Amitriptyline and Linezolid: 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
Linezolid
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) raises serotonin levels in your body, and linezolid (Zyvox), an antibiotic, also acts a bit like a mild antidepressant that boosts serotonin. When you take them together, serotonin can climb too high and cause a problem called serotonin syndrome.
Watch for things like agitation, confusion, a racing heart, sweating, shivering, twitching muscles, or a high fever. This is considered a serious combination, so please don't stop either medicine on your own. Your doctor and pharmacist can plan this safely, choose the right option, and keep a close eye on you.
Effect: Increased risk of serotonin syndrome / NMS-like reactions from additive serotonergic activity. Linezolid is a reversible, nonselective MAO inhibitor; amitriptyline is a serotonergic TCA. Neither is a prodrug relevant here, so the effect is additive PD, not PK.
Evidence: Probable. Severity: Major. Onset: unspecified.
- Avoid concurrent use unless clinically necessary and the patient is closely observed.
- If urgent linezolid is needed, the serotonergic agent may be stopped; monitor for 2 weeks or until 24 h after the last linezolid dose, whichever is first.
- Watch for agitation, hyperthermia, autonomic instability, clonus, hyperreflexia; discontinue offending agents and give supportive care if it develops.
What happens
An increased risk of serotonin syndrome
Interaction Deep Dive
When linezolid is given together with other serotonergic drugs, the likelihood of serotonin syndrome may rise. Linezolid should not be given to patients taking serotonergic agents unless it is clinically warranted and the patient is closely watched for indications of serotonin syndrome or neuroleptic malignant syndrome-like (NMS-like) reactions. There are situations in which a patient who is already on a serotonergic agent needs urgent linezolid therapy. When no other options besides linezolid exist and its expected benefits exceed the risks of serotonin syndrome or NMS-like reactions, discontinue the serotonergic agents and begin linezolid. The patient should be monitored either for two weeks or until 24 hours have passed since the final linezolid dose, whichever occurs sooner2. Should serotonin syndrome arise, stop the causative agents and deliver supportive care along with any additional treatment that may be needed 1.
Why it happens (mechanism)
Additive serotonergic effects
How to manage this interaction
Keep taking both medicines as prescribed unless your care team tells you otherwise, and let your prescriber and pharmacist know you take both.
Here is how a care team typically handles this:
- They may decide the combination isn't needed and choose an alternative antibiotic.
- If linezolid is truly needed, they may pause the amitriptyline and watch you closely for up to two weeks or until 24 hours after the last linezolid dose.
- They will monitor you for warning signs like agitation, fast heartbeat, sweating, shivering, muscle twitching, or fever.
If any of those symptoms appear, seek medical help right away.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) In an assessment of post-marketing data, 1 instance of serotonin toxicity was documented with the combined use of dextromethorphan and linezolid. Post-marketing adverse events submitted to the US Food and Drug Administration's Adverse Event Reporting System (AERS) database from November 1997 through September 2003 concerning serotonin toxicity with linezolid were reviewed. A serotonin toxicity case was characterized as having: (a) linezolid identified as the primary suspect drug, (b) simultaneous use of 1 or more secondary suspect drug possessing CNS serotonergic activity, and (c) serotonin toxicity, as characterized by the modified Hunter Serotonin Toxicity Criteria or by the individual reporting the adverse event. A total of 29 cases were found (age range 17 to 83 years), in which linezolid was administered along with 1 drug (n=20), with 2 drugs (n=6), and with 3 or more drugs (n=3). Although SSRIs were the drug class most frequently taken alongside linezolid (n=26), additional drug classes comprised tricyclic antidepressants (n=6), and atypical antidepressants (n=4). Furthermore, drugs taken concurrently comprised carbidopa-levodopa (n=2), dextromethorphan (n=1), lithium (n=1), metoclopramide (n=1), risperiDONE (n=1), and traMADol (n=1). Signs of serotonin toxicity comprised tremor, fever, seizure, clonus, sweating, agitation, akathesia, rigors, twitching, and muscle rigidity. Intervention that included hospitalization was needed in 13 patients, and 3 deaths were documented with concurrent SSRI use 3.
b) In a retrospective cohort study of older adults prescribed oral linezolid 600 mg twice daily (N=1134), serotonin syndrome developed in fewer than 6 patients (less than 0.5%) who were receiving a concurrent antidepressant (n=215). In the propensity score-matched cohort (n=332), there was no difference in the risk of clinically significant serotonin syndrome among patients receiving concurrent antidepressants and linezolid versus patients receiving linezolid without antidepressants (adjusted risk difference, -1.2%; 95% CI, -2.9% to 0.5%). There was likewise no difference in the rate of altered mental status or confusion, hospitalization, or death from any cause between the groups. Patients were aged 66 years or older, and among those receiving an antidepressant, 47.9% were receiving an SSRI, 16.7% were receiving an SNRI, 7% were receiving a tricyclic antidepressant, 3.3% were receiving a norepinephrine and dopamine reuptake inhibitor, and none were receiving an MAOI 4.
c) Voluntary reports of serotonin syndrome, including fatal cases, linked to the combined administration of linezolid and serotonergic agents, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs), have been documented 25. Signs of serotonin syndrome include neuromuscular abnormalities (such as hyperreflexia, tremor, muscle rigidity, clonus, peripheral hypertonicity, and shivering), autonomic hyperactivity (such as tachycardia, mydriasis, diaphoresis, the presence of bowel sounds, and diarrhea), and mental status changes (such as agitation and delirium). Serotonin syndrome may be life-threatening. If serotonin syndrome arises, discontinue the offending agents and provide supportive care and other therapy as needed 1.
d) A case report described serotonin syndrome in a 36-year-old woman after the combined use of linezolid and lithium. The patient, who had no history of seizures and whose medications included lithium, venlafaxine, and imipramine for bipolar disorder, depression, and headaches, respectively, presented to the emergency room (ER) with seizures. Ten days before her ER presentation, the patient had received vancomycin to treat MRSA empyema. However, treatment was changed to linezolid roughly 36 hours before her ER visit. At presentation, she had a blood pressure (BP) of 234/196 mmHg, a heart rate of 160 beats/min, a respiratory rate of 24 breaths/min, and diaphoresis. Her pupils were dilated with a slow reaction to light and she was unresponsive to verbal instructions. The patient was intubated and given multiple doses of LORazepam, which reduced her tremors and lowered BP to 150/85 mmHg. Her serum lithium level was 1.2 mEq/L and there were no electrolyte abnormalities. Within 3 hours of intubation, her mental status and breathing pattern returned to normal and she was extubated. While both imipramine and venlafaxine were held, lithium was maintained and linezolid was replaced with trimethoprim and sulfamethoxazole. The patient stayed alert and oriented in the following days and had reduced anxiety. Three weeks after discharge, the patient reported tremors and anxiety following the resumption of venlafaxine and imipramine. It was hypothesized that her 3 chronic serotonergic medications produced a baseline hyperserotonergic state, which was acutely worsened by the addition of linezolid 6.
Common questions
Can I take Amitriptyline and Linezolid together?
Combining amitriptyline with linezolid can push serotonin too high and trigger serotonin syndrome, so tell your doctor and pharmacist you take both; they can pick an alternative or monitor you closely and this can be managed safely. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Amitriptyline and Linezolid interaction?
It is rated major. Potentially serious — often needs a change or close monitoring.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Amitriptyline and Linezolid interaction managed?
Keep taking both medicines as prescribed unless your care team tells you otherwise, and let your prescriber and pharmacist know you take both. Here is how a care team typically handles this: They may decide the combination isn't needed and choose an alternative antibiotic. If linezolid is truly needed, they may pause the amitriptyline and watch you closely for up to two weeks or until 24 hours aft… 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 Linezolid 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 (6)
- Boyer EW & Shannon M: The serotonin syndrome. N Eng J Med 2005; 352(11):1112-1120. PubMed
- Product Information: ZYVOX(R) intravenous injection, oral tablets, oral suspension, linezolid intravenous injection, oral tablets, oral suspension. Pharmacia & Upjohn Company LLC (per FDA), New York, NY, 2024. DailyMed
- Lawrence KR, Adra M, & Gillman PK: Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis 2006; 42(11):1578-1583. PubMed
- Bai AD, McKenna S, Wise H, et al: Association of linezolid with risk of serotonin syndrome in patients receiving antidepressants. JAMA Netw Open 2022; 5(12):e2247426. PubMed
- Wigen C & Goetz M: Serotonin syndrome and linezolid. CID 2002; 34:1651-1652. PubMed
- Miller DG & Lovell EO: Antibiotic-induced serotonin syndrome. J Emerg Med 2011; 40(1):25-27. PubMed
Keep reading about Amitriptyline
Keep reading about Linezolid
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