Buprenorphine 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
Buprenorphine
Phenelzine
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.
Taking these two together is not recommended. Phenelzine (Nardil) is a type of antidepressant called an MAO inhibitor, and buprenorphine also affects a brain chemical called serotonin. When both are in your body at the same time, serotonin can build up too much and cause a serious reaction called serotonin syndrome.
Warning signs include feeling agitated or confused, a fast heartbeat, sweating, shivering, muscle twitching or stiffness, and fever. This can become dangerous. The good news is your care team can plan around this safely, often by spacing the two medicines apart in time or choosing a different option. Please talk with your doctor or pharmacist before making any changes.
Contraindicated combination. Phenelzine, a nonselective irreversible MAO inhibitor, plus buprenorphine (which has serotonergic activity) produces additive serotonergic effects, raising the risk of serotonin syndrome. Evidence is rated probable; onset unspecified.
- Direction: additive pharmacodynamic effect (not a CYP prodrug issue).
- Washout: allow at least 14 days between stopping phenelzine and starting the serotonergic agent, or vice versa. Account for clearance of active metabolites before initiating phenelzine.
- If unavoidable: monitor for agitation, autonomic instability (tachycardia, hyperthermia, diaphoresis), neuromuscular signs (clonus, hyperreflexia, rigidity), and altered mental status.
- If it develops: discontinue offending agents and provide supportive care.
What happens
An increased risk of serotonin syndrome
Interaction Deep Dive
Because it raises the likelihood of serotonin syndrome, taking phenelzine (an MAO inhibitor) together with serotonergic agents is contraindicated. A minimum of 14 days should separate stopping phenelzine and starting a serotonergic drug, or the reverse, though FLUoxetine is an exception to this interval. When phenelzine is to follow prior serotonergic therapy, enough time must elapse to permit clearance of the serotonergic drug along with its active metabolite1. Should combined use be unavoidable, watch patients for signs of serotonin syndrome. This condition may be life-threatening. If it occurs, stop the responsible agents and deliver supportive care as well as any other therapy that is needed 3.
Why it happens (mechanism)
Additive serotonergic effects
How to manage this interaction
This combination is generally avoided. Your care team manages it by keeping the two drugs apart rather than using them together.
- Typically at least 14 days is allowed between stopping phenelzine and starting a serotonergic drug like buprenorphine, or the other way around.
- If both are truly needed, your team will monitor you closely for signs of serotonin syndrome.
What you should do: Do not start, stop, or change either medicine on your own. Tell your pharmacist or prescriber that you take both so they can plan the safest timing or an alternative. Seek urgent care if you notice agitation, confusion, fast heartbeat, sweating, shivering, muscle stiffness, or fever.
Management is individual — confirm any change with your pharmacist or prescriber.
Literature reports
3 reports — tap to read
a) Serious reactions have been documented (including hyperthermia, rigidity, myoclonic movements, and death) when serotoninergic agents (eg, dexfenfluramine, FLUoxetine, fluvoxaMINE, PARoxetine, sertraline, citalopram, venlafaxine) have been used together with an MAO inhibitor 1.
b) FentaNYL is a proserotonergic, synthetic piperidine opioid that has been linked to serotonin syndrome when given together with other serotonergic agents, such as MAOIs. When feasible, consider substituting serotonergic opioids (eg, fentaNYL) with non-serotonergic opioids (eg, morphine) 2. If combined use cannot be avoided, watch patients for signs of serotonin syndrome. Serotonin syndrome may be life-threatening. Should serotonin syndrome occur, stop the responsible agents and deliver supportive care along with any other therapy that is required 3.
c) The interaction between St. John's Wort and MAO inhibitors rests on evidence that serotonin syndrome can occur from combining SSRIs with MAOIs 4. In theory, taking St. John's Wort together with a monoamine oxidase inhibitor (MAOI) could produce serotonin syndrome. The mild MAOI activity of St. John's Wort might add to heightened adverse effects of the MAOI and possible toxicity (hypertensive crisis), although this has never been described clinically. The importance of any monoamine oxidase inhibition by St. John's Wort remains disputed, even though components of St. John's Wort have shown mild monoamine oxidase inhibitory effects 56.
Common questions
Can I take Buprenorphine and Phenelzine together?
Combining phenelzine (an MAO inhibitor) with buprenorphine is contraindicated because of the risk of serotonin syndrome; usually a 14-day gap is kept between them. Talk with your doctor or pharmacist before making any changes. Always confirm with your pharmacist or prescriber before making any change.
How serious is the Buprenorphine 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 Buprenorphine and Phenelzine interaction managed?
This combination is generally avoided. Your care team manages it by keeping the two drugs apart rather than using them together. Typically at least 14 days is allowed between stopping phenelzine and starting a serotonergic drug like buprenorphine, or the other way around. If both are truly needed, your team will monitor you closely for signs of serotonin syndrome. What you should do: Do not start,… 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.
Questions for your pharmacist
- Does my dose of Buprenorphine 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: NARDIL(R) oral film coated tablets, phenelzine sulfate oral film coated tablets. Parke-Davis Div of Pfizer Inc (per DailyMed), New York, NY, 2020. DailyMed
- Rastogi R, Swarm RA, & Patel TA: Case scenario: opioid association with serotonin syndrome: implications to the practitioners. Anesthesiology 2011; 115(6):1291-1298. PubMed
- Boyer EW & Shannon M: The serotonin syndrome. N Eng J Med 2005; 352(11):1112-1120. PubMed
- Sternbach H: Danger of MAOI therapy after fluoxetine withdrawal (letter). Lancet 1988; 2:850-851. PubMed
- Thiede HM & Walper A: Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry Neurol 1994; 7 (Suppl 1):S54-S56. DOI
- Demisch L, Holzl J, Gollnik B, et al: Identification of selective MAO Type A inhibitors in Hypericum perforatum L. (Hyperforat(R)). Pharmacopsychiatry 1989; 22:194.
Keep reading about Buprenorphine
Keep reading about Phenelzine
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