Amitriptyline and Ethynodiol: 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
Ethynodiol
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.
Amitriptyline (Elavil) is an antidepressant, and ethynodiol is an estrogen-containing hormone medicine. When they are taken together, the hormone can change how your body handles the antidepressant. This can lead to something a little confusing: your depression symptoms may not be as well controlled as before, and at the same time you may notice more antidepressant side effects like drowsiness, dizziness when standing up, or restlessness.
This tends to matter most if you were already doing well on amitriptyline and then start the hormone. The good news is your care team can manage this by adjusting a dose and keeping a closer eye on how you feel. Keep taking both as prescribed and let them know about any changes.
Effect: Estrogen (ethynodiol) may alter tricyclic (amitriptyline) response, producing a paradoxical picture of reduced antidepressant efficacy alongside signs of TCA toxicity (drowsiness, orthostatic hypotension, akathisia).
Mechanism: Estrogen effects on hepatic microsomal metabolism, possibly enhancing or inhibiting TCA clearance; appears estrogen dose-related. Neither agent is a prodrug requiring activation.
- Onset: delayed
- Evidence: probable (isolated cases)
- Severity: moderate
Management: Highest risk when adding estrogen to a patient stabilized on a TCA. Monitor for altered mood control and anticholinergic/hypotensive toxicity. Dose of either agent may be adjusted and individualized; occasionally withdrawal is needed.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in rare instances, been reported to either heighten or diminish the pharmacologic activity of tricyclic antidepressants3. In some situations, this can present paradoxically, with the antidepressant benefit being lost while signs of tricyclic toxicity emerge at the same time 1. This interaction seems to depend on the dose of estrogen 2, and its clinical significance is likely to be greatest in patients already stabilized on tricyclic treatment who then begin estrogen therapy 6.
Why it happens (mechanism)
Possible estrogen-enhanced hepatic metabolism of the tricyclic antidepressant or estrogen inhibition of hepatic microsomal enzymes
How to manage this interaction
Keep taking both amitriptyline and your ethynodiol-containing hormone exactly as prescribed unless your prescriber tells you otherwise. This interaction is most relevant when the hormone is started after you are already stable on the antidepressant.
- Watch for signs your depression is less controlled, or new side effects like drowsiness, lightheadedness on standing, or restlessness.
- Report these to your pharmacist or prescriber. The dose of either medicine may need to be adjusted and individualized by your care team.
- Your team may monitor you more closely for a while after starting the combination.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) A study assessed the qualitative outcomes of giving estrogen together with tricyclic antidepressants (TCAs). In one trial, 30 depressed female prisoners were randomized into 4 treatment groups. Ten patients were given placebo, 10 received imipramine (150 milligrams/day) plus placebo, 5 patients received imipramine (150 milligrams/day) plus ethinyl estradiol (50 micrograms/day), and 5 patients received imipramine (150 milligrams/day) plus ethinyl estradiol (25 micrograms/day). The 10 patients on placebo showed no improvement across the 6 weeks of the trial. The 10 patients taking estrogen with imipramine showed significantly greater symptom improvement than the 10 patients on imipramine alone. However, after 2 weeks, the 5 patients receiving imipramine with high-dose estrogen had not improved as much as those on imipramine with low-dose estrogen. The only adverse effect noted was drowsiness, which occurred solely in patients taking imipramine. After stopping ethinyl estradiol, 2 weeks were needed before the high-dose estrogen group performed as well as the low-dose group. This finding was ascribed to residual estrogen remaining in the high-dose group. In a separate group, 5 women who took imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily did not improve as much as 10 patients on imipramine alone. In addition, the patients on the combination experienced severe adverse effects including lethargy, coarse tremor, and systolic hypotension 1.
b) A case report described an interaction in a 32-year-old woman taking conjugated estrogens 2.5 milligrams and imipramine 100 milligrams. She developed lethargy, tremors, and signs of depersonalization. After 2 years of treatment, she raised her estrogen dose to 5 milligrams and then to 7.5 milligrams daily. She became nauseated, had persistent headaches, and had low normal blood pressure. All laboratory tests were normal. When the estrogen was stopped, the adverse effects subsided 2. Some researchers have suggested that the adverse effects arose from heightened tricyclic antidepressant activity secondary to estrogen inhibition of hepatic microsomal enzymes 3.
c) A study examined women who received clomipramine plus oral contraceptives or clomipramine alone. At the start, 30 women were taking the combination, but 12 later withdrew. The 18 patients remaining 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 adverse effects between the groups; however, the groups were matched after patients had dropped out of the study. If the patients had been matched before the study began, different conclusions might have been reached 4.
d) A study assessed the effects of oral contraceptives on clomipramine in 42 women aged 18 to 40 years. Twenty-three women took clomipramine 25 milligrams at bedtime, while 19 took clomipramine 25 milligrams at bedtime along with oral contraceptives. Over the 4-week study, 3 patients in the control group (2 because of adverse effects) and 5 in the experimental group (2 because of adverse effects) dropped out. Venous blood samples were collected weekly to measure serum clomipramine concentrations. No difference in serum concentrations was observed between the groups. However, this outcome may be partly attributable to the low dose of clomipramine administered 5.
e) Three patients taking conjugated estrogens and tricyclic antidepressants concurrently developed akathisia. A 24-year-old patient taking clomipramine 120 milligrams/day for anorexia nervosa and conjugated estrogens 1.25 milligrams/day for amenorrhea developed restless legs and a constant urge to move continuously. Estrogen was stopped and benztropine 2 milligrams was given, producing marked reduction with resolution within 48 hours. Akathisia and disorientation arose in a 55-year-old patient on conjugated estrogens 1.25 milligrams/day who was prescribed amitriptyline 50 milligrams/day for depression. Within hours of taking amitriptyline, the patient was confused, restless, and had an inner urge to move continuously. Symptoms resolved after amitriptyline was discontinued. A positive rechallenge occurred at one week with doxepin 100 milligrams, with resolution after doxepin was stopped. A third case of akathisia was reported in a 35-year-old patient who received conjugated estrogens 1.25 milligrams/day and amitriptyline 50 milligrams/day. Akathisia developed within a few hours after the first dose of amitriptyline and resolved within 48 hours after the antidepressant was discontinued 6.
f) The absolute bioavailability of imipramine rose in women who received low-dose oral contraceptives (50 micrograms or less of ethinyl estradiol) from 27% to 44% (p less than 0.05), as shown by an increase in the AUC 7.
g) Estrogens may suppress the oxidation of tricyclic antidepressants (TCAs) by influencing hepatic microsomal enzymes 8. Many TCAs are metabolized through oxidation and conjugation pathways. Inhibiting the oxidation of TCAs could lead to accumulation and toxicity because of reduced clearance. Estrogens are thought to have additional effects on the central nervous system that produce an antidepressant effect 9.
Common questions
Can I take Amitriptyline and Ethynodiol together?
Adding an estrogen like ethynodiol can throw off your amitriptyline, sometimes reducing its antidepressant effect while also increasing side effects. Tell your care team about any changes so they can adjust a dose or monitor you more closely. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Ethynodiol interaction?
It is rated moderate. Can be significant — usually manageable with 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 Ethynodiol interaction managed?
Keep taking both amitriptyline and your ethynodiol-containing hormone exactly as prescribed unless your prescriber tells you otherwise. This interaction is most relevant when the hormone is started after you are already stable on the antidepressant. Watch for signs your depression is less controlled, or new side effects like drowsiness, lightheadedness on standing, or restlessness. Report these to… 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 Ethynodiol 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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