Amitriptyline and Drospirenone: 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
Drospirenone
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 a medicine for depression, and drospirenone is a hormone found in some birth control pills. When they are taken together, the estrogen-like hormone can change how your body handles the amitriptyline. This can cause an odd mix: your depression medicine may work less well, while at the same time you feel more of its side effects, like drowsiness, dizziness when you stand up, or restlessness.
This does not happen to everyone, and it tends to show up slowly rather than right away. The good news is your care team can manage it. Keep taking both as prescribed, and let your pharmacist or doctor know if your mood slips or you feel unusually sleepy or lightheaded.
Effect: Estrogen (drospirenone) may alter TCA disposition, producing paradoxical loss of antidepressant efficacy alongside signs of tricyclic toxicity (sedation, orthostatic hypotension, akathisia).
- Mechanism: Estrogen may enhance hepatic metabolism of the TCA or inhibit hepatic microsomal enzymes; effect appears estrogen dose-related. Neither agent is a prodrug, so effect direction can vary.
- Onset: Delayed. Evidence: Probable, from isolated cases. Severity: Moderate.
- Highest risk: Patients stabilized on amitriptyline who then start estrogen.
- Management: Monitor mood and anticholinergic/orthostatic toxicity; a downward dose adjustment of either component, individualized by the care team, may restore balance. Withdrawal occasionally required.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens may, in rare instances, either enhance or reduce the pharmacologic activity of tricyclic antidepressants3, and a paradoxical picture can occur in which the antidepressant benefit is lost while signs of tricyclic toxicity emerge at the same time 1. This interaction seems to depend on the estrogen dose 2, and its clinical relevance is likely greatest for patients already stabilized on tricyclic therapy who then begin estrogen treatment 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
Good news first: this is manageable, and you should keep taking both medicines as prescribed unless your care team tells you otherwise.
- Watch for changes: tell your team if your depression seems to be returning, or if you notice more drowsiness, dizziness on standing, or restlessness.
- Dose tailoring: if changes appear, your team may adjust the dose of either the amitriptyline or the hormone, individualized to you, to restore effectiveness or ease side effects.
- Closer follow-up: this is most relevant if you were already stable on amitriptyline and are now starting the hormone.
Do not change or stop either medicine on your own. Raise any concerns with 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 results of giving estrogen together with tricyclic antidepressants (TCAs). In one trial, 30 depressed female prisoners were randomly divided into 4 treatment groups. Ten patients were given placebo, 10 were given 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 on estrogen and imipramine had a significantly greater symptom improvement than the 10 patients on imipramine alone. However, after 2 weeks, the 5 patients receiving imipramine and high-dose estrogen had improved less than those receiving imipramine and low-dose estrogen. The only side effect noted was drowsiness, which occurred only in 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 leftover estrogen in the high-dose group. In a separate group, 5 women given imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily improved less than 10 patients on imipramine only. Additionally, patients on the combination experienced severe side effects such as 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 results were normal. When estrogen was stopped, the side effects subsided 2. Some investigators have suggested that the side effects arose from increased tricyclic antidepressant effects due to estrogen inhibiting hepatic microsomal enzymes 3.
c) A study looked at women who received clomipramine with oral contraceptives or clomipramine alone. At the start, 30 women were taking the combination, but 12 later withdrew. The 18 patients on the combination were paired with 18 patients on clomipramine alone. No significant difference was found in patient 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. If the patients had been matched before the study, 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. During 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 finding may be partly due to the low dose of clomipramine used 5.
e) Three patients taking conjugated estrogens and tricyclic antidepressants together developed akathisia. A 24-year-old patient on 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, 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 taking amitriptyline, the patient became confused, restless, and had an inner urge to move continuously. Symptoms resolved after amitriptyline was stopped. A 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 given conjugated estrogens 1.25 milligrams/day and amitriptyline 50 milligrams/day. Akathisia developed within a few hours of the first amitriptyline dose and resolved within 48 hours after the antidepressant was stopped 6.
f) The absolute bioavailability of imipramine rose in women receiving 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 inhibit 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 Drospirenone together?
Combining amitriptyline with drospirenone-containing hormones can make the antidepressant less effective while increasing its side effects, so watch for mood changes, drowsiness, or dizziness and let your care team adjust doses if needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Drospirenone 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 Drospirenone interaction managed?
Good news first: this is manageable, and you should keep taking both medicines as prescribed unless your care team tells you otherwise. Watch for changes: tell your team if your depression seems to be returning, or if you notice more drowsiness, dizziness on standing, or restlessness. Dose tailoring: if changes appear, your team may adjust the dose of either the amitriptyline or the hormone, indiv… 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 Drospirenone 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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