What happens when you take MAOIs with St. John's Wort?
St. John's Wort (Hypericum perforatum) is one of the best-studied herbal antidepressants, with dozens of randomized trials supporting modest efficacy for mild to moderate depression. The catch is that it is a legitimate psychoactive drug masquerading as a tea-aisle supplement. Hyperforin and hypericin, the main active constituents, inhibit the reuptake of serotonin, norepinephrine, dopamine, GABA, and glutamate. In vitro studies also show weak monoamine oxidase inhibition, though clinical MAO inhibition at standard doses is modest.
Monoamine oxidase inhibitors (MAOIs) like phenelzine, tranylcypromine, isocarboxazid, and high-dose selegiline block the breakdown of serotonin, norepinephrine, and dopamine in the brain and gut. Combine an MAOI with St. John's Wort and you stack reuptake inhibition on top of degradation blockade. Synaptic monoamines can rise to toxic levels, producing serotonin syndrome, and the residual MAOI activity of St. John's Wort plus the prescription MAOI raises the theoretical risk of hypertensive crisis as well.
Why is this important?
Serotonin syndrome is a clinical emergency. Early signs include agitation, sweating, shivering, dilated pupils, tachycardia, and hyperreflexia. Severe cases progress to hyperthermia above 40 C, muscle rigidity, rhabdomyolysis, seizures, disseminated intravascular coagulation, and death. There is no specific antidote; care is supportive. Onset can be within hours of combining the two agents.
The MAOI-plus-St. John's-Wort interaction is treated as a strict contraindication by major references including Mayo Clinic and Drugs.com, even though the published clinical literature is thinner than for SSRI plus St. John's Wort (where serotonin syndrome cases are well documented). The reason is pharmacological consistency: every mechanism by which the two drugs raise monoamine signaling is additive or synergistic, and the consequences of getting it wrong are severe enough that no clinician is willing to run the experiment.
A second concern is loss of antidepressant control. St. John's Wort is a powerful inducer of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein. It accelerates the metabolism of dozens of drugs including oral contraceptives, warfarin, digoxin, immunosuppressants, and antiretrovirals. Patients who add St. John's Wort to a stable medication regimen often see treatment failure of those other drugs, sometimes catastrophically (organ transplant rejection, contraceptive failure, HIV viral rebound). MAOI plus St. John's Wort patients risk both toxicity (from added serotonergic load) and reduced efficacy of co-prescribed drugs.
What should you do?
If you are on a prescription MAOI - phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), or selegiline at 9 mg/24h or higher (Emsam patch) or oral form - do not take St. John's Wort in any form. This includes capsules, tablets, teas, tinctures, topical preparations, and combination 'mood support' or 'calm' blends. Always read the supplement facts panel; St. John's Wort is sometimes listed under the Latin name Hypericum perforatum.
If you have been taking St. John's Wort and your prescriber wants to start an MAOI, discontinue the herb and wait at least 1 to 2 weeks before the first MAOI dose. CYP3A4 induction from St. John's Wort takes about two weeks to wash out, so any concomitantly prescribed CYP3A4 substrates may need dose review once the induction subsides. Going the other way, wait at least 2 weeks after the last MAOI dose (longer for high-dose phenelzine) before starting St. John's Wort.
If you accidentally take both, watch for serotonin syndrome symptoms (agitation, sweating, tremor, clonus, hyperreflexia, hyperthermia, mental status changes). Stop both substances and seek emergency care. Bring all bottles, including the supplement, so clinicians can identify everything you have ingested.
Which specific products are affected?
Prescription MAOIs and MAOI-like drugs:
- Phenelzine (Nardil)
- Tranylcypromine (Parnate)
- Isocarboxazid (Marplan)
- Selegiline (Emsam patch at 9-12 mg/24h, oral Eldepryl, Zelapar)
- Rasagiline (Azilect)
- Linezolid (Zyvox), tedizolid (Sivextro)
- Methylene blue intravenous
- Procarbazine (Matulane)
St. John's Wort products and combination supplements to watch for:
- Single-ingredient St. John's Wort capsules and tablets (often standardized to 0.3% hypericin or 3-5% hyperforin)
- St. John's Wort tinctures and teas
- Combination 'mood,' 'calm,' 'happy,' or 'serotonin support' blends
- Multi-herb sleep formulas
- Products labeled Hypericum perforatum
The bottom line
MAOIs and St. John's Wort should never be combined. Both raise brain serotonin, both can raise blood pressure, and stacking them invites serotonin syndrome and hypertensive crisis - either of which can be fatal. If you take a prescription MAOI, treat St. John's Wort as you would treat any prescription antidepressant: off limits. If you are taking St. John's Wort and your prescriber proposes an MAOI, stop the herb first and wait one to two weeks. The pharmacology here is not subtle, and the safety margin for guessing is zero.