Amitriptyline and Clonidine: 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
Clonidine
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.
If you take clonidine for blood pressure and also take amitriptyline (Elavil) for mood, nerve pain, or sleep, it helps to know these two can work against each other. Clonidine lowers blood pressure by calming certain nerve signals. Amitriptyline can push in the opposite direction, so your clonidine may not lower your blood pressure as well as it should.
This is not something that happens overnight, so there is no need to panic. The good news is your care team can manage it by checking your blood pressure and adjusting your clonidine dose if needed. Please keep taking both as prescribed and talk with your pharmacist or doctor.
Effect: Amitriptyline can reduce the antihypertensive efficacy of clonidine, potentially raising blood pressure.
Mechanism: Pharmacodynamic antagonism. Clonidine lowers BP via central pre-synaptic alpha-2 agonism (reducing noradrenaline release); TCAs block noradrenaline reuptake and increase synaptic noradrenaline, opposing this effect.
- Direction: Reduced clonidine effect (PD antagonism, not PK).
- Onset: Delayed.
- Evidence: Probable; severity major.
- Management: Monitor blood pressure; titrate clonidine as needed. Note mianserin did not show this impairment.
What happens
Reduced antihypertensive effects and may counteract the hypotensive effects of cloNIDine
Interaction Deep Dive
Taking cloNIDine together with amitriptyline (a tricyclic antidepressant) can raise blood pressure and may oppose cloNIDine's blood-pressure-lowering action 12. Blood pressure should be monitored and the cloNIDine dose adjusted when necessary 2. Tricyclic antidepressants boost noradrenaline release, most likely by blocking its re-uptake. CloNIDine, by contrast, diminishes noradrenaline release through stimulation of pre-synaptic alpha-2 adrenoreceptors, which serve to suppress noradrenaline release 45. In the case of mianserin, a tetracyclic antidepressant, the interference with cloNIDine's antihypertensive effect that occurs with tricyclic antidepressants was not observed 7.
Why it happens (mechanism)
Pharmacological antagonism at central alpha-2 receptors; unknown
How to manage this interaction
What your care team may do:
- Check your blood pressure more closely, especially after starting or changing either drug.
- Adjust and individualize your clonidine dose as needed to keep your blood pressure controlled.
- In some cases, consider whether a different antidepressant is a better fit for you.
What you should do: Keep taking both medications exactly as prescribed unless your prescriber tells you otherwise. Do not stop either one on your own. Let your pharmacist or doctor know if your home blood pressure readings climb, and mention every medicine you take.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
5 reports — tap to read
a) A single case report documents a prolonged cloNIDine withdrawal syndrome in a patient in whom cloNIDine and amitriptyline were stopped at the same time. Before undergoing jejunal resection surgery, a 73-year-old woman had cloNIDine (0.1 mg twice daily), amitriptyline (25 mg four times daily), and other medications discontinued. Following the operation, the patient developed raised arterial blood pressure (220/70 to 210/90), tachycardia (95 to 105), and severe anxiety. Symptoms were reversed with methyldopa and propranolol after four days of treatment. Anxiety has been described following the withdrawal of antidepressants. Tachycardia and hypertension are characteristics of a well-documented cloNIDine withdrawal syndrome. The continuation of this syndrome in this patient may have resulted from the long-term catecholamine elevations observed in patients receiving antidepressant therapy 3.
b) The interaction between cloNIDine and desipramine was examined in five hypertensive patients. This double-blind, placebo-controlled study found that adding the tricyclic antidepressant caused loss of blood pressure control in four of the five subjects within two weeks. The increase in arterial pressure was more marked in the supine position than in the upright position. Compared with the placebo period, the mean blood pressure rise during the desipramine period was 22/15 mm Hg lying down and 12/11 mm Hg standing 4.
c) A study enrolled eleven drug-free patients meeting the Research Diagnostic Criteria for Major Depressive Disorder to assess the effects of desipramine on central adrenergic function. Patients received a cloNIDine infusion after 0, 1, and 3 weeks of desipramine treatment. The findings showed that the sedative and hypotensive effects of cloNIDine were significantly inhibited following three weeks of desipramine treatment. This interaction was also present at one week but did not reach clinical significance. The authors concluded that the effects seen in the study were attributable to an acute drug effect rather than to a chronic adaptive change 5.
d) One case report describes a 65-year-old man who had perineal pain after excision of a carcinoma. Pain management with amitriptyline 75 mg at night and sodium valproate 500 mg three times daily was started after slow-release morphine alone provided only limited benefit. A cloNIDine spinal intrathecal injection of 75 micrograms was administered when the patient was considered to have become tolerant to opioid therapy. Within five minutes, the patient was found to be in severe pain, which resolved within 30 minutes after diamorphine was given. Two mechanisms were proposed for this interaction. In the first, the pain may have resulted from a cloNIDine-cholinergic interaction. In the second, the tricyclic enhancement of serotoninergic transmission may have revealed an effect of cloNIDine at central receptors that increased nociception 6.
e) Mianserin, a tetracyclic antidepressant, was not shown to produce the impairment of cloNIDine's antihypertensive effects observed with tricyclic antidepressants 78.
Common questions
Can I take Amitriptyline and Clonidine together?
Amitriptyline can blunt clonidine's blood-pressure-lowering effect, so your team will likely watch your blood pressure and adjust the clonidine dose as needed. Keep taking both as prescribed and report any rising readings. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Clonidine interaction?
It is rated major. Potentially serious — often needs a change or close 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 Clonidine interaction managed?
What your care team may do: Check your blood pressure more closely, especially after starting or changing either drug. Adjust and individualize your clonidine dose as needed to keep your blood pressure controlled. In some cases, consider whether a different antidepressant is a better fit for you. What you should do: Keep taking both medications exactly as prescribed unless your prescriber tells yo… 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 Clonidine 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 a safer alternative to one of these medications for me?
References (8)
- Product Information: Catapres-TTS(R) transdermal system, clonidine transdermal system. Boehringer Ingelheim Pharmaceuticals, Inc. (per Manufacturer), Ridgefield, CT, 2012. DailyMed
- Product Information: ONYDA(TM) XR extended release suspension, clonidine hydrochloride extended release suspension. Tris Pharma, Inc (Per FDA), Monmouth Junction, NJ, 2024.
- Stiff JL & Harris DB: Clonidine withdrawal complicated by amitriptyline therapy. Anesthesiology 1983; 59:73-74. DOI
- Briant RH, Reid JL, & Dollery CT: Interaction between clonidine and desipramine in man. Br Med J 1973; 1:522-523. DOI
- Glass IB, Checkley SA, Shur E, et al: The effect of desipramine upon central adrenergic function in depressed patients. Br J Psychiatry 1982; 141:372-376. PubMed
- Hardy PAJ & Wells JCD: Pain after spinal intrathecal clonidine. Anaesthesia 1988; 43:1026-1027. DOI
- Elliott HL, McLean K, Sumner DJ, et al: Pharmacodynamic studies on mianserin and its interaction with clonidine. Eur J Clin Pharmacol 1981; 21:97-102. PubMed
- Elliott HL, McLean K, Sumner DJ, et al: Absence of an effect of mianserin on the actions of clonidine or methyldopa in hypertensive patients. Eur J Clin Pharmacol 1983; 24:15-19. PubMed
Keep reading about Amitriptyline
Keep reading about Clonidine
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