Amitriptyline and Gestodene: 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
Gestodene
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 gestodene is an estrogen-like hormone found in some birth control. When you take them together, the hormone can change how your body handles the antidepressant. This can lead to something a little unusual: your depression symptoms may not feel as well controlled, while at the same time you might notice more side effects like drowsiness, dizziness when standing up, or restlessness.
This is most likely to show up if you were already doing well on amitriptyline and then start the hormone. The good news is your care team can manage this easily by adjusting a dose and keeping a closer eye on how you feel. Let them know if anything changes.
Effect: Estrogen (gestodene) may alter tricyclic (amitriptyline) response, producing simultaneous attenuated antidepressant efficacy and TCA toxicity (sedation, orthostatic hypotension, akathisia). Neither agent is a prodrug requiring activation, so effect is on TCA levels/response directly.
- Mechanism: estrogen-related modulation of hepatic microsomal metabolism (either enhanced metabolism or enzyme inhibition), yielding a paradoxical mixed picture.
- Direction/magnitude: variable, appears estrogen dose-related.
- Onset: delayed. Evidence: probable, isolated cases.
- Management: monitor mood and anticholinergic/orthostatic effects, especially when adding estrogen to a stabilized TCA patient; downward dose adjustment of either agent, individualized by the team, or withdrawal if needed.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in isolated instances, been reported to either heighten or diminish the pharmacologic actions of tricyclic antidepressants3, with the paradoxical situation of antidepressant efficacy 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 greatest for patients who had been stabilized on tricyclic treatment and are then beginning 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 medications as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team.
- Watch for signs your antidepressant may be working less well, or new side effects like drowsiness, feeling dizzy when standing, or restlessness.
- This is most likely to appear if you started the hormone after already being stable on amitriptyline, so speak up during that time.
- Your team may adjust the dose of either the amitriptyline or the estrogen to restore benefit or ease side effects, and they may monitor you more closely.
Report any changes in mood or new symptoms to your pharmacist or doctor.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) A study looked at the qualitative outcomes of giving estrogen together with tricyclic antidepressants (TCAs). In one trial, 30 depressed female prisoners were randomly placed into 4 treatment groups. Ten patients were given placebo, 10 were given imipramine (150 milligrams/day) plus placebo, 5 patients were given imipramine (150 milligrams/day) plus ethinyl estradiol (50 micrograms/day), and 5 patients were given imipramine (150 milligrams/day) plus ethinyl estradiol (25 micrograms/day). The 10 patients who received placebo showed no improvement across the 6 weeks of the study. The 10 patients taking estrogen with imipramine showed a significantly greater improvement in symptoms than the 10 patients taking imipramine on its own. However, after 2 weeks, the 5 patients given imipramine and high-dose estrogen had not improved to the same degree as those given imipramine and low-dose estrogen. The only side effect noted was drowsiness, which occurred only in patients taking imipramine. After ethinyl estradiol was stopped, a period of 2 weeks was needed for the high-dose estrogen group to perform as well as the low-dose group. This was attributed 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 10 patients given imipramine alone. Additionally, the patients on the combination experienced severe side 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, the patient 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 2. Some investigators have suggested that the side effects arose from heightened tricyclic antidepressant effects due 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, 30 women were taking the combination, but 12 later withdrew. The 18 patients on the combination were matched with 18 patients taking clomipramine alone. No significant difference was found 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 already dropped out of the study. Had the patients been matched before the study began, different conclusions might have been reached 4.
d) A study examined 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 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 seen between the groups. However, this outcome may be partly due to the low dose of clomipramine administered 5.
e) Three patients taking 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 move continuously. Estrogen was stopped and benztropine 2 milligrams was given, leading to marked reduction and resolution within 48 hours. Akathisia and disorientation developed in a 55-year-old patient taking 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 following discontinuation of doxepin. 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 taking 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 hinder the oxidation of tricyclic antidepressants (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 thought to have additional effects on the central nervous system that produce an antidepressant effect 9.
Common questions
Can I take Amitriptyline and Gestodene together?
Combining amitriptyline with the estrogen gestodene can, in some people, both weaken the antidepressant effect and increase side effects like drowsiness or dizziness; tell your care team about any changes so they can adjust the dose and monitor you. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Gestodene 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 Gestodene interaction managed?
Keep taking both medications as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team. Watch for signs your antidepressant may be working less well, or new side effects like drowsiness, feeling dizzy when standing, or restlessness. This is most likely to appear if you started the hormone after already being stable on amitriptyline,… 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 Gestodene 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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