St. John’s Wort

Hypericum perforatum L. belongs to Hypericaceae, a family older references fold into Clusiaceae or Guttiferae. NCBI Taxonomy files it as taxon 65561. It is an upright, branching perennial, usually knee- to waist-high, with paired, stalkless, oblong leaves and a two-ridged stem. The epithet perforatum describes the leaves: held up to the light, they show scattered translucent dots, which are oil glands, so the leaf looks pricked with a pin. The flowers are bright yellow with five petals and a burst of stamens. Their petal margins and the anthers carry tiny black dots. Crush one and your fingers turn purplish red. That pigment is hypericin.

The species is native to Europe, western Asia, and North Africa and has spread to temperate regions on every inhabited continent. In western North America it is a rangeland weed called Klamath weed or goatweed, both listed as common names by NCCIH. Livestock that graze heavily on it can develop hypericism: photosensitized skin that blisters and peels in sunlight. That veterinary problem is the same chemistry as the human sunburn warnings below, at grazing doses. Several other Hypericum species are sold as ornamentals or used locally, but the EU monograph, the Pharmacopoeia, and nearly all clinical trials concern H. perforatum only.

The medicinal part is the flowering top, harvested at or just before full bloom and dried. The European Pharmacopoeia standard requires a minimum content of total hypericins. Commercial dry extracts are made with methanol or ethanol at specified drug-to-extract ratios, and those ratios matter: the EU monograph assigns its well-established-use indication only to particular extract types. Herbal teas, tinctures, fresh-plant juices, and oily macerates are separate traditional preparations. A capsule labelled only St. John’s wort 300 mg has told you the weight, not the extract, the solvent, or the hyperforin content that drives interactions.

The chemistry falls into three groups. Naphthodianthrones, chiefly hypericin (PubChem CID 3663, C30H16O8) and pseudohypericin, are the red pigments and the photosensitizers. Phloroglucinols, chiefly hyperforin (CID 441298, C35H52O4) and adhyperforin, are the main candidates for both the antidepressant effect and enzyme induction; hyperforin is unstable to light and air, so content falls in poorly stored material and differs widely between products. Flavonoids such as hyperoside, rutin, and quercetin derivatives, and biflavonoids such as amentoflavone, make up the rest of the active fraction. EMA’s monograph credits all three groups with contributing to the effect. Older extracts were standardized to hypericin, often 0.3%. The reviews that matter now also ask about hyperforin.

Hypericum appears in Greek medical writing, and NCCIH notes use in Greek, Islamic, and Chinese traditions for depression, stomach ulcers, colds, and wound healing. Wort is simply the Old English word for a plant. The saint’s name comes from the timing: the flowers open around 24 June, the feast of John the Baptist, and the red stain from crushed flowers fed later legends about the saint’s blood. European folk custom hung the plant over doors on St. John’s Eve to keep away evil spirits. Behind the folklore sits a practical tradition: flowers steeped in olive oil for weeks produce a deep red oil that was rubbed on wounds, bruises, and burns. EMA still recognizes oily preparations as a traditional remedy for minor skin inflammation, sunburn, and minor wounds.

The modern career began in German-speaking clinics. By the 1990s Johanniskraut extracts were among the most prescribed antidepressants in Germany. In 1996 Linde and colleagues published a meta-analysis in the BMJ of 23 randomized trials with 1,757 outpatients, mostly with mild or moderately severe depression, and found extracts roughly 2.7 times as likely as placebo to produce a response, with fewer side effects than the older antidepressants. American sales exploded. Two large US academic trials followed, one of them co-funded by the National Institutes of Health. Both were negative, and both were published in JAMA, in 2001 and 2002.

At almost the same moment the interaction story broke. In February 2000 The Lancet published two letters side by side: an NIH study in which St. John’s wort cut exposure to the HIV drug indinavir by more than half, and a Swiss report of two heart-transplant patients whose cyclosporine levels fell and who developed acute rejection. Regulators in Sweden and the United Kingdom reviewed the reports, and product information for affected medicines was rewritten. In 2009 the EU’s Committee on Herbal Medicinal Products adopted its first monograph; the revision adopted on 23 November 2022 keeps the depression indication and adds a hyperforin threshold to its interaction warnings. The plant went from a midsummer charm to one of the most studied, and most cautioned, herbs in pharmacology within about a century.

For the antidepressant effect, EMA’s monograph gives the short version: hypericum dry extract inhibits the synaptosomal reuptake of noradrenaline, serotonin, and dopamine, and it behaves like synthetic antidepressants in animal models such as the forced swimming test. Hyperforin is the leading candidate for the reuptake effect, but hypericin, pseudohypericin, and flavonoids all contribute, and no single compound has been shown to account for the clinical result. The pharmacokinetics are slow: hypericin peaks 4–12 hours after a dose with an elimination half-life of about 19–36 hours, and hyperforin peaks at 3–4 hours with a half-life of about 15–63 hours. Hyperforin crosses the blood–brain barrier. EMA tells users to expect an effect within about four weeks.

The interaction mechanism is better understood than the antidepressant one. Moore and colleagues (PNAS 2000) showed that hyperforin binds the pregnane X receptor (PXR) with a Ki of 27 nM and that hypericum extract or hyperforin markedly induces CYP3A4 in human liver cells. PXR is a master switch: activate it and the cell makes more CYP3A4, CYP2B6, CYP2C9, CYP2C19, and P-glycoprotein. CYP3A4 alone handles more than half of marketed drugs. Because this is enzyme induction, not direct inhibition, it builds over days to about two weeks and wears off over about a week after stopping, which EMA states explicitly. Chrubasik-Hausmann and colleagues (2019) reviewed the interaction studies product by product and found that clinically significant interactions tracked hyperforin dose. That is why the 2022 EU monograph separates low-hyperforin traditional products from the rest.

Photosensitivity has its own mechanism. Hypericin absorbs light and generates reactive oxygen species. EMA reports that 1,800 mg of extract daily for 15 days increased skin sensitivity to UVA and lowered the minimum dose needed for pigmentation, while no phototoxicity was reported at recommended doses. The serotonergic effect explains the other important pharmacodynamic risk: combined with SSRIs or other serotonergic drugs, St. John’s wort can contribute to serotonin syndrome.

Depression is where the evidence is. The 2008 Cochrane review by Linde, Berner, and Kriston included 29 randomized double-blind trials with 5,489 patients with major depression. Against placebo, results varied widely: in nine larger trials the responder rate ratio was 1.28, in nine smaller trials 1.87. Against standard antidepressants, results were consistent: response rate ratios of 1.02 versus tricyclic or tetracyclic drugs and 1.00 versus SSRIs. Patients on hypericum dropped out because of side effects less often than those on older antidepressants (odds ratio 0.24) or SSRIs (0.53). The reviewers flagged a pattern that has not gone away: trials from German-speaking countries were more favourable to hypericum than trials elsewhere.

The two big US trials are the reason that pattern matters. Shelton and colleagues (JAMA 2001) randomized 200 outpatients with major depression and a baseline Hamilton Depression Scale (HAM-D) of at least 20 to extract (900–1,200 mg daily) or placebo for eight weeks; St. John’s wort was not effective. The Hypericum Depression Trial Study Group (JAMA 2002) randomized 340 outpatients to the LI 160 extract (900–1,500 mg), sertraline (50–100 mg), or placebo. On both primary outcomes neither active treatment beat placebo; full response was 31.9% on placebo, 23.9% on St. John’s wort, and 24.8% on sertraline. A trial in which the reference antidepressant also fails is hard to read, but the authors noted the complete absence of trends favouring hypericum. Both US trials enrolled moderately severe depression, the population where the European signal is weakest.

Later reviews land in the same place. Apaydin and colleagues (Systematic Reviews 2016) pooled 35 studies with 6,993 patients and found more responders than with placebo (risk ratio 1.53, with large heterogeneity), no difference from antidepressants (1.01), and fewer adverse events (odds ratio 0.67), in mild and moderate depression. Ng and colleagues (Journal of Affective Disorders 2017) compared St. John’s wort with SSRIs across 27 trials and 3,808 patients and found comparable response, while noting that all the trials lasted only 4 to 12 weeks and that the herb’s value in severe depression or high suicide risk is unknown. NCCIH’s summary matches: probably better than placebo and similar to standard antidepressants for mild or moderate depression, uncertain for severe depression or longer than twelve weeks.

Everything else is thin. NCCIH lists small studies suggesting help for menopausal hot flashes and somatic symptom disorder, and studies in ADHD, irritable bowel syndrome, obsessive-compulsive disorder, premenstrual syndrome, smoking cessation, and topical wound healing that have not clearly shown benefit. EMA’s traditional-use indications cover temporary mental exhaustion, minor skin inflammation and minor wounds (oily or tincture preparations applied to the skin), mild digestive discomfort, and nervous restlessness with difficulty falling asleep. Those rest on long use, not trials. The practical point is narrow: specific standardized extracts may help mild to moderate depression for a few months, in someone whose medication list has been checked.

EU well-established use (EMA/HMPC/7695/2021, revision 1, adopted 23 November 2022) covers dry extracts only. For mild to moderate depressive episodes: a methanol 80% extract (DER 3–7:1) at 300–600 mg one to three times daily, 600–1,800 mg per day; or an ethanol 80% extract (DER 3–6:1) at 900 mg once daily. For short-term treatment of symptoms of mild depressive disorders: an ethanol 50–68% extract (DER 2.5–8:1) at 600 or 612 mg once daily, or 250–600 mg two to three times daily. The effect should appear within four weeks; if symptoms persist, see a doctor. Use under 18 is not recommended. Extracts should be quantified for hypericin, with hyperforin and flavonoids declared.

EU traditional use covers a wider range: a 45% ethanol dry extract (60–180 mg two to three times daily), tinctures, fresh-plant juices, powdered herb, and tea. For temporary mental exhaustion the tea is 1.5–2 g of dried herb in 150 ml of boiling water, two to three times daily; for restlessness and difficulty falling asleep, 2–3 g twice daily. If symptoms last more than two weeks, see a doctor. For skin, oily macerates or tinctures are applied undiluted, or a 2 g infusion in 150 ml of water is used as a wash or compress several times daily, not under age 12, with intense UV exposure of the treated skin avoided. The monograph’s key distinction is hyperforin: where a product delivers no more than 1 mg of hyperforin a day and is used for no more than two weeks, no clinically relevant interactions have been reported. Above 1 mg, the full contraindication list applies.

In the trials, the most studied extracts were standardized to about 0.3% hypericin, and the eight trials in Apaydin’s review that used a combined specification carried 0.3% hypericin and 1–4% hyperforin. At 1–4% hyperforin, a typical 300 mg dose taken three times a day delivers roughly 9–36 mg of hyperforin daily, far above the EU’s 1 mg threshold. US supplements are not held to an extract specification, and label claims about hypericin say nothing about hyperforin. For interaction risk, assume any capsule sold for mood is a full-strength inducer unless the label proves otherwise.

Red oil, made by macerating fresh flowers in vegetable oil in the sun until the oil turns red, is the classic topical preparation; the colour comes from hypericin. It is a traditional remedy for minor burns and bruises and is not a treatment for infected or deep wounds; EMA tells users to see a doctor if signs of skin infection appear. Do not use it on skin about to be exposed to strong sun.