Amitriptyline and Dienogest: 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
Dienogest
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 dienogest, a hormone that acts a bit like an estrogen in the body. When these are combined, the hormone can change how your liver handles the antidepressant. This can lead to a tricky situation: your amitriptyline may work less well for mood, while at the same time you notice more of its side effects, like drowsiness, feeling dizzy when you stand up, or restlessness.
This doesn't happen to everyone, and it usually shows up slowly rather than right away. The good news is your care team can manage it easily by adjusting doses and keeping a closer eye on how you feel. Let them know if anything changes.
Effect: Estrogenic activity from dienogest may alter hepatic metabolism of amitriptyline (a TCA), producing a paradoxical picture: reduced antidepressant efficacy alongside signs of TCA toxicity (sedation, orthostatic hypotension, akathisia).
- Mechanism: Estrogen-mediated changes in hepatic microsomal enzyme activity (either induction or inhibition), reportedly dose-related.
- Direction: Variable; effect and toxicity can present simultaneously. Neither agent is activated to its effect by the affected pathway.
- Onset: Delayed. Evidence: Probable, mainly isolated cases.
- Management: Monitor mood response and TCA adverse effects, especially when initiating hormone therapy in a patient stabilized on amitriptyline. Downward dose adjustment of either agent, individualized by the care team, may restore balance; withdrawal is occasionally needed.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens can, in rare instances, either enhance or diminish the pharmacologic activity of tricyclic antidepressants3, sometimes producing the paradoxical situation in which antidepressant efficacy 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 among patients who were already stabilized on tricyclic treatment before estrogen therapy is initiated 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 exactly as prescribed unless your prescriber tells you otherwise. This interaction is usually manageable with attention from your care team.
- Watch for changes: tell your pharmacist or doctor if your depression seems to return or worsen, or if you feel unusually drowsy, dizzy on standing, or restless.
- Dose tailoring: if these signs appear, the dose of either the amitriptyline or the dienogest may need to be adjusted and individualized by your care team to restore the balance.
- Closer monitoring: this matters most when hormone therapy is started after you've been stable on amitriptyline, so your team may check in with you more often during that time.
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 randomly divided into 4 treatment groups. Ten patients received 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 across the 6 weeks of the study. The 10 patients receiving estrogen and imipramine had a significantly greater symptom improvement than the 10 patients receiving imipramine alone. Nevertheless, after 2 weeks, the 5 patients on imipramine and high-dose estrogen had improved less than those on imipramine and low-dose estrogen. The sole reported side effect was drowsiness, which affected only the patients taking imipramine. After ethinyl estradiol was stopped, the high-dose estrogen group needed 2 weeks to perform as well as the low-dose group. This was ascribed 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 on imipramine alone. Furthermore, 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. She developed lethargy, tremors, and signs of depersonalization. After 2 years of therapy, she raised her estrogen dose to 5 milligrams and subsequently 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 researchers have suggested that the side effects arose from heightened tricyclic antidepressant effects secondary to estrogen inhibition of hepatic microsomal enzymes 3.
c) A study looked at women who received clomipramine with oral contraceptives or clomipramine alone. At study onset, 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 suggested that there was no significant difference in side effects between the groups; however, the groups were matched after patients had dropped out of the study. If the patients had been matched before the study began, different conclusions might have been reached 4.
d) A study evaluated the effect 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 found between the groups. However, this finding may be partly attributable to 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 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. The symptoms resolved after amitriptyline was discontinued. Rechallenge one week later with doxepin 100 milligrams was positive, with resolution after doxepin was stopped. A third case of akathisia occurred in a 35-year-old patient receiving conjugated estrogens 1.25 milligrams/day and amitriptyline 50 milligrams/day. Akathisia arose within a few hours of 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 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 suppress 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 Dienogest together?
Combining amitriptyline with dienogest can, in some people, both weaken the antidepressant effect and increase side effects like drowsiness or dizziness; report any such changes so your care team can adjust the dose or monitor you more closely. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Dienogest 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 Dienogest interaction managed?
Keep taking both medications exactly as prescribed unless your prescriber tells you otherwise. This interaction is usually manageable with attention from your care team. Watch for changes: tell your pharmacist or doctor if your depression seems to return or worsen, or if you feel unusually drowsy, dizzy on standing, or restless. Dose tailoring: if these signs appear, the dose of either the amitrip… 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 Dienogest 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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