Norgestimate 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
Norgestimate
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 tricyclic antidepressant, and norgestimate is a hormone found in some birth control and hormone products. When they are taken together, the hormone can change how your body handles the antidepressant. Oddly, this can go two ways at once: your depression may feel less controlled, while at the same time you may notice more tricyclic side effects like drowsiness, dizziness on standing (low blood pressure), or restlessness.
This is uncommon and tends to show up gradually, mostly in people who were already doing well on amitriptyline and then start the hormone. The good news is your care team can manage this by adjusting a dose and keeping a closer eye on how you feel. Don't stop either medicine on your own, just let your pharmacist or doctor know.
Effect: Estrogenic component (norgestimate) may alter tricyclic (amitriptyline) response, with paradoxical loss of antidepressant efficacy plus signs of tricyclic toxicity (sedation, orthostatic hypotension, akathisia).
- Mechanism: Estrogen-related modulation of hepatic microsomal metabolism (either enhanced clearance reducing efficacy or enzyme inhibition raising tricyclic exposure); appears estrogen dose-related.
- Direction: Bidirectional/variable; neither drug is a prodrug.
- Onset: Delayed. Evidence: Probable, isolated cases. Severity: Moderate.
- Management: Monitor for altered antidepressant response and anticholinergic/orthostatic effects, especially in patients stabilized on a TCA who start estrogen. Downward dose adjustment of either agent may restore control; discontinuation occasionally required.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have, in a small number of instances, been reported to either enhance or diminish the pharmacologic activity of tricyclic antidepressants3, with a paradoxical presentation in which antidepressant efficacy is lost while tricyclic toxicity appears at the same time 1. This interaction seems to depend on the dose of estrogen 2, and its clinical significance is likely to be greatest in patients who were already stabilized on tricyclic therapy and are then beginning 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
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team.
- Watch for signs your depression is less well controlled, or new side effects such as drowsiness, lightheadedness when standing, or feeling restless.
- If those happen, the dose of either the amitriptyline or the hormone may need to be adjusted and individualized by your care team.
- Your team may monitor you more closely, especially in the weeks after starting the hormone product.
- Report changes to your pharmacist or doctor rather than changing doses yourself. In some cases stopping one medicine may be recommended by your 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 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) 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 over the 6 weeks of the study. The 10 patients receiving estrogen and imipramine had a 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 improved less than the patients on imipramine and low-dose estrogen. The only reported side-effect was drowsiness, which occurred only in patients receiving imipramine. After ethinyl estradiol was stopped, 2 weeks were needed before the high-dose estrogen group performed 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 improved less than 10 patients receiving imipramine alone. Additionally, the 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. The patient developed lethargy, tremors, and signs of depersonalization. After 2 years of treatment, she raised her estrogen dose to 5 milligrams and later to 7.5 milligrams daily. The patient experienced nausea, persistent headaches, and low normal blood pressure. All laboratory results were normal. When the estrogen was stopped, the side effects resolved 2. Some investigators have suggested that the side effects stemmed 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 study's outset, 30 women were taking the combination, but 12 later dropped out. The 18 patients on the combination were matched with 18 patients on 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 only after patients had 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) dropped out. Venous blood samples were collected weekly to measure serum clomipramine concentrations. No difference in serum concentrations was observed between the groups. However, this finding may be partly attributable 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 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 constantly. Estrogen was stopped and benztropine 2 milligrams was given, producing marked reduction and resolution within 48 hours. A 55-year-old patient on conjugated estrogens 1.25 milligrams/day who was prescribed amitriptyline 50 milligrams/day for depression developed akathisia and disorientation. Within hours of taking amitriptyline, the patient was confused, restless, and had an inner urge to move constantly. Symptoms resolved 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 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 discontinued 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 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 Norgestimate and Amitriptyline together?
Adding a norgestimate-containing hormone to amitriptyline can make the antidepressant work less well while also causing more tricyclic side effects like drowsiness and dizziness. Keep taking both, watch for these changes, and let your pharmacist or doctor fine-tune the dose if needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Norgestimate and Amitriptyline 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 Norgestimate and Amitriptyline interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is manageable with attention from your care team. Watch for signs your depression is less well controlled, or new side effects such as drowsiness, lightheadedness when standing, or feeling restless. If those happen, the dose of either the amitriptyline or the hormone may need to be adjusted and in… 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 Norgestimate 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.
Keep reading about Amitriptyline
Keep reading about Norgestimate
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