St. John's Wort Interactions, Stated Plainly
St John's Wort, Hypericum perforatum, induces the liver enzyme CYP3A4 and the transporter P-glycoprotein, and so lowers the blood levels of many drugs: oral contraceptives, with breakthrough bleeding and failure of contraception; ciclosporin and tacrolimus, with rejection of a transplanted organ; the HIV protease inhibitors and some antiretrovirals; digoxin; warfarin; theophylline; certain statins, simvastatin among them; some anticancer drugs, irinotecan and imatinib; and methadone. Taken with an SSRI, an SNRI, tramadol, or a triptan it adds serotonin to serotonin, with the risk of serotonin syndrome. These are the interactions modern herbalism states whenever the plant comes up, and they are the reason a person on any regular prescription does not add St John's wort to it without the prescriber knowing.
The plant
St John's Wort is the flowering top of Hypericum perforatum, gathered at midsummer, around the feast of St John on the twenty-fourth of June, when the yellow flowers are open and the leaf held to the light shows its translucent oil glands, the perforations of the name. The plant is warm and dry in the classical reckoning; Culpeper places it under the Sun in Leo. Its actions are nervine tonic, thymoleptic, which is the herbalist's word for an antidepressant, anti-inflammatory, vulnerary, astringent, and antiviral. It was a wound herb before it was a mood herb: Dioscorides and Gerard give it for wounds and burns, and the red infused oil of the fresh flowers, Oleum Hyperici, remains the tradition's preparation for nerve pain, bruises, and shallow wounds. The use for low mood, sleeplessness, and nervous exhaustion runs through the German tradition, is described in Weiss, and became the plant's principal use in the second half of the twentieth century.
The mechanism of the interactions
The constituent responsible for the enzyme induction is hyperforin, not hypericin. Hyperforin activates the pregnane X receptor, which raises the amount of CYP3A4 in the liver and gut wall and of P-glycoprotein in the gut, and any drug cleared by those routes is cleared faster and reaches a lower level in the blood. The effect builds over the first one to two weeks of use and fades over a similar time after stopping; a drug dose adjusted to the plant is too high once the plant is stopped. Extracts low in hyperforin induce less, and the German manufacturers have produced them for that reason, but the interaction is stated for the plant as a whole.
The serotonin interaction is pharmacodynamic rather than metabolic. The plant raises serotonergic tone by the same broad route the drugs do, and the two together can produce agitation, sweating, tremor, a fast heart, and confusion.
The knowledge is recent. The Commission E monograph of the 1980s approved the plant for depressive moods and anxiety without listing these interactions; the case reports of transplant rejection and of falling antiretroviral levels around the year 2000 established them, and the regulators of Europe and North America then required the warnings that the monographs now carry. This is the modern layer of the tradition, and the plant is used with it.
Dose and preparation
| Form | Strength | Adult dose |
|---|---|---|
| Dried herb, infusion | 2 to 4 g of herb per day, as the Commission E gives it | one cup, two or three times daily |
| Tincture | 1:5 in 45 percent alcohol, or 1:2 fresh in 95 percent | 2 to 4 ml, three times daily |
| Standardised extract | 0.3 percent hypericin, the strength of the clinical extracts | 300 mg, three times daily, or 900 mg once |
| Infused oil, external | fresh flowers in olive oil in the sun until red | applied to the skin as needed |
The mood effect is slow: the herbals and the monographs agree that four to six weeks of steady use are needed before it is judged, and the plant is used for the mild and moderate low mood of the person who is tired, tense, and sleepless, not for the severe depression that belongs to another kind of care. The fresh flower tincture, taken as deep red, is preferred by many herbalists over the dried.
Photosensitivity and other cautions
Hypericin is a photosensitiser, and the name hypericism describes the burning and blistering of fair-skinned grazing animals that eat the plant in quantity. At the ordinary human dose the effect is uncommon and appears as a heightened sunburn in fair skin at high doses or under strong sun; it is stated as the plant's own caution. St John's wort is not given in pregnancy or lactation, since the literature gives no safe dose, and it is stopped before surgery and anaesthesia because of the enzyme induction. It is not combined with the serotonergic drugs above, and where a person is changing from a prescribed antidepressant to the plant the two are not overlapped.
The plant is an American as well as a European weed, and the Eclectics used it little; the modern use came back to English-speaking practice from Germany. Chinese medicine records a related species, Guan Ye Lian Qiao, but the clinical literature is the Western one.
Not medical advice.