Amitriptyline and Mestranol: 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
Mestranol
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 mestranol is an estrogen. When these are taken together, the estrogen can change how your body handles the antidepressant. In some people this creates an odd mix: the amitriptyline may work less well for mood, yet at the same time you may notice more side effects like drowsiness, feeling lightheaded when standing up, or a restless, can't-sit-still feeling.
This tends to matter most if you were already stable on amitriptyline and are now starting an estrogen. The good news is your care team can manage this easily by fine-tuning your doses and watching how you feel, so please talk with your doctor or pharmacist before changing anything.
Effect: Estrogens (mestranol) may unpredictably alter tricyclic pharmacology, producing paradoxical loss of antidepressant efficacy alongside signs of TCA toxicity (drowsiness, orthostatic hypotension, akathisia).
- Mechanism: proposed estrogen effect on hepatic metabolism, either enhanced metabolism or inhibition of microsomal enzymes altering amitriptyline exposure. Neither agent is a prodrug.
- Direction: bidirectional/variable, appears estrogen dose-related.
- Onset: delayed. Evidence: probable, from isolated cases. Severity: moderate.
- Management: monitor clinical response and TCA adverse effects, especially when initiating estrogen in a patient stabilized on amitriptyline. Downward dose adjustment of either component may restore balance; withdrawal occasionally required.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in a small number of instances, been reported to either enhance or reduce the pharmacologic activity of tricyclic antidepressants3, with the coexistence of tricyclic toxicity and a paradoxical decline in antidepressant efficacy occurring at the same time1. This interaction seems to depend on the estrogen dose2 and is likely to carry clinical significance chiefly in individuals who have already been stabilized on tricyclic treatment and are then beginning estrogen therapy6.
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 medications as prescribed unless your prescriber tells you otherwise. This interaction is usually manageable with attention and small adjustments.
- Watch for signs your antidepressant may be working less well, or new side effects like daytime drowsiness, dizziness on standing, or restlessness.
- This is most relevant when an estrogen is started in someone already stable on amitriptyline, so mention timing to your care team.
- If changes show up, your doctor may adjust the dose of either the estrogen or the amitriptyline, and the dose may need to be individualized and monitored more closely by your team.
Do not start, stop, or change doses on your own. Bring any concerns to your pharmacist or prescriber.
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 arms. Ten patients received 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 study. The 10 patients receiving estrogen and imipramine exhibited significantly greater symptom improvement than the 10 patients on imipramine alone. However, after 2 weeks, the 5 patients on imipramine and high-dose estrogen had not improved to the same degree as those on imipramine and low-dose estrogen. The sole reported adverse effect was drowsiness, which occurred only in patients taking imipramine. After ethinyl estradiol was stopped, 2 weeks were needed for the high-dose estrogen group to perform as well as the low-dose group. This was ascribed to residual estrogen remaining in the high-dose group. In a separate group, 5 women given imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily did not improve as much as the 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 subsequently to 7.5 milligrams daily. She became nauseated, had persistent headaches, and had low normal blood pressure. All laboratory results were normal. When the estrogen was stopped, the adverse effects subsided 2. Some investigators have suggested that the adverse effects arose from increased tricyclic antidepressant effects secondary to estrogen inhibition of hepatic microsomal enzymes 3.
c) A study examined women who received clomipramine with oral contraceptives or clomipramine alone. At the outset, 30 women were taking the combination, but 12 later withdrew. The 18 patients on the combination were matched with 18 patients on clomipramine alone. No significant difference was observed 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 already dropped out of the study. Had the patients been matched before the study, different conclusions might have been reached 4.
d) A study evaluated 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. During 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) withdrew. Venous blood samples were collected weekly to measure serum clomipramine concentrations. No difference in serum concentrations was found between the groups. However, this outcome may be attributable in part to the low dose of clomipramine used 5.
e) Three patients receiving conjugated estrogens and tricyclic antidepressants at the same time developed akathisia. A 24-year-old patient receiving clomipramine 120 milligrams/day for anorexia nervosa and conjugated estrogens 1.25 milligrams/day for amenorrhea developed restless legs and a persistent urge to keep moving. Estrogen was stopped and benztropine 2 milligrams was given, producing marked reduction with resolution within 48 hours. Akathisia and disorientation developed 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 became confused, restless, and had an inner urge to keep moving. Symptoms resolved after amitriptyline was stopped. There was a positive rechallenge at one week with doxepin 100 milligrams, with resolution after doxepin was discontinued. 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 appeared within a few hours after the first dose of amitriptyline and resolved within 48 hours after the antidepressant was stopped 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 acting on 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 suspected of having additional effects on the central nervous system that produce an antidepressant effect 9.
Common questions
Can I take Amitriptyline and Mestranol together?
Combining amitriptyline with the estrogen mestranol can make the antidepressant less effective while also raising tricyclic side effects like drowsiness, dizziness, and restlessness. This is manageable, so report any changes and let your care team fine-tune the doses. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Mestranol 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 Mestranol interaction managed?
Keep taking both medications as prescribed unless your prescriber tells you otherwise. This interaction is usually manageable with attention and small adjustments. Watch for signs your antidepressant may be working less well, or new side effects like daytime drowsiness, dizziness on standing, or restlessness. This is most relevant when an estrogen is started in someone already stable on amitriptyl… 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 Mestranol 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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