Venlafaxine and St. John's Wort Interaction
Do not combine venlafaxine with St. John's wort due to the serious risk of serotonin syndrome, a potentially life-threatening condition. This combination is explicitly contraindicated in the FDA drug label for venlafaxine 1.
Mechanism of Interaction
- Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that increases serotonin availability in the central nervous system 1.
- St. John's wort has serotonergic activity and can trigger serotonin syndrome when combined with other serotonergic agents 1, 2, 3, 4.
- The FDA explicitly warns that concomitant use of venlafaxine with St. John's wort increases the risk of serotonin syndrome 1.
Clinical Manifestations of Serotonin Syndrome
If this combination occurs, watch for these specific symptoms:
- Mental status changes: agitation, hallucinations, delirium, coma 1
- Autonomic instability: tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia 1
- Neuromuscular symptoms: tremor, rigidity, myoclonus, hyperreflexia, incoordination, seizures 1
- Gastrointestinal symptoms: nausea, vomiting, diarrhea 1
Management Recommendations
If a patient is taking venlafaxine and wants to use St. John's wort (or vice versa):
- Discontinue venlafaxine completely and wait at least 7 days before starting St. John's wort 1.
- If switching from St. John's wort to venlafaxine, discontinue St. John's wort and allow adequate washout time before initiating venlafaxine 1.
- If serotonin syndrome develops, immediately discontinue both agents and initiate supportive symptomatic treatment 1.
Additional Pharmacokinetic Concerns
Beyond serotonin syndrome, St. John's wort is a potent inducer of CYP3A4 and P-glycoprotein:
- This induction could theoretically reduce venlafaxine plasma concentrations, though this is less clinically significant than the serotonin syndrome risk 2, 3, 4.
- St. John's wort has caused clinically significant interactions with numerous medications through enzyme induction 2, 3, 4.
Clinical Context
While St. John's wort has demonstrated comparable efficacy to SSRIs in mild-to-moderate depression with fewer side effects in monotherapy 5, 6, the NICE guideline actively recommends against its use in children and youth with depression 7.
The American College of Physicians found no significant difference in response or remission between St. John's wort and SSRIs in adults with major depressive disorder, though the evidence quality was low 7.
Common Pitfall to Avoid
Patients often fail to disclose herbal supplement use, including St. John's wort, when starting prescription antidepressants 1. Explicitly ask all patients starting venlafaxine about current or recent use of St. John's wort and other herbal supplements 1. Educate patients that "natural" does not mean "safe to combine" with prescription medications 1.