Estrone 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
Estrone
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 (a tricyclic antidepressant) along with estrone (an estrogen). In some people, estrogen can change how the body handles amitriptyline. This can create a tricky situation: your depression relief might feel weaker, and at the same time you could notice more side effects like drowsiness, dizziness when standing up, or restlessness.
This seems to depend on the estrogen dose and is most likely to show up if you started estrogen after already doing well on amitriptyline. The good news is this is considered a minor, manageable interaction. If you notice any of these changes, don't stop anything on your own. Just let your doctor or pharmacist know, and they can adjust your doses to get you feeling right again.
Effect: Estrogens (estrone) may alter tricyclic response, with paradoxical reduced antidepressant efficacy alongside signs of TCA toxicity (sedation, orthostatic hypotension, akathisia).
Mechanism: Probable inhibition of hepatic metabolism of amitriptyline, increasing exposure; effect appears estrogen dose-related. Neither agent is a prodrug.
- Direction/magnitude: Variable; can increase or decrease net TCA effect. Onset delayed.
- Evidence: Established, though based largely on isolated cases.
- Highest risk: Patients stabilized on a TCA who are then started on estrogen.
- Management: Monitor for altered response; downward dose adjustment of either agent may restore effect or resolve toxicity. Withdrawal occasionally required.
What happens
Possible attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in a small number of instances, been reported to either heighten or diminish the pharmacologic actions of tricyclic antidepressants3, with the paradoxical situation in which antidepressant efficacy is lost while tricyclic toxicity emerges at the same time 1. This interaction seems to depend on the dose of estrogen 2, and its clinical significance is most likely to arise in patients who had already been stabilized on tricyclic treatment and are subsequently commencing estrogen therapy 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 care team tells you otherwise. This interaction is manageable.
- Watch for changes: tell your team if your mood symptoms come back or if you feel unusually drowsy, dizzy on standing, or restless.
- Dose tailoring: if changes appear, your doctor may adjust the dose of either the estrogen or the amitriptyline to individualize your treatment.
- Timing matters: this is most likely when estrogen is added after you've been stable on amitriptyline, so mention any recent starts or dose changes.
- Don't stop on your own: raise any concerns with your pharmacist or prescriber first.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) Several studies examined the qualitative results of giving estrogen together with TCAs. In one trial, 30 depressed female prisoners were randomized into four treatment groups. Ten patients were given placebo, 10 received imipramine (150 mg daily) plus placebo, five patients received imipramine (150 mg daily) plus ethinyl estradiol (50 mcg daily), and five patients received imipramine (150 mg daily) plus ethinyl estradiol (25 mcg daily). The 10 patients given placebo showed no improvement across the six weeks of the study. The 10 patients on estrogen and imipramine had a significantly greater improvement in symptoms than the 10 patients on imipramine alone. However, after two weeks, the five patients receiving imipramine plus high-dose estrogen had not improved to the same degree as those receiving imipramine plus low-dose estrogen. The only reported adverse effect was drowsiness, which occurred only in patients taking imipramine. After ethinyl estradiol was stopped, the high-dose estrogen group needed a two-week interval to reach the same level as the low-dose group. This was ascribed to residual estrogen remaining in the high-dose group. In another group, five women taking imipramine 150 mg plus ethinyl estradiol 50 mrg daily did not improve to the extent seen in 10 patients on imipramine alone. In addition, the patients on the combination experienced severe adverse effects such as 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 signs of depersonalization. After two years of treatment, she raised her estrogen dose to 5 mg and subsequently to 7.5 mg daily. She became nauseated, experienced constant headaches, and had low normal blood pressure. All laboratory results were normal. When the estrogen was stopped, the adverse effects subsided. Some investigators have suggested that these adverse effects arose from increased TCA effects secondary to estrogen inhibition of hepatic microsomal enzymes 32.
c) In a study, women received either clomipramine with oral contraceptives or clomipramine alone. At the 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 found in how the patients responded to clomipramine. It was suggested that there was no significant difference in adverse effects between the groups; however, the groups were matched only after patients had dropped out of the study. Had matching been performed before the study began, different conclusions might have been reached 4.
d) The influence of oral contraceptives on clomipramine was investigated 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. Over the four-week study, three control patients (two because of adverse effects) and five in the experimental group (two because of adverse effects) withdrew. Venous blood samples were collected weekly to measure serum clomipramine concentrations. No difference in serum concentrations was seen between the groups. However, this finding may be partly attributable to the low dose of clomipramine administered 5.
e) Onset of akathisia was reported in 3 patients receiving conjugated estrogens and tricyclic antidepressants concurrently. A 24-year-old patient taking 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 continuously. 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 became 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 taking conjugated estrogen 1.25 mg daily and amitriptyline 50 mg daily. Akathisia arose within a few hours of the first amitriptyline dose and resolved within 48 hours after the antidepressant was stopped 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 suppress the oxidation of TCAs by acting on hepatic microsomal enzymes 8. Many TCAs are metabolized through oxidation and conjugation pathways. Suppressing the oxidation of TCAs could lead to accumulation and toxicity because of reduced clearance. Estrogens are also thought to have additional effects on the central nervous system that produce an antidepressant effect 9.
Common questions
Can I take Estrone and Amitriptyline together?
Estrogen (estrone) can change how amitriptyline works, sometimes weakening its antidepressant effect while causing more side effects like drowsiness or dizziness. Let your doctor or pharmacist know about any changes so they can adjust your doses. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Estrone and Amitriptyline 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 Estrone and Amitriptyline interaction managed?
Keep taking both medications as prescribed unless your care team tells you otherwise. This interaction is manageable. Watch for changes: tell your team if your mood symptoms come back or if you feel unusually drowsy, dizzy on standing, or restless. Dose tailoring: if changes appear, your doctor may adjust the dose of either the estrogen or the amitriptyline to individualize your treatment. Timing… 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 Estrone 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 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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