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St. John's Wort

Scientific Name(s): Hypericum perforatum L. Family: Hypericaceae

Common Name(s): St. John's wort , klamath weed , John's wort , amber touch-and-heal , goatweed , rosin rose , and millepertuis . Commercial preparations used in trials include Esbericum , Hyperforat , Hyperiforce , Kira , LI 160 , Neuroplant , Psychotonin , Sedariston , STEI 300 , WS 5573 , Ze 117 .


Meta-analyses of quality clinical trials support Hypericum 's place in the treatment of depression. Effectiveness is comparable with standard antidepressants, while adverse events are lower than with conventional antidepressants. Interactions with other drugs and quality control issues may limit use. Other areas of therapeutic research for St. John's wort include smoking cessation, premenstrual symptoms, somatoform disorder, and attention deficit hyperactivity disorder, as well as its possible role in treating cancer and HIV.


Preparations vary greatly in chemical content and quality, and may be standardized to quantity of hyperforin (commonly 3% to 5%) or hypericin (commonly 0.3%). Clinical trials evaluating the efficacy of St. John's wort in depression have commonly used 900 mg of extract daily in 3 divided doses, both in short-term treatment and for ongoing therapy, for periods of up to 1 year (range, 600 to 1,200 mg/day).


Use with cyclosporine, tacrolimus, irinotecan, and imatinib mesylate, as well as protease inhibitors and nonnucleoside reverse transcriptase inhibitors in HIV treatment, is contraindicated.


Avoid use. The use of St. John's wort in perinatal depression has been considered; however, insufficient data on efficacy or safety exist to support its use. St. John's wort should be avoided during pregnancy and lactation until further long-term studies demonstrate a lack of toxicity in the developing fetus and breast-feeding newborn.


St. John's wort has been reported to interact with numerous drugs. Drugs with a narrow therapeutic window should be monitored closely. Patients should be cautioned on the potential for interactions and the need to consult their health care provider before taking St. John's wort with prescription or nonprescription drugs. Drugs that are most prominently affected, and therefore for which concomitant use with St. John's wort should be avoided, include protease inhibitors (eg, saquinavir) and nonnucleoside reverse transcriptase inhibitors (eg, nevirapine) used in HIV, and cyclosporine, tacrolimus, irinotecan, and imatinib mesylate. Ethinyl estradiol is metabolized by CYP3A4; therefore, a high possibility of interaction exists. The risk of developing serotonin syndrome and other CNS adverse reactions cannot be ruled out; extreme caution is needed with combinations of psychotropic medications. Reviews of interactions with St. John's wort are available.

Adverse Reactions

Adverse reactions are usually mild. Potential adverse reactions include dry mouth, dizziness, constipation, and other GI symptoms, and confusion. Photosensitization also may occur. In clinical trials, adverse reactions and discontinuation with St. John's wort were usually less than those observed with standard antidepressants. Other possible rare adverse reactions include induction of mania and effects on male and female reproductive capabilities.


Limited information on genotoxicity exists. Potent inhibition of sperm motility was observed in vitro. A case report exists of an overdose of St. John's wort in a 16-year-old patient consuming 15 tablets (300 mcg strength) per day for 2 weeks, requiring management in an intensive care unit.


St. John's wort is a perennial plant native to Europe but found throughout the United States and parts of Canada. It is an aggressive weed that grows in the dry ground of roadsides, meadows, woods, and hedges. It generally reaches a height of 0.3 to 0.61 m, except on the Pacific coast where it has attained heights of 1.5 m. 1 The plant has oval-shaped leaves and yields golden-yellow flowers that bloom from June to September. The flower petals have black or yellow glandular dots and lines. There are approximately 370 species in the genus Hypericum , which is derived from the Greek words hyper and eikon meaning “over an apparition,” alluding to the plant's ancient use to ward off evil spirits. Perforatum refers to the leaf's appearance; when held up to light, the translucent leaf glands resemble perforations. 2 , 3 Harvest of the plant for medicinal purposes occurs in July and August, and the plant material must be dried immediately to avoid loss of potency. 4 The dried herb consists of the plant's flowering tops. 2


St. John's wort has been used as an herbal remedy for its anti-inflammatory and healing properties since the Middle Ages, 4 with many herbalists, including Hippocrates and Pliny, recording its medicinal properties. It was noted for its wound-healing and diuretic properties, as well as for the treatment of neuralgic conditions such as back pain. In 1633, Gerard's Herbal recorded the plant's use as a balm for burns, and its oil was also popular during this time. 2 A reddish-colored olive oil extract made from the fresh flowers has been taken internally for the treatment of anxiety but has also been applied externally to relieve inflammation and promote healing. Topical application was believed to be particularly helpful in managing hemorrhoids.

Although St. John's wort fell into disuse, a renewed interest has made it a component of numerous preparations for treating anxiety and depression. The plant has been used in traditional medicine as an antidepressant and a diuretic, as well as for gastritis and insomnia. 3


Several reports regarding the chemical components in St. John's wort are available. 5 , 6 , 7 , 8 , 9 , 10 The most commonly described constituents are naphthodianthrones, flavonoids, phloroglucinols, and essential oils.

Naphthodianthrones occur in St. John's wort in concentrations of less than 0.1% to 0.15%. The anthraquinone derivatives hypericin and pseudohypericin (also emodin-anthranol and cyclo-pseudohypericin) are the best known components of the plant. Isohypericin and protohypericin are also present. The reddish dianthrone pigment hypericin ( Hypericum red) ranges from 0.02% to 2.5%, depending upon harvesting period, drying process, and storage. 4 , 11 Hypericin content varies widely among growing regions, and concentrations are contingent on plant part, with flowers, buds, top leaves, and secondary stems yielding the highest percents. 2 Microscopic evaluation revealed that hypericin accumulates in secretory cell globules within these plant structures. 12 Numerous reports concerning high-performance liquid chromatography analysis of hypericin in St. John's wort exist. 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 Liposoluble pigments from the plant, including hypericin, carotenoids, and chlorophylls, have also been reported. 21 A review of the chemistry of phenanthroperylene quinones from hypericin reveals photosensory pigments. 22

Flavonoid concentrations in St. John's wort occur at less than 12% in flowers and approximately 7% in leaves/stalks, 2 and include kaempferol, quercetin, quercitrin, isoquercitrin, amentoflavone, luteolin, myricetin, hyperin, hyperoside, rutin, miquelianin, and astilbin. 2 , 4 , 11 , 23 The proanthocyanidins (approximately 12% of aerial parts) are certain forms of catechin and epicatechin. 2

Hyperforin and adhyperforin are in the phloroglucinol class of compounds. 2 , 3 , 24 Hyperforin appears in St. John's wort in concentrations of 2% to 4%, and its isolation, purity, and stability have been studied. 25 The recovery of hyperforin in plasma has been measured. 26 The related structure furohyperforin, an oxygenated analog of hyperforin, has been isolated from the plant, 27 as have other hyperforin analogs. 28 The essential oil component of St. John's wort is between 0.05% and 0.9%. 2 , 3 It consists of mono- and sesquiterpenes, mainly 2-methyl-octane (16% to more than 30%), n-nonane, alpha- and beta-pinene, alpha-terpineol, geraniol, and traces of myrecene, limonene, and caryophyllene, as well as others. 2 , 4 , 11

Other compounds present in St. John's wort include xanthones (1.28 mg per 100 g) and tannins (3% to 16%). One study reports that tannin content in extracts is influenced by parameters such as temperature of maceration. 29 Phenol constituents include caffeic, chlorogenic, p-coumaric acids, and hyperfolin. Other plant constituents include acids (eg, nicotinic, myristic, palmitic, stearic), carotenoids, choline, pectin, hydrocarbons, and long-chain alcohols. Amino acids include cysteine, gamma-aminobutyric acid (GABA), glutamine, leucine, lysine, and others. 2 , 3 , 4 , 11

St. John's wort products are not regulated by the US Food and Drug Administration as they are classified as dietary supplements. 30 Several reports evaluating commercial preparations of St. John's wort have found inconsistencies in active ingredients, such as variations from 47% to 165% of labeled hypericin concentrations, 31 different concentrations of major components among brands, 32 and marked deviations in hyperforin and adhyperforin amounts in certain St. John's wort preparations. 33 Several reports address these issues, with various proposed standardization methods. 34 , 35 , 36 , 37

Uses and Pharmacology


A large number of reviews of in vitro and animal experiments exist on proposed mechanisms of action, the pharmacokinetics of St. John's wort, and its individual chemical constituents. 10 , 38 , 39 With regard to depression, earlier studies considered hypericin to be the main chemical responsible for observed effects, but there is general agreement that hyperforin, obtained from ethanol extracts, is the active component. 10 , 39 The role of flavonoids (rutin, quercitrin, isoquercitrin, amentoflavone, and hyperoside) also appear relevant. Although, the mechanism of flavonoids remains unclear, amentoflavone does have potent GABA receptor activity. 40

A synergistic effect of rutin with hyperforin has been suggested. Hypericin has shown conflicting results with regard to monoamine oxidase (MAO) inhibition, but may have a minor role. A number of sites and mechanisms of action have been proposed, primarily the nonspecific inhibition of neurotransmitter uptake (such as serotonin, norepinephrine, dopamine) and, therefore, an increase in synaptic concentrations and an ability to modify the neuronal membrane fluidity via altered sodium conductive pathways. 10

Animal data

Studies conducted in animals are largely irrelevant considering the wide usage of St. John's wort preparations and the number of clinical trials conducted.

Clinical data

Meta-analyses, including a Cochrane meta-analysis, of quality clinical trials have been conducted of St. John's wort compared with placebo and antidepressant therapy. 41 , 42 , 43 , 44 In some studies of mild, moderate, and major 42 depression, St. John's wort was more effective than placebo and similarly effective as standard antidepressants. 41 , 42 , 43 , 44 , 45 , 46 Adverse effects are lower for St. John's wort than for standard antidepressants. 42 , 44 , 45 , 47 A previous Cochrane review found insufficient evidence to support the place in therapy for treating major depression 41 ; however, the inclusion of more recent trials and an analysis of participants meeting the criteria of major depression have led to a somewhat more positive, but cautious, recommendation for Hypericum . 42 Issues raised in the meta-analyses include the heterogeneity of older clinical trials, the wide variation and quality of Hypericum preparations, and the emergence of more favorable trials. 41 , 42 , 46 Limited evidence is available for use in depression in adolescents 46 , 48 , 49 or the elderly, or for comorbid conditions such as Alzheimer disease 50 or anxiety. 51

Further studies have shown St. John's wort to be effective at a range of dosages (600 to 1,200 mg daily) in the acute treatment of mild depression, 43 while long-term studies describe clinical advantage over placebo for St. John's wort 900 mg daily over 26 and 52 weeks with regard to time to relapse and overall relapse rates. 52 , 53 Drug-herb interactions with St. John's wort may compromise the efficacy of other drugs, and thereby limit its place in therapy. 42

Substance dependence/smoking cessation

A limited number of animal studies exist evaluating the role of Hypericum extracts in reducing craving and symptoms of withdrawal from ethanol and stimulant substances (eg, nicotine, caffeine, amphetamine). 54 , 55 , 56 Decreased self-administration of ethanol and withdrawal syndrome have been demonstrated in rodents, as well as no increased ethanol intake after periods of deprivation.

Clinical trials have produced equivocal results in smoking cessation, with some trials showing efficacy in quit rates with Hypericum at 12 weeks 57 and others showing no difference from placebo. 54 , 58 Differences in study populations, dosing, and formulation of preparations make comparisons difficult. Further quality studies are needed with a larger number of subjects.

Other CNS-related conditions

Based on efficacy in depression, Hypericum extracts have been recommended as appropriate therapy in mild or moderate depression with bipolar disorder as an alternative to standard antidepressant therapy. 59 A trial (N = 54) evaluating the efficacy of 900 mg of Hypericum extract daily in adolescents with attention deficit hyperactivity disorder found no difference compared with placebo at 8 weeks 60 and no difference of the same dosage in burning mouth syndrome. 61 St. John's wort 600 mg/day performed better than placebo in 6 primary outcome measures in patients with somatoform disorders. 62 Equivocal results have been demonstrated for Hypericum extracts in the management of premenstrual symptoms; however, different dosages were used. 63 , 64 , 65 Seasonal affective disorder, a type of depression in which symptoms occur in fall/winter and resolve in spring/summer, benefited from St. John's wort in combination with light therapy. 66

Other uses
HIV activity

Clinical trials are limited by the prevalence of interactions with standard HIV therapy. Hypericin and pseudohypericin inhibit a variety of encapsulated viruses, including HIV. 2 3-Hydroxy lauric acid obtained from H. perforatum exhibited light-independent, anti-HIV activity in an in vitro experiment. 67 One study found 16 of 18 patients had improved CD4 cell counts over a 40-month period. CD4/CD8 ratios also improved in the majority of patients. In late 1996, results from a study of hypericin as an investigational new drug indicated that viral load measured in 12 patients ranged from no change to 97% reduction. 68 However, research was discontinued after studies found that it was cytotoxic and not synergistic with licensed anti-HIV drugs. In 1999, a phase 1 study evaluating hypericin's effects in 30 patients concluded that hypericin had no antiretroviral activity, with phototoxicity being observed. 69

Other antiviral activity

Antiviral activity has been reported for influenza, herpes simplex types 1 and 2, Sindbis , poliovirus, retrovirus infection in vitro and in vivo, murine cytomegalovirus, and hepatitis C. 2 , 4 , 11 , 61 , 70 Hypericin and pseudohypericin exert unique and uncommonly effective antiviral actions, possibly because of nonspecific association with cellular and viral membranes. The antiviral activity may involve a photoactivation process, as exposure of hypericin to fluorescent light markedly increases antiviral activity. 4 , 67


The cytocidal activity of hyperforin and its effect on tumor growth inhibition have been demonstrated against human cell lines. 9 , 71 , 72 , 73 , 74 A pilot clinical study demonstrated clinical response (on histology) to an extract of H. perforatum with photodynamic therapy for actinic keratoses, basal cell carcinoma, and carcinoma in situ (Bowen disease). 75

Miscellaneous effects

Antibacterial activity has been described. 76 , 77 , 78 In vitro studies revealed that St. John's wort at low concentrations is capable of increasing immunity, but at high concentrations, it can suppress immunity. 79 , 80 , 81 , 82 Hypericin has been shown to inhibit T-type calcium channel activity 83 and has a cellular protective effect. 84 , 85


Preparations vary greatly in chemical content and quality, and may be standardized to hyperforin (commonly 3% to 5%) or hypericin (commonly 0.3%) content. 10 , 41


Clinical trials evaluating the efficacy of St. John's wort in depression have commonly used 900 mg of extract daily in 3 divided doses, both in short-term treatment and for ongoing therapy for periods of up to 1 year (range, 600 to 1,200 mg/day) 42 , 43 , 86 A starting dose of 450 mg/day, increasing to 900 mg/day of Hypericum extract, has been used in children between 6 and 16 years of age in a small trial. 49

A case report exists of an overdose of St. John's wort in a 16-year-old patient consuming 15 tablets (300 mcg strength) per day for 2 weeks, requiring management in the intensive care unit. 87


The use of St. John's wort in perinatal depression has been considered; however, insufficient data exist to support its use. 88 There is a lack of systematic evidence on the safety of Hypericum in pregnancy or lactation. 88 , 89 A small study of case-matched infants born to mothers consuming St. John's wort during pregnancy found an increase in colic, drowsiness, and lethargy. 89 Studies in rats suggest the preparation may have teratogenic and toxic effects, 90 , 91 while other studies suggest no changes in cognitive development or long-term behavior. 89 Emmenagogue and abortifacient effects due to uterine stimulant action have been suggested, 92 , 93 , 94 , 95 but evidence is weak. 89

Case reports exist of low levels of hypericin and hyperforin detected in breast milk, but not in the feeding infants. 88 , 96

St. John's wort should be avoided during pregnancy and lactation until further long-term studies demonstrate a lack of toxicity in the developing fetus and breast-feeding newborn. 88 , 97


St. John's wort has an excellent tolerability profile in monotherapy, 39 , 41 but has been reported to interact with numerous drugs. 98 , 99 , 100 The mechanisms of many of the drug interactions with St. John's wort involve, in part, an increase in intestinal and hepatic metabolism via the cytochrome P450 enzyme system and/or an increase in activation of intestinal P-glycoprotein efflux. 98 , 100 , 101 , 102 , 103

A number of factors including dose, dosage regimen, pharmacokinetics, and individual drug toxicities, as well as patient factors (eg, age, gender, concurrent conditions), affect the clinical importance of interactions with St. John's wort. 98 , 99 The concentration of active chemical constituents may also affect the likelihood of an interaction. No clinically important effect on CYP3A enzyme was observed for preparations delivering less than 4 mg/day of hyperforin. 104 In one study, CYP3A levels returned to normal in 1 week following cessation of St. John's wort, thus avoiding clinically important interactions. 105 This recovery time is also important in interpreting studies designed to evaluate interactions if a wash-out period is used. 105

Physicians should be aware of the potential for interactions as they emerge, anticipating a decrease or increase in efficacy of concurrent medications and the potential for adverse events. Drugs with a narrow therapeutic window should be monitored closely when starting, stopping, or changing the dose of St. John's wort. 98 , 100 , 106 Patients should consult their health care provider before taking St. John's wort with prescription or nonprescription drugs and be aware of potential interactions.

Drugs that are most prominently affected, and, therefore, for which concomitant use with St. John's wort should be avoided, include protease inhibitors (eg, saquinavir) and nonnucleoside reverse transcriptase inhibitors (eg, nevirapine) used to treat HIV, cyclosporine, tacrolimus, irinotecan, and imatinib mesylate. 98 The interaction with cyclosporine is well-documented and organ rejection has been reported. 100 , 107

Oral contraceptives may be affected, as reflected by reports of irregular bleeding and unwanted pregnancies. 108 , 109 Ethinyl estradiol is metabolized by CYP3A4, so a high possibility of an interaction exists. 110 No effect on the kinetics of progesterone or on low-dose oral contraceptives was observed in a study, while the concentration of hyperforin and hypericin in the preparation is also suggested to be relevant to the potential for an interaction. 104 , 110 Patients should be advised of this risk when these drugs are taken concurrently and additional nonhormonal methods of contraception are advised. 98 , 100

Reviews of interactions with St. John's wort have been published. 98 , 99 , 100 , 101 , 102 Drug plasma concentrations of the following drugs may be decreased by St. John's wort: alprazolam, amitriptyline, atorvastatin, cyclosporine, digoxin, docetaxel, erlotinib, fexofenadine, finasteride, gliclazide, imatinib, indinavir, irinotecan, ivabradine, loperamide, methadone, midazolam, nevirapine, nifedipine, nortriptyline, omeprazole, oral contraceptives, phenytoin, quazepam, rosuvastatin, simvastatin, sirolimus, tacrolimus, talinolol, theophylline, verapamil, and warfarin. See also the Appendix: Potential Drug Interactions with St. John's Wort.

Drugs for which an additive serotonin reuptake inhibition with St. John's wort is suspected include nefazodone, sertraline, and venlafaxine. 100 , 108 , 111 Because the risk of developing serotonin syndrome and other CNS adverse reactions exists, extreme caution is needed with combinations of psychotropic medications. 112 , 113 , 114 Interactions with buspirone, methylphenidate, and paroxetine have been noted. 98 , 100 Propofol or sevoflurane taken with St. John's wort may delay emergence from anesthesia (mechanism unknown). 115

Drugs that may affect plasma concentrations of St. John's wort constituents include carbamazepine (decrease) and cimetidine (increase). 116 Drugs that do not appear to interact with St. John's wort, based on available documentation, include dextromethorphan, ibuprofen, pravastatin, prednisone, and tolbutamide. 100 , 116

Adverse Reactions

A systematic review of current evidence concluded that Hypericum extracts are well tolerated and safe, aside from the potential for interactions with other drugs. 117 , 118 , 119 , 120 A number of studies report no serious adverse effects, and in a review of clinical trials, St. John's wort was associated with fewer and milder adverse reactions when compared with conventional antidepressants. 120 Adverse effects from H. perforatum were rare and mild. The most frequently described adverse reactions in clinical trials were GI complaints (eg, dry mouth, nausea, change in bowel habits), itching, photosensitization, fatigue, dizziness, jitteriness, insomnia, sleep disorders, and headache. 117 , 118 , 120 Induction of mania has been associated with St. John's wort. 121 , 122 The volatile oil of St. John's wort is an irritant. 11

One case report describes acute neuropathy after sun exposure in a patient using St. John's wort. 123 When ingested, hypericin can induce photosensitization characterized by inflammation of the skin and mucous membranes (including human keratinocytes and lens epithelial cells) following exposure to light. 124 , 125 , 126 , 127 , 128 , 129 A review on photodermatitis discusses mechanisms, clinical features, and treatment options. 130 However, most reports of photosensitivity have been limited to patients taking excessive doses of H. perforatum , primarily to treat HIV. 131 For example, both IV (eg, 0.5 mg/kg twice weekly) and oral dosing (eg, 0.5 mg/kg/day) of H. perforatum caused phototoxicity in 30 patients with HIV, with 16 of 30 discontinuing treatment for this reason. 70


Limited information on genotoxicity exists. Potent inhibition of sperm motility was observed in vitro. 132 A case report exists of an overdose of St. John's wort in a 16-year-old patient consuming 15 tablets (300 mcg strength) per day for 2 weeks, requiring management in the intensive care unit. 87


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