Sertraline and Phenelzine: 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
Phenelzine
Sertraline
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.
These two medicines should not be taken together. Phenelzine (Nardil) is an MAOI, and sertraline is an SSRI antidepressant. Both raise serotonin, a brain chemical. Taken together, serotonin can climb too high and cause a dangerous reaction called serotonin syndrome. Warning signs include agitation, a racing heart, high fever, sweating, shaking, muscle twitching, and confusion. This can become serious, even life-threatening.
The good news is this is very avoidable. Your care team keeps a gap of at least 14 days between stopping one and starting the other. If you have been prescribed both, or you are switching, please talk with your pharmacist or doctor right away so they can guide the timing safely.
Contraindicated combination. Phenelzine (irreversible MAOI) plus sertraline (SSRI) produces additive serotonergic effects: MAO inhibition blocks serotonin metabolism while sertraline blocks reuptake, risking serotonin syndrome or CNS toxicity (hyperthermia, hypertension, tachycardia, myoclonus, hyperreflexia, altered mental status). Reactions can be fatal. Evidence is probable. Neither drug's effect here depends on prodrug activation.
- Do not co-administer.
- Allow at least 14 days after discontinuing the MAOI before starting sertraline.
- Allow at least 14 days after discontinuing sertraline before starting an MAOI (longer washout is required for fluoxetine, not sertraline).
- Monitor for serotonergic toxicity during any transition; treat supportively if it occurs.
What happens
An increased risk of serotonin syndrome (hypertension, tachycardia, hyperthermia, myoclonus, mental status changes) or CNS toxicity
Interaction Deep Dive
Taking sertraline together with an MAOI is contraindicated. Before starting sertraline, allow a minimum of 14 days to pass after stopping an MAOI that was being used for psychiatric conditions. Likewise, once sertraline has been stopped, wait at least 14 days before beginning treatment with an MAOI prescribed for psychiatric conditions1. Giving sertraline and an MAOI inhibitor at the same time, or having their treatment periods overlap, can produce CNS toxicity or serotonin syndrome. This hyperserotonergic condition presents with signs including restlessness, myoclonus, altered mental status, hyperreflexia, diaphoresis, shivering, and tremor. Reactions that are severe and sometimes fatal have been documented 3465.
Why it happens (mechanism)
Additive serotonergic effects; inhibition of serotonin metabolism by monoamine oxidase
How to manage this interaction
This pair is not used together. Care teams manage this by separating the two drugs in time rather than adjusting a dose.
- Keep taking your medications exactly as prescribed, and do not start or stop either one on your own.
- When switching between them, your team allows a washout of at least 14 days so one drug fully clears before the other begins.
- If you were somehow prescribed both, or you are mid-switch and unsure of timing, contact your pharmacist or prescriber promptly.
- Seek urgent care for agitation, fever, sweating, shivering, muscle twitching, a fast heartbeat, or confusion.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
4 reports — tap to read
a) Taking serotonin specific reuptake inhibitors together with monoamine oxidase inhibitors may cause a toxic response referred to as serotonin syndrome 2.
b) A 26 year old woman who had been on isocarboxazid for eight weeks discontinued the medication for 11 days before starting sertraline. Following a single 100 mg dose of sertraline, she became restless and developed twitching of the legs. She was subsequently brought to the emergency room with diaphoresis, tachycardia, hyperreflexia, and assorted neuromuscular disturbances. Treatment with diazepam and propranolol did not lead to improvement. She was then administered two 4 mg doses of cyproheptadine one hour apart, and marked improvement in symptoms was seen after the second dose 3.
c) An interaction was documented in a 61 year old woman when sertraline 100 mg twice daily was added to a regimen that included lithium, phenelzine, thioridazine, and doxepin. Three hours after her first sertraline dose, she was discovered in a semicomatose condition, with raised body temperature, elevated pulse, increased respiration rate, and a blood pressure of 140/110 mmHg. Following transport to the hospital, she was initially misdiagnosed with neuroleptic malignant syndrome (NMS), a diagnosis later revised to serotonin syndrome resulting from a reaction between sertraline and phenelzine. The authors recommend that MAO inhibitor therapy be stopped for at least two weeks prior to starting a selective serotonin reuptake inhibitor (SSRI), and that before beginning a MAOI, SSRI therapy be stopped for at least 5 half-lives of the parent compound and any active metabolites 4.
d) Two case reports raised the possibility of an interaction between FLUoxetine and selegiline. In one case, a first episode of mania was noted roughly 1 month after selegiline was added to fluoxetine therapy. The patient improved 2 months after both agents were stopped, and no additional details were given. In the second case, diaphoresis, vasoconstriction, and cyanosis of the hands developed in close temporal association with the addition of FLUoxetine and selegiline. Both drugs were withdrawn, with comparatively rapid resolution of the symptoms. A rechallenge with FLUoxetine alone proceeded without incident 5.
Common questions
Can I take Sertraline and Phenelzine together?
Phenelzine and sertraline must not be taken together because of the risk of serious serotonin syndrome. Keep at least a 14-day gap when switching between them, and contact your pharmacist or doctor if you are ever prescribed both. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Sertraline and Phenelzine interaction?
It is rated contraindicated. These should generally not be used together.
How quickly could this interaction happen?
The documented onset is "unspecified". The timing of this interaction is not well characterized.
How is the Sertraline and Phenelzine interaction managed?
This pair is not used together. Care teams manage this by separating the two drugs in time rather than adjusting a dose. Keep taking your medications exactly as prescribed, and do not start or stop either one on your own. When switching between them, your team allows a washout of at least 14 days so one drug fully clears before the other begins. If you were somehow prescribed both, or you are mid-… 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 Sertraline or Phenelzine 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)
- Product Information: ZOLOFT oral tablets, oral solution, sertraline hydrochloride oral tablets, oral solution. Viatris Specialty LLC (per FDA), Morgantown, WV, 2023. DailyMed
- Sternbach H: The serotonin syndrome. Am J Psychiatr 1991; 148:705-713. PubMed
- Lappin RI & Auchincloss EL: Treatment of the serotonin syndrome with cyproheptadine. N Engl J Med 1994; 331:1021-1022. PubMed
- Graber MA, Hoehns TB, & Perry PJ: Sertraline-phenelzine drug interaction: a serotonin syndrome reaction. Ann Pharmacother 1994; 28:732-735. DOI
- Suchowersky O & de Vries JD: Interaction of fluoxetine and selegiline (letter). Can J Psychiatry 1990; 35:571-572. PubMed
- Bhatara VS & Bandettini FC: Possible interaction between sertraline and tranylcypromine. Clin Pharm 1993; 12:222-225.
Keep reading about Phenelzine
Keep reading about Sertraline
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