Amitriptyline and Dienestrol: 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
Dienestrol
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've been prescribed amitriptyline (an antidepressant) along with dienestrol, which is a form of estrogen. In some reports, estrogens can change how your body handles the antidepressant. This can lead to something a little odd: your depression treatment may feel less effective, while at the same time you might notice more antidepressant side effects like drowsiness, dizziness when standing, or restlessness.
I want to be clear that this is mostly a theoretical concern and rated as minor. It matters most if you were already stable on amitriptyline and then start estrogen. Please don't change anything on your own. Just let your pharmacist or doctor know how you're feeling, and they can adjust things easily.
Effect: Estrogens (dienestrol) may alter tricyclic pharmacologic response, paradoxically attenuating antidepressant efficacy while increasing TCA toxicity (sedation, orthostatic hypotension, akathisia).
Mechanism: Postulated estrogen-enhanced hepatic metabolism of amitriptyline, with effects appearing estrogen dose-related. Neither agent is a prodrug; amitriptyline is active.
- Onset: delayed
- Evidence: theoretical, isolated case reports
- Severity: minor
- Highest risk: patients stabilized on a TCA who are then started on estrogen
Management: Monitor for altered antidepressant response or emergent TCA toxicity. Downward dose adjustment of either component may restore efficacy or resolve toxicity; withdrawal is occasionally required.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have been reported, in a small number of instances, to either enhance or diminish the pharmacologic activity of tricyclic antidepressants3. In some situations, a paradoxical picture arises where antidepressant efficacy is lost at the same time that signs of tricyclic toxicity appear 1. This interaction seems to depend on the estrogen dose 2, and its clinical relevance is likely greatest in patients who had already been stabilized on tricyclic treatment and are then beginning estrogen therapy 6.
Why it happens (mechanism)
Possible estrogen-enhanced hepatic metabolism of the tricyclic.
How to manage this interaction
Good news: this interaction is usually manageable, and both medications are often used together safely.
- Keep taking both exactly as prescribed unless your care team tells you otherwise.
- Watch for changes: your depression symptoms returning, or new side effects like drowsiness, feeling faint when standing up, or restlessness.
- If you notice any of these, tell your pharmacist or prescriber. The dose of either the estrogen or the amitriptyline may need to be adjusted and individualized by your care team.
- This is most worth watching if you were already stable on amitriptyline before starting the estrogen.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) A study assessed the qualitative results of giving estrogen and TCAs together. 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 received imipramine (150 milligrams/day) plus ethinyl estradiol (50 micrograms/day), and 5 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 on estrogen and imipramine showed 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 as much as those on imipramine and low-dose estrogen. The only side-effect reported was drowsiness, which affected only the 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 effect was ascribed to residual estrogen remaining in the high-dose group. In a separate group, 5 women who received imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily did not improve as much as 10 patients on imipramine only. In addition, patients on the combination experienced severe side-effects including lethargy, coarse tremor, and systolic hypotension 1.
b) A case reported by 2 showed 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 therapy, 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 results were normal. When the estrogen was stopped, the side-effects subsided. Some investigators have suggested that the side effects arose from enhanced TCA effects secondary to estrogen inhibiting hepatic microsomal enzymes 3.
c) A study assessed women who 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 withdrawn from the study. If the patients had 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 between 18 and 40. 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 control patients (2 because of side-effects) and 5 in the experimental group (2 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 outcome may be partly attributable to the low dose of clomipramine administered 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 constant urge to keep moving. Estrogen was stopped and benztropine 2 milligrams was given, producing marked reduction and 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 amitriptyline, the patient was confused, restless, and had an inner desire to move continuously. Symptoms resolved after amitriptyline was stopped. Positive rechallenge occurred 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 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. 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 Dienestrol together?
Estrogen may make amitriptyline work less well while causing more of its side effects, but this is a minor, theoretical concern. Report any changes in mood or new side effects to your care team, who can adjust your dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Dienestrol 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 Dienestrol interaction managed?
Good news: this interaction is usually manageable, and both medications are often used together safely. Keep taking both exactly as prescribed unless your care team tells you otherwise. Watch for changes: your depression symptoms returning, or new side effects like drowsiness, feeling faint when standing up, or restlessness. If you notice any of these, tell your pharmacist or prescriber. The dose… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
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 Dienestrol 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.
Keep reading about Amitriptyline
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