St John's Wort and Antidepressants: A Combination Clinicians Warn Against

St John’s Wort is sold in pharmacies and health food stores as a natural mood supplement. In clinical and pharmacological literature, it carries one of the most firmly established drug interaction profiles of any herbal product.

Two separate problems

The interaction between St John’s Wort and SSRI antidepressants involves two distinct mechanisms, and both are concerning.

The first is pharmacokinetic. St John’s Wort is a strong inducer of the liver enzyme CYP3A4, which metabolises a large proportion of pharmaceutical drugs. When CYP3A4 is induced, drugs are broken down faster, reducing their blood levels. This affects SSRIs, benzodiazepines, oral contraceptives, antiretrovirals, immunosuppressants, and many other medications. The person may be taking a therapeutic dose while actually receiving sub-therapeutic levels.

The second is pharmacodynamic. St John’s Wort has independent serotonergic activity. It inhibits the reuptake of serotonin, dopamine, and noradrenaline. Combined with an SSRI or SNRI, which also increases serotonin by blocking its reuptake, the combined effect on serotonin levels in the brain can be excessive.

Serotonin syndrome

Serotonin syndrome is a potentially life-threatening reaction caused by excess serotonin activity. Its symptoms range from mild (shivering, diarrhoea) to severe (muscle rigidity, hyperthermia, seizures, and in extreme cases, death). It develops rapidly, usually within hours of the triggering dose change.

Case reports of serotonin syndrome following the combination of St John’s Wort with SSRIs appear in the medical literature going back to the late 1990s. A 1999 review published in the Lancet by Ernst documented multiple cases and called for clearer warnings on herbal product labelling.

Regulatory agencies in several countries, including the FDA, the UK’s MHRA, and the European Medicines Agency, have issued formal warnings against combining St John’s Wort with serotonergic medications.

The naturalness misconception

Part of what makes this interaction especially common is that users of St John’s Wort often see it as a natural alternative to antidepressants rather than as something that acts on the same system. Someone who decides to try St John’s Wort while already on an SSRI may not consider that “natural” and “prescription” could conflict.

The supplement does not know it is natural. Its active compounds, hyperforin and hypericin, act pharmacologically. That activity does not switch off because the product came from a plant.

What to do

Anyone currently taking an SSRI, SNRI, tricyclic antidepressant, or any other serotonergic medication should not take St John’s Wort without discussing it with their prescribing doctor. This is one of the higher-risk supplement-drug interactions in routine clinical use.

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Reference

1. Ernst E. "Second thoughts about safety of St John's Wort." Lancet, 1999. PubMed 10442165