Chlorotrianisene 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
Chlorotrianisene
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 an antidepressant, and chlorotrianisene is a form of estrogen. When taken together, the estrogen may change how your body handles the antidepressant. In a few reported cases, this led to an odd combination: the antidepressant seemed to work less well, while side effects like drowsiness, low blood pressure, or restlessness got worse at the same time.
This is based on older, theoretical reports, so it is not something to panic about. It matters most if you were already doing well on amitriptyline and then started the estrogen. Just keep an eye on how you feel, and let your care team know about any changes. They can easily adjust things to keep you feeling your best.
Effect: Estrogens may unpredictably alter tricyclic pharmacologic response, with simultaneous loss of antidepressant efficacy and emergence of TCA toxicity (drowsiness, orthostatic hypotension, akathisia).
- Mechanism: Possible estrogen-enhanced hepatic metabolism of amitriptyline; effect appears estrogen dose-related. Neither agent is a prodrug requiring activation.
- Onset: Delayed.
- Evidence: Theoretical, isolated case reports.
- Severity: Minor.
- Management: Monitor for altered tricyclic response, especially when initiating estrogen in a patient stabilized on amitriptyline. Downward dose adjustment of either agent may restore efficacy or resolve toxicity; discontinuation is occasionally required.
What happens
Attenuation of antidepressant effectiveness; tricyclic toxicity (drowsiness, hypotension, akathisia)
Interaction Deep Dive
Estrogens have been reported in a small number of cases to either enhance or diminish the pharmacologic activity of tricyclic antidepressants3, with a paradoxical combination in which antidepressant efficacy is lost while tricyclic toxicity appears at the same time 1. This interaction seems to depend on the estrogen dose 2, and its clinical relevance may be greatest for patients who had already been stabilized on tricyclic treatment and are then beginning estrogen therapy 6.
Why it happens (mechanism)
Possible estrogen-enhanced hepatic metabolism of the tricyclic
How to manage this interaction
This interaction is uncommon and based on limited, theoretical evidence, so there is no need to stop either medication on your own. Keep taking both exactly as prescribed.
- Watch for changes if you start the estrogen while already on amitriptyline: return of low mood, or new drowsiness, dizziness on standing, or restlessness.
- Report these to your care team. If needed, the dose of either the estrogen or the amitriptyline may be adjusted and individualized by your team to restore benefit or ease side effects.
- Your team may also monitor you a bit more closely during this period.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
7 reports — tap to read
a) A trial examined the qualitative outcomes when estrogen and TCAs were given together. In this study, 30 depressed female prisoners were randomized into four treatment arms. Ten patients were given placebo, 10 were given imipramine (150 mg daily) plus placebo, five patients were given imipramine (150 mg daily) plus ethinyl estradiol (50 mcg daily), and five patients were given imipramine (150 mg daily) plus ethinyl estradiol (25 mcg daily). The 10 patients on placebo showed no improvement across the six weeks of the study. The 10 patients on estrogen with imipramine showed significantly greater symptom improvement than the 10 patients on imipramine alone. Nevertheless, after two weeks, the five patients on imipramine with high-dose estrogen had not improved to the same degree as those on imipramine with low-dose estrogen. The sole reported adverse effect was drowsiness, which occurred only in patients taking imipramine. After ethinyl estradiol was stopped, a two-week interval was needed for the high-dose estrogen group to perform as well as the low-dose group. This was ascribed to residual estrogen in the high-dose group. In a separate group, five women given imipramine 150 mg and ethinyl estradiol 50 mcg daily did not improve as much as 10 patients on imipramine alone. Additionally, the patients on the combination experienced severe adverse effects, including lethargy, coarse tremor, and systolic hypotension 1.
b) A case described by 2 showed an interaction in a 32-year-old woman taking conjugated estrogens 2.5 mg and imipramine 100 mg. She developed lethargy, tremors, and signs of depersonalization. After two years of treatment, she raised her estrogen dose to 5 mg and subsequently to 7.5 mg daily. She became nauseated, had persistent headaches, and had low normal blood pressure. All laboratory results were normal. When the estrogen was stopped, the adverse effects subsided. Some investigators have suggested that the adverse effects arose from enhanced TCA effects secondary to estrogen inhibition of hepatic microsomal enzymes 3.
c) A study assessed women receiving clomipramine with oral contraceptives or clomipramine alone. At the study's outset there were 30 women on the combination, but 12 later withdrew. 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 adverse 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 evaluated the effects of oral contraceptives on clomipramine in 42 women aged 18 to 40 years. Twenty-three women took clomipramine 25 mg at bedtime, while 19 took clomipramine 25 mg at bedtime along with oral contraceptives. During the four-week study, three control patients (two owing to adverse effects) and five in the experimental group (two owing to adverse 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 attributable to the low dose of clomipramine administered 5.
e) Three patients receiving conjugated estrogens together with tricyclic antidepressants developed akathisia. A 24-year-old patient on clomipramine 120 mg daily for anorexia nervosa and conjugated estrogens 1.25 mg daily for amenorrhea developed restless legs and a persistent urge to move continuously. Estrogen was stopped and benztropine 2 mg was given, producing marked reduction and resolution within 48 hours. Akathisia and disorientation arose in a 55-year-old patient on conjugated estrogen 1.25 mg daily who was prescribed amitriptyline 50 mg daily for depression. Within hours of amitriptyline, the patient was confused, restless, and had an inner urge to move continuously. Symptoms resolved after amitriptyline was stopped. A third case of akathisia was reported in a 35-year-old patient given conjugated estrogen 1.25 mg daily and amitriptyline 50 mg daily. Akathisia arose 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 mcg 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 inhibit the oxidation of TCAs by acting on hepatic microsomal enzymes 8. Many TCAs undergo metabolism through oxidation and conjugation pathways. Inhibiting the oxidation of TCAs could lead to accumulation and toxicity as a result 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 Chlorotrianisene and Amitriptyline together?
Taking amitriptyline with chlorotrianisene (estrogen) may rarely weaken the antidepressant while increasing side effects like drowsiness and dizziness. Tell your care team about any changes, and they can adjust the dose to keep things on track. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Chlorotrianisene 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 Chlorotrianisene and Amitriptyline interaction managed?
This interaction is uncommon and based on limited, theoretical evidence, so there is no need to stop either medication on your own. Keep taking both exactly as prescribed. Watch for changes if you start the estrogen while already on amitriptyline: return of low mood, or new drowsiness, dizziness on standing, or restlessness. Report these to your care team. If needed, the dose of either the estroge… 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 Chlorotrianisene 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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