Tang Center for Herbal Medicine Research

St. John's Wort

Common names: amber, goatweed, klamath weed, hardhay


St. John’s wort is the common name for Hypericum perforatum, a flowering plant that can be found in Europe, Asia, Africa, Australia, and the Americas. It is so named because its yellow flower was traditionally gathered for the feast of St. John the Baptist. The herbal medication comes from the aerial parts of the plant harvested shortly before or during flowering.


St. John’s wort has been used since the Middle Ages for neuralgia, depression, and various “nervous” conditions. Today, St. John’s wort is primarily used as an antidepressant. It has the largest market share of antidepressants in Europe with $6 billion in sales in 1988. The popularity of St. John’s wort is reflected in the large number of clinical trials, meta-analyses, and reviews of its effectiveness as an antidepressant which have concluded that it is more effective than placebo in the treatment of mild to moderate depression and has a low incidence of side effects. In the treatment of major depression, however, St. John’s wort is not effective. Moreover, it is unclear whether St. John’s wort is as effective as conventional antidepressants. Some reviews concluded that John’s wort and the older tricyclic antidepressants are equally effective. Others concluded that St. John’s wort was less effective than tricyclic antidepressants. Still others believe that there is insufficient evidence to compare St. John’s wort to conventional antidepressants and have called for more studies comparing St. John’s wort to the newer serotonin reuptake inhibiting antidepressants. The methodology of many studies has been criticized with the implication that firm conclusions about the efficacy of St. John’s wort are premature. –

Phytochemistry and pharmacology

The constituents of St. John’s wort are the naphthodianthrones (hypericin and pseuodohypericin), acylphloroglucinols (hyperforin and adhyperforin), flavonol glycosides, biflavones, proanthocyanidins, and phenylpropanes (chlorogenic acid and caffeic acid). Among these constituents, hypericin and hyperfornin have received the most scientific interest. Hypericin was originally considered the active component in St. John’s wort, and commercial preparations are standardized to hypericin content. Recent evidence suggests that hyperforin and its analogues play a larger role in the pharmacological effects. Because hyperforin is an unstable compound and is susceptible to oxidative degradation, its concentration in St. John’s wort may vary considerably.

St. John’s wort inhibits reuptake of serotonin, norepinephrine, and dopamine. This property appears to be different than that found in conventional antidepressants. St. John’s wort also had antinociceptive effects in mice similar to those seen with tricyclic antidepressants.

Initially, monoamine oxidase (MAO) inhibition was considered a possible mechanism of action. Later studies have shown, however, that the inhibition of MAO by St. John’s wort is clinically insignificant. Adverse events that would be expected with MAO inhibition have not been reported with St. John’s wort.

The pharmacokinetics of hypericum extract have been studied. After oral administration in human volunteers, the median half-life for absorption was 0.6 hr, the median half-life for distribution was 6.0 hr, and the median half-life for elimination was 43.1 hr. In another study, peak plasma levels of hypericum extract were obtained 3-3.5 hr after oral dosing, and the elimination half-life was 9 hr. Plasma concentration time curves fit a two-compartment model. Hypericin and pseudohypericin are most likely conjugated and excreted in the bile.


When St. John’s wort is taken by healthy patients, it is generally well-tolerated. Adverse effects include photosensitivity, rash, nausea, fatigue, and restlessness. Serotonin syndrome was reported in patients taking St. John’s wort alone or in combination with conventional antidepressants. In patients who may have subclinical or undiagnosed bipolar disorder, induction of mania also was reported.

Patients taking prescription medications should be cautious taking St. John’s wort since significant herb-drug interactions can occur. It induces cytochrome P450 enzymes and increases the metabolism of protease inhibitors, oral contraceptives, cyclosporin, warfarin, digoxin, and many other concomitantly administered drugs. The metabolic activity of the cytochrome P450 3A4 isoenzyme is most affected, and its metabolic activity is approximately doubled. This isoform is the most abundant hepatic enzyme, responsible for the oxidative metabolism of over 50% of all conventional medications subject to cytochrome P450 oxidative metabolism. Interactions with substrates of the 3A4 isoform including indinavir, ethinyl estradiol, and cyclosporin have been documented. In one series of 45 organ transplant patients, St. John’s wort was associated with an average decrease of 49% in blood cyclosporin levels. Another group reported 2 cases of acute heart transplant rejection associated with this particular pharmacokinetic interaction. In addition to the 3A4 isoform, the cytochrome P450 2C9 isoform may also be induced. The anticoagulant effect of warfarin, a substrate of the 2C9 isoform, was reduced in 7 reported cases.

St. John’s wort also affects digoxin pharmacokinetics, possibly by altering a P-glycoprotein transporter. In volunteers, coadministration of St. John’s wort led to a 26% reduction in the Cmax and a 33% reduction of the Ctrough of digoxin.

Use during pregnancy or by nursing mothers is not recommended.

Preparations and dosage

St. John’s wort extracts are commercially available, and many are standardized to hypericin content. The recommended daily dosage of St. John’s wort is 2-4 g of St. John’s wort or 0.2-1 mg of hypericin.