Amitriptyline and Norethindrone: 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
Norethindrone
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 (Elavil) for mood and norethindrone, a hormone medicine. In some people, the hormone can change how the body handles amitriptyline. Oddly, this can pull two directions at once: your depression medicine may work less well, while side effects of amitriptyline (like drowsiness, feeling dizzy when standing, or restlessness) may go up.
This shows up gradually, mostly in people who were doing well on amitriptyline and then start the hormone. The good news is this is manageable. Don't stop either medicine on your own. Just let your doctor or pharmacist know if you notice new sleepiness, dizziness, restlessness, or your mood slipping, and they can adjust things.
Effect: Estrogen/progestin therapy may paradoxically attenuate TCA antidepressant efficacy while increasing TCA toxicity (sedation, orthostatic hypotension, akathisia).
- Mechanism: Hormone-mediated alteration of hepatic microsomal metabolism of amitriptyline (possible enzyme induction reducing effect and/or inhibition raising exposure). Neither agent is metabolized as a prodrug.
- Direction: Mixed/biphasic; dose-related to the hormone component.
- Onset: Delayed. Evidence: Probable, isolated cases.
- Population: Chiefly patients stabilized on TCA who then initiate hormone therapy.
- Management: Monitor for altered antidepressant response and TCA toxicity; downward dose titration of either component may restore balance, occasionally withdrawal is needed.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in rare instances, been reported to either heighten or diminish the pharmacologic action of tricyclic antidepressants3. This may present paradoxically, with the antidepressant benefit being lost while signs of tricyclic toxicity emerge at the same time1. The interaction seems to depend on the estrogen dose2, and its clinical significance is likely greatest in patients who had previously been stabilized on tricyclic treatment and are subsequently begun on 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
Both medicines can be taken together, and your care team can manage this. Keep taking each exactly as prescribed unless your prescriber tells you otherwise.
- Watch for changes: new drowsiness, lightheadedness or dizziness when standing, restlessness, or your depression symptoms returning.
- Report them: tell your pharmacist or doctor if you notice these, especially in the weeks after starting the hormone.
- What they may do: the dose of the amitriptyline or the hormone may be adjusted and individualized to restore effectiveness or ease side effects, and they may monitor you more closely.
Do not stop or change either medicine on your own.
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 groups. Ten patients were given placebo, 10 received imipramine (150 milligrams/day) plus 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 on placebo showed no improvement over the 6 weeks of the study. The 10 patients receiving estrogen and imipramine showed significantly greater symptom improvement than the 10 patients on imipramine alone. However, after 2 weeks, the 5 patients given imipramine and high-dose estrogen had not improved as much as those receiving imipramine and low-dose estrogen. The only side-effect reported was drowsiness, which affected only the 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 effect was ascribed to residual estrogen remaining in the high-dose group. In another group, 5 women receiving imipramine 150 milligrams and ethinyl estradiol 50 micrograms daily did not improve as much as 10 patients on imipramine alone. In addition, 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 therapy, she raised her estrogen dose to 5 milligrams and then 7.5 milligrams daily. She became nauseated, had constant headaches, and had low normal blood pressure. All laboratory work was normal. When the 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 inhibition of hepatic microsomal enzymes 3.
c) A study examined women who received clomipramine with oral contraceptives or clomipramine by itself. 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 seen in the patients' responses to clomipramine. It was proposed 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, different conclusions might have been reached 4.
d) A study evaluated how oral contraceptives affected 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 together with oral contraceptives. During the 4-week study, 3 patients in the control group (2 owing to side effects) and 5 in the experimental group (2 owing to 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 taking conjugated estrogens and tricyclic antidepressants at the same time 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 keep moving. Estrogen was discontinued and benztropine 2 milligrams was given, producing marked reduction and resolution within 48 hours. Akathisia and disorientation arose 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 was confused, restless, and had an inner urge to move continuously. Symptoms cleared 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 occurred in a 35-year-old patient who received conjugated estrogens 1.25 milligrams/day and amitriptyline 50 milligrams/day. Akathisia developed 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 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 other effects on the central nervous system that produce an antidepressant effect 9.
Common questions
Can I take Amitriptyline and Norethindrone together?
Combining amitriptyline with norethindrone can make the antidepressant work less well while raising side effects like drowsiness, dizziness, and restlessness. Tell your doctor or pharmacist about any such changes so they can adjust the dose. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Norethindrone 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 Norethindrone interaction managed?
Both medicines can be taken together, and your care team can manage this. Keep taking each exactly as prescribed unless your prescriber tells you otherwise. Watch for changes: new drowsiness, lightheadedness or dizziness when standing, restlessness, or your depression symptoms returning. Report them: tell your pharmacist or doctor if you notice these, especially in the weeks after starting the hor… 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 Norethindrone 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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