Diethylstilbestrol 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
Diethylstilbestrol
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 diethylstilbestrol, which is a form of estrogen. When these are used together, the estrogen may change how your body handles the antidepressant. In some people this has led to a strange mix: the antidepressant may work less well for mood, yet you might also get more side effects like drowsiness, feeling dizzy when standing up, or restlessness.
This is not common, and the evidence is mostly theoretical. It matters most if you were doing well on amitriptyline and then started estrogen. The good news is your care team can manage this easily by adjusting doses and watching how you feel, so please just keep them in the loop.
Effect: Estrogens may alter tricyclic response, with a paradoxical picture of reduced antidepressant efficacy alongside signs of TCA toxicity (sedation, orthostatic hypotension, akathisia).
Mechanism: Proposed estrogen-enhanced hepatic metabolism of amitriptyline; effect appears estrogen dose-related. Neither agent is a straightforward prodrug in this context.
- Direction: variable (efficacy may fall while toxicity emerges).
- Onset: delayed.
- Evidence: theoretical, isolated case reports.
- Highest risk: patients stabilized on a TCA who then start estrogen.
Management: Monitor mood and TCA toxicity. If altered response occurs, downward dose adjustment of either component may help; occasionally withdrawal is needed.
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 heighten or diminish the pharmacologic activity of tricyclic antidepressants3. In some situations, a contradictory pattern emerges in which antidepressant efficacy is lost while tricyclic toxicity develops at the same time1. This interaction seems to depend on the dose of estrogen2, and its clinical relevance is likely to be greatest among patients who had already been stabilized on tricyclic treatment and are then commenced on estrogen therapy6.
Why it happens (mechanism)
Possible estrogen-enhanced hepatic metabolism of the tricyclic
How to manage this interaction
Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise. This interaction is uncommon and mostly theoretical, but it is worth watching for.
- Watch for: your depression feeling less controlled, or new side effects like drowsiness, dizziness on standing, or restlessness.
- If that happens: your care team may lower the dose of either the estrogen or the amitriptyline, and the dose can be individualized to restore the right balance. In some cases they may adjust the plan further.
- Your part: report any mood changes or new symptoms to your pharmacist or doctor so they can monitor you more closely.
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 TCAs. In one trial, 30 depressed female prisoners were randomized to 4 treatment groups. Ten patients were given placebo, 10 were given imipramine (150 milligrams/day) with placebo, 5 patients received imipramine (150 milligrams/day) with ethinyl estradiol (50 micrograms/day), and 5 patients received imipramine (150 milligrams/day) with ethinyl estradiol (25 micrograms/day). The 10 patients given placebo showed no improvement across the 6 weeks of the study. The 10 patients taking estrogen and imipramine showed significantly greater symptom improvement than the 10 patients taking imipramine alone. However, after 2 weeks, the 5 patients receiving imipramine and high-dose estrogen had improved less than the patients receiving imipramine and low-dose estrogen. The only reported adverse effect was drowsiness, affecting solely the patients on imipramine. After ethinyl estradiol was stopped, 2 weeks were needed for the high-dose estrogen group to reach the same level as the low-dose group. This was attributed to residual estrogen persisting in the high-dose group. In another group, 5 women who received imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily improved less than 10 patients receiving imipramine alone. In addition, the patients on the combination experienced severe adverse effects including lethargy, coarse tremor, and systolic hypotension 1.
b) A case described by 2 showed an interaction in a 32-year-old female taking conjugated estrogens 2.5 milligrams and imipramine 100 milligrams. The patient 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, 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 the adverse effects arose from increased TCA effects secondary to estrogen inhibition of hepatic microsomal enzymes 3.
c) A study looked at women given 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 adverse effects between the groups; however, the groups were matched after patients had withdrawn from the study. Had matching occurred before the study, different conclusions might have resulted 4.
d) A study examined the effects of oral contraceptives on clomipramine in 42 women aged 18 to 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 due to adverse effects) and 5 in the experimental group (2 due to 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 partly reflect 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 taking 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 and resolution within 48 hours. Akathisia and disorientation occurred in a 55-year-old patient on conjugated estrogen 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 urge to keep moving continuously. Symptoms cleared after amitriptyline was discontinued. Rechallenge at one week with doxepin 100 milligrams was positive, with resolution after doxepin was stopped. A third case of akathisia occurred in a 35-year-old patient who received conjugated estrogen 1.25 milligrams/day and amitriptyline 50 milligrams/day. Akathisia arose 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 given 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 suppress the oxidation of 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 also suspected of having additional effects on the central nervous system that produce an antidepressant effect 9.
Common questions
Can I take Diethylstilbestrol and Amitriptyline together?
Estrogen may change how amitriptyline works, sometimes lowering its mood benefit while causing more side effects, but your care team can manage this by adjusting doses and monitoring you. Report any mood changes or new drowsiness or dizziness. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Diethylstilbestrol 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 Diethylstilbestrol and Amitriptyline interaction managed?
Keep taking both medicines exactly as prescribed unless your prescriber tells you otherwise. This interaction is uncommon and mostly theoretical, but it is worth watching for. Watch for: your depression feeling less controlled, or new side effects like drowsiness, dizziness on standing, or restlessness. If that happens: your care team may lower the dose of either the estrogen or the amitriptyline,… 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 Diethylstilbestrol 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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