Tibolone 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
Tibolone
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.
What this means for you: Amitriptyline (Elavil) is an antidepressant. Tibolone acts a bit like estrogen in the body. When people take estrogen-like medicines with a tricyclic antidepressant like amitriptyline, the mix can sometimes work in an odd way. The antidepressant may work less well, while at the same time you may notice more side effects like drowsiness, feeling lightheaded when you stand up, or restlessness.
This is only a possible effect based on theory and a few older reports, not something that happens to everyone. The good news is your care team can manage it easily by adjusting a dose if needed. Keep taking both as prescribed and let them know if anything feels off.
Mechanism/direction: Estrogenic activity of tibolone may enhance hepatic metabolism of amitriptyline while paradoxically increasing tricyclic pharmacologic effects, producing simultaneous loss of antidepressant efficacy and signs of TCA toxicity (sedation, orthostatic hypotension, akathisia). Neither agent is activity-dependent on the affected enzyme in a way that flips this. Effect appears estrogen dose-related.
- Onset: delayed
- Evidence: theoretical / isolated case reports
- Severity: minor
- At-risk group: patients stabilized on a TCA who then start estrogen/tibolone
Management: Monitor mood response and anticholinergic/orthostatic toxicity. Downward dose adjustment of either agent, individualized by the team, usually restores balance; occasionally withdrawal is needed.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens can, in rare instances, either heighten or diminish the pharmacologic actions of tricyclic antidepressants3, sometimes producing the paradoxical combination of reduced antidepressant efficacy alongside signs of tricyclic toxicity occurring at the same time 1. This interaction seems to depend on the estrogen dose 2, and its clinical relevance is likely greatest in patients already stabilized on tricyclic treatment who then begin estrogen therapy 6.
Why it happens (mechanism)
Possible estrogen-enhanced hepatic metabolism of the tricyclic
How to manage this interaction
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is uncommon and mostly theoretical, but it is worth watching for.
- Watch for signs your amitriptyline is working less well (returning low mood) or signs of too much effect (drowsiness, dizziness on standing, restlessness).
- If you notice any of these, tell your pharmacist or doctor. The dose of either the tibolone or the amitriptyline may need to be adjusted and individualized by your care team.
- Your team may also monitor you more closely, especially in the weeks after starting tibolone.
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 examined the qualitative outcomes of giving estrogen together with TCAs. In one trial, 30 depressed female prisoners were randomly divided into 4 treatment groups. Ten patients were given placebo, 10 received imipramine (150 milligrams/day) plus placebo, 5 received imipramine (150 milligrams/day) plus ethinyl estradiol (50 micrograms/day), and 5 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 with imipramine showed a significantly greater symptom improvement than the 10 patients on 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 adverse effect was drowsiness, which occurred only in patients taking imipramine. After ethinyl estradiol was stopped, 2 weeks were needed for the high-dose estrogen group to perform as well as the low-dose group. This finding was ascribed to residual estrogen present 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 alone. Furthermore, the patients on the combination experienced severe adverse effects such as lethargy, coarse tremor, and systolic hypotension 1.
b) A case documented by 2 showed an interaction in a 32-year-old woman taking conjugated estrogens 2.5 milligrams and imipramine 100 milligrams. She developed lethargy, tremors, and features 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 findings were normal. When the estrogen was stopped, the adverse effects subsided. Some researchers have suggested that the adverse effects were due to increased TCA effects arising from estrogen inhibition of hepatic microsomal enzymes 3.
c) A study assessed women who received clomipramine together with oral contraceptives or clomipramine alone. At the outset, 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 adverse effects between the groups; however, the groups were matched after patients had already dropped out of the study. Had the matching occurred before the study, different conclusions might have been reached 4.
d) A study evaluated how oral contraceptives affect clomipramine in 42 women aged 18 to 40. 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 control patients (2 because of adverse effects) and 5 in the experimental group (2 because of adverse effects) withdrew. Venous blood samples were collected weekly to measure serum clomipramine concentrations. No difference in serum concentrations was observed between the groups. However, this outcome may be partly attributable to the low dose of clomipramine used 5.
e) Three patients who took 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 move continuously. 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 amitriptyline, the patient became confused, restless, and had an inner urge to move continuously. Symptoms resolved 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 was reported in a 35-year-old patient given 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 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 area under the plasma concentration time curve 7.
g) Estrogens may suppress the oxidation of TCAs by acting on hepatic microsomal enzymes 8. Many TCAs are metabolized through oxidation and conjugation pathways. Suppressing 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 Tibolone and Amitriptyline together?
Combining amitriptyline with tibolone may rarely make the antidepressant less effective while increasing tricyclic side effects like drowsiness or dizziness; watch for changes and let your care team adjust the dose if needed. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Tibolone and Amitriptyline interaction?
It is rated minor. Usually limited clinical impact.
How quickly could this interaction happen?
The documented onset is "delayed". Effects tend to build up gradually over days to weeks.
How is the Tibolone and Amitriptyline interaction managed?
Keep taking both medicines as prescribed unless your prescriber tells you otherwise. This interaction is uncommon and mostly theoretical, but it is worth watching for. Watch for signs your amitriptyline is working less well (returning low mood) or signs of too much effect (drowsiness, dizziness on standing, restlessness). If you notice any of these, tell your pharmacist or doctor. The dose of eith… Management is individual — always follow your own care team's guidance.
How strong is the evidence for this interaction?
The evidence is graded "theoretical". Predicted from the drugs' pharmacology; not yet confirmed in people.
From our Q&A
Real reader questions about these medications, each personally answered by our pharmacist:
Questions for your pharmacist
- Does my dose of Tibolone 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.
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