1983; 18:721-725.
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