St John's wort

St John's wort (IPA pronunciation: , rhyming with hurt, or ) used alone refers to the species Hypericum perforatum, also known as Klamath weed or Goat weed, but is used with qualifiers to refer to any species of the genus Hypericum. H. perforatum is sometimes called Common St. John's wort to distinguish it. The species of Hypericum have been placed by some in the family Hypericaceae, but more recently have been included in the Clusiaceae.

The plant

Hypericum perforatum is a yellow-flowering, rhizomatous, perennial herb indigenous to Europe, which has been introduced to the Americas and grows wild in many meadows. The common name comes from the fact that it traditionally flowers by and is harvested on St John's day, 24 June. The genus name "hypericum" is derived from the Greek words hyper (above) and eikon (picture) in reference to the traditional use of the plant to ward off evil, by hanging plants over a picture in the house during St John's day. The species name "perforatum" refers to the small windows in the leaves, which can be seen when they are held against the light.

Although Hypericum perforatum is grown commercially in some regions of south east Europe, it is listed as a noxious weed in over twenty countries. Ingestion by livestock can cause photosensitization, central nervous system depression, spontaneous abortion, and can lead to death. Effective herbicides for control of Hypericum include 2,4-D, picloram, and glyphosate. In western North America three beetles Chrysolina quadrigemina, Chrysolina hyperici and Agrilus hyperici have been introduced as biocontrol agents.

Uses of the herb

The first recorded use of Hypericum for medicinal purposes dates back to ancient Greece, and has been used ever since. The herb was also used by Native Americans internally as an abortifacient and externally as an anti-inflammatory, astringent, and antiseptic. The aerial parts of the plant can be cut and dried for later use in the form of herbal tea, which has long been enjoyed both for its pleasant (though somewhat bitter) taste and for its medicinal properties.

In modern medicine, standardized Hypericum extract (obtained from H. perforatum) is commonly used as a treatment for depression and anxiety disorders. In homeopathy, Hypericum is used in the treatment of numerous medical problems, yet the rate of success has not been adequately documented. Historically, the flowers and stems of St John's wort have also been used to produce red and yellow dye.

St John's wort is today most widely known as an herbal treatment for depression. In some countries, such as Germany, Hypericum is prescribed for mild depression far more commonly than synthetic antidepressant medication. In most countries, standardized extracts are available over the counter – usually in tablet or capsule form, and also in teabags and tinctures.

Clinical evidence

Clinical studies of special St John's wort preparations have mainly focused on the efficacy of the herb in clinical depression. There have been mixed results over the efficacy of St. John's wort in clinical depression. Some studies have found it to be effective in the treatment of mild to moderate depression, with fewer side effects than many conventional antidepressants, while others show no benefit over placebos.

Evidence for efficacy

An early meta-study indicated that extracts of hypericum may be more effective than placebo for the treatment of mild to moderately severe depressive disorders. Linde K, Ramirez G, Mulrow CD, Pauls A, Weidenhammer W, Melchart D (1996). St John’s wort for depression – an overview and meta-analysis of randomised clinical trials. Br Med J 313, 253–258. This study, which covered the results from 23 smaller, earlier studies, is perhaps the most often cited by manufacturers and other supporters of St. John's wort.

This meta-analysis study was later updated to include further studies, for a total of 27, to form a Cochrane Review. The updated review found that Hypericum preparations were significantly superior to placebo (rate ratio 2.47; 95% confidence interval 1.69 to 3.61) and similarly effective as standard antidepressants (single preparations 1.01; 0.87 to 1.16, combinations 1.52; 0.78 to 2.94). Linde K, Mulrow CD (2003). St John's wort for depression (Cochrane Review). In: The Cochrane Library, Issue 3, 2004. Chichester, UK: John Wiley & Sons, Ltd.

Another meta-analysis, with stricter inclusion criteria, found that Hypericum was more effective than placebo; and as effective as tricyclic antidepressants, with fewer adverse drug reactions. Kim HL, Streltzer J, Goebert D (1999). St. John's Wort for Depression: A Meta-Analysis of Well-Defined Clinical Trials. J Ment Nerv Dis 187 (9), 532-538. This meta-analysis showed that the response rate for St. John’s wort was significantly greater than that for placebo (73.2 versus 37.9%, respectively, relative risk 1.48 and 95% CI 1.03–1.92) and similar to that observed with tricyclic antidepressants (64 versus 66.4% for St. John’s wort and tricyclic antidepressants, respectively, relative risk 1.11 and 95% CI 0.92–1.29).

Other more recent trials have also shown greater efficacy than placebo; and comparable efficacy to standard antidepressants with a superior adverse effect profile. Woelk H, et al (2000). Comparison of St John's wort and imipramine for treating depression: randomised controlled trial. Br Med J 321, 536-9. Schrader E, et al (2000). Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomised, controlled study in mild-moderate depression. Int Clin Psychopharmacology 15, 61-68. Laakmann G, Schule C, Baghai T, Kieser M (1998). St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry 31 (Suppl 1), 54-9. Harrer G, Schmidt U, Kuhn U, Biller A (1999). Comparison of equivalence between the St. John's wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung 49 (4), 289-96. Philipp M, Kohnen R, Hiller KO (1999). Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. Br Med J 319 (7224), 1534-8.

Additionally, a 2006 study involving 150 patients with minor depressive symptoms or dysthymia found that St. John's Wort has a clinical significant effect in minor depressed patients that are not suffering with dysthymia. It was concluded that St. John's Wort can be effective in the treatment of minor depressed patients with a Hamilton Depression Scale for Depression (HAM-D) score of up to 17. C. Randløv, J. Mehlsen, C.F. Thomsen, C. Hedman, H. von Fircks and K. Winther. "The efficacy of St. John's Wort in patients with minor depressive symptoms or dysthymia - a double-blind placebo-controlled study" Phytomedicine. 2006 March;13(4):215-221

Evidence against efficacy

A major study funded by the NIH in the United States, found a St John's wort product to be ineffective in treating major depression of moderate severity. (Hypericum Depression Trial Study Group, 2002) This study involved 340 patients, diagnosed with Major Depressive Disorder based on DSM-IV criteria and assessed using Hamilton Depression Rating Scale (HAM-D) and Clinical Global Impression (CGI) scores. The trial was a multi-centre randomised double-blind placebo-controlled trial, comparing one preparation of St John's wort (Li 160) to sertraline and placebo. Li 160 proved no more effective than placebo in alleviating moderately severe major depression. Sertraline was also no better than placebo in this study, based on the primary outcome measure (HAM-D). Lecrubier et al. "Efficacy of St. John's wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial." Am J Psychiatry. 2002 Aug;159(8):1361-6. Further studies on the herb's efficacy in alleviating mild depression are planned by the NIH.

Pharmacology

The exact mechanism by which St. John's wort — and even conventional antidepressants — function is unclear and subject to much conjecture.

The St. John's wort mechanism is believed to involve inhibition of Serotonin (5-HT) reuptake, much like the conventional SSRI antidepressants.

The major active constituents in St John's wort are thought to be hyperforin and hypericin, although other biologically active constituents present, e.g. flavonoids and tannins, may also be involved. Nahrstedt A, Butterweck V (1997). Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry 30 (Suppl 2), 129-34.

Some believe that Hyperforin is the major constituent responsible for antidepressant activity, and it has been shown to inhibit the uptake of 5-HT, dopamine, noradrenaline, GABA and glutamate. Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Muller WE (1998a). Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci 63 (6), 499-510. Discrepancies in the dose-response relationship imply that constituents other than hyperforin are likely to also be involved. Chatterjee SS, Noldner M, Koch E, Erdelmeier C (1998b). Antidepressant activity of hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry 31 (Suppl 1), 7-15. Also, a hyperforin free extract of St John's wort (Ze 117 - Remotiv) has been shown to have significant antidepressive effects. . Therefore current thinking is that the whole extract should be considered the "active ingredient" and that one or two constituents cannot explain the activity of the product.

Dose/Formulations

The dosage and content of St John's wort preparations vary greatly between formulations, due to variability in the plant source and preparation processes. The doses of St. John’s wort extract used in clinical trials generally range from 350 to 1800 mg daily (equivalent to 0.4 to 2.7 mg hypericin depending on the preparation). Due to the variable nature of herbal medicines, the clinical trial results using one product cannot be extrapolated to other products containing the same herb (just as a prize winning wine is not the same as everything else made from grapes). Only a handful of products made from St John's wort have been used in the clinical studies (e.g. Li 160 and Ze 117).

The recommended dosage for various forms of St John's wort as recommended by the British Herbal Medicine Association Scientific Committee (1983) are as follows:

dried herb: 2-4 g or by infusion three times daily
liquid extract 2-4 mL (1:1 in 25% alcohol) three times daily
tincture 2-4mL (1:10 in 45% alcohol) three times daily

In markets where standardised extracts are not available, the content of marketed products can vary widely. Some brands of over-the-counter St. John's wort can have totally different chemical profile than others. The same can even be true of two dosage units from different batches of the same brand. Even where extracts are standardised it is debatable whether using hypericin as the standard is useful, since other constituents including hyperforin are biologically active. Therefore the best way to ensure reliable results is to use the products which have been used in the clinical trials.

As with other antidepressants, Hypericum should be taken for at least four weeks before its effectiveness can be properly assessed.

Adverse effects

St John's wort is generally well tolerated, with an adverse effect profile similar to placebo. Ernst E, Rand JI, Barnes J, Stevinson C (1998). Adverse effects profile of the herbal antidepressant St. John's wort (Hypericum perforatum L.). Eur J Clin Pharmacol 54 (8), 589-94. The most common adverse effects reported are gastrointestinal symptoms, dizziness, confusion and tiredness/sedation. Barnes J, Anderson LA, Phillipson JD (2002). Herbal Medicines: A guide for healthcare professionals (2 ed.) London: Pharmaceutical Press. ISBN 0-8536947-4-5.

St John's wort is also known to cause photosensitivity. This can lead to visual sensitivity to light and to sunburns in situations that would not normally cause them, but the incidence is reported to be rare.

Some research shows that St John's wort may have negative effects on fertility in both men and women. Stahl, SM (2000). Essential psychopharmacology : neuroscientific basis and practical applications, Cambridge: Cambridge University Press, 2nd ed, page 266.

Drug interactions

Pharmacokinetic interactions

St John's wort has been shown to cause multiple drug interactions mainly through induction of the cytochrome P450 enzyme CYP3A4, but also CYP2C9. This results in the increased metabolism of those drugs, resulting in decreased concentration and clinical effect. The principal constituent thought to be responsible is hyperforin.

**Examples of drugs causing clinically-significant interactions with St John's Wort**
Class	Drugs
antiepileptics	carbamazepine, phenytoin
antiretrovirals	non-nucleoside reverse transcriptase inhibitors, protease inhibitors
benzodiazepines	alprazolam, midazolam
contraceptives	combined oral contraceptives
immunosuppressants	calcineurin inhibitors, ciclosporin, tacrolimus
others	digoxin, methadone, omeprazole, phenobarbitone, theophylline, warfarin
Reference: Rossi, 2005

Pharmacodynamic interactions

St John's Wort may also contribute to serotonin syndrome in combination with other drugs which may elevate 5-HT (serotonin) levels in the central nervous system (CNS). Rossi S (Ed.) (2005). Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3.

**Drugs which may contribute to serotonin syndrome with St John's Wort**
Class	Drugs
antidepressants	MAOIs, TCAs, SSRIs, mirtazapine, venlafaxine
opioids	tramadol, pethidine
CNS stimulants	phentermine, diethylpropion, amphetamines, sibutramine
5-HT₁ agonists	triptans
illicit drugs	methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), cocaine
others	selegiline, tryptophan, buspirone, lithium, linezolid, dextromethorphan,5-HTP
Reference: Rossi, 2005

References

Additional References

British Herbal Medicine Association Scientific Committee (1983). British Herbal Pharmacopoeia. West Yorkshire: British Herbal Medicine Association. ISBN 0-9030320-7-4
Hypericum Depression Trial Study Group (2002). Effect of Hypericum perforatum (St John's Wort) in Major Depressive Disorder. JAMA 287 (14), 1807-1814.

External links

St John's Wort Non-profit website for St. John's Wort users, with a forum for discussion.
See http://www.cc.nih.gov/about/news/press_room/2000/02_10_00_wortfinal.html for an example of drug interactions with St. John's wort
St John's wort information website note: semi-commercial site set up by interested party. It does not present a neutral point of view, nor adequately explain the risks.
QuackWatch article on St. John's wort Criticism of the use of St. John's wort to treat depression. Includes Food and Drug Administration (FDA) warnings about interference with treatments for heart disease, some cancers, AIDS and others.
St John's Wort: How Much To Take. Information on the doseage to take, as well as some references to get more information.

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